Comprehensive Organic Functional Group Transformations, Volume 3 (Synthesis:Carbon with One...

Comprehensive Organic Functional Group Transformations, Volume 3 Elsevier, 2003 Editors-in-Chief: Alan R. Katritzky, Otho Meth-Cohn, and Charles W. Rees

Synthesis: Carbon with One Heteroatom Attached by a Multiple Bond

Part I: Tricoordinated Carbon Functions, R2C=Y3.01 Aldehydes: Alkyl Aldehydes, Pages 1-52, Kevin E. B. Parkes and Stewart K. Richardson 3.02 Aldehydes: α,β-Unsaturated Aldehydes, Pages 53-79, Warren J. Ebenezer and Paul Wight 3.03 Aldehydes: Aryl and Heteroaryl Aldehydes, Pages 81-109, Gregory J. Hollingworth 3.04 Ketones: Dialkyl Ketones, Pages 111-204, Kevin E. B. Parkes and Stewart K. Richardson 3.05 Ketones: α,β-Unsaturated Ketones, Pages 205-276, Warren J. Ebenezer and Paul Wight 3.06 Ketones Bearing an α,β-Aryl or -Hetaryl Substituent, Pages 277-312, Daryl S. Walter 3.07 Aldehyde and Ketone Functions Further Substituted on Oxygen, Pages 313-327, Donald A. Whiting 3.08 Thioaldehydes and Thioketones, Pages 329-380, William G. Whittingham 3.09 Seleno- and Telluroaldehydes and -ketones, Pages 381-401, Frank S.

Guziec and Lynn J. Guziec 3.10 Imines and Their N-Substituted Derivatives: NH, NR and N-Haloimines, Pages 403-423, Graeme M. Robertson 3.11 Imines and their N-Substituted Derivatives: Oximes and their O-R Substituted Analogues, Pages 425-441, Graeme M. Robertson 3.12 Imines and Their N-Substituted Derivatives: Hydrazones and Other =NN Derivatives Including Diazo Compounds, Pages 443-490, J. Stephen Clark3.13 Synthesis of P, As, Sb and Bi Ylides (R P=CR , etc.)3 2 , Pages 491-500, by kmno4

Éamonn J. Coyne and Declan G. Gilheany 3.14 Doubly Bonded Metalloid Functions (Si, Ge, B), Pages 501-505, Tao Ye and M. Anthony McKervey 3.15 Doubly Bonded Metal Functions, Pages 507-523, Tao Ye and M. Anthony McKervey

Part II: Dicoordinated Carbon Functions, R2C=C=Y

3.16 Ketenes, their Cumulene Analogues and their S, Se and Te Analogues, Pages 525-554, David C. Harrowven and Shelagh T. Dennison 3.17 Ketenimines and Their P, As, Sb, and Bi Analogues, Pages 555-610, Joseph P. Michael and Charles B. De Koning

Part III: Dicoordinated Carbon Functions, R C Z

3.18 Nitriles: General Methods and Aliphatic Nitriles, Pages 611-640, Michael North 3.19 α,β-Unsaturated and Aryl Nitriles, Pages 641-676, Milton J. Kiefel 3.20 N-Substituted Nitriles and Other Heteroanalogues of Nitriles of the Type RCZ, Pages 677-692, R. Michael Paton

Part IV: Monocoordinated Carbon Functions

3.21 Isocyanides and their Heteroanalogues (RZC), Pages 693-726, Ian A. O’Neil 3.22 References to Volume 3, Pages 727-856

by kmno4

3.01Aldehydes: Alkyl AldehydesKEVIN E. B. PARKESRoche Products Ltd., Welwyn Garden City, UK

and

STEWART K. RICHARDSONUniversity of Notre Dame, IN, USA

2[90[0 SATURATED UNSUBSTITUTED ALDEHYDES 1

2[90[0[0 From Alkanes 12[90[0[1 From Alkenes 12[90[0[2 From Alkynes 22[90[0[3 From Halides 22[90[0[4 From Alcohols and their Derivatives 2

2[90[0[4[0 By oxidation of primary alcohols 22[90[0[4[1 From diols 62[90[0[4[2 Oxidation of alcohol derivatives 72[90[0[4[3 Rearranèment of allylic alcohols 7

2[90[0[5 From Epoxides 82[90[0[6 From Acetals\ Enol Ethers and Enol Esters 82[90[0[7 From Aldehydes or Ketones 09

2[90[0[7[0 From saturated aldehydes or ketones 092[90[0[7[1 From unsaturated aldehydes 012[90[0[7[2 From a!functionalized aldehydes 01

2[90[0[8 From Carboxylic Acids and their Derivatives 022[90[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives 022[90[0[8[1 Formylation reactions 032[90[0[8[2 Other preparations from acids and acid derivatives 04

2[90[0[09 From Sulfur!containin` or Other Lower!Chalcoèn!Containin` Precursors 042[90[0[00 From Nitroèn!containin` Precursors 06

2[90[0[00[0 From amines 062[90[0[00[1 From oximes\ hydrazones and their derivatives 072[90[0[00[2 From nitroalkanes 07

2[90[0[01 From Orànosilanes 072[90[0[02 From Orànoboranes 082[90[0[03 Methods Involvin` Umpolun` 08

2[90[0[03[0 Formyl anion equivalents 192[90[0[03[1 Other anion equivalents 19

2[90[1 b AND MORE REMOTELY UNSATURATED ALDEHYDES 10

2[90[1[0 Alkyl Aldehydes with One Double Bond 102[90[1[0[0 From aldehydes 102[90[1[0[1 Preparations involvin` rearranèments 102[90[1[0[2 Other preparations 12

2[90[1[1 Alkyl Aldehydes with More than One Double Bond 132[90[1[2 Alkyl Aldehydes with Aryl or Hetaryl Substituents 13

2[90[1[2[0 From aldehydes 132[90[1[2[1 Other preparations 13

0

1 Alkyl Aldehydes

2[90[1[3 Alkynyl!Substituted Alkyl Aldehydes 142[90[1[3[0 Fra`mentation reactions 14

2[90[2 HALOALKYL ALDEHYDES "a\ b AND MORE REMOTE HALOGEN# 15

2[90[2[0 Introduction 152[90[2[1 From Stable Enol Derivatives and Enamines 152[90[2[2 From Aldehydes 152[90[2[3 Miscellaneous Preparations 16

2[90[2[3[0 Functional `roup transformations 162[90[2[3[1 Carbon0carbon bond!formin` methods 16

2[90[3 ALDEHYDES BEARING AN OXYGEN FUNCTION 17

2[90[3[0 OH!functionalized Aldehydes 172[90[3[0[0 a!OH!functionalized aldehydes 172[90[3[0[1 b! and more remotely functionalized OH aldehydes 20

2[90[3[1 OR!functionalized Aldehydes 202[90[3[2 OX!functionalized Aldehydes 22

2[90[4 ALDEHYDES BEARING A SULFUR FUNCTION 23

2[90[4[0 SH! and SR!functionalized Aldehydes 232[90[4[1 Hi`her!coordinated Sulfur!functionalized Aldehydes 26

2[90[5 ALDEHYDES BEARING A SELENIUM OR TELLURIUM FUNCTION 26

2[90[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Aldehydes 26

2[90[6 ALDEHYDES BEARING A NITROGEN FUNCTION 28

2[90[6[0 NH1!\ NHR! and NR1!functionalized Aldehydes 282[90[6[0[0 a!NH1!\ NHR! and NR1!functionalized aldehydes 282[90[6[0[1 b! and more remotely NH1!\ NHR! and NR1!functionalized aldehydes 33

2[90[6[1 NHX! and NX1!functionalized Aldehydes 352[90[6[2 NY!functionalized Aldehydes 35

2[90[7 ALDEHYDES BEARING A PHOSPHORUS\ ARSENIC\ ANTIMONY ORBISMUTH FUNCTION 37

2[90[7[0 XR1\ X¦R2!functionalized Aldehydes 372[90[7[1 Hi`her!coordinated Phosphorus!\ Arsenic!\ Antimony! or Bismuth!functionalized Aldehydes 38

2[90[8 ALDEHYDES BEARING A METALLOID FUNCTION 40

2[90[8[0 Silicon!functionalized Aldehydes*a!silyl Aldehydes 402[90[8[0[0 From alcohols 402[90[8[0[1 From aldehydes or ketones 40

2[90[8[1 b!Silyl Aldehydes 41

2[90[0 SATURATED UNSUBSTITUTED ALDEHYDES

2[90[0[0 From Alkanes

No synthetically useful methods of oxidizing totally unactivated methyl groups to aldehydes havebeen reported\ although in view of the relatively high reactivity of aldehydes under oxidizingconditions this is perhaps not surprising[

2[90[0[1 From Alkenes

Although many oxidants will cleave alkenes to aldehydes\ relatively few do so cleanly or in highyield\ the most important and well!established exception being ozone ðB!58MI 290!90Ł[ In cases whereozone is not employed\ the conversion is generally achieved via the 0\1!diol by osmium"VIII# oxide!mediated hydroxylation\ followed by periodate\ or lead"IV# acetate\ cleavage[ Isolation of the diolintermediate is not necessary\ and hydroxylation and cleavage can be achieved in a single pot by amixture of osmium"VIII# oxide and sodium periodate ð45JOC367Ł[ The cleavage can also be achievedusing potassium manganate"VIII# under phase transfer conditions with careful control of pHð68CL332Ł[

Several methods have been developed for the homologative conversion of alkenes into aldehydes[Probably the most important of these methods\ and certainly the most important industrially\ is thehydroformylation\ or OXO reaction\ in which the alkene is treated with a mixture of hydrogen and

2Saturated Unsubstituted

carbon monoxide in the presence of a cobalt\ rhodium or ruthenium catalyst ð80COMC!I"3#802Ł[ Ingeneral\ the order of reactivity is terminal alkene×straight chain internal alkene×branched alkene\with the formyl group being delivered to the least hindered end\ although with highly polarizedalkenes\ formylation occurs at the more electron!de_cient carbon atom[ The reaction tolerates mostfunctional groups\ although halides usually interfere[ Recent developments include low!temperaturehydroformylation catalysts "½49>C# ð67BCJ2905Ł\ polymer!bound ruthenium hydroformylationcatalysts ð70JOC0890Ł\ and asymmetric versions of the reaction\ which in favourable cases giveenantiomeric excesses of over 79) "Equation "0## ð76JA6011Ł[

HCHO

H2, CO, SnCl2

60% conversion

78% ee

(1)

2[90[0[2 From Alkynes

Alkynes may be converted into aldehydes by hydroboration and oxidation of intermediatevinylboranes[ Although diborane and many simple mono! and dialkylboranes give very poorregioselectivity in the hydroboration\ excellent results can be obtained with either dimesitylboraneð72TL0322Ł or the thexyliodoboraneÐdimethyl sul_de complex ð82TL4002Ł\ followed by a con!ventional basic hydrogen peroxide workup "Equation "1##[

Bun

O

BunBun

OBHI•Me2S i,

ii, H2O2, OH–+

99.0 1.0:

(2)

2[90[0[3 From Halides

Primary alkyl halides may be oxidized to aldehydes by treatment with N!oxides or sulfoxides athigh temperatures in a reaction initially developed by Kornblum\ and which involves a nucleophilicdisplacement of the halide as a _rst step[ Most subsequent work has concentrated on developingmodi_ed oxide reagents which may be used under less vigorous conditions^ reagents include3!dimethylaminopyridine N!oxide in the presence of 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu#ð70BCJ1110Ł\ a variety of pyridone N!oxide reagents ð68JCS"P0#1382Ł\ and DMSO in the presence ofsodium hydrogen carbonate and sodium iodide ð75SC0232Ł "Equation "2##[ The conversion may alsobe achieved with more conventional oxidizing agents including tetrabutylammonium periodateð75SC32Ł\ tetrabutylammonium dichromate ð68CI"L#102Ł and iodine penta~uoride ð66S308Ł[0!Haloalkenes may be hydrolysed to aldehydes using mercury"II# acetate in formic acid ð65BSF0830Ł[

O

O

Ph

Br

DMSO, NaI

60%(3)O

O

Ph

O

2[90[0[4 From Alcohols and their Derivatives

2[90[0[4[0 By oxidation of primary alcohols

A mild\ versatile\ selective and practically convenient reagent for the conversion of primaryalcohols to aldehydes has been a long!standing objective of many research groups[ The availablemethods will be discussed in six categories] "i# metal reagents\ particularly chromium and rutheniumsalts^ "ii# activated DMSO reagents^ "iii# halogen!based oxidants^ "iv# Oppenauer!type oxidations^"v# electrochemical and photochemical oxidations^ and "vi# miscellaneous methods[

3 Alkyl Aldehydes

Recent research on oxidation methods has often been directed to developing low!cost methodswith increased environmental acceptability[ Thus catalytic methods\ particularly those using hydro!gen peroxide or t!butylhydroperoxide as the ultimate oxidant\ have received considerable attention[Also of interest from this point of view are solid!supported oxidants\ which allow the reaction tobe simply worked up by _ltration[ Such oxidants\ which often vary in selectivity and reactivity whencompared with the unsupported parent reagent\ have been the subject of a review ð68S390Ł[

"i# Usin` metal ion!based oxidants

"a# Chromium rea`ents[ Most traditional chromium!based oxidants have been found to be lessthan satisfactory reagents for aldehyde preparation[ They are often unstable or hazardous toprepare\ show little selectivity\ and need to be used in quite large excesses[ In addition\ the majorproduct is quite often not the aldehyde but a dimeric ester formed by preferential oxidation of thehemiacetal derived from the product aldehyde and starting material[ This discouraging picture hasbeen transformed by a number of new reagents\ of which perhaps the pre!eminent is pyridiniumchlorochromate "pcc#\ and which has been the subject of a review ð71S134Ł[ Despite its now estab!lished position\ occasional variations or improvements on the original method are still beingpublished\ and of particular note is an improved preparation of the reagent which is not only higher!yielding but also less hazardous ð89T3306Ł[ An important group of modi_cations is aimed atsimplifying the workup\ which can be complicated by di.culties separating the product from tarrychromium!containing residues[ These modi_ed reagents include polyvinylpyridinium chloro!chromate\ a polymeric analogue of pcc ð67S423\ 70JOC0617Ł\ a variety of polymer!bound quaternaryammonium chlorochromates ð75JOC3905Ł\ and 1\1?!bipyridinium chlorochromate\ which apparentlygives more tractable residues ð79S580Ł[ A wide range of other supported forms of chromic acid havealso been described\ including chromic acid adsorbed on silica gel ð67S423\ 68T0678Ł\ and chromateion bound to an anion exchange resin ð65JA5626Ł or to a poly"vinylpyridine# resin ð67JOC1507Ł[

One of the few disadvantages of pcc is its mildly acidic character\ which makes it unsuitable forthe oxidation of some sensitive substrates[ Several modi_ed reagents which reduce or overcome thisproblem have been reported\ the most important of which is probably pyridinium dichromate "pdc#in dichloromethane ð68TL288Ł\ and which\ like pcc\ is available in a resin!supported form ð78SC0206Ł[Other reagents with reduced acidity include pyridinium ~uorochromate ð71S477Ł\ pcc absorbed ontoalumina\ which will oxidize citronellol to citronellal in 89) yield\ whereas pcc gives pulegoneð79S112Ł\ and trimethylsilyl chlorochromate\ which is prepared in situ from chromium trioxide andchlorotrimethylsilane and allows oxidations to be performed under strictly neutral and anhydrousconditions ð72TL3256\ 74T1892Ł[ In addition\ the use of ultrasound in oxidations with silica gel!supported pcc\ leading to a signi_cant reduction in the length of time and the amount of reagentrequired\ has been described ð78JOC4276Ł\ and molecular sieves have been found to assist theoxidations of a variety of alcohols including carbohydrates and nucleosides ð71JCS"P0#0856Ł[Trimethylammonium chlorochromate has also been proposed as an alternative to pcc ð89S016Ł[

Several neutral organic soluble dichromate oxidants have been developed\ and o}er a number ofadvantages in comparison to pdc\ in particular allowing the oxidation of sensitive substrates\and short reaction times[ These include the 1! and 3!benzylpyridinium dichromates ð80SC308Ł\bis"benzyltriethylammonium#dichromate ð71S0980Ł and tetrakispyridinocobalt"II# dichromateð81SC0380Ł[ Bisphosphonium dichromate ð75TL0664Ł and 2!carboxypyridine dichromate "sometimesreferred to as nicotinium dichromate\ NDC# ð76T2852Ł\ although insoluble in organic solvents\ alsoappear to have advantages over pdc for some oxidations[ Lastly\ zinc dichromate has been reportedto display an unusual selectivity\ and e.ciently oxidizes primary alcohols while leaving the normallymore reactive allylic alcohols una}ected ð75S174Ł[ This reagent is also known in a polymer!supportedform ð80SC1966Ł[

Relatively little has been published on phase transfer!catalysed chromate oxidations\ althoughthe method seems to have considerable potential[ Although the earliest methods were only applicableto acid!stable substrates ð67TL0590Ł\ more modern methods are considerably milder ð68S023\79TL3542Ł\ and examples containing quite acid!sensitive functionalities\ such as an isoxazole ring areknown ð72SC706Ł[ High yields of aldehydes can also be obtained in oxidations with preformedquaternary ammonium chromates ð68S245Ł[

An important early oxidant was Collins reagent\ a solution of chromium trioxide in pyridine[The reagent is still occasionally of value\ although its preparation can be hazardous\ and a numberof variants are now known\ including solutions of chromium trioxide in DMSO ð81SC656Ł orhexamethylphosphoramide "HMPA# ð65S283Ł[ A rather di}erent way of modulating the reactivity


of chromium trioxide is by suspending it on Celite ð68S704Ł\ which has the additional advantage ofsimplifying the workup[

Peroxychromium species such as CrO4 =C4H4N ð66TL2638Ł\ and CrO6 ð75T608Ł\ and a number ofchromium"V# complexes ð79TL0472Ł have been used as reagents for primary alcohol oxidation\although despite some advantages\ in particular being neutral\ they have not achieved widespreaduse[

Lastly\ it is worth mentioning that\ despite the industrial and economic importance of the goal\relatively little progress has so far been reported in developing catalytic chromium systems for theoxidation of alcohols[ This area is clearly receiving some attention although\ unfortunately\ themethods reported so far do not appear to be applicable to the oxidation of primary alcohols toaldehydes[

"b# Manànese reaènts[ Simple manganate"VI# or manganate"VII# salts are very powerful andunselective oxidants\ which even in simple cases are of little synthetic use for the oxidation ofprimary alcohols to aldehydes since\ except in strongly basic solutions\ further oxidation to thecarboxylic acid is faster than the initial oxidation to the aldehyde[ Although a range of modi_edmanganese reagents is now available\ which are useful for the preparation of conjugated unsaturatedaldehydes and ketones\ only occasional examples of their use for the preparation of saturatedaldehydes have been reported ð72BCJ803\ 89T5758Ł[

"c# Ruthenium reaènts[ As with chromium and manganese reagents\ the challenge for chemistswanting to develop oxidants of this class has been to moderate the reactivity and improve theselectivity of simple ruthenium reagents[ In an interesting contrast to the other metal oxidants\where modi_ed stoichiometric reagents have been developed\ the most successful approach has beenthe development of catalytic systems[ Two distinct systems have been found to be useful[

The _rst\ and less widely used\ of these employs bis"triphenylphosphine#ruthenium"II# chloride\which appears to have some potential as a stoichiometric\ as well as a catalytic\ oxidant of primaryalcohols[ It was _rst reported with N!methylmorpholine N!oxide as a cooxidant ð65TL1492Ł\ althoughmore recent publications have used bis"trimethylsilyl#peroxide ð77BCJ2596Ł\ phenyliodosodiacetateð70TL1250Ł or m!iodosylbenzoic acid ð72HCA0689Ł as the cooxidant[ The stoichiometric version ofthe reaction is of interest since it allows the oxidation of primary alcohols in the presence ofsecondary ones ð70TL0594Ł[

Unquestionably the most important ruthenium oxidants\ and one of the most important recentdevelopments in oxidation methodology generally\ are the tetraalkylammonium perruthenatesdeveloped by Gri.th and by Ley[ These use a catalytic tetraalkylammonium perruthenate\ generallytetrapropylammonium perruthenate "TPAP#\ in the presence of 3A nm molecular sieves withN!methylmorpholine N!oxide as a regenerating oxidant to achieve the oxidation under very mild\neutral conditions[ The reagent is notable for the wide range of functionalities tolerated\ includingTHP and silyl ethers\ alkenes\ epoxides and esters "Equation "3##\ and the fact that chiral centres ato the newly formed carbonyl group are not epimerized ð76CC0514Ł[ The reagent has also been thesubject of a review ð89MI 290!90Ł[

O

O-TBDPS

OH

O

O-TBDPS

O

TPAP

70%(4)

TBDPS = t-butyldiphenylsilyl

"d# Miscellaneous metal oxidants[ Although catalytic molybdenum! and tungsten!based systemsare well established for the oxidations of secondary alcohols\ primary alcohols are generally una}ec!ted[ However\ two molybdenum peroxy complexes\ "0# ð79TL3732Ł and "1# ð76JOC4356Ł\ which areboth used stoichiometrically\ do oxidize primary alcohols to aldehydes[ Osmium tetroxide in etherhas the unusual selectivity of oxidizing primary alcohols in the presence of secondary alcohols\although the high reactivity of the reagent to other functionalities limits the application of thereaction ð73S844Ł[ Nickel"II# bromide catalyses the oxidation by benzoyl peroxide of primaryalcohols to aldehydes in high yield ð68JOC1844Ł[

A number of catalytic palladium systems for alcohol oxidation are known\ and the scope of themethod has been examined ð72JOC0175Ł[ The optimal conditions employ 0Ð2 mol) of either apalladium"9# or palladium"II# catalyst with bromobenzene as a reoxidant[ The oxidation canalso be performed under phase transfer conditions with iodobenzene as a reoxidant ð74TL5146Ł[

5 Alkyl Aldehydes

N

OMo

OPh

Ph

O

O

O O

N

O

Mo

O

O

OO

O

(1) (2)

O

Ytterbium"III# nitrate will catalyse the oxidation of alcohols by iodosobenzene[ Like osmiumtetroxide this reagent shows the unusual selectivity of oxidizing primary alcohols in preference tosecondary alcohols ð82CL460Ł[

"ii# Usin` DMSO reaènts

Since P_tzner and Mo}at|s serendipitous discovery in 0852 that alcohols were oxidized at roomtemperature by DMSO in the presence of dicyclohexylcarbodiimide and phosphoric acid ð52JA2916Ł\oxidations of alcohols by activated DMSO have become established as one of the mildest and mostgeneral methods for the oxidation of alcohols\ although today the most commonly used variant isthat developed by Swern and co!workers which uses oxalyl chloride as the activating agentð67JOC1379\ 67T0540Ł[ The method is of particular value for aldehyde preparations because of itsexceptionally mild nature and the fact that over!oxidation does not occur[

The area is well served by several good reviews[ The literature up to 0879 is covered in a classicreview by Manusco and Swern ð70S054Ł[ This has been updated to 0878 by Tidwell ð89S746Ł\ whohas also written an Orànic Reactions article on the subject\ which includes extensive tabulations ofexamples\ and a good discussion of the scope of the oxidation and of potential side reactionsð89OR"28#186Ł[ Relatively little can be added to the coverage provided by these reviews\ althoughbis"trichloromethyl#carbonate "triphosgene# recently has been reported to be a good activatingreagent\ and\ being a crystalline solid\ avoids the handling and scale!up problems associated withthe relatively toxic and corrosive reagents generally used ð80JOC4837Ł[

N!Chlorosuccinimide and diisopropyl sul_de will oxidize alcohols in a reaction which is probablymechanistically very closely related to the SwernÐMo}att oxidation ð73CC651Ł[ The method showsthe curious\ and unexplained\ feature that at 9>C primary alcohols are oxidized in preference tosecondary alcohols while at −67>C the opposite selectivity is found[

"iii# Usin` haloèn!based oxidants

Many electrophilic halogen"I# reagents can oxidize primary alcohols to aldehydes\ and some\such as trichloroisocyanuric acid ð81SC0478Ł and N!iodosuccinimide ð70S283Ł\ do so cleanly and ingood yield[ However\ more important as oxidants are the iodine"V# reagents\ and in particularperiodinane "2#\ which was _rst reported as an oxidant for alcohols by Dess and Martin in 0872ð72JOC3044Ł[ An improved preparation has been described ð82JOC1788Ł[ The oxidation occurs undervery mild conditions and is compatible with a wide range of other functionalities including secondaryamides\ sul_des\ alkenes\ furans and vinyl ethers ð80JA6166Ł[ The related alkoxyaryltri~uoro!periodinane "3# has also been reported to oxidize alcohols to aldehydes in moderate to high yieldsð68JA4183Ł[

I

O

OAc

OAc

AcO

O

(3)

I

O

F

F

F

(4)


"iv# Oppenauer and related oxidations

The oxidation of secondary alcohols by an aluminum alkoxide!catalysed hydrogen transfer to anacceptor ketone\ present in excess to drive the equilibrium in the desired direction\ was _rst reportedby Oppenauer ð26RTC026Ł[ The method was quite widely used in the older literature\ particularlyfor the oxidation of steroidal alcohols\ and was the subject of an early review ð40OR"5#196Ł[ Unfor!tunately\ the method\ despite the mild conditions\ cannot be directly applied to the oxidation ofprimary alcohols to aldehydes since the product aldehydes condense with the excess ketone presentas a hydrogen acceptor\ and until recently there was no general solution to this problem[ However\new catalysts which do not catalyse the aldol side reaction are now becoming available[ These includebis"cyclopentadienyl#zirconium hydride ð75JOC139\ 75S663Ł\ zirconium oxide with benzophenone asthe hydrogen acceptor ð80BCJ201Ł\ and a variety of lanthanide alkoxides ð73JOC1934Ł^ they makethe method an attractive option for the oxidation of sensitive substrates with the added bene_t ofavoiding any risk of overoxidation[

"v# Electrochemical and photochemical oxidations

Since an alcohol will not lose an electron at experimentally achievable electrode potentials\ thedirect electrochemical oxidation of alcohols is an impossibility[ However\ a number of systems areknown which use an intermediary species\ often referred to as an {electron carrier|\ which can oxidizethe alcohol chemically\ the resulting reduced form of the electron carrier being reoxidized at theanode to complete the cycle[ These include a number of traditional electron carriers such as iodoniumreagents ð68TL054Ł\ sulfur species ð68TL2750\ 79TL0756Ł\ molecular oxygen ð78S392Ł and nitroxylsð72JA3381Ł\ as well as established oxidants for alcohols such as ruthenium salts ð89SC288Ł\ in whatare e}ectively electrocatalytic versions of these oxidations[ Two!stage systems in which the oxidantis not reoxidized directly at the anode but via an electron carrier are also possible ð80BCJ685Ł[

The photochemical oxidation of alcohols to aldehydes is a very underexplored area of meth!odology\ although it is known that irradiation of an alcohol in the presence of a copper"II#\ iron"III#or silver"I# salt ð68JOC027Ł or platinum on titanium dioxide ð73TL2252Ł can give high yields ofaldehydes[

"vi# Miscellaneous oxidations

Dimesityl diselenide catalyses the oxidation of alcohols to aldehydes by t!butyl hydroperoxide[The method is extremely mild and is even compatible with the presence of phenylthio or phenylselenogroups ð71JOC726Ł[ The oxaminium salt "4# "X�OMe# has been found to be an e.cient oxidantwhich shows selectivity for primary over secondary alcohols ð74JOC0221Ł[ Variants of the reactionin which the reagent is used catalytically with sodium hypochlorite ð76JOC1448Ł\ sodium bromiteð89JOC351Ł or calcium hypochlorite ð89JOC351Ł as a cooxidant are also known[ A similar oxidationcan be achieved with the oxaminium salt "4# "X�H# and sodium hypochlorite as the cooxidant\and leads to less overoxidation to the corresponding carboxylic acid ð89TL1066Ł[ Another usefuloxidant is 0\0?!"azodicarbonyl#dipiperidine\ which provides a very mild method of oxidizing alcoholsvia their bromomagnesium salts ð66BCJ1662Ł[

N

X

O

Br–

(5)

+

2[90[0[4[1 From diols

Probably the most important route to aldehydes from 0\1!diols is by oxidative cleavage[ Manyoxidants\ particularly metal!based reagents\ will cleave vicinal diols\ although the major products

7 Alkyl Aldehydes

are often carboxylic acids[ However\ consistently high yields can be obtained with periodate\ lead"IV#acetate or bismuth reagents ðB!54MI 290!90\ B!58MI 290!91\ 70CC0121Ł[ Silica gel!supported sodiumperiodate has been found to be particularly convenient for the cleavage of 0\1!diols to aldehydesð78S53Ł[ Most glycol cleavages proceed by mechanisms that involve cyclic intermediates and there!fore cannot be used for the cleavage of trans!diols[ However\ cleavages with iodine"III# or iodine"I#acetates appear to be radical in nature and proceed equally well with cis! or trans!diolsð67JCS"P0#0372Ł[ Diols protected as their dibutylstannylene derivatives can also be cleaved with eitherperiodate or lead"IV# acetate ð70TL1774Ł[

2[90[0[4[2 Oxidation of alcohol derivatives

"i# Ethers

A wide range of alkyl and silyl ethers of primary alcohols react with hydride!abstracting reagentsto give an oxonium ion which is hydrolysed to give the aldehyde on workup[ Thus\ methyl ethersof primary alcohols are cleaved oxidatively by nitronium tetra~uoroborate ð66JOC2986Ł\ or uran!ium"VI# ~uoride ð67JA4285Ł\ and O!trimethylsilyl derivatives of primary alcohols can be oxidizedwith trityl tetra~uoroborate ð65JOC0368Ł[ Similarly\ sodium bromate\ in the presence of a catalyticamount of cerium"IV# ammonium nitrate\ will oxidize a wide range of ether derivatives\ includingmethyl\ benzyl\ trimethylsilyl and t!butyldimethylsilyl ð79S786Ł[

Trimethylsilyl ethers can be oxidized using DMSO:oxalyl chloride\ although the conditions"−29>C for 29Ð34 minutes# are appreciably more vigorous than are normally required for alcoholoxidations ð76JCS"P0#0110Ł[ t!Butyldimethylsilyl ethers are inert to the reaction conditions\ andhindered or secondary trimethylsilyl ethers react appreciably less rapidly\ allowing some interestingselective oxidations to be achieved "Equation "4## ð78S839Ł[ The oxidative deprotection and stabilityunder alcohol oxidative conditions of silyl ethers has been the subject of a very comprehensivereview\ which includes some useful tabulations of the reactivities observed ð82S00Ł[

O

O

OSiEt3

O-TMS

DMSO, (COCl)2

62%(5)

O

O

OSiEt3

O

"ii# Esters

Aldehydes may be prepared under strictly neutral conditions by the photolysis of the pyruvateesters of primary alcohols ð65JOC2929\ 65SC170Ł\ and the reaction has been applied to good e}ect inthe preparation of a number of delicate carbohydrate aldehydes ð66JOC0105Ł[ Alkyl nitrites areoxidized in a Kornblum!type reaction by DMSO ð75T3022Ł\ and alcohols can be oxidized via theiraci!nitro esters in a reaction that is probably mechanistically related ð68CC292\ 70TL1184Ł[

2[90[0[4[3 Rearrangement of allylic alcohols

A variety of primary allylic alcohols can be isomerized to aldehydes on treatment withN!lithioethylenediamine or N!lithioaminopropylamine in the amine as the solvent ð74CC701Ł[ Thereaction is somewhat capricious although in favourable cases very good yields of the expectedaldehyde are obtained "Equation "5##[ The main alternative to these strongly basic conditions is aruthenium"II#!catalysed rearrangement[ Although the optimal conditions are substrate!dependent\


good yields are frequently attainable\ and isolated double bonds and alcohols are una}ectedð80TL2928Ł[

OH

LiNHCH2CH2NH2

74%(6)

O

2[90[0[5 From Epoxides

The treatment of epoxides with Lewis acids can give respectable yields of aldehydes\ although theidentity of the carbonyl compound formed appears to depend both on the direction of ring openingand the migratory aptitude of the substituents[ Thus\ mono! and 0\0!disubstituted epoxides generallygive aldehydes\ but with 0\1!disubstituted and trisubstituted epoxides both the exact structure ofthe substrate and the conditions used are important[ For instance\ treatment of 0\1!disubstitutedepoxides with lithium bromide on alumina ð77S283Ł\ or trisubstituted epoxides with methylaluminumbis"3!bromo!1\5!di!t!butylphenoxide# ð80SL380Ł\ gives aldehydes selectively[ The subject is discussedin greater depth in a review of epoxide chemistry ð73S518Ł[

2[90[0[6 From Acetals\ Enol Ethers and Enol Esters

The chief importance of acetals in organic synthesis is as protecting groups for carbonylcompounds[ As well as simple dialkylacetals\ 0\2!dioxanes and 0\2!dioxolanes\ many more complexacetals have been used as protecting groups\ and allow the preparation and deprotection of aldehydesunder a remarkably wide range of conditions[ Readers particularly interested in these aspectsshould refer to one of the specialist works on protecting groups such as that by Greene and WutsðB!80MI 290!90Ł\ since the following discussion is only intended to highlight some of the moreimportant approaches to preparing aldehydes from simple acetals[

Traditional methods of aldehyde preparations from acetals are variants on the theme of acid!catalysed hydrolysis\ and these have now been extended to use supported or heterogeneous acidssuch as Amberlyst!04 ð73S0910Ł\ or wet silica gel ð67S52Ł\ which permit the reaction to be workedup more easily[ However\ a more important objective of research in this area has been to developless strongly acidic conditions for the reaction\ and to _nd methods that allow highly selectivedeprotections to be performed[ One important approach to the former goal is to use trans!acetalizations which are catalysed by very mild reagents such as pyridinium tosylate ð68S613Ł\and palladium"II# bis"acetonitrile# dichloride ð74TL694Ł\ although actual hydrolyses with neutralreagents\ such as aqueous DMSO ð78CL890Ł\ are also possible[

A relatively recent discovery is the ability of a number of reagents to e}ect the {hydrolysis| ofacetals under strictly nonaqueous conditions[ These methods appear to involve an electrophilicattack on one of the acetal oxygens leading to an oxonium ion which is cleaved to the aldehyde bynucleophilic attack on the alkyl group[ The proposed mechanism is illustrated in Scheme 0 for thecase of iodotrimethylsilane ð66TL3064Ł[ Another reagent which appears to work in this way is amixture of acetyl chloride and zinc chloride\ and has the advantage of allowing the cleavage ofdimethyl and diethyl acetals derived from aldehydes in the presence of ketone!derived acetals\ silylethers and dioxolanes "Equation "6## ð81SC0106Ł[

O O

R

O O+

R

TMS +O

R

O-TMSO

R

TMS-II

O-TMSI–

I–

+

Scheme 1

09 Alkyl Aldehydes

O O

OMeO

OMe

O O

OO

AcCl, ZnCl2DMSO

63%(7)

Enol esters and silyl enol ethers are most often prepared from aldehydes as intermediates inother reactions[ They are\ in general\ relatively labile compounds hydrolytically\ making theirtransformations back to aldehydes relatively straightforward should it be required[ Tributyltin~uoride has been recommended for the hydrolysis of more stable silyl enol ethers ð72JA4692Ł[

2[90[0[7 From Aldehydes or Ketones

2[90[0[7[0 From saturated aldehydes or ketones

"i# Alkylation

Although\ in principle\ aldehyde alkylations provide a powerful way of elaborating aldehydes\simple alkylations of metal enolates su}er from a number of drawbacks which limit their use[ Theseinclude poor or no diastereomeric and enantiomeric control\ the occurrence of O! as well asC!alkylation\ and a propensity to give a mixture of singly and polyalkylated products[ However\ arange of alternative methods are now available which o}er solutions to all these problems[

The fundamental problem underlying the polyalkylation of sodium and potassium enolates is thefact that alkylation and proton transfer proceed at similar rates[ In contrast\ lithium enolates\probably because of the more covalent nature of the lithiumÐoxygen bond\ undergo proton transferfar less rapidly and allow monoalkylations to be performed[ The alkylation of metal enolates\ inparticular alkylations involving preformed metal enolates which have the advantage of giving lessaldol by!product than base!catalysed conditions\ has been well reviewed by Caine ðB!68MI 290!90Ł[

Several important methods of aldehyde alkylation involve nitrogen derivatives of the aldehyde\of which the _rst to be introduced were enamines ð43JA1918Ł\ quickly followed by metallated iminesð52AG"E#572Ł\ and\ lastly\ metallated hydrazones ð65TL2Ł[ The alkylation of aldehydes via theirnitrogen derivatives has been the subject of a Synthesis review ð72S406Ł[ One particularly importantapplication of these methods is for the enantioselective alkylation of ketones\ with probably thebest established method being that developed by Enders ðB!72MI 290!90Ł[ This employs hydrazonesderived from "S#!"−#! or "R#!"¦#!0!amino!1!methoxymethylpyrrolidine "abbreviated to SAMP andRAMP\ respectively# and gives reliably high enantioselectivities of predictable sense\ making it themethod of choice for most chiral alkylations "Scheme 1# ðB!73MI 290!90Ł[ Good enantioselectivitiescan also be obtained with metallated imines derived from suitable homochiral primary aminesð68TL2818Ł[

NN

Ph

OMe

i, baseii, MeI

79%

NN

Ph

OMe

H3O+

80%

O

Ph

Scheme 2

Although the reaction of silyl enol ethers derived from ketones with tertiary alkylating agentsunder Lewis acid catalysis to give\ after workup\ good yields of alkylated ketone is well established\examples with aldehyde!derived silyl enol ethers are uncommon ð71AG"E#85Ł[ The reaction is impor!tant in that it complements enolate chemistry both in using acidic rather than basic conditions and\most importantly\ by allowing the introduction of tertiary alkyl groups[

"ii# Homolo`ation

Although any preparation of functionalized aldehydes involving carbon0carbon bond formationand starting from a ketone or aldehyde can be thought of as a homologation\ this section will only


deal with reactions which increase the number of carbon atoms without any increase in the functionalgroup complexity of the molecule[

Homologation of aldehydes generally involves alkenation to give a functionalized alkene whichcan be converted into the required aldehyde in a second step "Scheme 2 and Table 0#[ The reagentscan often also be applied to the preparation of aldehydes from ketones\ and use a wide range ofalkenation methodologies\ including Wittig and related phosphorus chemistry\ and Peterson reac!tions[ A variety of enol ether and enamine precursors to homologated aldehydes can also be preparedvia the diazoalkene derivative resulting from the reaction of an aldehyde or ketone with dimethyldiazomethylphosphonate "Scheme 3# ð72JOC337Ł[

Scheme 3

RX

ROR O

Table 0 Preparation of aldehydes by the homologation of aldehydes to ketones[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐX Rea`ent Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐOMe Ph1P"O#CH1OMe 68JCS"P0#2988

Ph2P1CHOMe 79TL2424Me2SiCH1OMe 68CC711

O!MEM "EtO#1P"O#CH1O!MEM 67TL2518O!THP "EtO#1P"O#CH1O!THP 68JOC3736OSiEt2 "Me1N#1P"O#CH1OSiEt2 68JA260OBn BnOCH1CO1H 68S277OCH1CH1!TMS Ph2P1CHOCH1CH1SiEt2 72TL462Morpholine Ph1P"O#CH1!morpholine 68TL1322NMePh Ph1P"O#CH1NMePh 79TL1560SMe Ph2P1CHSMe 66CI"M#728*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

O •

N2OMe

53%

(MeO)2P(O)CHN2

KOBut, MeOH

Scheme 4

Corey et al[ have developed a variant of the Peterson strategy in which the carbon atom isintroduced by cyanohydrin formation\ which\ although employing several steps\ is useful for thepreparation of aldehydes from very hindered ketones ð79JA0631Ł[ A very di}erent homologativeapproach to aldehydes\ which also introduces the carbon atom at the acid oxidation level\ uses thedithiolane containing WadsworthÐEmmons reagent "5# and involves the borohydride reduction ofa ketene thioacetal intermediate "Scheme 4# ð76S68Ł[

O

S

S+ (MeO)2P(O)

S

S

S

S

(6)

+

BF4–

NaBH4

98%

S

S

–

100%

CHO

HBF4

HgO, HBF4 (aq.)

90%

Scheme 5

01 Alkyl Aldehydes

2[90[0[7[1 From unsaturated aldehydes

"i# Conjuàte reduction

Conjugate reduction of the carbon0carbon double bond of an a\b!enal is inherently more di.cultthan of an enone because of the greater reactivity of the aldehyde group\ and the range of reagentsavailable is therefore more limited[ The conjugate reduction of enones to saturated ketones hastraditionally been achieved with dissolving metal reagents\ particularly lithium in liquid ammonia\and\ although the number of examples is rather small\ this does also appear to work for enalsð65OR"12#0Ł[ An alternative dissolving metal method employing aluminum powder in the presenceof nickel"II# chloride has also been reported ð80T7476Ł[

Relatively little success has been reported in developing modi_ed hydride reagents with reasonable0\3! versus 0\1!selectivity in the reduction of a\b!unsaturated aldehydes[ One reagent with therequired selectivity is the copper hydride cluster ð"PPh2#CuHŁ5\ all six hydrides of which are trans!ferable ð77JA180\ 77TL2638\ 78TL4566Ł[ Rhodium!catalysed hydrosilation and hydrolysis of the result!ing silyl enol ether ð61TL4924Ł\ triethylborane!catalysed triphenylsilane reduction ð80BCJ1474Ł\ andtransfer catalytic hydrogenation ð67JOC2874Ł have also been used for the saturation of conjugatedenals[

"ii# Conjuàte additions of carbon nucleophiles

a\b!Unsaturated aldehydes are ambident electrophiles which can react with carbon nucleophilesin both a 0\1! and a 0\3!sense[ The outcome is partly determined by the electronic nature of thereagent\ with soft\ polarizable species tending to give predominantly the 0\3!product[ Unfortunately\steric factors do play a signi_cant role and account for the conjugate addition to enals beingappreciably more di.cult than to enones[ Conjugate additions to b\b!disubstituted enals are par!ticularly problematic[

Easily the best established class of reagents for conjugate additions is the organocuprates\ which\since they have been the subject of a considerable number of reviews\ will not be discussed in detailhere[ The early literature has been described by Posner\ one of the pioneers in the area\ in an OrànicReactions article ð61OR"08#0Ł\ and the coverage has been updated by Lipshutz\ whose researchgroup has also made major contributions to cuprate chemistry ð81OR"30#024Ł[ Speci_c aspects oforganocuprate chemistry such as copper!catalysed reactions of Grignard and organolithium reagentsð73T530Ł\ and organocopper conjugate additionÐenolate trapping reactions ð74S253Ł\ have also beenthe subject of reviews[ Dialkyl zinc reagents in the presence of catalytic Ni"acac#1 have been foundto be particularly useful for conjugate additions to b\b!disubstituted enals ð74JOC4650\ 74TL718Ł[

2[90[0[7[2 From a!functionalized aldehydes

Because of the ready reducibility of the aldehyde functional group the selective reductive cleavageof any a!functionality is di.cult\ and no general methods have been reported[ However\ 0\2!dimethyl!1!phenylbenzimidazole "6# "X�H# will reduce a!haloaldehydes in high yield ð75JOC4399Ł\and multistep a!dehalogenations via a!haloaldimines and 1!aza!0\2!dienes are also possible and givequite respectable overall yields ð81JOC4650Ł[

N

N

Me

Me

Ph

X

(7)


2[90[0[8 From Carboxylic Acids and their Derivatives

2[90[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives

The high reactivity of an aldehyde under reducing conditions makes the development of reagentswhich can selectively reduce a carboxylic acid or carboxylic acid derivative to an aldehyde\ withoutover!reduction to the primary alcohol\ a challenging undertaking[ Indeed\ the reliability of modernoxidants\ in particular the SwernÐMo}at oxidation\ for the selective oxidation of primary alcoholsto aldehydes makes a two!step conversion via full reduction to the primary alcohol the favouredoption for many chemists\ particularly since the reactions can be performed in a single pot ð68S693Ł[Nevertheless\ a number of very successful methods for the single!step reduction of carboxylic acidor carboxylic acid derivatives to aldehydes are known[

Probably the oldest of these methods is the Rosenmund reduction in which an acid chloride isreduced catalytically with a poisoned palladium catalyst and which overcomes the problems ofselectivity by combining a very reactive substrate with very mild reducing conditions ð37OR"3#251Ł[Modern approaches to this transformation have tended to concentrate on borohydride!derivedreagents[ In fact\ even sodium borohydride can be used provided pyridine ð71SC728Ł or cadmium"II#chloride ð79JCS"P0#16Ł is included in the reaction mixture and appropriate care is taken during theworkup\ although appreciable amounts of primary alcohol are also formed[ More selective are thecopper"I# borohydride complexes developed by the groups of Fleet ð67TL0326Ł and Sorrellð79JOC2338Ł\ although they have the dual disadvantages of being very high molecular weight sourcesof a single hydride\ and requiring the presence of two equivalents of phosphine from which theproduct must eventually be separated[ The latter drawback can be avoided by the use ofbis"triphenylphosphine#copper"I# cyanoborohydride ð79TL702Ł[ Acid chlorides can also be reducedto aldehydes with tributyltin hydride under palladium"9# catalysis ð70JOC3328Ł\ or with 0\2!dimethyl!1!phenylbenzimidazole "6# "X�H#[ The latter is of particular value in allowing the preparation ofdeuterated aldehydes with "6# "X�D# ð75JOC4399Ł[

The reduction of simple esters to aldehydes is a particularly useful transformation because of theirconsiderable importance as functional groups[ Fortunately\ diisobutylaluminum hydride "dibal!H#at low temperature "−69>C# has been found to achieve the transformation very successfully\tolerating a wide range of other functionalities\ and even allows the selective reduction of methylor ethyl esters in the presence of t!butyl esters ð64S506Ł[ Diisobutylaluminum deuteride "dibal!D#can be used for the preparation of deutero aldehydes ð73T2276Ł[ Thiol esters can also be reduced toaldehydes\ most traditionally with Raney nickel deactivated by boiling in acetone ð43OR"7#107Ł\ butalso with triethylsilane in the presence of palladium on carbon ð89JA6949Ł[

The reduction of simple amides to aldehydes is a particularly challenging transformation becauseof their low reactivity to nucleophilic reducing agents[ However\ the preparation of aldehydes fromprimary carboxamides by treatment with lithium tris"diethylamino#aluminum hydride ð80TL5892Ł\and from tertiary N\N!dimethylamides with lithium tri!s!butylborohydride "L!selectride# in thepresence of an alkyl tri~ate ð89JCS"P0#646Ł have been reported[ The latter reaction\ which probablyproceeds via an imidate intermediate\ is compatible with ester\ alkene and nitrile functionalities"Equation "7##[ A number of aldehyde preparations use speci_c amide precursors\ of which the mostimportant are probably the N!methoxy!N!methyl "Weinreb# amides\ which may be reduced withexcess lithium aluminum hydride or dibal!H to give good yields of the required aldehyde[ Littleoverreduction occurs because the N!methoxy group stabilizes the tetrahedral intermediate byinternal coordination ð70TL2704Ł[ The preparation of aldehydes by the dibal!H reduction of acylimidazoles ð68CC68Ł\ and acyl thiazolidine derivatives "7# ð68BCJ444Ł\ has also been reported[ Nitrilescan be reduced with dibal!H to imines\ which are hydrolysed to aldehydes on workup ð64S506Ł\ andalso\ via nitrilium salts\ with triethylsilane ð70JOC591Ł[

MeO NMe2

O OEtOTf, L-selectride

69%(8)

MeO

O O

Perhaps surprisingly\ carboxylic acids themselves may be directly reduced to aldehydes witha variety of reagents[ These include the thexyl chloroboraneÐdimethyl sul_de complex\ which isincompatible with alkene functionality ð76JOC4399Ł\ and the thexyl bromoboraneÐdimethyl sul_decomplex\ which although compatible with alkenes requires dimethyl sul_de as the solvent ð76JOC4929\76TL1278Ł[ In neither case is the workup particularly straightforward[ Probably more convenient isbis"N!methylpiperazinyl#aluminum hydride\ which may be prepared as a stock solution in THF\

03 Alkyl Aldehydes

SN

S

R

O

(8)

and e}ects the reduction in high yield ð73JOC1168Ł[ The pentavalent silane "8# has also been usedfor this reduction ð76TL2830Ł[ Despite this range of reagents\ in practice carboxylic acids are mostoften reduced to aldehydes in multistep sequences\ either via the primary alcohol or a heterocyclicderivative such as a benzimidazoles "Scheme 5# ð70S292Ł[

NMe2

Si

HPh

H

(9)

O

N

N

OH

O

NH2

NH2 HO

N

N

MeO

Me

Scheme 6

OO

polyphosphoric acid

70%

i, NaOEt ii, MeI

iii, NaBH4 89%

+

HCl

66%

2[90[0[8[1 Formylation reactions

Tertiary formamides such as DMF have long been known to give aldehydes on reaction withGrignard reagents\ although it is necessary to control the reaction temperature carefully and avoidany excess of the Grignard reagent if satisfactory results are to be obtained ð73S117Ł[ The reactionhas been the subject of a study which compared a number of tertiary formamides and found thatless secondary alcohol by!product is formed if the electrophile contains an additional chelatinggroup ð72TL0032Ł[ The preferred reagent was N!"N!formyl!N!methylamino#piperidine "09#[ Thepreparation and formylation of the organometallic species can also be achieved in a single step bythe ultrasonication of an alkyl halide in the presence of lithium metal and DMF ð71TL2250Ł[

N

NMe

O

(10)

Probably the most widely used formylating reagent for Grignard reagents after DMF is triethylorthoformate\ although comparative studies suggest that higher yields are obtained if the cyclicorthoester "00# is used ð79JCS"P0#645Ł[ Other formates have not been widely exploited as formylatingagents\ although both methyl formate and sodium or lithium formates can be used to formylate


organometallic reagents[ The former reagent requires very low temperatures "−009>C# if secondaryalcohol formation is to be avoided in its reaction with alkyllithium reagents ð75JOC840Ł\ whereasthe latter requires elevated temperatures if a reasonable rate of reaction with Grignard reagents isto be obtained ð73TL0732Ł[

OO

OMe

O

O

(11)

Several procedures are available in which the formyl group derives ultimately from carbonmonoxide[ The carbon monoxide can either be gaseous\ as in the reaction of tetraalkylstannaneswith carbon monoxide under palladium"II# catalysis ð68TL1590Ł\ or in the form of a metal carbonylas in the protonation of acyl ferrates prepared from the reaction of Grignard reagents with pen!tacarbonyliron ð71BCJ0552Ł[ The latter method may be used to prepare 0!deuteroaldehydes if deut!eroacetic acid is used to decompose the intermediate[ 0\2!Benzodithiolium tetra~uoroborate "01#has also been reported as a useful synthon for the preparation of deutereoaldehydes ð71BCJ1178Ł[

S

SD

+

(12)

2[90[0[8[2 Other preparations from acids and acid derivatives

A simple one!carbon homologative preparation of aldehydes from esters involves the treatmentof the ester with bromomethyllithium to form the lithium ynolate\ which is reduced with cyclo!hexadiene to give the lithium enolate of the aldehyde with one extra carbon atom "Scheme 6#ð75JA0214Ł[

OMe

CO2Me

OMe OLi

OMe

OLi

OMe

CHO

i, LiTMP, CH2Br2ii, BunLi

i, TMS-Clii, H3O+

61%

Scheme 7

2[90[0[09 From Sulfur!containing or Other Lower!Chalcogen!Containing Precursors

The hydrolyses of thioacetals and vinyl sul_des are closely related processes which involve acommon sulfenium ion intermediate "Scheme 7#[ The mechanism is analogous to that of the closelyrelated hydrolysis of acetals and vinyl ethers\ although the reaction di}ers since the equilibrium inthis case lies predominantly towards the thioacetal rather than the carbonyl compound[ For thisreason it is necessary to drive the hydrolysis to completion by removing the thiol produced\ and anumber of methods have been developed for doing this\ the most important of which are theformation of an insoluble transition metal thiolate\ and oxidation of the thiol to a higher oxidation

05 Alkyl Aldehydes

state of sulfur[ References to a selection of methods are contained in Table 1\ and the subject hasbeen discussed in rather more detail by Gro�bel and Seebach ð66S246Ł[ Thioacetals have an importantapplication as protecting groups\ and a useful discussion of this aspect may be found in Greene andWuts ðB!80MI 290!90Ł[

R2

SR1

SR1

R2

SR1

–R1S–

+H+R2

+SR1H2O

R2

O

Scheme 8

Table 1 Preparation of aldehydes from thioacetals[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐRea`ent Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐTransition metal reagents

HgO\ HBF3 70S40PbO1\ BF2 = Et1O 71S479

Alkylating reagentsMeOSO1F 61S450

Oxidizing reagentsTl"NO2#2 68SC290Electrochemical 89TL1488mcpba 76S002

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

The Pummerer reaction allows the preparation of an a!functionalized sul_de from a sulfoxidebearing at least one a hydrogen atom\ in an internal redox process that results in the reduction ofthe sulfoxide with concomitant oxidation of a neighbouring carbon atom from the alcohol to thealdehyde oxidation state ð80OR"39#046Ł[ The reaction provides an important approach to aldehydesfrom alkyl aryl sul_des since the product a!functionalized sul_des can be readily hydrolysed to thealdehydes "Scheme 8# ð67S770Ł[ a!Silyl sulfoxides\ prepared by silylation of sulfoxide!stabilizedanions\ spontaneously undergo a Pummerer rearrangement at room temperature to give a!silyloxysul_des\ which can be hydrolysed to the required aldehyde under very mild conditions ð64TL1906Ł[Related aldehyde precursors\ a!chlorosul_des\ can be prepared by NCS chlorination of sul_des\and are hydrolysed in the presence of mercury"II# or cadmium"II# salts ð65SC464Ł[ The chlorinationand hydrolysis can alternatively be achieved in the same pot by sequential treatment of a sul_dewith sulfuryl chloride and silica gel ð72JOC2460Ł[

BnOSOPh

TFAA

2,6-lutidine

BnOSPh

OTf

BnO

ONaHCO3

53%

TFAA = trifluoroacetic anhydride

Scheme 9

Anions of sulfones can be oxidized directly to aldehydes with bis"trimethylsilyl#peroxideð72JOC3321Ł\ or alternatively by boration of the anion with dimethyl chloroborate followed bytreatment with the sodium salt of mcpba "Scheme 09# ð74TL1222Ł[ Both reactions proceed via ana!oxygenated sulfone which immediately eliminates benzenesul_nic acid[

The cleavage of selenoacetals has been the subject of a systematic study which found thatmercury"II# chloride in wet acetonitrile\ and hydrogen peroxide or benzeneseleninic anhydride inTHF\ gave good results ð68S766Ł[


SO2Ph SO2Ph

B(OMe)2 i, BunLi

ii, ClB(OMe)2

O

Na salt of mcpba

72%

Scheme 10

2[90[0[00 From Nitrogen!containing Precursors

2[90[0[00[0 From amines

Although the conversion of an amine into a carbonyl compound is a relatively common biologicaltransformation\ which can occur by ~avin!\ NADP! or pyridoxyl!mediated processes\ it is onlyrarely performed chemically[ Despite this there is a range of methods for achieving an oxidativedeamination\ including methods involving a pyridoxal!like prototropic rearrangement of an imine"Scheme 00# ð71JA3335Ł[ The imine tautomerization may also be achieved via a base!inducedfragmentation of an oxaziridine\ prepared by peracid oxidation of a Schi} base ð68TL2190Ł[ Thedirect oxidation of an amine to an imine is also possible with an arylsulfonyl peroxide in the presenceof strong base\ and can be followed by hydrolysis to the aldehyde ð73JOC3900Ł[ Alternatively\ theoxidation and hydrolysis can be achieved in a single pot by nitroxyl!mediated electrooxidationð72JA5621Ł[ Anodic methoxylation of carbamates also provides a simple route to aldehydes via theirdimethylacetals ð72JOC2227Ł[

NBun NH2 + Me CHO N Me

N

Bun

N Me

PhSO2–

+

+

N

Bun

dbu+

H3O+

84%BunCHO

Scheme 11

Although the ease of hydrolysis of imines makes them a particularly attractive intermediate in anamine to aldehyde conversion\ a recent method which involves the oxidation of a metallatedsilylamine with dry air to give an oxime appears attractive[ The oxime intermediate is hydrolysedto the required aldehyde during ~ash chromatographic puri_cation\ and the conditions are com!patible with phosphine\ thioether and tertiary amine functionalities "Scheme 01# ð77TL5690Ł[

HNTMS

NOTMS

OLi

NO

NOH

O

i, BunLi

ii, dry air

SiO2, H2O

87%

Scheme 12

07 Alkyl Aldehydes

2[90[0[00[1 From oximes\ hydrazones and their derivatives

Probably because they are relatively stable derivatives of aldehydes\ and have the reputation ofonly being hydrolysed under fairly vigorous conditions\ oximes and hydrazones are relativelyinfrequently considered as potential precursors or protecting groups\ despite the very sizeable bodyof literature describing methods of achieving this sort of transformation[

Classical oxime and hydrazone hydrolyses use fairly vigorous acidic conditions^ however\ thetransformation can be achieved with milder heterogeneous acid catalysts such as Amberlyst!04 resinfor tosylhydrazones\ dinitrophenylhydrazones and semicarbazones ð77JCS"P0#1452Ł or Dowex!49resin for oximes and semicarbazones ð77JOC767Ł[ Dimethylhydrazones may also be hydrolysed bya Lewis acid!catalysed transfer of the hydrazine to acetone ð65S345Ł[ One important method offacilitating the C1N hydrolysis of hydrazones is by metal complexation of the nitrogen to activatethe carbon atom to attack by water[ The metal ion most commonly used for this purpose iscopper"II#\ which also has the advantage of driving the reaction to completion by scavaging theliberated hydrazine derivative ð65TL2556Ł[

Probably the largest group of methods for preparing carbonyl compounds from C1N derivativesare those employing oxidizing agents[ These include nitrosating reagents\ which\ like the copper"II#complexation\ work by activating the carbon atom to attack by water by removing electrons fromnitrogen[ An example of this type of method is the hydrolysis of oximes mediated by a mixture ofsodium nitrite and chlorotrimethylsilane which provides an in situ source of nitrosyl chlorideð89TL5566Ł[ Active oxygen reagents can also be used[ For instance\ aryl hydrazones have beencleaved with basic hydrogen peroxide ð67S808Ł\ and the recently introduced magnesium mon!operoxyphthalate has been found to be particularly valuable in cleaving hydrazones without a}ect!ing the stereochemical integrity of a chiral centre a to the aldehyde product ð89SL614Ł[Dimethylhydrazones have also been regenerated with bu}ered periodic acid ð65TL2Ł[

Conventional high!valent metal oxidants can also be employed in the preparation of aldehydesfrom oximes or hydrazones[ Thus\ bis"trimethylsilyl#chromate has been found valuable for thepreparation of aldehydes from oximes ð81SC1314Ł\ and thallium"III# acetate can be used to regeneratealdehyde tosyl hydrazones ð68TL3472Ł[ Benzeneseleninic anhydride will also cleave a range ofC1N derivatives\ including oximes\ aryl and tosyl hydrazones\ and semicarbazones\ but not N\N!dimethylhydrazones or O!methyl oximes[ The reagent appears to be particularly e}ective for theregeneration of hindered substrates ð79JCS"P0#0101Ł[

Although the majority of new publications describe the use of oxidative reagents\ it is also possibleto achieve the transformation under reducing conditions^ for example\ both Raney nickelÐsodiumhypophosphite ð75SC792Ł and vanadium"II# chloride ð79S119Ł can be used for deoximation[ Despitethe variety in types of reducing agent used\ they all appear to involve an initial reduction to animine\ which is hydrolysed under either the reaction or workup conditions[

Lastly\ it has recently been reported that both oximes ð80JCS"P0#1945Ł and hydrazones ð80TL1546Łcan be cleaved enzymatically with baker|s yeast[ The hydrolysis\ which is greatly aided by sonication\gives near!quantitative yields of the aldehyde[

2[90[0[00[2 From nitroalkanes

The preparation of a carbonyl compound from a primary or secondary nitroalkane is usuallyknown as the Nef reaction[ The conversion was originally achieved by treatment of the nitronatesalt derived from a nitroalkane with a strong acid\ but the extremely vigorous nature of theseconditions\ and the occurrence of a number of side reactions\ has led to the development of a widerange of alternative conditions[ These methods have been comprehensively reviewed in a volume ofOr`anic Reactions ð89OR"27#544Ł[

2[90[0[01 From Organosilanes

Probably the most important organosilane precursors of unsubstituted aldehydes are vinyl silanes[Provided that the silicon bears an electronegative substituent\ such as alkoxy\ these can be oxidizeddirectly to the aldehyde with hydrogen peroxide ð73TL210Ł[ More generally the conversion can beachieved by epoxidation followed by boron tri~uoride etherate!catalysed rearrangement to give thealdehyde silyl enol ether ð73JCS"P0#008Ł\ or by mineral acid treatment to give the aldehyde directlyð60JA1979Ł[ Both methods result in formation of the aldehyde at the silicon!bearing carbon atom[


Vicinal hydroxylation of a vinylsilane followed by acid treatment yields aldehydes by a silapinacolrearrangement "Equation "8## ð75TL3158Ł[ Because of the preferential migration of the silicon group\good control of the product distribution from an unsymmetrical diol is observed[

OH

TBDMS

HO TFA

86%

O

TBDMS

(9)

Aldehydes have also been prepared by the catalytic hydrogenation of acyl silanes containing aphenyl group bound to silicon ð80TL346Ł[ Remarkably\ the reaction can be performed in the presenceof other hydrogenolizable functionalities\ such as benzyl and benzyloxymethyl ethers\ and acid!sensitive groups such as t!butyldimethylsilyl and methoxymethyl ethers "Equation "09##[

OO

PhMe2Si

O OBn

H2, Pd (cat.)

82%

OO

OBnO

(10)

2[90[0[02 From Organoboranes

Hydroboration reactions are most often worked up with alkaline hydrogen peroxide to give analcohol[ In cases where an aldehyde is required it is generally obtained in a second oxidation step\although it is also possible to achieve the transformation in a single step by using pyridiniumchlorochromate as the oxidant ð72TL520Ł[

Trialkylboranes can be carbonylated with carbon monoxide to give aldehydes after oxidativework up with hydrogen peroxide "Scheme 02# ð68S690Ł[ Two!carbon homologations can be achievedby reaction with dimethoxyethenyllithium to give an ate complex\ which can be rearranged to thealdehyde by treatment with Lewis acid and a hydrolytic workup "Scheme 03# ð72SC0038Ł[

Bn-C6H13 B

OH

n-C6H13

O

CO, KBH(OPri)3

n-C6H13

H2O2, pH 7

87%

Scheme 13

MeO

Br

OMe MeO

Bu3B

OMe

Scheme 14

–

O

Bu i, BunLi

ii, Bu3B

i, BF3•OEt2ii, H3O+

82%

2[90[0[03 Methods Involving Umpolung

Although reactions involving polarity reversal\ such as the benzoin condensation\ have beenknown since the earliest days of organic chemistry\ it is only since the mid!0859s that the concepthas really played an important role in synthetic chemistry[ Much of the early development of thearea and the nomenclature used in this review are due to Seebach ð68AG"E#128Ł[ Although a vastrange of umpolung synthons have been developed for aldehyde preparation\ by far the mostimportant are the d0 "formyl anion# reagents\ and the d2 "homoenolate# equivalents[

19 Alkyl Aldehydes

2[90[0[03[0 Formyl anion equivalents

An enormous number of d0 synthons have been described which vary in importance from widelyused reagents to mechanistic curiosities[ A compilation of synthons reported up to the early 0879sis available and includes useful detail on the types of electrophiles used and reactivities seen "e[g[\0\1!versus 0\3!addition to an a\b!unsaturated system# ð70MI 290!90Ł[ The general topic of nucleophilicacylation has also been reviewed ð65T0832Ł[

The large number of formyl anion synthons available can actually be divided into quite a smallnumber of reagent types\ of which easily the largest group are those reagents based on sulfur[ Thisincludes one of the earliest\ and still one of the most important\ formyl anion synthons\ 1!lithio!0\2!dithiane\ which itself has been the subject of several reviews ð66S246\ 78T6532Ł[ Although themajority of sulfur!based formyl anion synthons contain sulfur"II#\ reagents containing sulfur"VI#\such as "02# ð80SL490Ł\ are also valuable[ The major drawback of the sulfur reagents is the di.cultyof their hydrolysis\ which\ despite the considerable amount of attention the problem has received\can still present problems[ One solution has been the development of reagents such as "03# whichcontain both sulfur and silicon\ and which can be deprotected very easily by oxidation to thesulfoxide and sila!Pummerer rearrangement ð79TL0448\ 79TL0566Ł[ The chemistry of silicon!containing carbonyl equivalents has been reviewed ð71CSR382Ł[

ButO SO2Ph

(13)

PhS TMS

(14)

The largest remaining group of d0 formyl synthons used for simple alkyl aldehyde preparationsare those based on nucleophilic metal carbonyl derivatives[ The best known example of these is theCollman reagent Na1Fe"CO#3\ which reacts with primary and secondary halides and sulfonates togive an alkyl iron complex which rearranges to the acyl complex in the presence of carbon monoxideor a phosphine[ Treatment of the acyl complex with mineral acid then liberates the aldehyde"Equation "00##[ The reagent tolerates ketone\ ester or nitrile functionalities\ but has the drawbackof being somewhat basic\ causing elimination of some substrates\ in particular tertiary halides andsulfonates ð64ACR231Ł[ A number of related ionic iron carbonyl complexes ð78TL5260Ł\ includingpolymer!supported variants ð67JOC0487Ł\ can also be used[ A quite remarkable formylation of analkyl acetate involves its treatment with octacarbonyldicobalt in the presence of a trialkylsilane[The immediate product is a silyl enol ether which can either be isolated\ or hydrolysed with potassium~uoride in methanol "Scheme 04# ð72JA0269Ł[

ClBr

ClCHO

i, Na2Fe(CO)4, THF, COii, HOAc

82%(11)

But

OAc

But

OSiEt2Me

But

MeEt2SiH, Co2(CO)8CO, 200 °C

63%

O

KF

100%

Scheme 15

The d0 reactivity of cyanohydrins that underlies the benzoin condensation has also inspired anumber of formyl anion synthons such as the N\N!diethylaminoacetonitrile anion "Et1NCHCN#\which\ after alkylation\ is hydrolysed with oxalic acid in aqueous THF to give the required aldehydeð67TL4064Ł[

2[90[0[03[1 Other anion equivalents

Although homoenolates of nonenolizable carbonyl compounds can be formed with very strongbases\ the chemistry is of limited synthetic generality\ and d2 synthons are generally preferred[ The

10b and More Remotely Unsaturated

majority of homoenolate equivalents are substituted allyl anion species\ and consequently can su}erproblems controlling the selectivity of the alkylation to the required g position[ A useful introductionto the chemistry of both homoenolates and their equivalents has been provided by Werstiukð72T194Ł[

2[90[1 b AND MORE REMOTELY UNSATURATED ALDEHYDES

The unconjugated alkene functionality is relatively unreactive\ and many of the methods describedin Section 2[90[0 can be used for the preparation of remotely unsaturated aldehydes simply byusing an appropriately unsaturated precursor[ One very signi_cant restriction to this generalizationconcerns b\g!unsaturated aldehydes\ where the ease with which the double bond can migrate intoconjugation restricts the choice of reagents[ This section describes methods in which the unsaturationis a necessary or integral part of the chemistry[ The reactions consequently have no direct analogieswith the preparation of saturated aldehydes[ Indeed\ some of the methods\ with the inclusion of a_nal hydrogenation step\ can become powerful approaches to saturated aldehydes[

2[90[1[0 Alkyl Aldehydes with One Double Bond

2[90[1[0[0 From aldehydes

"i# Allylation of saturated aldehydes

Since allyl halides are highly reactive alkylating agents\ conventional base!catalysed and metalenolate!based alkylation methods may be employed for the allylation of aldehydes\ although withthe usual attendant problems of polyalkylation and poor regiocontrol "see Section 2[90[0[7[0#[Potassium enolates of aldehydes in tetrahydrofuran have been reported to give clean C!alkylationwith primary allyl halides ð67TL380Ł[

2[90[1[0[1 Preparations involving rearrangements

"i# Claisen rearran`ements

The Claisen rearrangement\ the ð2\2Ł sigmatropic rearrangement of an allyl vinyl ether can be auseful route to g\d!unsaturated aldehydes ð64OR"11#0\ 66S478Ł[ The chief di.culty of the reaction liesin the preparation of the allyl vinyl ether substrate\ which is normally achieved by a mercury"II#!catalysed vinyl ether exchange reaction "Scheme 05#\ although a number of alternatives have beenreported[ These include the palladium on charcoal catalysed prototropic rearrangement of diallylethers "Equation "01## ð71TL1962Ł\ and the cohalogenation of alkenes in ethylene oxide\ a reactionwhich appears to be relatively general "Scheme 06# ð82S288Ł[ Claisen rearrangements have also beenused in tandem with Cope rearrangements to prepare aldehydes with both b\g! and o\z!unsaturation"Equation "02## ð71JA6070Ł[ Thio and aza analogues of the Claisen rearrangement which give vinylsulphide ð62JA1582Ł or imine ð77JOC3378Ł precursors of aldehydes are also known\ and o}er someadvantages in terms of ease of preparation of the precursors[

HO O

CHO

Hg(OAc)2, ethyl vinyl ether200 °C

85%

Scheme 16

11 Alkyl Aldehydes

O

O

Pd-C, ∆

58%(12)

O

O

O

Br

Br

O

O

Br2, oxirane, –80 °C

81%

ButOK, 18-crown-6

93%

190 °C

77%

Scheme 17

O

∆O

(13)

"ii# Oxy!Cope rearran`ements

The oxy!Cope rearrangement is a ð2\2Ł sigmatropic rearrangement of a hexa!0\4!dien!2!ol systemto form a d\o!unsaturated ketone\ and is generally performed under thermal conditions "×199>C#"Equation "03## ð64OR"11#0Ł[ Oxy!Cope rearrangements of tertiary dienols\ which yield ketonicproducts\ are greatly accelerated by the formation of an alkali metal\ particularly potassium\ salt ofthe starting dienol[ These conditions have greatly extended the scope and application of the reactionfor ketone preparations "see Section 2[92[1[0[2"ii##\ but have only infrequently been applied to therearrangement of secondary dienols to prepare aldehydes\ although examples are known ð66TL1448Ł[

OOH

220 °C

90%(14)

The preparation of the appropriate starting material for an oxy!Cope rearrangement is not alwaystrivial[ One particularly ingenious way of overcoming this problem is to use a tandem ð1\2Ł WittigÐoxy!Cope rearrangement of a diallyl ether ð71CL0238Ł[ Unfortunately\ studies of this chemistry withchiral cyclohexenyl systems have shown that the ð0\1Ł Wittig rearrangement\ which leads to theenantiomeric product\ competes to a minor extent with the ð1\2Ł rearrangement "Scheme 07#ð71TL2820Ł[

O

OH OH

O O

BunLi

[1,2]Wittig

BunLi

[2,3]Wittig

KH, 18-crown-6oxy-Cope

KH, 18-crown-6oxy-Cope

minor major

Scheme 18


2[90[1[0[2 Other preparations

"i# Formylation reactions

A useful hydroformylation approach to g\d!unsaturated aldehydes involves the addition of azirconium hydride complex to a 0\2!diene[ The hydrozirconation is speci_cally 0\1 in orientationand shows good selectivity for the less hindered double bond of an unsymmetrical diene[ Thereaction of the unsaturated zirconium derivative with carbon monoxide gives the aldehyde "Scheme08# ð65JA151Ł[ Allylic halides can also be formylated at their less substituted terminus with carbonmonoxide and tributyltin hydride in the presence of a palladium"9# catalyst ð75JA341Ł[

OZr

Cl

ZrCp2HCl

80–90%

i, COii, H3O+

98%

Scheme 19

Nucleophilic formylation of unsaturated electrophiles can be achieved with many of the d0

synthons discussed in Section 2[90[0[03[0[ In addition\ methods have been developed for the for!mylation of allylic halides at their more hindered termini[ These involve the ð1\2Ł sigmatropicrearrangement of a sulfur ð79CC0985Ł or nitrogen ð65BSF0334\ 73TL2346Ł ylide formed by the treatmentof an initially formed allyl sulfonium or allyl ammonium salt with a base "Scheme 19#[b\g!Unsaturated aldehydes have also been prepared by the electrophilic formylation of allylGrignard reagents with 3\3!dimethyl!1!oxazolines ð65BSF0764Ł[

Br NMe2

CN CHONMe2

CN

+

Scheme 20

AgNO3, H2OEt2O, THF

Me2NCH2CNK2CO3, DMF

"ii# Miscellaneous preparations

A novel approach to g\d!unsaturated aldehydes involves the oxidation of a!trimethylstannyl zincreagents with dry air at −09>C\ a reaction which is thought to proceed by insertion of oxygen intothe carbon to zinc bond[ The complete sequence\ including the preparation of the a!trimethylstannylzinc reagents by trimethylstannylation of the product from the reaction of an allylzinc bromide witha vinyl Grignard reagent\ is depicted in Scheme 10 ð77TL5586Ł[

MgBr

ZnBr

n-C6H11n-C6H11

MgBr ZnBr

SnMe3

O

n-C6H11

O-TMS

SnMe3

ZnBr

n-C6H11

Me3SnCl

dry air, TMS-Cl

On-C6H 11

Scheme 21

+

87%

13 Alkyl Aldehydes

2[90[1[1 Alkyl Aldehydes with More than One Double Bond

Aldehydes containing more than one nonconjugated double bond are generally prepared bymethods that are directly analogous to those used for the preparation of saturated aldehydes "seeSection 2[90[0# or aldehydes with a single nonconjugated double bond "see Section 2[90[1[0#[

The oxy!Cope rearrangement\ a powerful approach to d\o!unsaturated aldehydes and ketones"see Sections 2[90[1[0[1 and 2[92[1[0[1#\ has been extended by several workers to give compoundswith two or more double bonds[ So far these variants have been applied only to unsaturatedketone preparations "see Section 2[92[1[1#\ although in view of the success of the basic oxy!Coperearrangement for the preparation of aldehydes\ there seems to be no obvious chemical reason forthis limitation[

2[90[1[2 Alkyl Aldehydes with Aryl or Hetaryl Substituents

2[90[1[2[0 From aldehydes

"i# Arylation of saturated aldehydes

Far less attention has been given to the arylation of aldehydes than of ketones\ and very fewgeneral methods are available[ One approach involves the FriedelÐCrafts!type reaction of an arenewith an a!chloroaldimine in the presence of aluminum chloride\ followed by the hydrolysis of theimine\ although proton loss from the presumed a!imidoylcarbenium ion intermediate to give theunsaturated imine is a yield!limiting side reaction "Scheme 11# ð71TL1742Ł[

N

Et6N HCl

40%

CHO

Et

Cl

N

Et

+AlCl3, ∆

Scheme 22

"ii# Conju`ate addition of aryl nucleophiles to a\b!unsaturated aldehydes

The conjugate addition of benzyl groups to a\b!unsaturated aldehydes is complicated by thetendency of benzyl halides to undergo Wurtz coupling during the formation of an organometallicderivative\ and by the poor thermal stability of benzylic cuprates[ However\ with careful control ofthe conditions\ counterion and Lewis acid additive\ very good results have been obtained in theconjugate addition of benzylmagnesium chloride!derived copper reagents to enals "Equation "04##ð81TL1272Ł[

Ph OBnMgCl, CuI

TMS-Cl, HMPA, THF

62%

Ph O

Ph

+ (15)

16 : 1

Ph OH

Ph


The well!established use of palladium chemistry for the formation of aryl to carbon bondshas been exploited in several syntheses of aryl!substituted aldehydes[ For example\ palladium"9#!catalysed cross!couplings of aryl halides with 1!ethoxyvinylboranes ð71JOC1006Ł\ or with acrylamideð80S428Ł\ gives functionalized styrene derivatives which can be converted to the required aldehydeby hydrolysis\ or by Hofmann rearrangement and hydrolysis\ respectively "Schemes 12 and 13#[


More remotely aryl!substituted aldehydes can be prepared by the palladium"II#!catalysed couplingof aryl halides with terminal alkenols in the presence of a mild base[ The reaction\ which involvesthe palladium!catalysed double bond migration of an initial styrene product\ is successful even withundecen!00!ol\ although the regioselectivity of the initial carbonÐcarbon bond!forming reaction isonly moderate "Equation "05## ð78TL5518Ł[ Chiral 1!aryl aldehydes of modest to fair enantiomericexcess have been prepared by the alkylation of cinnamyl ethers prepared from the atrolactic acidderived\ and recoverable\ chiral auxiliary "04# "Scheme 14# ð71CL0526Ł[

O

OEt

O

Br

BOEt

3

+

O

O

H3O+

Scheme 23

Pd(PPh3)4

96%

Cl

Cl

NH2

Cl

Cl

I H2CCHCONH2Pd0, NaOAc, 100 °C

87%

i, NaOCl, MeOHii, H3O+

38%

Cl

Cl

O

Scheme 24

O

IOH

(16)+

+Pd0

91%

110

11

OO

111011

88 : 12

O Ph

OMePh

OH

OMePh

O

OMePh

Ph

Bun

HClO4

O Ph

NaH, cinnamyl bromide

90%

(15)

Bun

i, KNPri2, Et2O

ii, BunI

65%

75% ee

+ (15)

Scheme 25

2[90[1[3 Alkynyl!Substituted Alkyl Aldehydes

2[90[1[3[0 Fragmentation reactions

The fragmentation of an a\b!epoxy ketone on reaction with tosyl hydrazide to give an alky!nylketone was _rst described by Eschenmoser|s group\ and is now generally referred to as anEschenmoser fragmentation ð56HCA697Ł[ The reaction is not particularly satisfactory for the prep!aration of aldehydes\ although mesitylenesulfonyl hydrazide has been found to give signi_cantlybetter results "Equation "06## ð70S165Ł[ N!Aminoaziridine hydrazone derivatives of epoxy ketones

15 Alkyl Aldehydes

fragment in a similar manner on heating and give good yields of aldehydes "Equation "07##ð61HCA0165Ł[

O +CHO

SO2NHNH2

O

42%(17)

O

N

140 °C

61% CHO

N Ph

Ph

(18)

2[90[2 HALOALKYL ALDEHYDES "a\ b AND MORE REMOTE HALOGEN#

2[90[2[0 Introduction

The literature to mid!0875 on the synthesis and chemistry of a!halo aldehydes containing one ortwo halogen atoms has been the subject of an excellent chapter by De Kimpe and Verhe in one ofthe Updates to the Chemistry of the Functional Groups monographs edited by Patai and RappoportðB!77MI 290!90Ł[

a!Halo aldehydes are considerably more reactive than are a!halo ketones\ and satisfactory generalmethods for their preparation have only become available since the mid!0859|s[ Their isolation anduse can also be di.cult because of the frequently high stability of many of their hydrates\ and theease with which they can oligomerize[ One recently reported solution to the problem involves thepreparation of an aldehydeÐLewis acid complex by treatment of the oligomer with methylaluminumbis"1\5!diphenylphenoxide#[ The resulting complex can then be employed directly in reactions withnucleophiles ð82JA2832Ł[ Because of these di.culties\ the literature is considerably more sparse thanfor a!halo ketones\ and this discussion is arranged by starting material rather than by halogen[

More remotely substituted halo aldehydes are generally prepared by methods typical of unfunc!tionalized aldehydes or halo compounds\ and few general methods speci_cally aimed at this classof compounds have been reported[

2[90[2[1 From Stable Enol Derivatives and Enamines

Although the control of regioselectivity\ which constitutes the major advantage of preparinga!halo ketones from enol derivatives\ is irrelevant to the preparation of a!halo aldehydes\ thereactions of halogens with enol silanes has proved to be a very successful route to a!chloro anda!bromo aldehydes ð63JOC0674Ł[ Impressively\ the reaction can also performed with 4) ~uorine innitrogen to give a!~uoro aldehydes\ although the products were found to be unstable both toattempted distillation and on standing "Equation "08## ð75TL1604Ł[

O-TMSF2/N2, CFCl3, –78 °C

72%

F

O

(19)

2[90[2[2 From Aldehydes

The direct halogenation of aldehydes\ although free of the regiochemical problems that plaguethe halogenation of ketones\ is in fact rather less satisfactory due to the higher reactivity of the

16Haloalkyl

aldehyde function\ and the possibility of other side reactions\ such as acid halide formation[Fortunately\ a number of reagents for both chlorination and bromination are known[ For example\the bromination of aldehydes can be achieved in very high yields by treatment with bromo!trimethylsilane ð75JCR"S#315Ł\ or t!butyl bromide in DMSO ð73T1924Ł[ The reaction can also beperformed with chlorotrimethylsilane to give a!chloro aldehydes\ although the yields are con!siderably worse[ Brominations of aldehydes have also been reported with the related brominatingagents dibromobarbituric acid "05# ð74CB3177Ł and dibromo!Meldrum|s acid "06# ð67S039Ł[

NH

HN

O

O

O

Br

Br

(16)

O

O

O

O

Br

Br

(17)

The literature on the preparation of a!iodo aldehydes is particularly sparse\ although several verysatisfactory synthetic approaches have been described[ These include iodination of aldehydes byiodine in the presence of mercury"II# chloride ð75S567Ł\ of aldehyde enolates with iodine ð68TL1706Ł\and the halogen exchange of a!chloroaldehydes with sodium iodide in dry acetonitrile ð75OPP68Ł[

a\a!Dihalo aldehydes can be prepared from aldehydes by reaction with either chlorine or brominein the presence of pyrrolidine hydrohalide salt as a catalyst ð74SC866Ł[

2[90[2[3 Miscellaneous Preparations

2[90[2[3[0 Functional group transformations

a!Fluoro and a\a!di~uoro aldehydes have been prepared from bromo~uoroalkanes by a routethat involves nucleophilic introduction of sulfur and Pummerer rearrangement[ The authors rec!ommend that the product aldehydes\ which are unstable to storage at ordinary temperatures\ onlybe released from the stable acetoxy sul_de precursor when they are actually required "Scheme 15#ð89T3150Ł[

F

n-C8H17Br

F

n-C8H17SPh

F

n-C8H17SPh dibal-H

92%OAc

F

n-C8H17

O

i, mcpba

ii, Ac2O, NaOAc 46%

PhSNa

89%

Scheme 26

dibal-H = diisobutylaluminum hydride

The preparation of a\a!dichloro aldehydes from primary alcohols with chlorine in a dimethyl!formamideÐchloroformÐmagnesium chloride system has been reported to give better results thanpreviously described conditions ð77BSB414Ł[

a!Bromo aldehydes can be prepared by the haloboration of terminal alkynes[ The reaction\ whichis compatible with halide ester and alkene functionalities\ involves a modi_ed alkaline peroxideoxidative workup designed to reduce the base!catalysed elimination of hydrogen bromide from theproduct "Scheme 16# ð74S395Ł[

2[90[2[3[1 Carbon0carbon bond!forming methods

Halooxazines "07# can be metallated with butyllithium to give a ~uoroacetaldehyde ð89TL068Ł orchloroacetaldehyde ð63JOC507Ł enolate equivalent which will react with a range of electrophilesincluding alkyl halides[ Unmasking the aldehyde is achieved in two steps by reduction and acidhydrolysis "Scheme 17#[ Both a!chloro and a!bromo aldehydes can be prepared by the reaction of

17 Alkyl Aldehydes

Br

BBr2

Br

BBr3

O

i, pH 5 buffer ii, KOAciii, H2O2

60%

Scheme 27

a dihalomethyllithium with a ketone[ The reaction\ which involves an a!halo epoxide intermediate\appears to be fairly general for cyclic ketones and can be applied to quite sensitive structures\ suchas protected sugars "Equation "19## ð80CL0358\ 82JOC4382Ł[ a!Chloro and a!bromo aldehydes canalso be prepared by the formylation of the related a!haloalkyllithium reagents\ which are preparedby metal halogen exchange of 0\0!dihaloalkanes at −099>C\ with methyl formate "Equation "10##ð79S533Ł[

O

N

X

i, BunLi

ii, RBr

(18)

O

N

X

i, NaBH4

ii, H3O+

R

O

R

X

X = F, Cl

Scheme 28

O

O

O

O

O

O

i, Cl2CHLiii, NaOAc, 15-crown-5

77%

O

O

O

O

OCl

O

(20)

Bun

Br

Br

i, LDA, –100 °Cii, HCO2Me

73%Bun

Br

CHO(21)

2[90[3 ALDEHYDES BEARING AN OXYGEN FUNCTION

2[90[3[0 OH!functionalized Aldehydes

Although many methods exist for the preparation of hydroxy aldehydes\ the isolation of theproducts is not always straightforward due to competing dimerization\ polymerization or elim!ination reactions[ Thus\ many methods for the synthesis of hydroxy aldehydes are designed toincorporate a protecting group on the hydroxyl or carbonyl groups[

2[90[3[0[0 a!OH!functionalized aldehydes

Perhaps the most common method for the synthesis of an a!hydroxy aldehyde is the addition ofa heteroatom!stabilized formyl anion equivalent to an aldehyde or ketone having one less carbonatom[ The success of the method depends on the e.ciency of the addition and the ability to unmaskthe formyl group without causing side reactions\ such as elimination[ A comprehensive account ofmuch of the early work in this area has already appeared ðB!76MI 290!90Ł\ and there has also been a

18Bearin` an Oxy`en

review on the use of 0\2!dithiane ð78T6532Ł[ In other developments since that time\ Katritzky andco!workers have reported that the benzotriazole "08# gives\ on treatment with BunLi\ an anion whichreacts with aldehydes and ketones[ The adducts can be hydrolysed in situ to the hydroxy aldehydes\which are isolated as the corresponding hydrazones ð80JOC1032Ł[ This paper has an extensive list ofreferences for other formyl anion equivalents[ Dondoni and co!workers\ and others\ have dem!onstrated that a thiazole ring can be equivalent to a formyl group[ 1!Lithiothiazoles react even withsterically hindered or highly enolizable aldehydes and ketones[ Quaternization at nitrogen andreduction gives the thiazoline\ from which the aldehyde should be available by hydrolysis "Scheme 18#ð77BCJ2526Ł[ 1!TMS!thiazole will also directly attack aldehydes[ Several features are notable aboutthis sequence[ First\ the reaction occurs without the need for anion formation by a strong base[Second\ the reaction with alkoxy aldehydes can be highly stereoselective\ giving rise to the antiadducts\ whilst stereoselectivity for amino aldehydes depends on the protecting groups "Scheme 29#[Finally\ this reagent can be used in an iterative manner to prepare long!chain\ polyoxygenatedaldehydes ðB!81MI 290!90Ł[ 1!Lithiothiazole will attack amino acid esters^ subsequent reduction undernonchelation controlled conditions then gives the syn adducts ð81TL6148Ł[

NN

N

N

(19)

N

S

N

S OH

R2

R1

N

S OH

R2

R1

Me

i, BunLi, –78 °C

ii, R1R2CO, –78 °C

i, MeI, DMF, heat

ii, NaBH4, EtOH

Scheme 29

N

STMS + NBOCO

CHO

NBOCO

HO N

S

N

STMS +

60%, de 80%

NHBOC

CHOBnO

BOCNH

BnO

OH

N

S

85%, de 92%

Scheme 30

Very few methods are available for the asymmetric addition of formyl anions to achiral aldehydes\but one successful approach uses the enolate derived from the racemic iron complex "19#[ Thecopper enolate gives predominantly the RRS "SSR# adduct\ whereas the aluminum enolate isselective\ at least 3 ] 0\ for the RRR "SSS# isomer "Equation "11##[ In an attempt to obtain homochiralmaterials\ the menthyl complexes were prepared\ and the two diastereoisomers readily separated bycolumn chromatography[ The "R# isomer "10#\ via its aluminum enolate\ reacts with iso!butyraldehyde to give preferentially the "RRR# adduct in a 04 ] 0 excess[ Under the same conditionsthe "S# enantiomer gives a complex mixture of all four diastereoisomers\ indicating\ in this case\ amismatched stereochemical in~uence ð78TL1860Ł[ Epoxy sulfones\ for example "11#\ prepared via aDarzens reaction between a chlorosulfone and a ketone\ undergo base!catalysed ring opening tohydroxy aldehydes[ A list of references for much of the early work on the preparation of oxygenatedaldehydes has been published in this same paper ð73JOC0267Ł[

29 Alkyl Aldehydes

FeP

Ph PhOC

O OBn

(20)

ROBn

OBn

OH

(22)

i, BunLi, –78 °C ii, Et2AlCl, –40 °C

iii, RCHO, –100 °Civ, Br2, BnOH

FeP

Ph PhOC

O OBn

(21)

FeP

Ph PhOC

O O-menthylTHP-O

O

SO2Ph

(22)

Oxidative and reductive transformations can be used to prepare a!hydroxy aldehydes[ O!Silyl!protected cyanohydrins can be reduced to a!hydroxy aldehydes using dibal ð80SL368Ł\ and opticallyactive hydroxy aldehydes ð83T1710Ł are available from the corresponding optically active cyano!hydrins ð82SL796Ł[ A complementary reduction which gives carbonyl!protected hydroxy aldehydesis the baker|s yeast!mediated reduction of cyclic and acyclic acyl dithioacetals to give\ usually\ the"S#!alcohols in high enantiomeric excess ð89S0\ 80CRV38Ł[ In fact\ baker|s yeast!mediated reductionscan be used to establish a range of remote hydroxy carbonyl relationships\ although usually onlyone enantiomer is available directly[ Both epimers of the same alcohol\ however\ can be preparedfrom the stereocomplementary reduction of a ketone using the same chiral auxiliary "Equation "12##ð81CL1062Ł[

OS

OO

SO

S

OHOH+

::

197

993

Zn(BH4)2NaBH4/YCl3

(23)

Nucleophilic attack of vinyl anions to carbonyl groups\ followed by ozonolysis of the alkene\is a well!established method for the synthesis of a!hydroxy aldehydes\ and developments havedemonstrated that this method can be used to prepare homochiral products[ Addition of 0\1!propadienyltributylstannane to aldehydes in the presence of a chiral borane has been shown tooccur with ×88) ee[ Protection of the alcohol and ozonolysis of the allene gives enantiomericallypure products ð80TL4602Ł[ Alternatively\ optically pure acyl diene iron tricarbonyl complexes "12#have been shown to give a single diastereoisomer of a tertiary alcohol on treatment with organo!lithium reagents[ Exhaustive ozonolysis then gives the desired products "Scheme 20# ð89SL530Ł[Terminal 0\1!diols can be oxidized selectively using catalytic Cp1ZrH1 at 049>C to give a!hydroxyaldehydes ð75S663Ł[

R1

O(CO)3Fe

(23)

R1

(CO)3FeOH

R2

O

OH

R1

R2

R2Li, –78 °C i, H2O2, NaOH

ii, O3, MeOH

Scheme 31

20Bearin` an Oxy`en

2[90[3[0[1 b! and more remotely functionalized OH aldehydes

A well!established method for the synthesis of b!hydroxy aldehydes relies on the addition of allylorganometallics to aldehydes\ followed by cleavage of the alkene with ozone[ A wide variety ofmetals has been shown to promote the allylation\ and the high chemoselectivity and increasing abilityto predict and control the relative and absolute stereochemistry during the addition ð82CRV1196Ł hasallowed this to become a very powerful procedure for the synthesis of b!oxygenated aldehydes[ Theuse of chiral catalysts with achiral aldehydes and ketones has been shown to give homoallylic alcoholsin excellent enantiomeric excess ð82JA6990\ 82JA7356\ 82JOC5432Ł[ Many formyl anion equivalents willsuccessfully attack epoxides to give b!hydroxy aldehydes\ and this method has been highlighted inseveral reviews ðB!76MI 290!90\ 78T6532Ł[

Apparently few methods exist for the oxidation of 0\2!diols to 2!hydroxy aldehydes\ perhapsdue to the facile dehydration of the product[ However\ one method which is successful usesN!oxoammonium salts ð89JOC351Ł\ and the yields are very high[ In the oxidation of 0\3! and 0\4!diols the intermediate hydroxy aldehydes often undergo further in situ oxidation to the cor!responding lactones[ As might be expected\ more remote hydroxy aldehydes can be successfullyisolated ð78JOC1869Ł[

The selective reduction of ketones in the presence of aldehydes is di.cult without a priorprotection step[ However\ the greater reactivity of the latter can be exploited using speci_cconditions\ where protection occurs in situ[ Among the conditions developed to achieve this areNaBH3:CeCl2 ð70TL3966Ł and LiAl"OBut#2H:ButNH1 ð71T0716Ł[

Homoenolate anions derived from protected aldehydes can add to other carbonyl groups to givehydroxy aldehydes[ The reagents that have been developed for this purpose include "13#\ whichreacts with aldehydes\ ketones and a!silyloxy ketones leading to hydroxy or dihydroxy aldehydesð81JOC649\ 82T3812Ł\ "14#\ prepared from reductive lithiation of the corresponding sul_des ð81JOC5Ł\and "15# ð83T2326Ł[ The development of other nucleophilic three!carbon homologating agents\including homoenolate anions\ has been covered in an early review ð73CRV398Ł[

O

O

Li

(24)

O

O Li

(25)

R1

R2

Li

OEt

(26)

2[90[3[1 OR!functionalized Aldehydes

Many O!alkyl or O!acyl a!hydroxy aldehydes are interchangeable with the corresponding hydroxyaldehydes "see Section 2[90[3[0[0# via protectionÐdeprotection sequences on suitable intermediates[In fact\ the well!known instability of hydroxy aldehydes due to isomerization\ oxidation or dimer!ization means that it may be bene_cial to isolate them in protected form[ For example\ many ofthe nucleophilic formylation procedures proceed via protected hydroxy aldehydes[ In additionalexamples\ phenylsulfonylmethyl t!butyl ether acts as a formyl anion in its reaction with aldehydes\and the resulting alcohol can be acylated prior to release of the carbonyl ð80SL490Ł\ and methyl!thiomethyl p!toluene sulfone can be used in a similar manner ð75TL2554Ł[ Allylic ethers\ which areeasily prepared from the corresponding alcohols\ undergo ozonolysis to a!oxygenated aldehydesð89JOC4947Ł[ An oxidative cleavage used to prepare b!oxygenated aldehydes is shown in Equation"13# ð80TL256Ł[

O

OO

RNaIO4, MeOH

75–85%

O

RCHO

CHO

(24)

Direct oxidation of aldehydes or their enol derivatives to the corresponding a!oxygenated deriva!tives is less facile than for the corresponding ketones\ at least in part because of the greater reactivityof aldehyde enolates[ However\ some methods have been applied to this transformation\ includingthe use of mcpba ð64JOC2316Ł and lead tetraacetate ð72T750Ł to give a!acyloxy aldehydes\ and SAMP

21 Alkyl Aldehydes

or RAMP hydrazones to give a!alkoxy aldehydes ð77TL1326Ł[ The oxidative transformation of asulfoxide to an aldehyde\ via a Pummerer rearrangement\ has been known for many years ð67S770Ł\and the mild conditions allow it to be used for the synthesis of functionalized aldehydes "Scheme21# ð82CC873Ł[ A method for the synthesis of a!alkoxy aldehydes which could have wide applicabilityis shown in Scheme 22[ Thus\ diastereospeci_c hydroxylation of an Evans imide\ followed by amideexchange\ protection and reduction\ gives the product in high overall yield ð81JA8323Ł[ b!Alkoxyimides\ generated by an Evans aldol approach\ can be reduced to b!alkoxy aldehydes via a similarprocedure ð81JOC0956Ł[ The enolate formed from 1!acetylthiazole undergoes aldol reactions with arange of aldehydes[ Reduction of the ketone\ protection of the resulting alcohol and unmasking ofthe aldehyde gives anti 1\3!dioxygenated aldehydes ð78TL5952Ł[

SAr

F

OBn O

SAr

F

OBn

OCOCF3

CHO

F

OBn

Scheme 32

CuCl, K2CO3


TFAA, pyridine

NO

O

Bn

Oi, ii

80%N

O

MeO

Me OH

iii, iv

78%

O

PMB-O

i, NaHMDS, 2-(phenylsulfonyl)-3-phenyloxaziridine, –78 °C; ii, AlMe3, MeONHMe•HCl, 45 °C; iii, NaH, p-MeOC6H4CH2Br, 0 °C; iv, dibal, –78 °C

Scheme 33

Nucleophilic displacement of the halide from a!halo aldimines or a!halo aldehydes by oxygennucleophiles is not always a predictable reaction whose outcome depends on the substrate andthe conditions used "for a review\ see ðB!77MI 290!90Ł#[ Alkoxides are frequently the least usefulnucleophiles\ but carboxylate salts can be used more successfully ð71JOC0090Ł[ A novel\ ~exible anditerative procedure for the synthesis of polyhydroxy aldehydes involves electrochemical oxidationof alkoxysilanes "Scheme 23# ð81JOC0210Ł[

OMe

TMSHO

OMe

OMeMeO2CO MeO2CO TMS

i, ii iii, iv v, vi

vii, viii

i, anodic oxidation, Et4NOTs, MeOH; ii, ClCO2Me, C5H5N; iii, H3O+; iv, Br2CH-TMS, CrCl2; v, LiAlH4;vi, (+)-diisopropyl tartrate, Ti(OPri)4, ButO2H; vii, NaH, BnBr; viii, BF3•Et2O, MeOH

Scheme 34

BnO TMS

OH

OMe

Low!molecular!weight\ optically active\ polyoxygenated aldehydes\ which are excellent buildingblocks for organic synthesis\ are available via the modi_cation of naturally occurring materials "forreviews\ see ðB!72MI 290!91Ł and ðB!81MI 290!91Ł#[ Optically active a!alkoxypropanals have beenprepared from the reduction of lactic acid esters ð72JOC4079Ł or amides ð78BCJ2927Ł without race!mization[ The enzymatic resolution of 1!acyloxy 2!heterosubstituted propenals has been reportedby Wong and co!workers[ Aldehydes having N2\ RO and halogens at C!2 gave excellent enanti!oselectivities\ with both enantiomers being available by the same route "Scheme 24#[ In the case ofcompounds with a b halogen\ treatment with a base gives an epoxide "Scheme 24# which is ideallyfunctionalized for the introduction of other substituents at C!1 or C!2[ In addition\ both thiiranesand aziridines were available from appropriate intermediates "Equations "14# and "15## ð89JOC3786Ł[

22Bearin` an Oxy`en

Similar aldehydes can also be resolved using a transketolase "Equation "16##\ although in this caseonly one enantiomer is available directly ð81TL4046Ł[

Cl OEt

OH

OEt>98% ee

Cl OEt

OAc

OEt>98% ee

+

KOH, EtOHKOH, EtOH

O

OEt

OEt

95% 92%

O

OEt

OEt

Cl OEt

OAc

OEt

LP-80-lipase, pH 7

50% conversion

Scheme 35

O

OEt

OEt

S

OEt

OEt

thiourea

100%(25)

OEt

OEt

HN

OEt

OEt

PPh3

40%N3

OH

(26)

R1 OH

OOH

OH

72–82%52–78%, >98% ee

+R1

CHO

OH

LiO2COH

O

+R1

CHO

OHtransketolase

(27)

R1 = SH, R2S, R3O, F, CN, Me

2[90[3[2 OX!functionalized Aldehydes

Transition metal!catalysed carbonyl insertion reactions are proving extremely useful\ and theyare widely used for the introduction of one additional carbon atom[ In one example\ aldehydes wereconverted into a!silyloxy aldehydes via a silylformylation[ Aromatic and aliphatic aldehydes act assubstrates\ and the aldehyde group in the product does not undergo further reaction ð82JA1948Ł[Reduction of O!TMS or O!TBDMS cyanohydrins can be used to prepare racemic or optically activea!silyloxy cyanohydrins ð80SL368\ 83T1710Ł[

A number of reagents are known to exploit the di}erential stability of trialkyl silyl ethers to theextent that TMS or triethylsilyl "TES# ethers undergo in situ deprotective oxidation in the presenceof TBDMS ethers to give remote silyloxy aldehydes[ Alternatively\ in polyols where all hydroxylgroups are derivatized with the same silyl group\ the primary group can be selectively oxidized dueto steric and:or electronic e}ects[ This whole area of selective oxidations has been the subject of areview ð82S00Ł[ Some of the methods outlined in Section 2[90[3[0[0 for the synthesis of a!hydroxyaldehydes either proceed via silyloxy aldehydes ð80TL4602Ł or could be used for their preparation[In addition\ in isolated cases\ the oxidation of silyl enol ethers with dimethyldioxirane "see Section2[93[3[0[0# has been applied to the synthesis of a!silyloxy aldehydes ð78JOC3138Ł[ Optically active a!"silyloxy#propenals have also been prepared from the reduction of lactic acid derivatives ð72JOC4079Ł[The carbonylative ring opening of epoxides to give b!oxygenated aldehydes has been limited by therequirement for a large excess of epoxide in order to prevent side reactions[ It now appears that theuse of rhodiumÐamine catalysts is crucial to the success of this reaction\ and\ undera carbon monoxide atmosphere\ cyclohexene oxide gives predominantly trans!1!"trialkyl!silyloxy#cyclohexane carboxaldehyde in 71) yield[ Nonsymmetrical epoxides are cleaved pref!erentially at the least substituted position ð82JOC3076Ł[ The Lewis acid!catalysed rearrangement of

23 Alkyl Aldehydes

epoxy silyl ethers appears to be a very useful method for the synthesis of highly functionalized b!silyloxy aldehydes[ As the substrates can be prepared in homochiral form from the Sharplessoxidation of allylic alcohols\ and the rearrangement is concerted\ with the silyloxy alkyl groupapproaching anti to the epoxide\ then the products are also enantiomerically pure "Equation"17##[ Of the Lewis acids tried\ the sterically hindered methyl aluminum bis"3!bromo!1\5!di!t!butylphenoxide# was the most successful[ The substitution pattern on the substrate is crucial to thesuccess of the reaction[ Thus\ g\g!dialkyl\ g!aryl and g!alkenyl epoxides behave as expected\ butg!monoalkyl epoxides do not rearrange under these conditions ð80T5872Ł[ A related rearrangement\involving proton transfer\ has been reported "Equation "18## ð82JA0197Ł[ Using the strongly basicLDA:KOBut mixture\ epoxy ethers\ "16#\ undergo a selective deprotonation at the a carbon to givevinyl ethers[ These can be silylated and hydrolysed to give b!silyloxy aldehydes ð81SL792Ł[ In areaction that invokes participation of a common solvent\ the SAMP and RAMP hydrazones ofaldehydes attack THF in the presence of TMS!OTf to introduce a 3!silyloxybutyl group at the aposition[ The aldehyde group can be deprotected using ozone without loss of the silyl group to give5!trimethylsiloxy aldehydes ð82S0981Ł[

Ph O-TBDMS

O75–87%, 98% ee

O-TBDMS

CHO

Ph

(28)

(29)OH

O TES-OTf

collidine80%

O-TES

CHOPh Ph

Bun

O OMe

O

(27)

α

2[90[4 ALDEHYDES BEARING A SULFUR FUNCTION

2[90[4[0 SH! and SR!functionalized Aldehydes

The chemistry of a!thiol aldehydes is restricted by their existence as the cyclic dimers "17# whichcan be puri_ed but are insoluble in some organic solvents[ Under basic conditions there is anequilibrium between cyclic and acyclic forms[ They can be prepared from the corresponding bromoaldehyde or acetal using sodium hydrogen sul_de\ but an excess of sul_de is required in order toprevent formation of "18# "Scheme 25# ð64JOC0183Ł[ More recently\ the same compounds have beenprepared by reduction of "29# ð72CJC0761Ł[ b!Thiol aldehydes can be prepared from the hydrolysisof the corresponding thioacetates "20#\ although their isolation cannot be readily achievedð66JOC1012Ł[ The synthesis of thiol aldehydes has been part of a previous review ð66HOU"6:1C#1206Ł[

S

SR

HO

OH

R

O

R

S

R

O

(28) (29)

NaSHHS

R

O

Br

R

O

NaSH

Scheme 36

S

O

O

R

(30)

AcSCHO

(31)

24Bearin` a Sulfur

Direct sulfenylation of aldehydes or their derivatives is\ perhaps\ the most useful preparation ofa!sulfenyl aldehydes\ and a number of procedures have been developed to achieve this[ The lithiumenolates of alkyl aldehydes\ generated from the treatment of a silyl enol ether with methyl lithium\react with sulfenyl chlorides to give the desired products in fair yield ð62TL4002Ł\ while potassiumenolates react with dialkyl or diaryl disul_des ð68TL1706Ł[ The latter method works best for aldehydeswith only one a proton[ Metalloenamines also undergo reaction with disul_des to give similarproducts ð63TL2844Ł[ Enamines derived from a chiral amine lead to enantiomerically enriched a!sulfenyl ketones ð76S048Ł[ Other papers have shown that enol ethers ð74T3338Ł and silyl enol ethersð80JCS"P0#340Ł react with phenyl sulfenyl chloride in the absence of organometallic reagents to givea!sulfenyl aldehydes directly[ Despite the reactive nature of the electrophile\ dioxolanes\ ethers andTHP ethers have been shown to survive the sulfenylating conditions[ Hydrocinnamaldehyde reactsdirectly with "methoxycarbonyl#sulfenyl chloride in the absence of a base to give a!"methoxy!carbonylsulfenyl#hydrocinnamaldehyde "21# in 51) yield[ Under the reaction conditions\ elim!ination does not appear to be a problem\ and the experimental procedure is very simple ð81JOC0942Ł[

S

CHOPh

CO2Me

(32)

As a contrast to these methods which require electrophilic sulfenylating agents\ nucleophilicattack by thiolate anions at a!halo aldehydes can also be used to prepare a!sulfenyl aldehydes oracetals ð79TL3060\ 71TL0554\ 73S35\ 76S548\ 83T2238Ł or a\a!disulfenyl aldehydes ð73S35Ł[ The di.cultyin preparing a!halo aldehydes means that it is often more e.cient to use a!halo acid derivativesand adjust the oxidation state after sulfenylation ð66JCS"P0#0020\ 66JCS"P0#1152Ł[ A review on thedisplacement of halogens by sul_des from a!halo aldehydes has been published ðB!77MI 290!90Ł[

A combination of nucleophilic displacement and enolate alkylation has been used by Enders andco!workers in an asymmetric synthesis of a!sulphenyl aldehydes[ The diethyl acetal of bromo!acetaldehyde reacts with a range of thiols to give the corresponding sul_de\ which can then beconverted into the SAMP or RAMP hydrazones[ Either of these undergo e.cient reaction withalkyl halides\ and\ under carefully controlled conditions\ the hydrazone can be cleaved to thealdehyde without oxidation at sulfur "Scheme 26#[ Epimerization at the a position does not appearto be a problem throughout the sequence and the enantiomeric excesses obtained are high ð83T2238Ł[

OEt

OEtBr

R1SNa then

SAMP65–90%

N

R1S

N

OMe

LDA, R2X

then O345–80%

O

R1S

R2

LDA = lithium diisopropylamideSAMP = (S)-(–)-1-amino-2-methoxymethylpyrrolidine

Scheme 37

The reaction of the formyl anion equivalent "22# with ketones results in an adduct which canundergo rearrangement to an a!sulfenyl aldehyde on treatment with SOCl1 "Scheme 27# ð70TL776\76RTC378Ł[ Although "22# will also add to aldehydes\ subsequent rearrangement does not proceedsmoothly unless SOCl1 is replaced by methanesulfonyl chloride ð77JA4198Ł[ This reaction is thoughtto proceed via a 0\1!rearrangement of the phenylsulfenyl group\ and a similar mechanism must alsobe involved in the bromination and hydrolysis of vinyl thioethers "Equation "29## ð63LA1974Ł[Formylation of the anion derived from the boronate ester "23# with ethyl formate gives\ followingcleavage of the carbon0boron bond by hydrolysis\ a!sulfenyl aldehydes[ In a subsequent reaction\a!sulfenyl aldehydes can undergo alkylation at the a position with reactive benzyl or allyl halidesð71JOC1368Ł[ Stereocomplementary reduction of the oxazolidine "24# under chelation! or non!chelation!controlled conditions can lead to either enantiomer of the corresponding hydroxy!oxazolidine[ Thiolysis of each of these leads to enantiomerically pure a!"arylsulfenyl#propanalð82JOC2054Ł[

25 Alkyl Aldehydes

Li

PhS OMe

(33)

R1R2CO

SPh

OMeR2

OHR1

SOCl2 OR2

SPhR1

Scheme 38

R2

R1 SPh Br2 then H2O

R2

R1

PhS

O(30)

OB

O

N

OH

Ts

O

PhS

R1

Ph

(34) (35)

The use of electrolytic methods for the interconversion of functional groups is attractive becauseof the absence of expensive reagents and the reduced environmental hazards associated with thedisposal of by!products[ As part of the continuing search to exploit such procedures\ terminalalkenyl sul_des ð70CC152\ 77CC0357Ł and alkenyl silanes ð82T1900Ł can be oxidized to a!phenylsulfenylaldehydes in the presence of thiophenol and O1[ For both substrates\ the same transformation canbe achieved without using electrolysis\ although the reaction is much slower[ For alkenylsilanes\isolated alcohols and ketones can survive the reaction conditions[ Terminal alkenyl sulfoxides arealso intermediates to a!sulfenyl aldehydes[ The reaction involves treatment of a b!aryl or b\b!dialkylsulfoxide with NaOAc and Tf1O\ and proceeds via the acylals "Scheme 28# ð80TL5862Ł[ In a procedurethat has been widely adopted for the synthesis of a!heterosubstituted carbonyl compounds\ PhSNaadds to a\b!epoxy sulfoxides\ for example "25#\ at the b position to give a!sulfenyl aldehydes afterelimination of phenylsulfenic acid ð74BCJ1738\ 81SL344Ł[ Amines\ THP ethers and alkyl chlorides aresome of the groups that remain una}ected[ The epoxy sulfoxides are easily prepared via a Darzensreaction between the anion of a 0\0!chlorosulfoxide and a ketone[ Apparently\ fewer methods areknown for the synthesis of more remote sulfenyl!substituted aldehydes[ The addition of thiophenolto acrolein has been reported\ but the product was only isolated after protection of the aldehydegroup with propane 0\2!dithiol ð68TL2056Ł[

Ar i, NaOAc, Ac2O, Tf2O

ii, NaHCO3 Ar

PhS O

SOPh Ar

PhS OAc

OAc20–85%

K2CO3, MeOH

60–65%

Scheme 39

O NR2

Li

O

(37)

O

O-THPPhOS

(36)

Silyl enol ethers derived from aldehydes react with chloroalkyl sul_des to give b!sulfenyl alde!hydes ð68TL1068\ 77T3196Ł[ Many homenolate anions derived from aldehydes have been developedðB!76MI 290!91Ł\ and some of these\ for example "26#\ have been shown to react with electrophilicsulfenylating agents at the g position to give protected b!sulfenyl aldehydes ð63JA4459\ 70AG"E#016Ł[The silyl enol ether derived from isobutyraldehyde reacts with trimethylthio orthoformate in thepresence of SnCl3 to give 1\1!dimethyl!2\2!bis"methylthio#propanal ð74TL5402Ł "for reactions ofenolate donors with thionium ions to give g!sulfenyl ketones\ see Section 2[92[4[0#[5!"Phenylsulfenyl#hexanal can be prepared in good yield by the photolytic cleavage of 1!"phenyl!sulfenyl#cyclohexanol[ The application of this method to other ring sizes or more highly substituted

26Bearin` a Selenium or Tellurium

systems would enhance its usefulness\ as the sulfenyl alcohols can be readily prepared from thecorresponding alkenes via the epoxides ð89TL52Ł[ The synthesis of a!sulphenyl aldehydes and ketoneshas been part of a previous review ð66HOU"6:1C#1206Ł[

2[90[4[1 Higher!coordinated Sulfur!functionalized Aldehydes

Hydrazones derived from aldehydes undergo metallation and trapping with menthyl p!toluene!sul_nate to give enantiomerically enriched a!sul_nyl hydrazones\ although attempts to removethe protecting group were unsuccessful ð71S718Ł[ a!Sulfonyl aldehydes can be prepared from theformylation of lithiomethyl phenyl sulfone ð65S395Ł\ and oxidation of allylic sulfones gives b!sulfonyl enals "Scheme 39# ð74JOM"179#158Ł[ a\b!Epoxy sulfoxides have been shown to be usefulintermediates to a!sulfenyl aldehydes "see Section 2[90[4[0#\ but for the corresponding sulfones a0\1!migration of the sulfonyl group leads to a!sulfonyl enamines "Equation "20## ð72S517Ł[

pcc

SO2Ph

OH

SO2PhSO2Ph

O+

hν, PdII, O2

Scheme 40

pcc = pyridinium chlorochromate

OAr

SO2Ar

Ar

ArO2SNR1R2

i, BF3•Et2O

ii, R1R2NH(31)

2[90[5 ALDEHYDES BEARING A SELENIUM OR TELLURIUM FUNCTION

2[90[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Aldehydes

The primary interest in the synthesis of a!alkylselenyl or arylselenyl aldehydes and ketones liesin their ready oxidation to the corresponding selenoxides and subsequent elimination of a selenicacid to give the corresponding a\b!unsaturated carbonyl compounds[ This usually occurs undermild conditions\ often spontaneously at room temperature\ to result in a transformation for whichthere are relatively few attractive alternatives[ The success of this overall procedure is attested toby the numerous examples that can be found in the literature "for reviews\ see ð67T0938\ 74T3616\B!75MI 290!90Ł and ðB!76MI 290!91Ł#[ As already demonstrated\ however\ in Sections 2[90[3 and 2[90[4on a!oxygenated and a!sulfenylated aldehydes\ respectively\ and Sections 2[92[3 and 2[92[4 onketones\ there is usually a paucity of methods to prepare otherwise identical aldehydes comparedto ketones[

The most widely used method for the synthesis of a!selenyl aldehydes is the reaction between analdehyde or derivative and a selenium"II# reagent\ of which a number are available[ In fact\ the _rstreported procedure for the phenylselenylation of aldehydes used neutral or mildly acidic conditionsin which aldehydes react directly in the presence of esters ð62JA5026Ł[ Presumably\ this re~ects theability of aldehydes to exist in the enol form to at least some extent under the reaction conditions[This enolization can be enhanced\ in di.cult cases\ by the presence of a catalytic amount of acid orby using higher temperatures[ Chemoselectivity is very high and elimination can occur withoutoxidation "Equation "21## ð70JA613Ł[ Phenylselenyl chloride is the most frequently used selenylatingagent under these conditions[ Elimination of a 1!pyridylselenyl group has been reported to occurunder milder conditions and give higher yields than using a phenylselenyl group[ The selenoxide isavailable from the selenide\ which is introduced using 1!pyridylselenyl bromide despite the fact thatPhSeBr can act primarily as a brominating agent under comparable reaction conditions ð73JOC2685Ł[A useful chemoselective introduction of a phenylselenyl group has been developed using selenamides"Equation "22##[ Selenylation occurs at room temperature in the absence of a base\ and introducesthe phenylselenyl group a to an aldehyde in the presence of malonate ester or ketone groupsð70TL2450Ł[ Normally\ diselenides are insu.ciently electrophilic to react with aldehydes withoutprior enolate formation[ However\ on treatment with SeO1\ a more reactive selenylating agent is

27 Alkyl Aldehydes

generated in situ which will react directly with aldehydes[ The requirement for the presence of acatalytic amount of acid\ H1SO3\ may limit the types of functional groups which will survive thereaction conditions ð71TL3702Ł[ N!"Phenylselenyl#phthalimide also acts as a selenylating agent inthe presence of one equivalent of p!TsOH ð82TL6644Ł[ b!Keto aldehydes react from the centralcarbon atom with PhSeCl in the presence of pyridine ð70JOC1819Ł[

O

AcO

O

OAcH

OHCH

O

AcO

O

OAc

OHCPhSeCl, 60 °C

(32)

CHO

OPhSeNEt2, CH2Cl2

72%(33)

CHO

O SePh

A number of aldehyde derivatives have been used as enolate donors during phenylselenylationreactions[ For example\ enamines react directly with PhSeCl at −009>C ð79TL3306Ł or with selen!amides to give mono! or bis!a!selenyl aldehydes ð71TL0446Ł\ and enol ethers react with PhSeBrð68HCA0395Ł or PhSeCl ð68S871Ł to give a!phenylselenyl aldehydes[ In the latter case there are someinteresting examples of chemoselectivity as\ at low temperatures\ silyl ethers\ isolated alkenes anddioxolanes survive the reaction conditions "Equation "23##\ whereas at room temperature cyclicacetals give selenylated products "Equation "24##[ Dihydropyran undergoes a regioselective additionusing PhSeCl in water to give a 1!hydroxy!2!"phenylselenyl#tetrahydropyran ð71TL1396Ł\ and silylenol ethers ð66S763Ł or silyl dienol ethers "Equation "25## ð67SC100Ł can be derivatized in the sameway[ Further examples of the selenylation of aldehydes can be found in the excellent review by BackðB!76MI 290!92Ł[

O

O OMe

PhSeCl, –78 °C

88%

O

O

CHO

SePh(34)

(35)PhSeCl, RT

70%O

O

O

O

SePh

(36)

O

SePh

TMS-O PhSeCl

67%

Terminal alkenes can undergo oxyselenylation to give a!phenylselenyl aldehydes and:or a!phenyl!selenyl ketones\ depending on the regiospeci_city of the addition[ As might be expected\ the lattergenerally predominate\ although the ratio can be as low as 0 ] 0 ð70BCJ2099Ł[ The directing e}ect ofthe oxygen atom in allylic ethers or silyl ethers results in regiochemically controlled addition to giveb!oxygenated a!phenylselenyl aldehydes "Equation "26## ð70BCJ2409Ł[ This directing e}ect of theoxygen is strongly dependent on distance\ as the corresponding homoallylic ethers give no betterthan a 2 ] 0 mixture of selenyl aldehyde to selenyl ketone ð70BCJ2409Ł[ The presence of a heteroatomon the alkene can also control the regiochemistry of the addition "Equation "27## ð79CC840Ł[

Ph

O

SePh

TBDMS-O

(37)Ph2Se2, (PhSeO)2O

81%Ph

TBDMS-O

TBDMS = t-butyldimethylsilyl

n-C9H19SeMe

n-C9H19 CHO

SeMe

(PhSeO)2O

78%(38)

28Bearin` a Nitro`en

The p!toluenesulfonyl hydrazones of a!bromo aldehydes undergo direct substitution of the halidewith PhSeH at −67>C[ For the hydrazones derived from ketones the carbonyl group can beregenerated using BF2 =Et1O ð71JCS"P0#1608Ł[ Bromoacetaldehyde diethyl acetal reacts with Na1Se1

to give\ following hydrolysis\ bis"1!oxoethyl#diselenide ð73CC78Ł[ In general\ nucleophilic dis!placement of halides by selenate ions is compatible with a range of functional groups\ although notlactones\ esters or epoxides\ and so this approach should be applicable to more complex systems[In a complementary approach\ selenium!stabilized carbanions\ prepared via Se:Li halogen exchangein diselenoacetals\ react with DMF to give a!selenyl aldehydes directly ð65TL342\ 89SL044Ł[

The conjugate addition of selenates to a\b!unsaturated aldehydes is potentially the most directsynthesis of b!selenyl aldehydes\ and it can be achieved using a number of di}erent conditions[Benzeneselenol adds even to sterically hindered b\b!disubstituted aldehydes in the presence of aceticacid ð79S553Ł\ whilst potassium phenyl selenate\ generated from PhSe!TMS and KF\ will alsofunction in this way ð67TL4976Ł[ Other papers have appeared that describe the use of PPh2 or TMS!I for activating PhSe!TMS towards conjugate addition ð67TL4980\ 68TL3078Ł[ Sodium hydrogenselenide adds to cinnamaldehyde to give the product of 0\3!addition[ There appears to be no wayof preventing a second addition to give the observed product "27# ð80SC840Ł[ The use of selenium!stabilized carbocations has lead to an e}ective synthesis of b\b!diselenyl aldehydes via the reactionof silyl enol ethers with trimethylseleno or triphenylseleno orthoformate in the presence of a Lewisacid ð74TL5402Ł[

(38)

Ph

SeOHC

Ph

CHO

Diisobutylaluminum phenyltellurolate\ which can be easily prepared by the reduction of diphenylditelluride with diisobutylaluminum hydride\ delivers a phenyltelluro group to the b position ofacrolein to give 2!"phenyltelluro#propanal[ This compound is somewhat sensitive to air\ but can beisolated following treatment of the reaction mixture with degassed HCl ð78CL596Ł[

2[90[6 ALDEHYDES BEARING A NITROGEN FUNCTION

2[90[6[0 NH1!\ NHR! and NR1!functionalized Aldehydes

The synthesis and reactions of amino!substituted aldehydes is an area of active research and onewhich cannot be completely covered in the available space[ Excellent reviews dealing with thesynthesis and reactions of amino aldehydes have appeared which incorporate additional materialð78CRV038\ 89OPP288\ 80AG"E#0420Ł[

2[90[6[0[0 a!NH1!\ NHR! and NR1!functionalized aldehydes

There has been an increase in activity in the synthesis and reactions of a!amino!substitutedaldehydes\ attributable\ in part\ to their role as mimics of the tetrahedral intermediates found inmany enzyme!catalysed reactions[ For example\ a!amino aldehydes undergo a ready hydrationwhich may be simulated in vivo\ using an enzyme!bound serine residue[ Alternatively\ treatment ofan a!amino aldehyde with an organometallic reagent gives a chiral 0\1!amino alcohol which canmimic the transition state of some proteolytic enzymes ðB!89MI 290!90Ł[ Amino aldehydes are\ infact\ excellent intermediates to a whole range of polyfunctional compounds\ but their value iscompromised by their con_gurational and chemical instability[ Usually\ speci_c e}ort must bedirected to stop epimerization at the a position\ and the products are normally isolated in partiallyprotected form to minimize dimerization[

The ready availability of the naturally occurring homochiral a!amino acids and their derivativeswould indicate that these represent ideal starting materials for the synthesis of amino aldehydes\requiring only a reduction step[ This can be achieved in a number of ways[ The most readilyavailable amino acid derivatives are the carboxylic acid esters\ and these can be reduced to N!protected a!amino aldehydes using dibal!H ð71JCS"P0#296\ 76T2952Ł[ In many cases\ however\ variableamounts of the corresponding alcohol are produced due to overreduction[ a!Amino acid

39 Alkyl Aldehydes

chlorides can be selectively reduced to aldehydes using Bu2SnH in the presence of a palladium"9#catalyst ð83TL0070Ł and mixed anhydrides with LiAl"ButO#2H ð83HCA464Ł[ Perhaps the bestmethods\ however\ employ the reduction of the easily prepared N!a!protected cyclic or acyclichydroxamates with LiAlH3[ Under these conditions\ neither racemization at the a position noralcohol formation is usually a problem "Scheme 30# ð76JA125\ 89S342Ł[ Racemization in general isminimized by the use of the 8!"8!phenyl~uorenyl# protecting group on the a nitrogen ð76JA125Ł[Other heterocycles have been used to activate acids towards selective reduction including imidazoles\for example "28# ð65JOC2206Ł\ and pyrazoles\ for example "39# ð71TL414Ł[ Only in the _rst of theseexamples was any alcohol detected[ A method has been reported which may compete with the bestknown methods for this conversion[ It involves the reduction of the easily prepared thiol ester withEt2SiH ð89JA6949\ 82JOC1202Ł\ and the reaction shown in Equation "28# has been performed on a39 g scale with no racemization[

N OR2HN

O

R1

NR2HN

O

R1

Me

OMe

LiAlH4, 0 °C

R1 = Pri, 70%

R2HN

O

R1

LiAlH4, 0 °C

R1 = Me, 90%

Scheme 41

N

N

Ph

O

NHZ

(39)

N

N

O

NHZ

(40)

O

MeO OMe

OMe

t-BOCHN

(39) i, Et3SiH, Pd on C

ii, CSA, MeOH 95%, 100% ee

O

MeO SEt

O

t-BOCHN

t-BOC = t-butoxycarbonylLSA = camphorsulfonic acid

In cases where the chemoselectivity for the reduction is low\ that is\ appreciable alcohol formationresults\ it may be more favourable to use excess reducing agent and then oxidize the resulting alcoholback to the aldehyde[ Many reagents have been reported for the reduction\ including LiAlH3 ð80SC0Ł\borohydrides ð82JOC2457Ł and sodium metal ð83TL0666Ł^ whilst for the subsequent oxidation theParikhÐDoering conditions "DMSO\ SO2 =py# often result in the least racemization\ although manyother useful procedures are known ð76AG"E#0030\ 89OPP288\ 83JA0205Ł[ 0\1! or 0\2!Amino alcoholsprepared using other methods can be oxidized in the same way to a! or b!amino aldehydes ð81T3120Ł[

Dipeptides containing serine can be prepared by the oxidative cleavage of a glucosamine amidein which the sugar acts as the source of the serine residue "Scheme 31# ð81AG"E#0280Ł[ As might beexpected from this\ the oxidative cleavage of alkenes ð73TL0960Ł or 0\1!diols ð68CC764\ 75JOC4183\78TL5658Ł having proximal amino groups has been used to prepare amino aldehydes[

The methods described above are ideal for the synthesis of N!protected a!amino aldehydes butare less suitable if the requirement is for carbonyl!protected derivatives[ These can be made in acomplementary approach involving adjustment of the oxidation state at the amino terminus\ andthis is an ideal method for making low!molecular!weight building blocks in racemic or homochiralform[ In one early example\ it was demonstrated that diethoxy acetonitrile was susceptible tosuccessive nucleophilic attack by organometallics to give a!disubstituted amino acetals "Scheme 32#ð79S778Ł[ Glyoxal is an ideal starting material for a!amino aldehyde synthesis due to its low cost\but methods for the selective functionalization of one of the aldehyde groups have not been widelyavailable[ However\ it has been demonstrated that the monoacetal of glyoxal can be prepared usinga number of di}erent alcohols in a very simple but high!yielding procedure[ The remaining aldehydegroup was subjected to a reductive amination\ using primary amines or ammonia\ also in high yield"Scheme 33# ð77BSF84Ł[ As a logical extension of this work\ a number of groups have investigatedthe use of chiral auxiliaries as a way of generating optically active amino aldehydes[ Chastrette and


O

OH

OHHN

HO

OH

O

NHZ

R

O

OH

OH

NH3Cl

HO

OH

OH

O

ZHN

R

OHN

OHO

ZHN

R

+iii, iv

80–90%

i, ii

60–72%

i, NaOMe, DMF; ii, dicyclohexylcarbodiimide, hydroxybenzotriazole; iii, NaBH4, EtOH; iv, NaIO4, H2O

Scheme 42

co!workers have prepared a number of hydrazino acetals using di}erent diols "Scheme 34# anddetermined that the acetals "30# and "31# give the best results\ with the addition of BunLi or MeLito "30# or "31# giving at least 73) diastereomeric excess[ Reduction of the hydrazine group thengives the free amino acetal[ The enantiomer of the diol leading to "30# is available\ and so bothenantiomers of the amino acetal might be prepared using this approach ð89TL0318\ 81BSF050Ł[Coordination of the nucleophile to the chiral auxiliary accounts for the transfer of chirality and thiscan also be achieved using a chiral hydrazine[

CN

EtO

EtOPhMgBr, RT

EtO

EtO NMgBr

Ph

i, BunLi, RT

ii, H3O+

90%EtO

EtO

Ph

NH2

Bun

Scheme 43

R1ONH2(NHR2)

R1OOHC–CHO

R1OH, Lewis acid or

Brønsted acids R1O CHO

R1O NH3 or R2NH2

H2, 90–100 bar, Ni

Scheme 44

MeONNMe2

MeO

MeO CHO

MeO H2NNMe2 O

ONNMe2

Php-TsOH

95%

HO

Ph

OH

Scheme 45

90%

O

O

O

OMeMeO

MeO NNMe2

(42)

O

O

OTr

NNMe2

(41)

The addition of Grignard or organolithium reagents to "32# in the presence of CeCl2 gives in mostcases at least 69) diastereomeric excess[ The N!protected amino aldehyde can be unmasked asshown in Scheme 35\ with some observable loss of stereochemical integrity during the _nal stepð82SL248Ł[ Using "S#!0!phenylethylamine as the chiral auxiliary\ the acetal of alanine can be preparedin high chemical and stereochemical yield "Scheme 36#\ although the method works less well forother amino aldehydes ð78S597Ł[ Alexakis and co!workers have used a C!1 symmetrical diamine as

31 Alkyl Aldehydes

the chiral auxiliary and achieved excellent yields of stereocomplementary products[ The addition oforganolithium reagents to the aminal "33# gives\ generally as a single diastereoisomer\ the adduct"34# "Scheme 37#\ arising from the approach of the nucleophile from the bottom face of thehydrazone ð80TL0060Ł[ Under identical reaction conditions Grignard reagents do not react^ however\in a less polar solvent\ nucleophilic attack occurs from the opposite face with good selectivityð81JOC3452Ł[ The amino aldehydes can be unmasked under mild conditions and the chiral diaminerecovered\ if required[ Katritzky and co!workers have extended their elegant work using the chem!istry of benzotriazole to the synthesis of amino aldehydes in excellent yields ð89S0062\ 80T1572Ł[Primary and secondary amines can be introduced in this manner\ and variation of the group at thea position is possible using the appropriate organometallic reagent "Scheme 38#[

OMe

MeO CHO

OMe

MeON

N

OMe

OMe

MeON

N

OMe

But

CO2Bui

OHCHN OBui

OBui

i, BuiMgCl, CeCl3

ii, BuiOCOCl 92%, 88% de

i, Li, NH3

ii, TMS-I92%, 86% ee

(43)

SAMP

Scheme 46

OMe

OMe

NPh

OMe

OMe

O

(S)-1-(phenyl)ethylamine

p-TsOH

H2, 5 bar, Ni on Al

92%, 90% de

OMe

OMe

NHPh

OMe

OMe

NH2

HCO2NH4, Pd on C

96%, 92% ee

Scheme 47

NMe

MeN Bun

NH

NMe2Ph

Ph

NMe

MeN

NNMe2Ph

Ph

NMe

MeN Bun

NH

NMe2Ph

PhBunMgBr, PhMe, THF

95%, >99% de

BunLi, Et2O

60%, >99% de

(45)(44)

Scheme 48

NH

NN OHCCH(OEt)2

R1R2NH70–80%

NN

N

R1R2N

OEt

OEt

i, R3MgX

ii, HCl 60–90%

R3

R1R2N CHO

Scheme 49

Several research groups have used the thiazole moiety as an equivalent of the formyl anion anddemonstrated its ability to attack carbonyl compounds to give a!hydroxy aldehydes "see Section


2[90[3[0#[ Dondoni and co!workers have studied its reaction with C1N systems and found anexcellent spectrum of reactivity with nitrones[ With nitrones derived from alkoxy aldehydes\ antiaddition is preferred and the initial products can be further elaborated to the desired systems"Scheme 49# ð81TL3110Ł[ 0\2!Dithiane reacts with disubstituted imines to give amino aldehydesð63BSF220Ł or with nitriles to give the enamine "35#\ and reduction of this compound with diboranegives the protected amino aldehyde "36# ð76CC664Ł[ Relatively few other formyl anion equivalentsare reactive enough to add to simple imines\ although those that do are included in an earlier reviewðB!76MI 290!90Ł[

OO

N+ Ph

OO

O–

N

S

N

HOPh

OO

CHO

NHBOC

2-lithiothiazole

62%, 93% de

3 steps

Scheme 50

S

S NH2

Ph S

S NH2

Ph

(46) (47)

A number of papers have demonstrated the 0\1!migration of an amino group as part of a synthesisof a!amino aldehydes[ The anodic oxidation of n!tosylamines generates the corresponding imine\which rearranges to the enamine[ This enamine is su.ciently electron!rich to react with a positivebromine species\ generated in situ\ and following aziridine formation the desired product is isolatedin reasonable yield "Scheme 40#[ The conversion is independent of steric factors\ as isolated yields aresimilar for a!unsubstituted\ monosubstituted or disubstituted amino aldehydes ð75TL5972\ 89JA1257Ł[Similar products are obtained from the treatment of enol ethers with N!halo amides ð67CJC008Ł[N\N!Dialkyl enamines demonstrate a preference for the migration of the more electron!rich aminogroup "Scheme 41# ð68AG"E#822Ł[

R1

R2NHTs

R1

R2NHTs

R1

BrNHTs

OMe

R2

R1

TsHNOMe

OMe

R2TsN

OMe

R1

R2

–2 e– Br+/MeOH

50–60%

Scheme 51

Scheme 52

NR1R2NR1R2

NHTs

H3O+ +

p-TsNHCl

ClNHTs

NR1R2

O

R1R2N

The outcome of the reaction between ammonia or amines and a!halo aldehydes is stronglydependent on the speci_c reagents\ but frequently fails to give the desired a!amino aldehydes[Displacement with ammonia cannot be controlled in such a way as to prevent dimerization orpyrazine formation\ whilst for primary amines the ambident reactivity\ carbonyl addition versushalide displacement\ of the halo aldehyde tends to result in mixtures of products[ Using secondaryamines the initial products\ "37#\ can give rise to isomeric amino ketones "38# via an intramolecular

33 Alkyl Aldehydes

rearrangement "Scheme 42#\ although by careful control of the reaction conditions either productcan be obtained selectively[ Some of the problems associated with this transformation can be over!come by protection of the aldehyde group as the acetal or imine prior to aminolysis ðB!77MI 290!90\89JOC301Ł[

O

X

R1R2R3NH

O

NR2R3

R1

(48) (49)

O

R1NR2R3

Scheme 53

The addition of heteroatom nucleophiles to a\b!epoxy sulfoxides is directed to the b position\with a subsequent 0\0!elimination generating an a!substituted ketone[ The use of appropriatenucleophiles has led to the synthesis of a!oxygenated\ a!sulfenylated and a!aminated aldehydesð81SL344Ł[ Aliphatic and aromatic amines can be introduced in this way\ and the method is applicableeven to a\a!disubstituted aldehydes "Equation "39##[

CHO

N

O SOPh piperidine

78%(40)

2[90[6[0[1 b! and more remotely NH1!\ NHR! and NR1!functionalized aldehydes

Many of the methods outlined in the previous section for the synthesis of protected a!aminoaldehydes are potentially applicable to the synthesis of more remote positional isomers[ Thus\procedures involving oxidation\ reduction using the Rosenmund reaction ð89HCA394Ł or LiAlH3

ð89TL6208Ł\ halide displacement\ nucleophilic addition and oxidative cleavage are all appropriatefor the synthesis of a variety of amino aldehydes[

The reductive amination of aldehydes or ketones is often done using conditions where acid!sensitive groups do not survive[ Using Ti"OPri#3 as a Lewis acid catalyst and NaBH2CN as thereducing agent\ cyclic and acyclic acetals remain intact\ demonstrating the usefulness of this pro!cedure for the synthesis of a wide range of carbonyl!protected amino carbonyl compoundsð89JOC1441Ł[

The conjugate addition of amines to a\b!unsaturated aldehydes has rarely been reported as auseful route to b!amino aldehydes\ presumably due to the competing decomposition of the highlyreactive anionic intermediates[ However\ Marko and co!workers have developed a set of conditionsthat allow for the formation of the desired products in good yield[ The key to the transformation isthe use of THF as the solvent and a catalytic amount of dbu[ Without either of these a rapidpolymerization takes place[ Using these conditions\ secondary amines add in a 0\3!manner in goodyield\ even using weakly nucleophilic amines such as N!methylaniline[ Although the amino aldehydescannot be isolated without polymerization\ they can be subjected to further derivatization in situ\to give isolable products "Scheme 43# ð89SC2056\ 81SL164Ł[ Benzophenone imine has been used as anammonia equivalent in the Michael addition to a\b!unsaturated carbonyl compounds[ In oneexample it was shown to add to acrolein\ although no attempt was made to remove the diphenyl!methyl protecting group ð78S248Ł[

The SAMP or RAMP hydrazones derived from a monoacetal of malondialdehyde show ×64)diastereoselectivity\ which is raised to ×84) diastereomeric excess by chromatography\ on reactionwith alkyl\ allyl or aryl organolithium reagents[ The protected amino acetals can be released withoutracemization by treatment with Li:NH2 "Scheme 44# ð82SL115Ł[ Hydroboration of propargylicamines\ for example "49#\ proceeds as expected to give predominantly the terminal vinyl borane[Oxidation under bu}ered conditions then liberates the free aldehyde group in good overall yieldð89SC1980Ł[

The creation of acyclic molecules from cyclic ones can be a powerful method to establish relativestereochemistry\ but it may also serve as a means of protecting reactive combinations of functionalityuntil a _nal deprotection step[ In this regard\ the cycloaddition of 0\2!dipoles to alkenes can represent


N

OH

N

O

N OH

NCO2Me

N

OH

CO2Me

MgBr

Scheme 54

NaBH4

78%

LDAmethyl crotonate

67%85%

Ph3PCHCO2Me

86%

O

O

NN

OMeO

O

NN

OMe

MeO2C

O

O

HN

O

OMe

Li, NH3, –33 °C

92%, 95% ee88%, 79% de

i, EtMgBr, CeCl3, –100 °C to RT

ii, MeOCOCl, RT, 18 h

Scheme 55

N(EtO)2PO

Me

(50)

a useful method for the preparation of 0\2!bisheterosubstituted alkanes[ For example\ the reactionof alkenes with nitrile oxides or nitrones leads to cyclic products which contain a masked b!aminoalcohol "Scheme 45#[ This can be released by reduction and:or ring cleavage "for reviews on 0\2!dipolar cycloaddition reactions\ see ð80COS"3#0958Ł and ð80COS"3#0000Ł#[ In order to form the desiredamino aldehyde an additional oxidation step is required\ but this can be avoided by the use of anenol ether rather than an alkene "Scheme 46# ð73JA4487Ł[

ON

R4

R5

R1 R2

R1

R2

ONR3

R1 R2

R3 N O–

R4

N+

O–R5

Scheme 56

The Mannich reaction to prepare b!amino carbonyl compounds is one of the best known reactionsfor the preparation of amino ketones "see Section 2[92[6[0"ii##\ but it has rarely been applied to thesynthesis of amino aldehydes\ perhaps because under classical Mannich reaction conditions thealdehyde undergoes rapid self!condensation[ The dimethylaminomethyl group can\ however\ beintroduced using an in situ!formed iminium salt and a silyl enol ether in DMSO "Equation "30##ð79CL0102\ 71BCJ423Ł or an iminium salt and an enolate anion at lower temperature in THF ð66JA833Ł[

35 Alkyl Aldehydes

O

OO

NH2

OH

NO–

Ph

+

OEt

O

O

N

OPh

OEt

HH

OMe

HCl, MeOH, H2, Pd(OH)2

74%93%

Scheme 57

O-TMSCHO

NMe2

Me2NCH2NMe2

ClCH2I71%

(41)

2[90[6[1 NHX! and NX1!functionalized Aldehydes

The reduction of nitro groups to hydroxylamines can be achieved in neutral conditions usingSmI1[ Diethyl acetals and dioxolanes adjacent to\ for example "40#\ or more remote from thenitro group remain una}ected\ allowing this method to be used for the synthesis of protectedhydroxylamino aldehydes ð80TL0588Ł[

OEt

EtONO2

(51)

2[90[6[2 NY!functionalized Aldehydes

Although nitro aldehydes themselves appear to be poorly reported compounds\ a number ofroutes are available for the preparation of their corresponding acetals "for a review\ see ð89OPP696Ł#[For example\ the diethyl acetal of nitroacetaldehyde was prepared from triethyl orthoformate andnitromethane ð70S767Ł\ and other acetals can be prepared from this by acetal exchange ð73T1088Ł[The presence of an alkyl substituent adjacent to the nitro group results in only low isolated yields\and so an alternative procedure has been developed which involves conjugate addition of an alkoxideanion to a b!chloro! or b!phenylsulfenylnitroalkene "Equation "31## ð67BSB582\ 89S583Ł[ The additionof formaldehyde dimethylhydrazone to a nitroalkene results in a spontaneous Michael additionwithout the need for acid or base catalysis[ The hydrazone can be cleaved to release the aldehydegroup in excellent overall yield\ even for multifunctional systems "Scheme 47# ð81TL2580Ł[ The b!nitroaldehyde acetals "41# can be prepared from the corresponding bromides using NaNO1 and acationic resin ð71JOC3939\ 76S421Ł[ Their lithium or potassium nitronate salts react with acyl imi!dazoles to give a variety of more complex systems "Equation "32##[ In fact\ the acetals "41# act as atypical nitronate anion in the nitro aldol reaction with aldehydes[ The resulting 1!nitro alcohol canbe oxidized to the a!nitro ketone ð73T2798Ł[ The parent aldehyde 2!nitropropanal can be formedfrom the acid!catalysed conjugate addition of nitrite to acrolein[ It can be isolated and stored forseveral weeks without decomposition and converted as required into a variety of carbonyl!protectedderivatives ð75S424Ł[ Nitro groups have been demonstrated to be stable to a number of oxidativecleavage conditions "Equations "33# and "34##\ and\ hence\ such methods are appropriate for thesynthesis of nitro aldehydes ð74TL5158\ 75JOC143Ł[


Et

NO2

PhSNO2

BnO

OBn

EtO–, THF

77%(42)

AcO NO2

OAc

OAc

OAc

OAc

AcO

OAc

OAc

OAc

OAc

NO2

N

NMe2

NMe2

N

H

H91%

+

Scheme 58

enantiomeric selectivity 3.6 : 1

i, O3

ii, Me2S 85%

AcO

OAc

OAc

OAc

OAc

NO2

CHO

NO2

EtO2C OR1

OR1

O2N OR1

OR1

NNEtO

O

i, LiOEt

ii,

91%

(43)

(52)

TBDPS-O

NO2

OH

O

O2N

OMeTBDPS-O i, O3, Me2S

ii, MeOH, H+

76%

(44)

O2N

O

CHO

O

BnO

OHNaIO4

92%(45)

O2N

OHOBn

CHO

The conjugate addition of any nucleophile to an a\b!unsaturated aldehyde is complicated by theinstability of the enal and a ready polymerization driven by the intermediate aldehyde enolate[ Thissituation is compounded for primary nitronate anions by the possibility of the addition of a secondmolecule of the enal to the initial adduct[ Because of this\ there has been considerable interest inthe development of new procedures for the controlled Michael addition of nitroalkanes to enals[One procedure which works well\ even for acrolein\ is done in the absence of solvent ð75S126\75S0913Ł[ An aldehyde enolate has been shown to attack a nitro enamine in a conjugate additionÐelimination procedure "Equation "35##[ The intermediate nitroalkene was relatively unstable and sowas reduced immediately with the Hantzsch ester ð76S618Ł[ This reduction of oxonitroalkenes hasbeen shown to be generally applicable ð77BCJ3918Ł[

(46)O

NCHO NO2

CHONO2

+ i, LDA, –78 °C to 0 °C

ii, reduction 55%

Among the more unusual nitrogen!substituted aldehydes that have been prepared\ a\a!disubstituted aldehydes react\ via their silyl enol ethers\ with NOCl to give a!nitroso aldehydes[ Theproducts are stable at 9>C but dimerize at higher temperatures and decompose on silica gelð63JOC1447Ł[

Diazoacetaldehyde dimethyl acetal can be prepared from the corresponding amino compoundð56CB0380Ł[ A more general procedure\ and one which gives the free diazo aldehyde\ involves thereaction between a b!amino a!substituted enal and p!TsN2\ which may proceed via the intermediate

37 Alkyl Aldehydes

triazoline "Scheme 48# ð69CCC2507\ 60OPP116Ł[ The chemistry of diazo compounds has been thesubject of a monograph ðB!75MI 290!91Ł[

NN

NR1

CHOR2R3N

R2R3N

Ts

CHOR1

N2

R1 CHOp-TsN3

Scheme 59

The addition of nucleophiles to a\b!epoxy sulfoxides to generate a!amino aldehydes has alreadybeen mentioned "see Equation "39##\ and a similar approach using NaN2 and a\b!epoxy sulfoneshas been used to introduce an azide group at the a position ð67JOC1955Ł[ Oxidative cleavage ofalkenes and 0\1!diols are well!known routes to aldehydes\ and the azide group has been shown tosurvive both transformations ð80JOC2738\ 82TL392Ł[ Azide is\ in fact\ a relatively powerful nucleophilewhich attacks enals at the b position to give b!azido aldehydes or b!azido acetals "Equation "36##ð40JA4137\ 78JA2813\ 80JOC2480Ł[

O

BzOCHO

OHBzO

N3

OHNaN3, AcOH

95%(47)

2[90[7 ALDEHYDES BEARING A PHOSPHORUS\ ARSENIC\ ANTIMONY OR BISMUTHFUNCTION

2[90[7[0 XR1\ X¦R2!functionalized Aldehydes

The use of phosphonium salts for the construction of alkenes\ via the Wittig reaction\ explainsthe vast amount of literature dealing with the synthesis and reactions of these species and theirderived ylides[ Such a body of literature cannot be covered comprehensively here\ but other reviewsare available ð77CSR0\ 78CRV752\ 80COS"5#060\ B!83MI 290!90Ł[ The most common methods for thesynthesis of formyl!substituted phosphonium salts\ or compounds in which the formyl group isprotected as an acetal\ are the treatment of the appropriate halides with trialkyl phosphines\ andthe formylation of phosphonium ylides[

Phosphonium salts are not the only species which participate in Wittig!type reactions\ as arsoniumylides have attracted some attention[ A number of factors are responsible for this interest[ Arsoniumylides are\ in many cases\ more reactive than the corresponding phosphonium ylides for the for!mation of double bonds\ and can be used to generate alkenes where phosphonium ylides fail[ Also\depending on the nature of the arsonium ylide\ the predominant product may be an epoxide "42#\an outcome that is only rarely observed using phosphonium ylides\ or an alkene "43# "Scheme 59#[In general\ stabilized arsonium ylides give alkenes whereas nonstabilized ones give epoxides\ theproducts being predominantly or exclusively trans in each case[ For semistabilized ylides\ the choiceof solvent and base dictates the product ratio[ The nonvolatile nature of arsonium salts and theirylides means that extreme precautions during their handling and use are not essential\ although iftheir preparation involves the use of arsines then these should be considered as extremely hazardous[

R2R1 R2CHO

R1 = CO2EtAr3As R1

R2CHO

R1 = alkyl

+

R2R1

O

(53)(54)

Scheme 60

The preparation of simple arsonium salts is the same as for phosphonium salts involving dis!placement of a halide by an arsine[ Thus\ triphenylarsonium acetaldehyde "44# has been preparedin 89) yield from the reaction between triphenylarsine and bromoacetaldehyde ð74TL5336\ 77TL2838Ł\and the arsines "45# and "46# are also known ð75TL3472\ 78TL068Ł[ Arsonium ylides stabilized by two

38Bearin` a P\ As\ Sb or Si

carbonyl groups\ "i[e[\ "47## can be prepared directly from the condensation of an arsine oxide witha 0\2!dicarbonyl compound[ Reviews on arsonium ylides have been published ð76CSR34\ B!89MI 290!91Ł[

Ar3As CHOPh3As CHO Ar3As OPri

OPri

+O

R R

O

(55)

+

(56)

AsPh3

(57)

–

+

(58)

+

2[90[7[1 Higher!coordinated Phosphorus!\ Arsenic!\ Antimony! or Bismuth!functionalized Aldehydes

The synthesis of formyl!substituted phosphonates has not attracted as much attention as thecorresponding keto phosphonates^ nevertheless\ a number of methods have been developed for theirsynthesis "for an early review\ see ð62RCR427Ł#[ The most direct and attractive method may be theformylation of alkyl phosphonate anions with HCO1Et ð76TL394Ł or DMF[ The latter has beenused for the synthesis of a variety of derivatives "Scheme 50#\ least successfully for a!unsubstitutedcompounds "R0�H#\ but more so using mono! or disubstituted phosphonates[ The intermediatealkoxide is stabilized by chelation\ and\ in one case\ the enamine "48#\ arising from dehydration\ hasbeen isolated ð72S523\ 73JOM"153#8\ 78TL3676Ł[ Enamines derived from formyl phosphonates can beprepared directly by phosphonylation of the t!butylimine of acetaldehyde using diethyl chloro!phosphate "Equation "37## ð67JOC2677Ł or by condensation of a formyl phosphonate with an amine[In the latter case\ further methylation or benzylation of the magnesium salt occurs exclusively oncarbon "Scheme 51# ð58JCS"C#359Ł[ The parent compound for this class\ formylmethyl phosphonicacid "59#\ is a known compound ð58JOC644Ł[

P

O

R2OR2O

R1 P

O

R2OR2O

P

O

R2OR2O

CHO

OLi

R1

NMe2

BunLi then DMF H3O+

50–90%

R1

Scheme 61

P

O

PriOPriO

NMe2

(59)

P

O

EtOEtO

NHButNBut i, LDA, –78 °C

ii, (EtO)2POCl(48)

P

O

EtOEtO

Nc-C6H11

H

P

O

EtOEtO

CHO P

O

EtOEtO

Nc-C6H11

H

i, EtMgBr

ii, MeI 40%

cyclohexylamine

75%

Scheme 62

P

O

HOHO

CHO

(60)

49 Alkyl Aldehydes

The attack of phosphorus"III# nucleophiles at imines or halides has been used to prepare formyl!substituted phosphonates[ Addition to the former "Equation "38## has been demonstrated to givehigh yields of adducts\ and to occur chemoselectively in the presence of aldehydes and ketonesð89T6064Ł[ In the latter\ the substitution occurs with bromoacetaldehyde diethyl acetal and also with2!bromopropionaldehyde diethyl acetal\ where substitution at the a or b positions of the acetal istolerated[ Additional substituents can then be introduced by alkylation adjacent to the phosphonategroup "Equation "49## ð70T0266Ł or by a Mannich reaction to give intermediates to a range ofheterocycles "Equation "40## ð74T316Ł[ The Arbuzov reaction of trialkyl phosphites with a!haloaldehydes cannot be used as a method for the preparation of formyl phosphonates due to thepredominance of two competing reactions "Scheme 52# ðB!77MI 290!90Ł[

PO(Ph)OBu

NBn

H

EtO

OEt

BuO(Ph)PO-TMS

81%(49)

NBnEtO

OEt

P

O

EtOEtO

OEt

OEt

P

O

EtOEtO

OEt

OEtEt

i, BunLi

ii, EtI 70%

(50)

P

O

EtOEtO

CHO P

O

EtOEtO

DMF, heat CHO

NMe2

(51)

O-TMS

PO(O-TMS)2R1

X

P(O-TMS)3 CHOR1

X

P(OR2)3

OPO(OR2)2R1

Scheme 63

In a reaction related to that shown in Scheme 50\ the b!keto esters "50# undergo a furtherformylation via their a\g!dianions to give "51# ð81SC108Ł[ Aldehyde enolates react from the a positionwith diethyl chlorophosphite\ and exposure of the adducts to air gives the phosphonates "Scheme 53#ð80JOC4445Ł[

P

O

EtOEtO

R1

O

R2 P

O

EtOEtO

(61)

R1

O

CHO

R2

(62)

OKH

OK O

PO(OEt)2

i, ClP(OEt)2

ii, air 41%

Scheme 64

Treatment of the vinylphosphonium salts "52# with ethoxide had been postulated to give theylides "53#\ but a re!examination of the evidence has lead to the reassignment of the products as thephosphine oxides "54# "Scheme 54# ð81TL750Ł whilst similar products can be made from the additionof phosphorus halides to ethyl vinyl ether ð76JGU192Ł[ The presence of a chlorine on the epoxide"55# directs nucleophilic attack by trialkyl phosphites to the b position[ A carbonyl group is formedby a 0\0!elimination of chloride\ which then proceeds to promote an Arbuzov reaction to give "56#ð71CB590Ł[

40Bearin` a Metalloid

OEtPh3P

OEt

NaOEt

R1

(64)OEt

+PPh3

(63)

R1

OEt

P(O)Ph2

(65)

R1

Scheme 65

NaOEt

O Cl

R1 PO(OEt)2

R1 CHO

(67)(66)

Among the methods that have been developed to deliver a phosphorus nucleophile to the bposition of an enone "see Section 2[92[7[1"ii##\ very few have been reported as being e}ective forenals\ and those that are tend to give 0\1 adducts also[ One approach that does work involves simplemixing of diethyl methyl phosphinate with an enal to give "57# ð77JOC3958Ł[

O

PMe

OEt

EtO

R2EtO

R1

(68)

2[90[8 ALDEHYDES BEARING A METALLOID FUNCTION

2[90[8[0 Silicon!functionalized Aldehydes*a!silyl Aldehydes

2[90[8[0[0 From alcohols

b!Hydroxy silanes\ which may be conveniently prepared by the reaction of an organocopperreagent with an a!epoxy silane ð82TL2584Ł\ can be oxidized to a!silyl aldehydes with tetra!kis"triphenylphosphine#rhodium hydride in the presence of an enone as a hydrogen acceptorð74TL3118Ł\ or using Swern conditions ð82TL2584Ł[ The TFA!mediated silapinacol rearrangement ofa\b!dihydroxy silanes has been found to provide a general route to a!t!butyldimethylsilyl aldehydes[Because of the stabilization of cations b to silicon and the good migratory aptitude of silyl groups\the reaction is both regiospeci_c and high!yielding "Equation "41## ð75TL3158Ł[

TBDMS n-C6H13

TBDMS

n-C6H13

O

HO OHTFA

86%(52)

2[90[8[0[1 From aldehydes or ketones

Homochiral trialkylsilyl aldehydes can be prepared by the reaction of metallated "S#!"−#! or "R#!"¦#!0!amino!1!methoxymethylpyrrolidine!derived aldehyde hydrazones with t!butyldimethylsilyltri~ate\ followed by hydrolysis[ Although the overall yields of the sequence are quite modest\ theenantiomeric excesses of the products are excellent "Scheme 55# ð76AG"E#240Ł[

41 Alkyl Aldehydes

O

Ph

NOMeN

Ph

NOMeN

Ph

TBDMS

O

TBDMS

PhSAMP i, LDA

ii, TBDMS-OTf

O3

42% overall, >96% ee

Scheme 66

2[90[8[1 b!Silyl Aldehydes

b!Trialkylsilyl aldehydes can be prepared by the conjugate addition of trialkylsilyl cuprates toenals\ although relatively few examples have been reported[ Conjugate additionÐenolate trapping isalso possible and proceeds with high diastereoselectivity "Equation "42## ð73CC17Ł[

O

Ph

i, (PhMe2Si)2CuLiii, MeI

74%

O

Ph

PhMe2Si

+

O

Ph

PhMe2Si

92 : 8

(53)

All Rights Reserved# Copyright 1995, Elsevier Ltd. Comprehensive Organic Functional Group Transformations

3.02Aldehydes: a,b-UnsaturatedAldehydesWARREN J. EBENEZER and PAUL WIGHTZENECA Specialties, Manchester, UK

2[91[0 ALDEHYDES BEARING AN a\b!ALKENIC BOND 43

2[91[0[0 a\b!Unsaturated Aldehydes Without Further Unsaturation 432[91[0[0[0 By elimination reactions 432[91[0[0[1 By oxidations of alcohols and their equivalents 462[91[0[0[2 Oxidation of allylic methyl `roups 472[91[0[0[3 By formylations of alkenes 472[91[0[0[4 By rearranèments of a!acetylenic alcohols 482[91[0[0[5 By displacements of b!leavin` `roups 482[91[0[0[6 By aldol condensation reactions 482[91[0[0[7 By Witti` reactions 592[91[0[0[8 By DielsÐAlder reactions 502[91[0[0[09 By isomerisations 502[91[0[0[00 By reductions 502[91[0[0[01 From epoxides 512[91[0[0[02 Miscellaneous methods 51

2[91[0[1 a\b!Unsaturated Aldehydes With Further Unsaturation 512[91[0[1[0 By elimination reactions 512[91[0[1[1 By formylations of dienes 532[91[0[1[2 By oxidations of alcohols and reductions of acids 532[91[0[1[3 By rin` openin` reactions of pyrilium salts and furans 532[91[0[1[4 By Witti` reactions 542[91[0[1[5 From cyclopropanes 542[91[0[1[6 Miscellaneous reactions 55

2[91[0[2 Haloènated a\b!Unsaturated Aldehydes 552[91[0[2[0 1!Haloènated a\b!unsaturated aldehydes 552[91[0[2[1 2!Haloènated a\b!unsaturated aldehydes 57

2[91[0[3 Oxyèn Substituted a\b!Unsaturated Aldehydes 602[91[0[3[0 1!Oxyèn substitution 602[91[0[3[1 2!Oxyèn substitution 60

2[91[0[4 a\b!Alkenic Aldehydes with Sulfur Substituents 612[91[0[4[0 1!Thio a\b!unsaturated aldehydes 612[91[0[4[1 2!Thio a\b!unsaturated aldehydes 61

2[91[0[5 Selenium Substituted a\b!Unsaturated Aldehydes 632[91[0[6 Nitroèn!Substituted a\b!Unsaturated Aldehydes 63

2[91[0[6[0 a!Nitroèn substituted a\b!unsaturated aldehydes 632[91[0[6[1 b!Nitroèn substituted a\b!unsaturated aldehydes 64

2[91[0[7 a\b!Alkenic Aldehydes with P\ As\ Sb\ or Bi!based Substituents 662[91[0[8 a\b!Alkenic Aldehydes with Si!based Substituents 662[91[0[09 a\b!Alkenic Aldehydes with Metal Substituents 67

2[91[1 ALDEHYDES BEARING AN a\b!TRIPLE BOND 67

42

43 a\b!Unsaturated Aldehydes

2[91[0 ALDEHYDES BEARING AN a\b!ALKENIC BOND

2[91[0[0 a\b!Unsaturated Aldehydes Without Further Unsaturation

2[91[0[0[0 By elimination reactions

"i# By oxidative elimination of H1

Aldehydes can be oxidised to a\b!unsaturated aldehydes in a palladium promoted dehydro!genation "Equation "0## ð72CL0196Ł[ The conditions in this reaction are such that ketones are nota}ected[ Silyl enol ethers of aldehydes can be oxidised to enals with lead tetraacetate ð72T750Ł\ andenols can be oxidised to a\b!unsaturated aldehydes by 1\2!dichloro!4\5!dicyano!0\3!benzoquinone"ddq# ð55TL3002\ 56CRV042Ł[

O

O

O

O(1)

PdCl2(PhCN)2N-methyl morpholine

AgOTf, THF

62%

"ii# By elimination of halide from a!halo aldehydes

a!Halo aldehydes give a\b!unsaturated aldehydes when treated with base[ The a!halo aldehydesthemselves are often made by halogenation of the aldehyde "Equation "1## ð38JCS626Ł[ The reactionworks best in cases where over halogenation is not possible*i[e[\ where only one a!hydrogen ispresent\ but even in these cases side reactions can lower the yield in the elimination step[ "For furtherexamples see ð46JA345\ 52MI 291!90Ł[# A more convenient procedure seems to be to _rst convert thealdehyde to its imine\ then chlorinate\ eliminate and hydrolyse to give the product "without isolation#ð89BSB30Ł[ Alternatively\ the enol acetate can be brominated and undergoes elimination to givegood yields of the enal ""E# stereochemistry# "Equation "2## ð68S496Ł[ a\b!Unsaturated aldehydescan be prepared from ketones in a 0!carbon homologation\ the _nal step of which is elimination ofHCl from an a!chloro aldehyde "Equation "3## ð62TL1354\ 89JCS"P0#0890Ł[

(2)

O O i, Br2, CaCO3, CHCl3ii, PhNEt2, 100 °C

77%

n-C5H11OAc

i, NBS, CCl4ii, NaOH, MeOH

86%n-C4H9

O

(3)

OO+ Li

Cl

Cl

(4)

i, THF, -95 °Cii, LiClO4, CaCO3, 130 °C

74%

"iii# By elimination from alkoxy enol ethers and thioenol ethers

Corey et al[ have developed a synthesis of a\b!unsaturated aldehydes which involves\ e}ectively\the hydrolysis and elimination of thioether groups from "a#\ which are themselves prepared frombismethylthio allyl anion "Scheme 0# ð60JA0613Ł[ Julia and co!workers have used the facile hydrolysisof allylic alkoxy thioenol ethers in a synthesis of a\b!unsaturated aldehydes ð72TL3714Ł\ whereasTrost has used the hydrolysis of allylic thioenol alcohols "Equation "4## in a scheme that e}ects a1!carbon homologation of ketones ð64JA3907Ł[ "For related examples see ð64S616\ 68TL1798\71TL3720Ł[# The starting materials for this scheme can also be made by the addition of thiophenol to

44a\b!Alkenic Bond

propargylic alcohol "Equation "5## ð73TL078Ł[ The corresponding enol ethers can also be hydrolysed"Equation "6## ð66CL234\ 72TL3718\ 78JOC1668Ł[

MeS SMe–

Li+n-C5H11

SMe

SMe

n-C5H11

Scheme 1

On-C5H11Br +

HgCl2, MeOH, H2O

84%

(a)

(5)HO

SPh O

HgCl2

66%

(6)HOO

i, PhSHii, H+

60%

Ph

OMe

SPh

Ph

O(7)

i, HCl, H2O, MeCNii, HgCl2, HCl

98%

"iv# By elimination from b!hydroxy and alkoxy aldehydes

Many methods have been described for e}ecting the elimination to unsaturated aldehydes fromalkoxy and hydroxy aldehydes\ often with the aldehyde group _rst being protected as an acetal[Direct methods include the use of acid catalysts\ for example\ H2PO3 "Equation "7## ð48CB0453Ł\ orbase\ for example\ 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# "Equation "8## ð60JOC255Ł[ Acids suchas formic acid or 1) HCl have often been used to simultaneously eliminate and remove theacetal "Equation "09## ð38JA2357\ 70S026Ł[ For related reactions see ð51CR"144#0016\ 62CC008Ł[ Thetransformation of b!ketoaldehydes to a\b!unsaturated aldehydes can be performed by _rst protectingthe aldehyde group as an enol ether\ then reducing the ketone to a hydroxy\ followed by aneliminationÐdeprotection step to give the product\ for example\ Equation "00# ð40HCA617\ 75TL1460\77HCA057Ł[ Elimination from b!hydroxy substituted aldehydes made from epoxides is also known"Equation "01## ð67TL4064Ł[ Parsons has described the synthesis of enals as outlined in Scheme 1ð70TL1910Ł\ which involves a rearrangement and hydrolysis reaction\ i[e[\ an allylic elimination[Formation of a mesylate from a b!hydroxy aldehyde\ followed by elimination using dbu has alsobeen used ð70JA3486Ł[

OH

O

OH

HOH

O

H

(8)H3PO4

89%

EtOO

EtO

OAcEtO

O

EtO

dbu

77%(9)

dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene


(10)EtO

OEt

EtO

OHCO2H, HCO2Na, H2O, 100 °C

82%

(11)

O OH OPh i, TMS-Cl, Et3N

ii, PhCH2MgCliii, p-TsA, pyr

65%

i, LDA, HMPAii, (CO2H)2

50%

O

n-C5H11

+ Et2N CN n-C5H11 O (12)

LDA = lithium diisopropylamideHMPA = hexamethylphosphoramide

OH

TMS

OH

TMS O

Scheme 2

LiAlH4

i, PhSCl, Et3Nii, AgNO3, H2O

68%

"v# By elimination of selenoxides

The a!selenation of aldehydes\ followed by oxidation to the selenoxide and elimination is less wellknown than with ketones\ but can be a useful route to a\b!unsaturated aldehydes\ especially wherethe aldehyde is already a!substituted "Equation "02## ð71JOC0507\ 78JOC3234Ł[ The aldehyde can beformed by a sigmatropic rearrangement of an allylic selenium compound as in Equation "03#ð71JOC0507Ł[

H

H

O O

H

O O

(13)

i, PhSeCl, pyrii, H2O2

100%

PhSe SePh +

O

OHO

(14)

i, LDA, THF ii, ketoneiii, H2O2

77%

"vi# By elimination of sulfones

Elimination of b!sulfonyl aldehydes can give excellent yields of a\b!unsaturated aldehydes "Equa!tion "04## ð64BSF0252Ł[ The sulfone can be made by oxidation of the sul_de with NaIO3 ð68TL1068Ł\or ozone\ in which case the aldehyde group can be made simultaneously by ozonolysis of a doublebond "Equation "05## ð71JA3886\ 71TL1288Ł[ For an example of alkylation a to the sulfone of ab!sulfonyl acetal\ followed by elimination and deprotection see ð64TL0996Ł[

46a\b!Alkenic Bond

PhSO2 O

n-C6H13

n-C6H13 O(15)

Na2CO3, EtOH

99%

i, O3, –78 °C ii, Me2Siii, CCl4, 70 °C

66%

O SPh O

O (16)

"vii# Miscellaneous reactions

a!Epoxy aldehydes undergo an elimination type reaction to a\b!unsaturated aldehydes "Equation"06## ð76TL1988\ 78TL2582Ł[ The a!epoxy aldehydes can be made from the reaction of an arsoniumylide with a carbonyl compound "Equation "07## ð78TL068Ł[ See ð71JOC4906Ł for an example ofelimination of nitrous acid from a b!nitro aldehyde\ and ð70ACS"B#532\ 73TL4244Ł for ring openingand elimination from isoxazolidines leading to enals[

OH

AcO

O

H AcO

O

OAc

(17)

i, (COCl)2, DMSO ii, Et3Niii, Ac2O, pyr

70%

(18)Ph3As OEt

OEt

58%

O OH

O

++ –

2[91[0[0[1 By oxidations of alcohols and their equivalents

The oxidation of primary allylic alcohols to a\b!unsaturated aldehydes is one of the commonestmethods of preparing this functional group[ There are a very large number of reagents with varyingselectivities[ One of the mildest is manganese dioxide "e[g[\ Equation 08#\ ð57JA4505\ 64S142\ 65S022Ł[Other reagents include pyridinium chlorochromate "pcc# ð64TL1536Ł\ sodium dichromate ð68JA6020Ł\oxalyl chloride:DMSO "Swern oxidation# ð75OS"53#053Ł\ pyridinium sulfonate:DMSO ð56JA4494Ł\silver carbonate:celite ð64JCS"P0#0346Ł\ and use of nitroso compounds ð30HCA0928\ 75CL1924Ł[ Varioustransition metal catalysed systems have also been described\ for example\ Cp1ZrH1 ð70JOC139Ł\ andRuH1"PPh2#3 ð75TL0794Ł[ For a list of reagents see ðB!78MI 291!90Ł[ The oxidation of allylic tertiaryalcohols can lead to a\b!unsaturated aldehydes\ although generally a mixture of "E#:"Z# isomers isobtained "e[g[\ Equation "19## ð66JOC571\ 66JOC702\ 68S245Ł[ Nef reactions of allylic nitro compoundsto give a\b!unsaturated aldehydes have been reported "Equation "10## ð67AG"E#347\ 76S068Ł[ Theoxidation of allylic thioamides by deprotonation\ capture of the anion with a sulfur electrophileand deprotection has been used to give "E#!a\b!unsaturated aldehydes "Equation "11## ð63TL2514\66TL1314Ł[ The Pummerer rearrangement can be used to prepare enals ð77SC0894Ł[ Allylic iodidescan be oxidised to a\b!unsaturated aldehydes with DMSO:base "the Kornblum reaction# "Equation"12## ð61TL1632\ 68CJC534\ 73S597Ł[ Allylic halides can also be oxidised with other reagents\ notablypotassium dichromate ð65CC089Ł\ N!ethyl morpholine oxide ð75BCJ2176Ł and nitrocyclohexaneð48JGU2814Ł[ See also ð71CL0876\ 72TL666Ł for oxidations of other allylic compounds[

(19)OH

O

MnO2, hexane, 0 °C

97%


(20)pcc, 25 °C

90%

OH

O

pcc = pyridinium chlorochromate

(21)NO2 O

i, 3M NaOHii, H2SO4

68%

SOn-C5H11

n-C5H11 NMe2

S(22)

i, LDA, THF ii, Me2S2iii, HgCl2, H2O

78%

(23)Ph OPh IDMSO, NaHCO3, 130 °C

2[91[0[0[2 Oxidation of allylic methyl groups

Selenium dioxide can give good yields of enals from the corresponding methyl alkene ð78CI"L#422Ł[The reaction gives the "E#!enal "Equation "13## ð60JA4200Ł\ and the most electron!rich double bondis usually that which is oxidised allylically ð76T3370Ł[

(24)MeO2C MeO2C OSeO2, EtOH, 50 °C

48%

2[91[0[0[3 By formylations of alkenes

Vinyl silanes can be formylated with dichloromethyl methyl ether "Equation "14## ð67CL748Ł\usually with TiCl3 as the catalyst[ The reaction proceeds with retention of con_guration but theproducts isomerise to the "E#!enals under the reaction conditions ð66S610\ 66TL2206\ 73S880Ł[ Vinyllithium or magnesium species undergo formylation to enals with electrophiles such as DMFð74JCS"P0#336\ 75RTC55Ł\ methyl formate ð70TL0326Ł and N!methyl!N!formyl!1!aminopyridine "Equa!tion "15## ð67S392Ł[ Vinyl lithium species have been formed in situ by a Shapiro reaction\ and canthen be trapped by DMF "Equation "16## ð68S33\ 70JOC0204Ł[ Vinyl iodides can be formylated withcarbon monoxide to give good yields of enals\ using a palladium catalyst\ followed by a reduction"one!pot# "Equation "17## ð72JA6064Ł[

TMSO

+ MeO

Cl

Cl(25)

i, TiCl4, CH2Cl2, –78 °Cii, H2O

79%

PhMgBr

Ph

O+

N NMe

CHO

(26)HCl, 0 °C

70%

NN

O2S

Pri Pri

Pri

H

i, BusLiii, DMF

56%

O (27)

i, Pd(PPh3)4ii, Bu3SnH, toluene

83%I

O

CHO

O+ CO (28)

48a\b!Alkenic Bond

2[91[0[0[4 By rearrangements of a!acetylenic alcohols

Although a!acetylenic alcohols would normally rearrange to a\b!unsaturated ketones with acidcatalysts "see Section 2[94[0[0[6#\ alternative conditions have been found that give a\b!unsaturatedaldehydes[ This is e}ectively the anti!Markovnikov hydration of the alkyne[ The commonest reagentis "Ph2SiO#VO and the reaction is proposed to go through a vanadate ester\ as in Scheme 2 ð65S14Ł[For other examples see ð74TL4474\ 89TL6410Ł[

(Ph3SiO)3VO, 146 °C

91%

H

OHO

O

H HH

OO

O

H H

V O

OSiPh3

Ph3SiO

Scheme 3

H

O

O

H H

O

2[91[0[0[5 By displacements of b!leaving groups

b!Alkoxy ð74SC260Ł\ silyloxy ð75CB0626Ł\ and dialkylamino ð75TL1460Ł enals can be treated withnucleophiles to give carbon substituted a\b!unsaturated aldehydes\ for example\ Equation "18#ð76S0Ł[ The chlorine of b!chloroenals can be removed with a Zn:EtOH reduction ð61CPB298Ł[

EtO O O

S

SS S

(29)+ i, BuLi

ii, H+

2[91[0[0[6 By aldol condensation reactions

Probably the most important and versatile route to a\b!unsaturated aldehydes is the aldol con!densation^ the reaction of the enol or enolate of an aldehyde with a second activated carbonyl\followed by dehydration of the resulting adduct[ This is commonly observed intramolecularly with0\5!dialdehyde systems to yield cyclopentenals "Equation "29## ð77JOC0512Ł "also see ð38JA2209\42JA273\ 70HCA0039Ł#\ the 0\5!dialdehyde often being generated by the oxidation of a diene or cyclicalkene ð65CL18\ 70TL0910\ 77S586Ł[ 0\6!Dialdehydes behave similarly ð62TL1298\ 76TL0782\ 78TL4250Ł[The regioselectivity of the intramolecular aldol reaction can be controlled by the conditions used"Equation "20## ð70CPB655\ 73JA3447Ł or by the use of an enamine or similar group ð76HCA334Ł[

O

CHO

OHC

H

CHO

H

(30)

piperidinium acetatePhH, 80 °C

77%


CHOO

(31)TiCl4, PhNH2Me•O2CCF3

50%O O

CHO

Intermolecular aldol condensations are equally facile occurring under a range of conditions"Equation "21## ð40HCA0371\ 57JOC664\ 64JCS"P0#0416\ 66JOC1012Ł[ The control of the regio chemistryfor unsymmetrical condensations can be achieved by the use of enol ethers and enamines ð66JA6254\76JOC3677\ 77TL3606Ł or a!lithioimines and a!lithiohydrazones ð58JOC0011\ 65TL6\ 67JOC2677Ł[ TheMannich reaction\ followed by elimination of the b!amino group from the intermediate Mannichbase\ is closely related to the aldol condensation and is often used to prepare a!methylene!aldehydesð32CB0379\ 72TL0060\ 78CL0172Ł[

(32)C6H13CHO C6H13CHO

C5H11H2BO2, m-xylene, 138 °C

100%

2[91[0[0[7 By Wittig reactions

The Wittig reaction is also a well used reaction in the synthesis of a\b!unsaturated aldehydes[ Themajor route to these systems involves the reaction of a formyl phosphorane with an aldehyde andgenerally leads to the "E#!isomer stereoselectively "Equation "22## ð81TL3942Ł^ see also ð63JCS"P0#26\68S155\ 73JA159\ 77SC0802Ł[ The corresponding stabilised arsonium ylides have also been investigatedð76JOC2447Ł[ An analogous WadsworthÐEmmons type Wittig reaction can be achieved using thephosphonate "0#^ this has the added advantage of allowing reaction with ketones which are toostable to react with a!formyl phosphoranes "Equation "23## ð57TL3248\ 76JOC3936Ł[ The use of thephosphorane "1# also leads cleanly to a\b!unsaturated aldehydes after hydrolysis of the enol ether"Equation "24## ð66TL2764Ł[ The Peterson alkenation is a related reaction enabling the preparationof a\b!unsaturated aldehydes from lithiated a!silylimines and aldehydes "Equation "25## ð74TL1280\78TL4124Ł[

CHO

O+

Ph3P CHO

O

CHO (33)PhH, reflux

55%

(OEt)2P

HN

O

+

O CHO

(34)

i, NaHii, H3O+

25 °C

86%

(1)

Ph3P OMe

(2)

+ Ph CHO OPh (35)

MeO CHO

TBDMS-O

+N

TESLi

MeO

TBDMS-O

CHO

(36)

i, THF, –20 °C ii, TFA, 0 °C

iii, H2O, 0 °C


50a\b!Alkenic Bond

2[91[0[0[8 By DielsÐAlder reactions

The DielsÐAlder reaction enables the synthesis of cyclic a\b!unsaturated aldehydes via the use offormyl substituted diene systems ð71TL1700\ 78CB474Ł or alkynic aldehydes "Equation "26## ð70TL514\72AG"E#309\ 76JOC3024Ł[

CHO +

OAc

OAc

OAc

OAc

OHC

(37)70 °C

89%

2[91[0[0[09 By isomerisations

The isomerisation of bg!unsaturated aldehydes also furnishes a\b!unsaturated aldehydes and canoccur under acidic ð68S021\ 76JCR"S#185Ł or basic conditions ð79HCA0554Ł[ The isomerisation ofpropargylic ethers to allenic ethers followed by hydrolysis similarly furnishes a\b!unsaturated alde!hydes "Equation "27## ð54RTC20\ 61TL0704Ł[ g!Hydroxy!a\b!unsaturated aldehydes can be preparedby the deprotection and hydroxy!rearrangement of tertiary carbinols such as "2# "Equation "28##ð67TL0294\ 76SC044Ł[

(38)OEt

CHO i, NaNH2, NH3, –33 °Cii, 5N H2SO4, 70 °C

70%

HO S

S

OH

CHO

(39)

(3)

HgO, HBF4H2O, THF, reflux

84%

2[91[0[0[00 By reductions

a\b!Unsaturated aldehydes can be prepared by the diisobutylaluminum hydride "dibal!H#reduction of a\b!unsaturated nitriles ð70JOC3706\ 70TL0068Ł or the reduction of a\b!unsaturatedacid chlorides using poor hydride donor reducing agents such as NaBH"OMe#2 "Equation "39##ð47CB1341Ł[ In a similar fashion oxazines have been used as protected carboxylic acid equivalentsand can be reduced and hydrolysed to the aldehyde using sodium borohydride "Equation "30##ð62JOC25\ 63JOC512Ł[ Benzoisothiazoles have been used in an analogous fashion in the synthesis ofa\b!unsaturated aldehydes\ acting as a formyl anion equivalent ð67TL4Ł[

COCl

OAc

AcO

AcO CHO

OAc

AcO

AcO

(40)NaBH(OMe)3

(41)O

N

+

CHOOHC

i, BunLi, –78 °C ii, NaBH4, EtOH, –40 °Ciii, H3O+

53 °C


2[91[0[0[01 From epoxides

Epoxides are useful intermediates in the synthesis of a\b!unsaturated aldehydes[ Thus theDarzensÐClaisen reaction was used by Isler et al[ in the _rst synthesis of vitamin A "Scheme 3#ð36HCA0800Ł "also see ð47JOC046Ł#[ Related reactions involve the acid catalysed rearrangement ofa!epoxy sulfoxides\ ð66TL0266\ 78JA6493Ł\ a!epoxy nitriles ð52JIC003Ł and a!epoxy silanes ð71CL0886Łyielding a\b!unsaturated aldehydes[ The pinacol type rearrangement of an a!hydroxy epoxidesimilarly leads to an unsaturated aldehyde ð62JOC0279Ł as does the oxidation of a terminal epoxideusing sulfuryl chloride ð76TL1064Ł "Equation "31##[

O

CO2EtO

Cl CO2Et

Scheme 4

+NaOEt, –10 °C

stepsCHO

15% NaOH, MeOH, 5 °C

80% overall

Vitamin A

HOO

H CO2Me

H HOO

H CO2Me

H

(42)CHO

O

SO2Cl2, CH2Cl2, 39 °C

90%

2[91[0[0[02 Miscellaneous methods

The oxidative ring opening of furans with a variety of oxidising agents leads to unsaturatedaldehydes ð64JHC0214\ 68TL1186\ 74TL1758\ 75TL1646\ 75TL3872\ 78IJC"B#2\ 78JOC4075Ł as does the carefulozonolysis of various dienes "Equation "32## ð62TL1306\ 64S670\ 77JA3624\ 89S0922\ 89TL4468Ł[ The use ofoxy!substituted cyclopropanes in the synthesis of a\b!unsaturated aldehydes has also been reportedð67TL2936\ 67TL2940\ 74TL2502Ł[

(43)CO2Me

CHOO3, Na2CO3, MeOH, CH2Cl2, –78 °C

71%

2[91[0[1 a\b!Unsaturated Aldehydes With Further Unsaturation


Eliminations of hydroxy or alkoxy groups b or d to an aldehyde\ usually under acidic conditions\can give dienals[ For example\ reaction of lithium acetylide "Equation "33## with an enone furnishesa tertiary propargylic alcohol[ Removal of the thioenol ether protecting group gives the aldehydefunction\ and under the acidic conditions the b!hydroxy group eliminates to give the mainly"E#!unsaturated enal ð68TL1798Ł[ This reaction also works if the ketone is reduced to a secondaryalcohol with LiAlH3 "58) yield#[ Similarly\ partial reduction of an alkoxy alkyne "Equation"34## followed by deprotection and elimination gave the "E\E#!trienal ð37RTC862Ł[ The hydroxycompound can be made in situ from an a\b!unsaturated aldehyde and a b!lithio enol ether ð35JCS826\70JOC2630Ł[ The elimination of a b!alkoxy group has also been used ð45HCA138Ł[ Formation of amesylate and elimination under weakly basic conditions has often been used\ especially in the _eldof leukotriene chemistry "Equation "35## ð79JA0325\ 72TL3788Ł[

52a\b!Alkenic Bond

Ph SBut

O

Ph

O

i, ii, H2SO4

98%

Li

(44)

(45)

OH

EtO O

i, H2/Pd-BaSO4ii, HCl

85%

O

H H

OO

H H

O

Bu3SnOEt (46)+

i, BuLi ii, MsCl, Et3N

iii, NaHCO3

d!Hydroxy groups can be eliminated from a\b!unsaturated aldehyde as part of a similar procedurethat a}ords a 3!carbon homologation "Equation "36## ð89SC1872Ł[ "1"E#\3"E##!Isomers are exclus!ively formed from aldehydes in this reaction\ whereas use of unsymmetrical ketones gives mixturesof "1"E#\3"E## and "1"E#\3"Z##!isomers[ The 3!lithioalkoxydiene can also be made by hydro!stannylation of an alkoxyenyne\ followed by tin:lithium exchange ð67TL606Ł[ Alternatively\ thealkoxyenyne can be used directly "Equation "37##\ with the alkyne then being partly reduced withLiAlH3\ followed by acid!catalysed hydrolysis and elimination ð45JCS3971Ł[ See ð47JOC0479Ł for asimilar example\ and also note ð76HCA0399Ł for an example of d!OH elimination using basicconditions "NaHCO2:THF#[ d!Methoxy groups are often eliminated under basic conditions\ forexample\ dbu ð64CL0190\ 66BCJ0050Ł\ or NaOMe ð61CC752Ł[

Ph O

O

Ph+

TMS-O

Br

(47)

i, ButLi ii, Aldehydeiii, HCl

72%

OMe

O

OMe

O

Li

OMe

(48)+

i, aldehyde ii, LiAlH4iii, H2SO4

52%

Elimination of b!sulfoxides ð67CC813Ł and sulfones ð89JCS"P0#086Ł is known\ as is elimination ofd!sulfoxides "Equation "38## ð70TL3026Ł[

OS

Ph

OO

(49)toluene/reflux

85%


2[91[0[1[1 By formylations of dienes

Direct Vilsmeier formylation of dienes and trienes is possible\ especially if they are electronicallyactivated or electron rich\ "Equation "49## ð66TL1018Ł[ Cycloheptatriene reacts similarly ð67CL30Ł\as do dihydropyridines "Equation "40## ð89JOC181Ł^ see ð55CB1368\ 55CB2946Ł for other examples[The b!methyl enone in Equation "41# is formylated under similar conditions to give a good yield ofa chlorodienal ð65RTC297Ł[ Lithio dienes can also be used as the nucleophile ð65ZN"B#0543Ł[ Avinylogous formylation a}ording a 2!carbon homologation can be achieved using b!dimethyl!aminopropenal ð89TL0254Ł or triformylmethane ð61CB0704Ł[ Takahashi and co!workers have inves!tigated the use of a Rh3"CO#01 catalyst to hydroformylate enynes\ producing dienals ð75TL3386\77BCJ3242Ł[

POCl3, 25 °C

80%+ N

Me

Me

Cl

+

O

(50)

NPh

SiPri3

CO2PhN

SiPri3

CO2Ph

O

(51)DMF, POCl3, CH2Cl2

97% Ph

(52)

O Cl

O

DMF, POCl3, 80 °C

80%

2[91[0[1[2 By oxidations of alcohols and reductions of acids

Oxidation of dien!0!ols to dienals proceeds in much the same way as the oxidation toa\b!unsaturated aldehydes without further unsaturation "see Section 2[91[0[0[1#[ Common reagentsinclude MnO1 ð40JCS1576\ 78JCS"P0#0828Ł\ pyridinium dichromate "pdc# "Equation "42## ð71LA0105Ł\and DessMartin periodinane "a very mild hypervalent iodine species# ð76TL1810Ł[ Matsumoto hasused a RuCl1"PPh2#2 catalyst in the presence of O1 ð70CC896Ł[

(53)

HO

O

pdc, CH2Cl2, 20 °C

86%

Ried has investigated reduction of dienoic acids\ via the acid chlorides\ which are reacted with2\4!dimethylpyrazole\ and subsequently reduced with LiAlH3 "Equation "43## ð48LA"511#26Ł*thisalso works for vitamin A acid[

(54)Cl

O O i, 3,5-dimethylpyrazoleii, LiAlH4

74%

2[91[0[1[3 By ring opening reactions of pyrilium salts and furans

Taylor and co!workers have investigated the ring opening of pyrilium salts with nucleophiles\ forexample\ Equation "44# ð56G286\ 80S219Ł[ The reaction also gives the "1"E#\3"Z## stereochemistry

54a\b!Alkenic Bond

with phenyl acetylide and phenyl lithium ð74CC671\ 78JCS"P0#572Ł[ 1!Monosubstituted furans can ringopen to dienals when a!deprotonated "Equation "45## ð67JOC3124\ 70TL3376Ł[

(55)Li

O

O+

+THF, –78 °C

69%

ONHCOPh O NHCOPh (56)

i, LDA, THFii, NH4Cl

95%


The Wittig reaction provides a facile route to a\b!unsaturated aldehydes possessing furtherunsaturation[ This can be achieved by the reaction of an aldehyde with two equivalents offormylphosphorane ð70TL868Ł or by reaction of an aldehyde with the corresponding vinylogousphosphorane "3#\ which yields a mixture of cis\trans and trans\trans products "Equation "46##ð71TL056Ł[ The corresponding arsonium ylide has also been described ð75TL3472Ł[ The reaction ofa protected formyl phosphonium ylide with an unsaturated aldehyde followed by deprotection issimilarly known ð77SC40Ł[ The use of the more reactive WadsworthÐEmmons methodology requiresthe protection of the aldehyde function on the phosphonate\ and conversion of the carbonyl to itsimine ð77ACS458Ł or acetal ð89TL2018Ł has been reported "Equation "47##[

OHCO

CO2Me

H

H

OHC PPh3

OCO2Me

H

H

+ (57)

OHC

CH2Cl2, 25 °C

73%(4)

(E),(Z):(E),(E) 4:1

P(OEt)2

O

O

O + OHCOHC

(58)

i, ButOK, THFii, H3O+

78%

2[91[0[1[5 From cyclopropanes

The reaction of a!ketocarbenes with furans followed by in situ electrocyclic ring!opening of theintermediate cyclopropane\ yields doubly unsaturated aldehyde systems\ predominantly\ as thecis\trans isomers\ in high yield "Equation "48## ð54TL710\ 62TL1764\ 70CC09\ 72TL4074\ 73TL24\89JCS"P0#78Ł[ The thermolysis of the isolated cyclopropanes\ giving rise to the same products\ hasalso been reported ð52LA"557#08\ 62TL0524Ł[ This reaction has also been observed intramolecularly"Equation "59## ð63TL1144\ 76HCA0318Ł\ and yields an ynenal if the carbene generated is a to thefuran system "Equation "50## ð63JOC1828\ 67JA6816\ 67JA6823\ 68JA0292Ł[

N

SN2

OCO2CHPh2

N

S

OCO2CHPh2

CHO

+O

(59)Rh2(OAc)4, 0 °C

100%


O

N2

O

CHO

O

(60)Rh2(OAc)4, CH2Cl2, 20 °C

95%

OCO2Et

N2

OHC

CO2Et

(61)CH2Cl2

100%

2[91[0[1[6 Miscellaneous reactions

There are relatively few examples of aldol condensations in the synthesis of a\b!unsaturatedaldehydes with further unsaturation\ probably due to problems associated with controlling theregiochemistry ð79S787Ł[ The reaction of a!cyclocitral with benzaldehyde occurs via a vinylogousaldolisation and leads to the aldehyde "4# in 77) yield "Equation "51## ð70JHC438Ł[ The hydrolyticring opening of pyridinium salts is a useful route to dienal systems such as "5# "Equation "52##ð52AG"E#279\ 57LA"604#095\ 70T1264Ł[ Closely related reactions include the ring opening of pyridineswith thiophosgene ð63JCS"P0#0430\ 72CC63Ł and the Fujiwara reaction ð70JOC2064Ł[ Other ring openingreactions yielding dienals as products are mainly oxidative ð66JCS"P0#0235Ł "Equation "53## ð45CB1113\50TL619\ 56CB2061\ 68TL0596\ 71TL762Ł[ Propargylic aldehydes are reported to react with b!amino!acrylates to give d!aminodienals\ in the same way as propargylic ketones "Equation "54## ð46CB1154Ł[Allylic propargylic tertiary alcohols can isomerise to dienals under acidic conditions ð45JOC527Ł[

(62)CHO

CHO

Ph

PhCHO, 37% HCl, 20 °C

88%

(5)

HO–

73%

N

NO2

NO2

+

O2N

NH

OHC

NO2

(63)

(6)

(64)mcpba, PhH, 20 °C

32%OOHC

CHO

O +H2N

CO2Et

NH2

EtO2C

O

(65)EtOH, 78 °C

90%

2[91[0[2 Halogenated a\b!Unsaturated Aldehydes

2[91[0[2[0 1!Halogenated a\b!unsaturated aldehydes

Alkoxychloro~uorocyclopropanes can be obtained in good yield from the reaction of enol ethers\dichloro~uoromethane and aqueous potassium hydroxide[ The resulting cyclopropane system then

56a\b!Alkenic Bond

undergoes clean ring opening at re~ux temperature in an aqueous medium to give the 1!~uoro!1!alkenals usually as a mixture of "E# and "Z# stereoisomers "Scheme 4# ð66HCA0628\ 74S643Ł[ Theaddition of dihalocarbenes to silyl enol ethers has also been investigated and gives a!chloro anda!bromo alkenals in high yields ð65S085Ł[

Scheme 5

OMeFCl

OMe

CHO

FHCCl2F, KOH, H2O

66%

RSO3Na, H2O

70%

A second general method for the preparation of 1!~uoro!1!alkenals involves the reduction andsubsequent rearrangement of 0\0\1!tri~uoro!2!hydroxy alkenes[ Thus 0\0\1!tri~uoro!2!hydroxy!0!alkenes "6# are prepared in good yield by the addition of tri~uorovinyllithium to carbonylcompounds[ Nucleophilic replacement of one ~uorine atom by hydride is achieved using lithiumaluminum hydride in ether and the resulting di~uorovinyl alcohols "7# undergo rearrangement in85) sulfuric acid at low temperature to give the ~uoro aldehyde product "8# generally as a mixtureof stereoisomers "Scheme 5# ð67S017Ł[ The use of 0!chloro!1\1!di~uorovinyl lithium in place oftri~uorovinyl lithium in an analogous reaction yields the corresponding 1!chloro!1!alkenals in verygood overall yield ð67S347Ł[

O

R2

R1F

F F

Li

MO

R1

R2

F

F

F

MO

R1

R2

F

F

Scheme 6

THF, Et2O R2

R1

F(8)

LiAlH4, Et2O

76–82%

CHO

(7) (9)

98% H2SO4

40–69%

The use of 0!bromo!1!methoxyvinyl lithium as a synthon for the bromoacetaldehyde anionenables the synthesis of several 1!bromo!alkenals[ Thus reaction of 0!bromo!1!methoxyvinyl lithiumwith acetone followed by in situ allylic rearrangement of the intermediate alcohol gave a 36) yieldof the bromo!aldehyde "09#\ "Equation "55## ð72JOC1984Ł[

OCHO

Br

i,

ii, H3O+

47%

MeO Li

Br

(66)

(10)

1!Iodo!1!alkenals "00# can be prepared under mild conditions in a one!pot procedure fromacetylenic alcohols "01# using a pdc oxidation of the derived iodine complex "Equation "56##[ Yieldsare good and unsymmetrical aldehydes yield a single geometric isomer as the product ð70TL0930Ł[

R1

HOR2

R2

R1 CHO

I(67)

i, I2, RTii, pdc, RT

30–66%

pdc = pyridinium dichromate

(12) (11)

The substitution of a!hydrogen for a halogen in a\b!unsaturated aldehydes can be achieved byseveral means[ Common reagents include molecular halogen\ via an addition elimination mechanismfor molecules where a hydrogen b to the carbonyl is the most acidic "Equation "57## ð34OS"14#81\44OSC"2#620Ł[ Alternatively\ hypohalous acid can be used for less b!acidic cases "Equation "58##


ð42OS"22#04Ł[ a!Bromination has also been noted to occur with thionyl bromide "Equation "69##\and a radical mechanism has been proposed ð70JPR562Ł[

(68)

CHO CHO

Br

i, Br2ii, Na2CO3

85%

(69)

O O

ClCl2, H2O

(70)

O O

Br

SOBr2

85%

The Wittig reaction has been used to prepare a!halo alkenals ð51CB2992Ł[ The formyl methylene!phosphorane "02# is _rst halogenated with molecular halogen to give the haloformyl methylenephosphorane "03#[ This reacts with aldehydes in the normal manner to give the desired 1!haloalkenals"Scheme 6#[ Preparation of the "Z#!1!bromo!alkenal "04# can be achieved stereospeci_cally from thereadily available "E#!bromoacetal "05# by formolysis accompanied by concomitant "E# to "Z#!isomerisation in 66) yield "Equation "60## ð66S531Ł[ 1!Chloro!1\3!pentadienal "06# was formed bythe thermolysis in quinoline of the pyran "07#\ which is easily prepared from 1\2!dihydrofuran"Equation "61## ð53T1980Ł[

Ph3PO

Ph3PO

X

O

X

Ph

Scheme 7

(13) (14)

X2

X = Br, Cl

PhCHO

X = Br, 34%X = Cl, 52%

MeO2CBr

MeO OMe

MeO2CCHO

Br(71)

i, HCO2Hii, H2O

77%

(16) (15)

(72)

O

Cl

Cl O

Cl

(18) (17)

quinoline, 120 °C

44%

2[91[0[2[1 2!Halogenated a\b!unsaturated aldehydes

b!Halo acroleins are not inde_nitely stable and decompose\ sometimes suddenly\ even whenrefrigerated\ giving hydrogen halide and a tar[

"i# By VilsmeierÐHaackÐArnold reaction with carbonyl compounds

The VilsmeierÐHaackÐArnold reaction is the most important and widely used reaction for makingb!halo substituted a\b!unsaturated aldehydes[ The starting material is an enolisable carbonyl com!pound which is formylated and halogenated according to the mechanism in Scheme 7 ð48CCC1267\77CB888Ł[ Unsymmetrical carbonyl compounds possessing two enolisable sites introduce a regio!chemistry problem ð72JOC0810Ł[ Mixtures of regioisomers are usually produced in such cases[ In

58a\b!Alkenic Bond

addition\ mixtures of "E# and "Z# stereoisomers are often possible\ although this does not appearto have been discussed much ð69JCS"C#1373Ł[ The simplest cases are for symmetrical\ and:or cyclicketones\ for example\ Equation "62# in which only a single regio! and stereoisomer is possibleð59CB1632Ł[ Regiochemistry problems can be circumvented by introducing a nonenolisable site[However\ in one example Katritzky et al[ have shown that SN1? attack by hydroxide can lead tosigni_cant quantities of allylic alcohols as by products "Equation "63## ð77CB888Ł[ Aromatic ketonesalso react extremely well\ producing mixtures of stereoisomers "Equations "64# and "65## ð48CCC1274\79T1014Ł[ The regiochemistry has also been shown to be strongly in~uenced by steric factors\ forexample\ in Equation "66# the ratio of product "a# ] "b# increases from 59 ] 39 for the cyclopentanoneto 099 ] 9 for the cyclooctanone ð72JOC0810Ł[ Single regioisomers can result if one of the intermediateenols is produced preferentially "Equation "67## ð89JHC654Ł[ Phosphorus oxybromide has also beenused to make the bromo analogues*a single regioisomer in this case "Equation "68## ð66T1916Ł[b!Dimethylamino a\b!unsaturated carbonyl compounds have also been used^ these are formalintermediates in the VilsmeierÐHaackÐArnold reaction[ Thus\ Arnold prepared the b!chloroacrolein"08# by halogenation and hydrolysis of "19# "Equation "79## ð48CCC1267Ł[ Alkoxy acroleins havealso been shown to react with thionyl chloride to give the b!halo unsaturated aldehydes\ with allylchloromethyl ether compounds "10# being the proposed intermediates "Scheme 8# ð53JGU098Ł[

R1

R2

O

R1

R2

O

NMeMe

R1

R2

O

NMeMe

Cl–, H2OR1

R2

O

NMeMe +

N

Me

Me +

R1

R2

Cl

CHO

Scheme 8

+

+

+

(73)

O

DMF, POCl3

83%

CHO

Cl

N

O

CHO

POCl3

O Cl

OHC

Cl

OH

(74)+

(75)

O Cl

CHO

POCl3, DMF

91%

(76)

N O N

Cl

CHO

POCl3

50%


(77)

( )n

O

( )n

Cl

CHO( )n

ClOHC

+POCl3, DMF

(a) (b)

n1234

(a)609095

100

::::

(b)401050

(78)

OCHO

Cl

POCl3, DMF

84%

(79)

O Br

CHOPOBr3, DMF

85%

(80)

O

NMe2

Cl

CHO

(20) (19)

i, ClCOClii, H2O

84%

O

OMe

Cl

OMeCl

Cl

O

Scheme 9

(21)

SOCl2 H2O

57% overall

"ii# Miscellaneous

Dialkyl alkynes can be chloroformylated with dichloromethyl ether and boron trichloride"alkenes\ however\ add twice to this reagent under these conditions# "Equation "70## ð77CB080Ł[Again\ a mixture of "E# and "Z# stereoisomers results from this reaction[ No nonsymmetric alkyneswere considered in this paper so the regiochemistry of this reaction is unknown[ Treatment of thetrichloromethyl substituted cyclohexadienol "11# with 09) sulfuric acid at room temperature yieldsthe b\b!dichloroalkenal "12# in 89) yield\ "Equation "71## ð45JOC527Ł[

(81)

OMeCl

Cl Cl

O

BCl351%

60a\b!Alkenic Bond

(82)

Cl3C

HO

O

Cl

Cl(22) (23)

10% H2SO4

2[91[0[3 Oxygen Substituted a\b!Unsaturated Aldehydes

2[91[0[3[0 1!Oxygen substitution

Few routes to a!alkoxyacroleins are known[ Williams et al[ have devised a route starting fromalcohols such as "13# via a Swern oxidation and b!elimination "Equation "72## ð76S897Ł[ Theoxidation of 1!alkoxy substituted allylic alcohols is also known ð62LA1967Ł[ Other methods includethe reaction of a dimethoxy vinyl lithium species with an aldehyde "Equation "73## ð65SC008Ł\ orthe rearrangement of propargylic esters ð89CL0694Ł[

(83)Br O

OH

S

Br O

O

(24)

i, DMSO, (ClCO)2ii, Et3N

79%

(84)

OMeMeO

Br

OMePh

O

i, BunLi ii, PhCHOiii, HCl, H2O

76%

2[91[0[3[1 2!Oxygen substitution

The uses of b!alkoxyacroleins in organic synthesis has been reviewed ð66S0Ł[ They are generallyprepared from enol ethers by a b!formylation reaction[ This can be achieved using Vilsmeier typeconditions\ i[e[\ POCl2:DMF "Equation "74## ð53TL622\ 60JOC599Ł or with triethyl ortho!formate:BF2

ð48HCA733\ 60CB554Ł[ Dihydropyran has been formylated by a ð1¦0Ł cycloaddition\ followed byring expansion and contraction reactions "Scheme 09# ð69JOC2199Ł[ Similar compounds have beenprepared by a cycloaddition reaction of vinyl ethers and malonaldehyde derivatives "Equation "75##ð53CB0848\ 71TL0036\ 77TL1750Ł[

(85)

O PhO Ph

O i, DMF, POCl3ii, 5% NaOH

58%

O O Cl

Cl

O OBut

Cl

O

O

Scheme 10

Cl3CCO2Et

EtO–

ButO– H+


EtO+

O

OBun

O

Bun O

EtO

(86)63%

The addition of alcohols to propargylic esters\ followed by reduction to the allylic alcoholsand subsequent oxidation constitutes a useful and stereoselective synthesis of 2!alkoxy acroleins"Equation "76## ð72TL4198Ł[ 2!Alkoxy substituted allylic alcohols have also been oxidised by otherreagents\ for example\ pcc ð66CC797\ 53CB0848Ł[ Other methods reported for the synthesis of 2!oxygensubstituted acroleins are] the reaction of the corresponding 2!halo "or ammonium# acroleins withalcohols ð66JPR0931\ 89CB288Ł and Pd catalysed oxidation of a!silyl substituted allylic tosylatesð74TL728Ł[

(87)CO2MeMeO

O

i, MeOH ii, dibal-Hiii, MnO2

70%

2[91[0[4 a\b!Alkenic Aldehydes with Sulfur Substituents

2[91[0[4[0 1!Thio a\b!unsaturated aldehydes

The 1!thio!1!alkenal "14# was prepared in good yield via the hydrolytic ring opening of thealkoxybromothiocyclopropane "15# derived in turn from the dibromoalkoxycyclopropane "16#"Scheme 00# ð67TL2936Ł[ The enol ether "17# has been cleaved under mild nonacidic conditions togive the a!thioalkenal "18# in quantitative yield "Equation "77## ð79TL2848Ł\ whereas tri~uoroaceticacid in chloroform was used to produce the a!sulfonyl!alkenal "29# from the enol ether "20# "Equation"78## ð76TL878Ł[

(27) (26) (25)

BrBr

OEt

SPhBr

OEt

O

SPh

Scheme 11

i, BunLi

ii, PhSSPh

i, EtOH, K2CO3ii, H3O+

74% overall

SPh

MeO

SPh

CHO

(88)

(28) (29)

i, NaI, MeCNii, TMS-Cl

100%

Ph OH

PhSO2OMe

Ph

OHC SO2Ph(89)

(31) (30)

TFA, CHCl3

83%

2[91[0[4[1 2!Thio a\b!unsaturated aldehydes

The displacement of a halogen leaving group from an activated 2!chloro!1!alkenal by a sulfurnucleophile has been used to prepare b!thio!alkenals in very high yields[ Thus\ Gallagher et al[treated 2\2!dichloropropenal "21# with propane!0\2!dithiol "22# to give the aldehyde "23# in 83)yield "Equation "89## ð78JCS"P0#0682Ł[ Similarly the thiophene precursor "24# was prepared bytreatment of the chloroenal "25# with sodium sul_de and subsequent alkylation with an a!bromoester"Equation "80## ð64CR"170#24Ł[ The thiapyran "26# was prepared by treating 2!chloro!1!methyl!but!

62a\b!Alkenic Bond

1!enal "27# with sodium sul_de and proceeded via an intermediate mercaptovinylaldehyde "Equation"81## ð61T4086Ł[ An analogous procedure utilising a nitrogen leaving group led to the aldehyde "28#in high yield "Equation "82## ð66JPR0931Ł[

Cl

OCl HS

HS S

OS

(90)+NaOH, H2O, Et2O, 0 °C

94%

(32) (33) (34)

O

Cl

O

S CO2Et

Ph (91)

(36) (35)

i, Na2Sii, PhCHBrCO2Et

85%

O

Cl

S

O

(92)

(38) (37)

Na2S, H2O, MeOH

92%

SH

CO2MeO NMe3

+ ClO4–

S

CO2Me

O

(93)+H2O, NaOH

90%

(39)

The aldehyde "39# was prepared in 71) yield via a simple Wittig condensation with glyoxalat room temperature\ using triethylamine to generate the requisite ylide in situ "Equation "83##ð69JCS"C#1301Ł[

S

S

S

SPPh3

+ BF4–

S

S

S

S O(94)

(40)

i, TEA, THFii, glyoxal, H2O

82%

The 0\1!dithiole "30# has been prepared by ring opening of the thiopyran "31# and subsequentintramolecular oxidative coupling "Equation "84## ð58CC355\ 61T4086Ł[ Other routes to these2!acylmethylene!2H!0\1!dithioles are also available ð47CB0113\ 52JA2133\ 55JOC2378\ 57JCS"C#1432\61BSF3465Ł[

S

O

PhS

S

CHO

Ph(95)

(42) (41)

i, NaOH, H2O, DMFii, K3Fe(CN)6

77%

A Vilsmeier formylation of an activated alkene or heterocycle has also been used to prepareb!thioalkenals[ Thus the diene "32# was formylated at 9>C to yield the unsymmetrical aldehyde "33#"Equation "85## ð78TL4178Ł\ and the 0\3!benzooxathiin "34# was formylated at room temperature togive the corresponding aldehyde "35# "Equation "86## ð59JOC42Ł[ Formylation of the 0\3!benzodithiin"36# provides the a\b!dithioalkenal "37# in moderate yield "Equation "87## ð42JA0536\ 43JA0957Ł[Similarly formylation of tetrathiafulvalenyl lithium "38# with dimethylformamide produced thecorresponding aldehyde "49# "Equation "88## ð68JOC0365Ł[


S

S

S

S

MeO2C

MeO2C

CO2Me

CO2Me

S

S

S

S

MeO2C

MeO2C

CO2Me

CO2Me

CHO

(96)

(43) (44)

(COCl)2, DMF, 0 °C

75%

(97)

(45) (46)O

S

O

S

CHO

POCl3, DMF

27%

(47) (48)S

S

S

S

CHO

(98)POCl3, PhNMeCHO

54%

S

S

S

S Li

S

S

S

S CHO

(99)

(49) (50)

DMF, –70 °C to –20 °C, Et2O

44%

2[91[0[5 Selenium Substituted a\b!Unsaturated Aldehydes

a!Selenium substituted enals can be made by the reaction of enals with morpholino!benzoselenamide "Equation "099## ð73TL0876Ł[ Alternatively\ vinyl selenides can be transmetallatedand formylated as shown in Equation "090# ð71TL2300Ł[ A rearrangement reaction starting from anallylic alcohol has also been reported ð68TL2350Ł[ b!Selenium substituted enals have been made bynucleophilic displacement of chlorine from a b!chloroenal with a selenol ð62JHC156Ł[ Other routesinclude hydroselenation of propynal ð62JHC156Ł\ and oxidation of selenium substituted allylicalcohols ð70TL1072Ł[

OO

SePh

PhSe N O

(100)65%

n-C10H21SeMe

SeMen-C10H21

SeMe

O

i, BuLi

ii,O

NHMe(101)

2[91[0[6 Nitrogen!Substituted a\b!Unsaturated Aldehydes

2[91[0[6[0 a!Nitrogen substituted a\b!unsaturated aldehydes

Substitution by nitrogen at the a!position of a\b!unsaturated aldehydes is not widely reported\although they have been prepared by a VilsmeierÐHaackÐArnold reaction[ For example\ the ene!diamine "40# reacts with "COCl#1 and POCl2 ð62CCC0057Ł to give the a\b!diaminoacrolein "41#\ whichcan be selectively hydrolysed further to the a!amino!b!hydroxy acrolein "42# "Scheme 01#[ Similarly\the dipiperidino compound "43# yields the asymmetrically substituted diaminoacrolein "44# in DMF"Equation "091## ð62AG"E#212Ł[ a!Amino substituted ketones can also undergo a VilsmeierÐHaackÐ

64a\b!Alkenic Bond

Arnold reaction\ and give the corresponding a!amino substituted a\b!unsaturated aldehydes "45#"Equation "092## ð60BSF2874\ 77CCC0408Ł[

Me2NNMe2

Me2N

NMe2

O

HO

NMe2

O

Scheme 12

(51) (52) (53)

NaOH i, (COCl)2 or POCl3, DMF, CHCl3ii, K2CO3, 60–70 °C

65%

NN

Me2N

N

CHO

(102)

(54) (55)

i, (COCl)2, DMF, CHCl3ii, K2CO3, 60–70 °C

20%

MeO

MeO

N

O

SO2Me

MeO

MeO

N

Cl

SO2Me

CHO

(103)

i, POCl3, DMFii, H2O

25%

(56)

Propynol undergoes oxidative aminomercuration with secondary amines to give bis"1\2!N!alkyl!amino#!propenals "46# "Equation "093## ð75CC0079Ł[

OH +

NHMe

NMe

O

NPh

Me

Ph

(104)

i, Hg(OAc)2, Et3Nii, NaBH4

54%

(57)

2[91[0[6[1 b!Nitrogen substituted a\b!unsaturated aldehydes

The reaction of 0\2!dicarbonyl compounds\ in particular malonaldehyde derivatives\ with nitrogennucleophiles a}ords b!amino!a\b!unsaturated aldehydes[ Thus acetamide "or amines# react with thesymmetric malonaldehyde derivative "47# to give the enaminoacrolein "48# "Equation "094##ð78CB72Ł[ Anilines "59# also react "Equation "095## ð73LA538Ł[ Alkoxy acroleins are also known toundergo aminolysis to b!aminoacroleins "Equation "096## ð76S0\ 89JCS"P0#0348Ł[

O OH

CO2MeNH2

O O N

CO2Me

H

O

(105)+toluene, Na2SO4

60%

(59)(E):(Z) 95:5

(58)


(106)

O O

+

NH2

NO2

(60)

20 °C

40%

O NH

NO2

(107)OCHO

MeO2CHN

CHO

NaOMe, MeOH

MeO2C NH3+

b!Nitrogen substituted acroleins can also be prepared by a VilsmeierÐHaackÐArnold reactionwith amides[ Thus the azapine "50# reacts with DMF:POCl2 in moderate yield to give the formylatedproduct "51# "Equation "097## ð78JCS"P0#1984Ł[ Diformylation of "50# is also possible in 54) yield[Similarly the benzazepine!1!one "52# gives the b!amino substituted a\b!unsaturated aldehyde "53#"Equation "098## ð61CPB0214Ł[ In an analogous manner\ vinyl ethers can undergo an aminomethyl!eneation reaction\ followed by partial hydrolysis to the b!amino acroleins[ For example\ the methylvinyl ether "54# reacts cleanly to give the amino acrolein "55# in good yield "Equation "009## ð62TL2868\73LA538Ł[

(108)NCl O

Ph

NCl Cl

Ph

CHO

(61) (62)

i, POCl3, DMF, CH2Cl2ii, NaOAc

35%

(109)

(63) (64)

N

HO

N

HCl

CHOPOCl3, DMF

23%

(110)

(65) (66)

OMeNMe2

O i, POCl3, DMFii, K2CO3

71%

A related method involves reacting the lithium salts of alkanoic acids with an aminomethyl!eneating reagent\ preferably N\N!dimethylmethoxymethaneiminium methyl sulfate "56#\ to give theamino compounds "57# via a decarboxylative double formylation "Equation "000## ð73JOC0177Ł[ "Z#!b!Aminoacroleins have been prepared from b!lithioenamines\ which are themselves prepared bymetal halogen exchange[ Thus in Scheme 02\ the enamine "58# is _rst halogenated and then thehalogen is exchanged for lithium to give the stereochemically pure "Z#!b!lithioenamine[ This canthen be reacted with DMF to a}ord the enaminoaldehyde "69# ð72JCR"S#111Ł[

(111)

(67) (68)

PhCO2H

N

MeO

MeMe+ Ph

NMe2

O

+LDA (2 equiv.)

35%

Oxidative addition of amines to propargylic alcohols in the presence of activated MnO1 has beenreported\ and gives moderate to good yields of b!amino!acroleins "Equation "001## ð60ZOR1019Ł[Alternatively\ alcohols can be added to 2!amino!propynals[ Thus 2!N\N!dimethylaminopropynal

66a\b!Alkenic Bond

(69) (70)

N

But

O

N

But

O

Br

N

But

O

CHO i, Br2

ii, Et3N

i, BunLi

ii, DMF

Scheme 13

"60# reacts smoothly with methanol "or ethanol# to give the enaminal "61# "Equation "002##ð57AG"E#359\ 58HCA1530Ł[

HN

+ OHN

O

(112)MnO2

86%

(71) (72)

O

Me2N

OMeO

Me2N

(113)MeOH

92%

Photolysis of isoxazilines such as "62# "Equation "003## has been shown to lead to the formationof b!nitrogen substituted a\b!unsaturated aldehydes "63# ð62TL1172\ 64T0262\ 66H"5#0448\ 73JCS"P0#1092\75CCC1056Ł[

(73) (74)

ON

PhPh

ONH2

PhPh

(114)hν, MeCN

86%

Sodium azide reacts with the chlorinated cycloalkenal "64# to give the azidocycloalkenal "65#without cyclisation to the isoxazole as expected "Equation "004## ð77SC0364Ł[

(75) (76)

CHO

Cl

CHO

N3

(115)NaN3, DMSO

80%

2[91[0[7 a\b!Alkenic Aldehydes with P\ As\ Sb\ or Bi!based Substituents

As of mid!0884\ no compounds of this type have been reported[

2[91[0[8 a\b!Alkenic Aldehydes with Si!based Substituents

2!Silyl!1!alkenals can be obtained by the formal silylformylation of alkynes in the presence ofRh3"CO#01 as the catalyst[ Thus reaction of an alkyne with dimethylphenylsilane and trimethylamineunder carbon monoxide gas gives an excellent yield of the aldehyde\ the stereochemistry of whichwas dependant on the substitution of the starting alkyne "Equation "005## ð78JA1221\ 89JA5019Ł[ Asimilar concept involves the selective hydroformylation of a silylalkyne[ This occurs in two steps]"i# initial nickel"9# catalysed hydrocyanation of the silylalkyne\ followed by^ "ii# dibal!H reductionð76S0922Ł[ A novel synthetic method yielding b!trimethylsilyl!a\b!unsaturated aldehydes wasreported in 0874 utilising the allylic sul_de "66# as a homoenolate dianion equivalent\ which


is unmasked by treatment with aqueous sodium periodate in dioxane ð74TL1566Ł[ Pyridiniumchlorochromate can be used to oxidise the allylic alcohol "67# to give the silyl aldehyde "68# "Equation"006## ð68T510Ł[

R1 R2

OHC

R1 R2

SiMe2Ph OHC

R2 R1

SiMe2Ph

(116)+CO, Rh4(CO)12

PhH, Et3N, 100 °C

PhS OMe

TMS

(77)

HO TMSOHC

TMS (117)

(78) (79)

pcc

CH2Cl267%

2[91[0[09 a\b!Alkenic Aldehydes with Metal Substituents

Alkynyl aldehydes can be hydrostannylated using hexamethyldistannane in the presence of apalladium"9# catalyst to give the corresponding "Z#!2!"trimethyl!stannyl#!prop!1!enal "79#\ stereo!selectively and in high yield[ The reaction is successful in the presence of a number of di}erentfunctional groups ð78JCS"P0#1013Ł "Equation "007##[ HMn"CO#4 also adds to alkynl aldehydes in atrans fashion to give the adduct "70# in low yield "Equation "008## ð66IC2013Ł[

R1 CHO

R1

CHOMe3Sn

(118)

(80)

(Me3Sn)2, Pd(Ph3P)4, THF

(81)

CHO + HMn(CO)5CHO(CO)5Mn

(119)

2[91[1 ALDEHYDES BEARING AN a\b!TRIPLE BOND

Oxidations of propargylic alcohols to propargylic aldehydes can be performed in much the sameway as for allylic alcohols "see section 2[91[0[0[1#^ however propargylic aldehydes are very reactiveand decompose easily[ As expected manganese dioxide can be used "Equation "019## ð62CB1644Ł\and chromium trioxide:pyridine has been reported as useful by several authors ð46JCS1656\ 51OS"30#702\62TL3388Ł[ Atkinson et al[ have investigated the use of NiO1 ð58JCS1062Ł and Ni1O2 ð56CC607Ł"Equation "010##[ Propynal has been made by the oxidative deamination of a propargylamine usingbisdiphenylphosphorinylperoxide "Equation "011## ð77S896Ł[

S S

OH

S S

O(120)

MnO2, 20 °C

65%

Ni2O3, 20 °C

70%Ph

OH

Ph

O(121)

ON

H

i,

ii, H+

59%

O

Ph2P O

(122)

2

68a\b!Triple Bond

Alkynals can be prepared simply by the formylation of acetylide anions\ and this has beenreported using a formate ester or DMF ð47JCS0943\ 67S296Ł[ Terminal alkynes can also be formylatedunder acidic conditions using an ortho!ester in the presence of a Lewis acid catalyst at hightemperature "Equation "012## ð52OSC"3#790Ł[ Eliminations of HBr from 1\2!dibromoaldehydes leadto alkynals in moderate yield ð34OS"14#81Ł\ as does the reaction of formyl phosphorane with acidchlorides followed by elimination of triphenylphosphine oxide ð74S048Ł[

Ph + HC(OEt)3 Ph CHO (123)

i, ZnI2, 214 °Cii, 7% H2SO4, 100 °C

64%


OFA038

3.03Aldehydes: Aryl and HeteroarylAldehydesGREGORY J. HOLLINGWORTHUniversity of Nottingham, UK

2[92[0 GENERAL METHODS FOR THE SYNTHESIS OF ARYL ALDEHYDES 71

2[92[0[0 Reduction of Aromatic Carboxylic Acids and Their Derivatives 712[92[0[0[0 Reduction of benzoic acids 712[92[0[0[1 Reduction of benzoyl halides 722[92[0[0[2 Reduction of aromatic esters 732[92[0[0[3 Reduction of anhydrides 732[92[0[0[4 Reduction of thiol esters 742[92[0[0[5 Reduction of amides 742[92[0[0[6 Reduction of aromatic nitriles 75

2[92[0[1 Oxidation of Aromatic Methyl Groups and Benzyl Alcohols\ Halides and Amines 752[92[0[1[0 Oxidation of toluenes to benzaldehydes 752[92[0[1[1 Oxidation of aryl ethylenes 762[92[0[1[2 Oxidation of benzylic alcohols 762[92[0[1[3 Oxidation of benzyl halides 772[92[0[1[4 Oxidation of benzylamines 78

2[92[0[2 Synthesis of Benzaldehydes from Aryl Orànometallic Reaènts 782[92[0[2[0 Aryl palladium reaènts 782[92[0[2[1 Aryl lithium reaènts and aryl Gri`nard reaènts 89

2[92[0[3 Other Formylation Reactions of Arenes 802[92[0[3[0 The Duff reaction 802[92[0[3[1 The ReimerÐTiemann reaction 802[92[0[3[2 The VilsmeierÐHaack reaction 802[92[0[3[3 The GattermannÐKoch reaction 812[92[0[3[4 The Gattermann reaction 812[92[0[3[5 Dichloromethyl methyl ether as formylation reaènt 812[92[0[3[6 Miscellaneous formylations 82

2[92[1 BENZALDEHYDE AND SUBSTITUTED BENZALDEHYDES 82

2[92[1[0 Benzaldehyde 822[92[1[1 Alkyl Benzaldehydes 822[92[1[2 Halobenzaldehydes 832[92[1[3 Oxyèn!substituted Benzaldehydes 852[92[1[4 Sulfur!substituted Benzaldehydes 872[92[1[5 Nitroèn!substituted Benzaldehydes 87

2[92[2 POLYAROMATIC ALDEHYDES 88

2[92[3 HETEROCYCLIC ARYL ALDEHYDES 091

2[92[3[0 O!Heterocyclic Aldehydes 0912[92[3[0[0 Furan and benzofuran carboxaldehydes 091

2[92[3[1 S\ Se and Te Heterocyclic Aldehydes 0932[92[3[1[0 Thiophene and benzothiophene carboxaldehydes 0932[92[3[1[1 Se and Te heterocyclic aldehydes 095

2[92[3[2 N!Heterocyclic Aldehydes 095

70

71 Aryl and Heteroaryl Aldehydes

2[92[3[2[0 Pyrrole and indole carboxaldehydes 0952[92[3[2[1 Pyridine and quinoline carboxaldehydes 096

2[92[3[3 Miscellaneous Heterocycles] Oxazoles\ Thiazoles and Imidazoles 098

2[92[0 GENERAL METHODS FOR THE SYNTHESIS OF ARYL ALDEHYDES

The vast majority of methods for the synthesis of aromatic aldehydes fall into one of four maincategories] "i# reductions of carboxylic acids and their derivatives^ "ii# oxidations of alcohols\ halidesor activated alkyl groups^ "iii# reactions of an organometallic reagent with a formylating reagent\and "iv# {classical| formylations by electrophilic!substitution reactions of arenes[ It is in these broadsections that the synthetic methods towards aromatic aldehydes are presented[ For a review ofaromatic aldehydes\ see ð68COC"4#0094Ł[

2[92[0[0 Reduction of Aromatic Carboxylic Acids and Their Derivatives

Many methods are available for the direct partial reduction of aromatic acids and derivatives toaldehydes[ The vast majority of these methods use metal hydride reducing agents\ and this area hasbeen reviewed ð78OPP340\ 80COS"7#148Ł[ There is\ however\ a selection of other methods which havealso been reviewed ð43OR"7#107\ 80COS"7#172Ł[

2[92[0[0[0 Reduction of benzoic acids

Reductions of aromatic acids to the corresponding aldehydes are less general than for aliphaticacids[ For example\ treatment of an aromatic acid with lithium metal in ethyl! or methylamine isinapplicable due to concurrent reduction of the aromatic ring under the reaction conditionsð52JOC1807\ 69JA4663Ł[

Many metal hydride reagents\ however\ may react to give aromatic aldehydes although thereactions tend to be sluggish compared to those with aliphatic acids[ This feature reduces the scopeof the reaction since other reducible groups may react preferentially[ Therefore\ only relativelysimple benzaldehydes with substituents such as halo\ nitro\ amino and alkoxy groups have beenprepared in this manner[ A whole host of borane reagents have been developed\ mainly by Brownand Cha\ and yields on the whole are moderate to good[ Reagents which have been utilised includeboraneÐdimethyl sul_de complex\ then pyridinium chlorochromate "pcc# "the latter to oxidisethe intermediate trialkoxyboroxine# ð68S693Ł\ t!thexylborane ð61JOC1831Ł and t!hexylhaloboraneÐdimethyl sul_de complexes "Equation "0## ð73JA7990\ 75JOC4153\ 76JOC4929\ 76JOC4399\ 76MI 292!90\76TL1278\ 77MI 292!90Ł[ Reactions of aromatic acids with 8!borabicycloð2[2[0Łnonyl "8!BBN!H# giveacyloxy!8!borabicycloð2[2[0Łnonanes which have been reduced with a number of reagents suchas ButLi:8!BBN!H ð76TL5120Ł\ lithium!8!boratabicycloð2[2[0Łnonane ð76TL3464Ł\ LiAlH3:pyridineð89MI 292!90Ł and lithium tris"diethylamino# aluminum hydride ð81OPP216Ł[ Acid salts are reducedto aldehydes by 8!BBN!H alone ð77H"16#0484Ł[

CO2H

H2N

CHO

H2N

(1)t-hexBHBr•SMe2

90%

Since diisobutylaluminum hydride "dibal!H# was _rst observed to reduce acids to aldehydesð53ZOB0918Ł\ a variety of aluminum!based reagents have been used for this transformation[ Benzoicacid itself has been reduced by bis"N!methylpiperazinyl# aluminum hydride in 75) yield ð63CL0336\73JOC1168Ł[ Other suitable reducing agents include lithium tris"dialkylamino# aluminum hydridesð81MI 292!90Ł and bis"dialkylamino# aluminum dihydrides ð83MI 292!90Ł[

Treatment of simple benzoic acids with certain hypervalent silicon species leads to a silyl carboxy!late\ which on pyrolysis gives aldehydes in moderate to good yields "49Ð85)# "Equation "1##ð76TL2830Ł[ Sato|s titanium!catalysed Grignard reagent method tends to over!reduce aromatic acidsð70S760Ł[ Aromatic acids also react with oxalyl chloride:DMF to form carboxymethylene iminiumchlorides\ which can then be reduced in situ with LiAlH"OBut#2 and a CuI catalyst to aldehydes inmoderate yield "Scheme 0# ð72TL0432Ł[

72General Methods

CO2H

F

CHO

F

i,

ii, heat

94%

NMe2SiH2Ph

(2)

CO2H

O2N

CHO

O2NO2N

O

O

NMe

Me

+(COCl)2

DMF

LiAlH(OBut)3

CuI

Scheme 1

Other less widely used reducing methods include the use of sodium amalgam ð35JA1491Ł andelectrochemical reduction ð61JOC0402\ 83CPB093Ł[

An indirect method of reduction involves treatment of the carboxylic acid with a dithiaborinanereagent ð76JOC1003\ 76PAC0994\ 76TL0802Ł^ the product dithioacetals are then readily hydrolysed tothe corresponding aldehydes[

2[92[0[0[1 Reduction of benzoyl halides

For many years\ the main method of reducing acyl chlorides to aldehydes was by catalytic partialhydrogenation\ using the Rosenmund procedure ð37OR"3#251\ 75JA1597Ł[ The reaction has variousmodi_cations but requires forcing conditions with aromatic acyl chlorides ð65S656Ł[ As a conse!quence\ hydride!based methods have now almost totally replaced the Rosenmund procedure[ Themost widely used hydride reagent is lithium tri"t!butoxy#aluminum hydride ð45JA141\ 47JA4266Ł whichreduces meta! and para!substituted aromatic acyl chlorides to aldehydes in moderate yields\ andortho!substituted acyl chlorides in somewhat lower yields[ Tolerated groups include halo\ alkoxy\nitro and cyano functions[ Much improved yields\ however\ have been reported using sodiumtri"t!butoxy# aluminum hydride as reducing agent "Equation "2## ð82JOC3621Ł[ Another aluminumhydride\ sodium diethyldihydroaluminate in the presence of piperidine has also been reported toe}ect the transformation ð82SC0664Ł[ Sodium borohydride with a variety of additives ð79JCS"P0#16\70TL00\ 71SC728Ł\ and complex copper borohydrides ð67TL0326\ 67TL1362\ 79TL702Ł also reduces aro!matic acyl chlorides to aldehydes in moderate yields\ but normally these methods also give smallamounts of over!reduced products[

COCl

OMe

CHO

OMe

(3)NaAlH(OBut)3

88%

Benzoyl bromide may be cleanly reduced to benzaldehyde by tributylstannane ð55JA460Ł\ but thisreducing agent works well for chlorides only if a palladium catalyst\ normally Pd"PPh2#3\ is presentgiving high yields of simple benzaldehydes "Equation "3## ð79CC321\ 70JOC3328Ł^ tributyl!germane:Pd"PPh2#3 has also been used ð78JOM"265#30Ł[ Triethylsilane may act as a reducing agentin the presence of a palladium ð58JOC0866Ł\ platinum ð69CC0692\ 64JCS"D#1535Ł or a rhodium catalystð64JCS"D#1359Ł[ The former procedure requires the least harsh reaction conditions\ whilst the lattertends to produce signi_cant quantities of diaryl ketones in addition to the desired product[ Excellentyields have been obtained using hypervalent silicon hydrides ð77TL0160Ł[ Some iron complexesreduce aromatic acyl halides to aldehydes\ such as Collmans reagent\ Na1Fe"CO#3 ð60BCJ1458Ł andthe hydridoiron tetracarbonyl anion HFe"CO#3− ð66TL670\ 89CRV0930Ł[ Various other transitionmetal complex reducing agents have also been used for this transformation ð73OM0590\74JOM"181#114Ł[ Finally\ yields of over 79) for the reductions of aromatic acyl chlorides havebeen reported using the heterocyclic hydride donor 0\2!dimethyl!1!phenyl benzimidazoline "DMBI#"Equation "4## ð75JOC4399Ł[


COCl CHO

(4)Bu3SnH, Pd(PPh3)4

92%

COCl CHO

MeO MeO

N

N

Me

Me

Ph

(5)MeCN, AcOH

85%

2[92[0[0[2 Reduction of aromatic esters

The best!known reagent for the reduction of aromatic esters to aldehydes is dibal!H "for example\as shown in Equation "5## ð51TL508Ł[ The yields\ however\ are generally lower for aromatic estersthan for aliphatic ones\ and for this reason much fewer examples have been reported[ Sodiumaluminum hydride has also been used but again aromatic esters give lower yields ð52TL1976Ł^ asimilar outcome is found with sodium di!isobutyl aluminum dihydride ð51TL508Ł[ The knownreduction of phenyl esters by lithium tri!t!butoxy aluminum hydride fails for those derived fromaromatic carboxylic acids ð61S106Ł[

CO2Et CHO

MeO MeO

(6)dibal-H

70%

Moderate yields with simple benzoate esters have been achieved\ however\ with bis"3!methyl!0!piperazinyl# aluminum hydride "BMPA# ð64CL104Ł[ Another reagent\ Red!Al "NaAlH1

"OC1H3OCH2#1#\ reduces aromatic esters in low yield ð69MI 292!90Ł\ but when an equivalent ofN!methylpiperazine is added to the Red!Al prior to the ester\ the modi_ed reagent produces benz!aldehyde in 74) yield ð65S415Ł "isolated as its 1\3!dinitrophenylhydrazine "DNP##[ Two promisingreducing agents reported in the early 0889s\ for this transformation are sodium diethylpiperidinoaluminum hydride ð80MI 292!90Ł and lithium tris"diethylamino# aluminum hydride ð81OPP224Ł[

2[92[0[0[3 Reduction of anhydrides

Anhydrides of aromatic acids may be reduced to aldehydes by disodium tetracarbonylferrate inmoderate yields ð62TL2424\ 64BCJ1389Ł[ Benzoic anhydride gave 62) benzaldehyde using this reagentand phthalic anhydride gave 1!formyl benzoic acid via the acylcarbonylferrate intermediate "0#shown in Scheme 1[

O

O

O

O–

Fe(CO)4

O

O

–

2Na+

CHO

CO2H

Scheme 2

Na2Fe(CO)4

(1)

Mixed aryl and alkyl anhydrides show little selectivity as to which C0O bond is cleaved[ Relatedaromatic carboxylic ethyl carbonic anhydrides\ however\ react to give moderate yields of simplebenzaldehydes ð64TL0952Ł[

Triphenylacetic benzoic anhydride on treatment with lithium metal gave complete selectivity\with benzaldehyde being the only aldehyde product ð81TL2626Ł[ A similar result was observed forthe same substrate when the C0O bond was cleaved photochemically ð82JA71Ł[

74General Methods

2[92[0[0[4 Reduction of thiol esters

Aromatic carboxylic acids have been converted into aldehydes in two steps via their thiol esters[Hydrogenolysis of thiol esters in the presence of Raney nickel then produces the correspondingaldehydes in moderate yields ð48CB429\ 43OR"7#107Ł[ The 1!thiazoline!1!thiol ester of benzoic acidhas been reduced to benzaldehyde in 82) yield by dibal!H ð67CC229Ł[ Other reducing agents foraromatic thiol esters are lithium metal ð81TL2626Ł\ and triethylsilane in the presence of a catalyticamount of palladium on carbon ð89JA6949Ł[ The latter method appears to tolerate a wide range offunctional groups including esters\ amides\ acetals and sul_des\ and has been used in many naturalproduct syntheses\ although the vast majority of reported cases are for aliphatic thiolesters[

2[92[0[0[5 Reduction of amides

A wide variety of N\N!disubstituted carboxylic amides have been partially reduced to theiraldehydes[ For a list of amide types and reagents\ see ðB!78MI 292!90Ł[ Almost invariably the reducingagent is an aluminum hydride reagent[ One exception is the use of disiamyl borane which reducesN\N!dimethylbenzamide to benzaldehyde in 78) yield ð69JA6050Ł[ Of the remaining methods\ manygive only moderate yields when applied to aromatic amides^ those methods giving high yields arediscussed below[ A good general method is the reduction of aromatic N\N!dimethylamides withlithium di! or triethoxy aluminum hydrides ð53JA0978Ł[ Chloro!\ methoxy! and nitrobenzylamidesare reduced in 59Ð89) yield[ N\N!Dimethylamides are also reduced in good yield by NaAlH3

ð58T4444Ł[ Similar yields are observed for the reductions of 0!acyl imidazoles with LiAlH3

ð51AG"E#240Ł[ Benzaldehyde itself is produced in 89) yield from its 0!acyl!2[4!dimethyl pyrazole"1# derivative using LiAlH3 ð47AG054Ł[

N

O

(2)

N

Reductions of 2!acyl thiazolidine!1!thiones "2# with either dibal!H or lithium tri"t!butoxy# alumi!num hydride give greater than 79) yield for benzaldehyde and p!chloro! and p!nitrobenzaldehydesð68BCJ444Ł\ and dibal!H also reduces the Weinreb amide N!methyl!N!methoxybenzamide "3# tobenzaldehyde in 60) yield ð70TL2704Ł[ Newer hydride reagents which reduce primary carboxamidesin good yield include lithium n!butyl diisobutyl aluminum hydride ð73JOC0606Ł and lithium tris!"diethylamino# aluminum hydride ð80TL5892Ł[ The reduction of tertiary amides has also beenaccomplished using ethyl tri~ate and L!selectride ð89JCS"P0#646Ł[

N

O

S

S

N

O

OMe

Me

(4)(3)

For aromatic aldehyde syntheses some of the older methods are still amongst the best[ Theseearlier methods have been reviewed ð43OR"7#107Ł[ 0!Aroyl!1!cyano!0\1!dihydroquinolines "or Reis!sert compounds "4## are readily formed from acyl chlorides\ and may be hydrolysed under acidicconditions to give good yields of benzaldehydes[ The McFadyen and Stevens procedure is a goodmethod for the preparation of benzaldehydes containing hydroxy\ alkoxy\ alkyl and halo substitu!ents\ by basic decomposition of 0!acyl!1!arylsulfonylhydrazines "5#[ Alkoxy and alkyl benzaldehydeshave been prepared by the method of Sonn and Mu�ller in moderate to good yields fromN!phenylaromatic amides in a three!step sequence via an imido chloride and Schi}s base[


N

O Ar

CN Ar NH

HN

SO2Ar

O

(6)(5)

2[92[0[0[6 Reduction of aromatic nitriles

One of the older methods for converting aromatic nitriles into aldehydes is that devised byStephen ð14JCS0763Ł[ Treatment of the nitrile with HCl and SnCl1 gives the corresponding crystallinealdimine stannichloride salt "6#\ which can then be readily hydrolysed to the aldehyde[ Variousalkyl\ alkoxy and halo substituents are tolerated ð28JA1137\ 43OR"7#107\ 44OSC"2#515\ 45JCS0575Ł\ andyields are generally good^ notable exceptions include 1!methylbenzaldehyde and 0!naphthaldehyde[

NH•HCl•SnCl4Ar

(7)

Inevitably newer methods have been developed using metal hydride reagents[ Dibal!H\ LiAlH3

and NaAlH3 reduce benzonitrile to benzaldehyde in 26)\ 81) and 89) yields respectivelyð48JOC516\ 53JA0968\ 82JOC3616Ł\ but a more general method uses Li"EtO#2AlH ð48TL8\ 53JA0974Ł[Again alkyl\ alkoxy and halo substituents are tolerated[ More modern hydride reagents that havebeen used for this transformation in high yield include t!hexylbromoboraneÐdimethyl sul_de com!plex ð76MI 292!91Ł\ sodium diethylpiperidino hydroaluminate "SDPA# "Equation "6## ð82JOC0830Łand lithium tris"dihexylamino# aluminum hydride ð81MI 292!91\ 81OPP220Ł[ This latter reagent isreported to leave aliphatic nitriles untouched[

SDPA

99%N

O

Me

Me

(7)

CHO

A relatively mild two!step procedure which converts aromatic nitriles into benzaldehydes involvesalkylation of the nitrogen of the CN bond to _rst form the activated N!alkylnitrilium ion "7#\ whichis then reduced in good yield by triethylsilane to the N!alkylaldimine^ hydrolysis _nally gives thealdehyde[ Alkylation of the nitrile can be accomplished with either triethyloxonium tetra!~uoroborate\ or with isopropyl chloride in the presence of FeCl2 ð63CC34\ 70JOC591Ł[ Alkyl\ alkoxy\halo and notably nitro and carbethoxy substituents are tolerated[

Ar N R

(8)

+

Aromatic aldehydes have also been produced by reactions of nitriles with Raney nickel inre~uxing aqueous HCO1H ð54JCS4664Ł and\ in 0878\ in excellent yields\ by wet Raney nickel usingtriethylammonium hypophosphite hydrate as a hydrogen source[ Under these controlled conditionshydrogenation of the nitrile is facile\ but hydrolysis of the product imine predominates overhydrogenation\ thus leading to the aldehydes with little or no over!reduction ð78JOC838Ł[

2[92[0[1 Oxidation of Aromatic Methyl Groups and Benzyl Alcohols\ Halides and Amines

2[92[0[1[0 Oxidation of toluenes to benzaldehydes

A whole host of reagents have been utilised for the oxidation of toluenes to benzaldehydes[Originally Etard used chromyl chloride "CrO1Cl1# ð47CRV0Ł as oxidant\ but in the 0889s otherreagents are preferred[ Of these\ one of the most popular is the use of cerium"IV# ion as oxidant inan acidic medium\ for example\ cerium ammonium nitrate "can# which will oxidise toluene tobenzaldehyde in 81) yield[ Substituents which are tolerated include halo\ nitro\ and N!acetylamino

76General Methods

groups ð55TL3382Ł[ This oxidant has been used for oxidation of the aromatic methyl group ofsteroidal compounds "Equation "7## ð57JCS"C#1804Ł[

MeO

H H

H

O

CHO

MeO

H H

H

O

(8)can, AcOH, H2O

70%

Other oxidants which give this transformation include 1\2!dichloro!4\5!dicyano!0\3!benzo!quinone "ddq# ð68S033\ 73TL1890Ł\ bromine ð42JA623Ł\ silver"II# oxide ð56TL3082Ł\ potassium per!manganate:triethylamine ð78S182Ł and dioxygen with a copper catalyst ð89TL1596Ł[

2[92[0[1[1 Oxidation of aryl ethylenes

The oxidative cleavage of styrenes or 0\1!diols derived from styrenes is very facile using a numberof reagents\ notably ozone or OsO3:NaIO3[ A particularly unusual example was used by Bremnerand co!worker in the key step to a functionalised 2!azað8Ł meta!cyclophane system "Equation "8##ð80AJC024Ł[

MeO

MeON

CN

MeO

MeON

CN

CHO

O

(9) i, O3

ii, Me2S

Perhaps a more synthetically useful procedure than oxidative cleavage of simple styrenes is theozonolysis of benzofurans to 1!hydroxy benzaldehydes ð82CPB0055Ł[ This strategy was used byGammill and co!worker\ who treated khellin with OsO3:NaIO3 and produced the hydroxy benz!aldehyde in 62) yield\ which was then used in the synthesis of various khellin analogues "Equation"09## ð73TL1842\ 75JOC2005Ł[

OsO4, NaIO4, THF, 50 °C

O O

OMe

OMe

O

O

OMe

OMe

O

(10)

OHC

HO

2[92[0[1[2 Oxidation of benzylic alcohols

The oxidations of benzylic alcohols are very facile[ Like allylic alcohols\ they are {activated| withrespect to saturated alcohols and therefore are generally oxidised more readily[ There are very manyreagents for carrying out the oxidations of alcohols to aldehydes and\ due to the reactivity ofbenzylic alcohols\ most are applicable "for a list of reagents and references see ðB!78MI 292!90Ł#\however\ caution must be exercised in some cases to avoid over!oxidation[ The most popularmethods of alcohol oxidation and their applicability to benzyl alcohols are discussed in this section[In addition\ some mild oxidants\ capable of chemoselectively oxidising benzyl alcohols in thepresence of other alcohol functions are presented[

Probably the most popular and mild method for the oxidation of benzylic alcohols is the use ofactivated manganese dioxide ð65S54Ł[ This reagent oxidises benzylic alcohols much faster thanaliphatic ones and has been used extensively\ for example\ Equation "00# ð50JOC1862\ 57JOC2985\63JA824Ł[


O

O

OH

OMe

O

O CHO

OMe

(11)MnO2, 6 h, RT, CHCl3

Other manganese oxidants such as potassium permanganate:triethylamine ð78S182Ł andcetyltrimethyl ammonium permanganate ð73CL1020Ł also work for this transformation\ and yieldsare generally good[ Various chromium reagents ð77OPP422Ł including pyridinium dichromate"pdc#:TMS!Cl ð75CJC114Ł\ pyridinium chlorochromate "pcc# ð71S1348\ 76JOC2894Ł and pyridinium~uorochromate ð71S477Ł have been applied to the general oxidation of benzyl alcohols[ Otherchromium reagents\ however\ have been shown to be useful for selective oxidations[ 3!"Dimethyl!amino# pyridinium chlorochromate has been used for the oxidation of various simple primarybenzyl alcohols in good yield\ but also shows remarkable selectivity for benzyl alcohols over aliphaticalcohols "Equation "01## ð71JOC0676Ł^ the product shown in the equation contained ³1) of thedialdehyde[

OH

HO

CHO

HO

Me2N NH ClCrO3–

(12)

+

62%

Bis"tetrabutylammonium# dichromate ð79SC64Ł\ bis"benzyltriethylammonium# dichromateð71S0980Ł\ and tetrabutylammonium chlorochromate ð72S638Ł also show quite good selectivity forbenzyl alcohols\ and give good yields of benzaldehydes[

Of the general methods for the oxidation of alcohols using activated DMSO\ most would appearapplicable to benzyl alcohols\ although relatively few examples have been reported presumably dueto the e.ciency of other methods[ However\ benzyl alcohol itself has been oxidised to benzaldehydeby DMSO:tri~uoroacetic anhydride and by DMSO:oxalyl chloride in 79) and 87) yields respec!tively ð70S054Ł^ see also ð56CRV136\ 78TL1926Ł for the oxidation of a naphthyl derivative[

Other oxidants which have been successfully applied for the selective oxidation of benzylicalcohols include potassium ferrate ð67CL0286\ 73S755Ł and\ in good yields\ silver ferrate ð75SC100Ł\air and a catalytic amount of can ð72TL1288Ł\ silver"II# oxide ð56TL3082Ł\ benzeneseleninic anhydrideð67CC841Ł and oxygen using a catalytic mixture of CuCl and 1\1\5\5!tetramethyl piperidinyl!0!oxy"TEMPO# ð73JA2263Ł[

Two new methods giving excellent yields from simple benzyl alcohols\ use as oxidant chro!mium"VI# trioxide in the presence of wet alumina ð89BCJ1322Ł and t!butylhydroperoxide with eithera titanium or zirconium catalyst ð89CB0246Ł[

2[92[0[1[3 Oxidation of benzyl halides

Benzaldehydes may be produced in moderate to good yields "49Ð79)# from benzyl halides usingthe Sommelet reaction\ by treatment with hexamethylenetetramine "HMT#^ this reaction has beenreviewed ð43OR"7#086Ł[ The reaction proceeds via a hexaminium salt to the benzylamine\ which thenreacts with more HMT at mildly acidic pH to give the aldehyde[ Tolerated groups include halo\nitro\ alkyl\ alkoxy and ester[ 1!Substituted benzyl halides give lower yields due to steric hindrance\and 1\5!disubstituted benzyl halides fail completely[ Accumulation of electron!withdrawing groupshinders the reaction\ and the procedure is not general for phenols\ although some examples areknown[ For the preparation of aromatic dialdehydes see ð49JA1881Ł[ The related Kro�hnke procedurewhich involves formation of a pyridinium salt\ treatment with 3!nitrosodimethylaminobenzene andhydrolysis has been used but it is less general than the Sommelet reaction ð28CB339Ł[

Benzyl halides react with the sodium salt of 1!nitropropane in ethanol giving moderate to goodyields "57Ð66)# of simple 3!substituted benzaldehydes containing substituents such as alkyl\ halo\keto\ cyano\ ester and tri~uoromethyl groups "Equation "02## ð38JA0656\ 52OSC"3#821Ł[ The use ofDMSO as co!solvent has extended the scope of this reaction ð55JOC1507\ 57JOC2166Ł[ One of the mostpopular methods for the oxidation of benzyl halides to benzaldehydes is that reported by Kornblumusing DMSO as oxidant "sometimes after _rst converting them to their tosylates using silver tosylate#ð48JA3002\ 56CRV136Ł[ It has been found that addition of a silver salt to the DMSO solution of the

78General Methods

halide facilitates direct conversion into the aldehyde in good yield^ for examples see "Equation "03##ð73S493\ 82TL2408Ł[ Other oxidants used in Kornblum!type oxidations include bis"3!methoxyphenyl#selenoxide ð73CL780Ł and either dimethyl selenoxide or potassium benzene selenite in the presenceof potassium hydrogen phosphate ð73S636Ł[ Excellent yields are reported for a wide range ofpolysubstituted benzyl halides[

Br

Br

CHO

Br

(13)[Me2CNO2]– Na+

75%

Br

OMe

CHO

OMe

(14)DMSO, AgNO3, NaHCO3

Other reagents which have been used for the oxidation of benzyl halides to benzaldehydes includevarious amine oxides\ particularly pyridine N!oxide ð46JOC0024Ł\ dimethylaminopyridine N!oxideð70BCJ1110Ł and N!methylmorpholine N!oxide ð81SC0856Ł[ McKillop et al[ have reported the reac!tion between various benzyl bromides and mercury"I# nitrate which leads to nitrate esters\ whichthen decompose to benzaldehydes on treatment with aqueous ethanolic alkali\ for example\ Equation"04# ð63SC34Ł[ Finally\ a whole host of chromium!based oxidants e}ect the transformation ð65CC089\65TL2874\ 78BSB110\ 81SC0380\ 82BSB188Ł^ see also ð67S508Ł[

Cl

Cl

Br

Cl

Cl

CHO(15)

i, Hg2(ONO2)2, DMEii, NaOH (aq.), EtOH

71%

2[92[0[1[4 Oxidation of benzylamines

Many of the oxidants mentioned for the oxidation of benzyl halides to benzaldehydes also oxidisebenzyl amines^ for example the Sommelet reaction "which actually proceeds via the amine#[ Becausethe halides are more readily available\ the oxidations of amines will not be discussed in detailhere[ Occasional publications however concentrate on the latter\ for example by DMSO oxidationð89BSB234Ł or oxidation via sul_namide intermediates ð70JOC3506Ł[

2[92[0[2 Synthesis of Benzaldehydes from Aryl Organometallic Reagents

2[92[0[2[0 Aryl palladium reagents

An excellent synthesis of benzaldehydes reported by Stille may be accomplished from aryl iodidesby reaction with carbon monoxide and tributylstannane in the presence of a palladium catalystð72JA6064\ 75AG"E#497\ 75JA341Ł[ The reaction proceeds by CO insertion into the aryl palladium bondof the initial complex\ followed by hydrideÐhalo exchange with the tin hydride\ and _nally reductiveelimination of the aldehyde product[ Iodides react much more e.ciently than other halides\ soselective reactions of dihaloarenes can be achieved[ Many functional groups are tolerated\ forexample ester\ CF2\ Br\ Cl\ CH1OH\ MeO[ If electron!donating groups are present\ the reactionusually occurs at 0 atm CO pressure^ for electron!withdrawing groups slightly higher CO pressuresare required to minimise the competitive reduction reaction[ Even so\ low yields are found for nitroderivatives[ Otherwise yields are often ×74)\ for example\ Equation "05#\ but slightly lower for1!substituted halides\ presumably due to steric hindrance[

I

MeO2C

CHO

MeO2C

(16)CO, Bu3SnH, THF, Pd(PPh3)4 (cat.)

91%


Aryl halides have been converted into their aldehydes in similar palladium!catalysed reactionsusing dihydrogen to reduce the intermediate acyl palladium complex[ However\ the shortfall of thismethod is the high pressure required for reaction "7[2MPa "0199 psi## ð63JA6650Ł[ Use of poly"methylhydrosiloxane# as hydrogen donor allows the reaction to be carried out under the reducedpressure of 49 psi ð73JOC3998Ł\ but the practical ease of the Stille procedure makes it more generallyuseful[ Various other palladium!catalysed formylations are known ð65BCJ0570\ 73JOM"169#172\78CC0705Ł\ with some starting from aryl diazonium salts[

Carbonylations of aryl halides under radical conditions have also been accomplished\ althoughonce again high pressures of CO are required ð89TL5776Ł[

2[92[0[2[1 Aryl lithium reagents and aryl Grignard reagents

A vast number of benzaldehydes have been made from reactions of aryl lithium reagents or arylGrignard reagents with various formylating agents\ and this remains one of the most popularmethods for their synthesis[

The organometallic reagents may be made either by halogenÐmetal exchange from aryl halidesor by ring deprotonation of activated arenes "i[e[\ those with ortho!directing groups# with strongbases[

The most common early method was the formylation of a Grignard reagent with DMF\ forexample\ ð50JOC1114\ 66JOC2297Ł^ for a later improved procedure see ð73S117Ł[ The reaction is notreported to be as e}ective using aryl lithium reagents\ although good examples exist ð69JCS"C#116Łand later good yields were achieved for the preparation of benzaldehyde from bromobenzene\lithium metal and DMF under ultrasonic irradiation "Equation "06## ð75TL0680Ł[ Other formylatingreagents which give good yields of benzaldehydes from either aryl lithium or Grignard reagentsafter hydrolysis include N!formylpiperidine ð70AG"E#767\ 75AG"E#0915Ł\ lithium "or sodium# formateð73TL0732Ł\ 1!"N!methyl!N!formyl# amino pyridine ð67S392Ł\ the related imidazolidinium salt "8#ð68CC006Ł and oxazolinium salt "09# ð69JA5565\ 63OS"43#31Ł[ A more direct method to aldehydes isthe reaction of Fe"CO#4 with organolithium reagents ð53BCJ230Ł or Grignard reagents ð71BCJ0552Ł[The latter gives higher yields of benzaldehyde but few examples of this reaction have been reportedup to 0884[

Br CHO

(17)Li, DMF, ultrasound, THF

81%

NNMe Ac

I–

+

N

O

Me

(9) (10)

I–+

Various arenes may be deprotonated adjacent to certain existing functionality capable of sta!bilising the anion formed\ that is\ directed metallation groups "DMGs#[ The resulting aryl lithiumreagents can then be formylated using one of the agents described above\ normally DMF[ Theproducts are thus 1!substituted benzaldehydes[ There are a vast number of DMGs "for excellentreviews see ð68OR"15#0\ 77BSF56Ł# and an {order of metallation| has been established for these groups[Most appear applicable to the synthesis of benzaldehydes especially the alkoxy function\ for example\Equation "07# ð68S895Ł[ For a later example see ð82T0310Ł[

OMe

O OMe

OMe

O OMe

CHO(18)

i, BunLi

ii, DMF

Other important DMGs that have been applied to the synthesis of benzaldehydes include t!butylsulfonyl ð78JOC13Ł\ tertiary amido ð71ACR295Ł\ and ~uoro groups ð81TL6388Ł[

80General Methods

2[92[0[3 Other Formylation Reactions of Arenes

2[92[0[3[0 The Duff reaction

Treatment of activated arenes such as phenols with hexamethylenetetramine "HMT# in an acidicmedium gives\ after hydrolysis of the imine intermediate\ substituted benzaldehydes[ The originalDu} reaction was carried out in acetic acid\ then later in glycerol:glyceroboric acid mediumð30JCS436Ł\ and formylates ortho to the activating group\ "or para if this position is blocked# althoughyields do tend to be low[ A much improved procedure was later employed using TFA ð61JOC2861Ł\giving much higher yields\ for example\ Equation "08#[ The new conditions allow even simple alkylbenzenes to be formylated\ and tend to give para!substitution^ they also tolerate more functionality\including halogen\ ester and amine substituents[ For other examples see ð76IJC"B#803\ 77CPB863\81CL890\ 81S0110Ł[

HO HO

CHO

(19)HMT, TFA, reflux, 12 h

95%

2[92[0[3[1 The ReimerÐTiemann reaction

Treatment of phenols with chloroform and hydroxide ion leading to ortho!hydroxy benzaldehydesis called the ReimerÐTiemann reaction ð71OR"17#0Ł[ Unfortunately yields are generally less than 49)although the use of ultrasound ð89SC598Ł has improved these yields somewhat[ Ortho!formylationgenerally predominates and is enhanced by phase transfer catalysts ð68TL2642Ł[ Various modi!_cations can make the reaction para!selective ð49JCS656\ 75S458Ł\ although the formation of mixturesis common[ Halo\ alkoxy and carboxylic acid substituents are amongst those tolerated^ an exampleis given in Equation "19# ð66IJC"B#0945Ł[

ON

HOO

N

HO

CHO

(20)NaOH, CHCl3

40%

2[92[0[3[2 The VilsmeierÐHaack reaction

Active aromatic substrates containing electron!donating substituents\ for example amino\hydroxy\ alkylthio and alkoxy groups\ react with electrophilic chloromethylene iminium salts\ whichare then readily hydrolysed to the corresponding aldehydes\ thus achieving overall formylations[This is the most common method for the formylation of aromatic rings\ and is known as theVilsmeierÐHaack reaction^ for reviews see ðB!53MI 292!90\ 62MI 292!90Ł[

The chloromethylene iminium intermediates are formed by reaction of a dialkylformamide\normally DMF with an acid chloride\ normally phosphorus oxychloride "POCl2#\ for exampleEquation "10# ð63JCS"P0#0242Ł^ see also ð44BSF0483\ 52OSC"3#220Ł[ N!methylformanilide "MFA# hasalso been used in place of DMF\ for example\ Equation "11# ð78M654Ł[ Yields are often high andformylation occurs at a position ortho or para to an activating substituent[

MeO OMe MeO OMe

CHO

(21)POCl3, DMF

83%

O

O

OMe

O

O

OMe

CHO(22)

MFA, POCl3

63%


Other acid chlorides have also been used\ including thionyl chloride\ oxalyl chloride\ phosgene\phosphorus pentoxide\ phosphorus tribromide\ phosphorus pentachloride and pyrophosphorylchloride[ In the last example a more reactive electrophilic species serves as formylating agent\ andhigher yields and regioselectivity than normal have been observed "Equation "12## ð81SL66\ 82T3904Ł[

OMe

OMe

OMe

OMe

OHC(23)

P2O3Cl4, DMF

100%

Another modi_cation\ which leads to improved yields for less active substrates\ makes use of thereactive iminium salt produced from tri~uoromethane sulfonic anhydride and DMF ð89CC0460Ł[

An indirect method for the preparation of benzaldehydes under Vilsmeier conditions hasbeen developed using aryl trialkylstannanes[ Thus treatment of trimethylphenylstannane withPOCl2:DMF at room temperature gives 45) benzaldehyde via electrophilic ipso!substitution withloss of a stannyl cation ð78T840Ł[

2[92[0[3[3 The GattermannÐKoch reaction

The GattermannÐKoch reaction converts benzene and simple alkyl and halobenzenes into alde!hydes in moderate to good yield ð38OR"4#189Ł[ Formylation takes place using hydrochloric acid anda FriedelÐCrafts catalyst\ normally AlCl2 or AlBr2 under high pressures of CO\ or atmospheric COpressure if CuCl is used as a promoter[ The reaction fails for hydroxy\ alkoxy and amino benzenesand polyaromatics^ see also ð79JOM"083#110Ł[ Good para!selectivity is observed for monoalkyl ben!zene formylations[

2[92[0[3[4 The Gattermann reaction

The Gattermann reaction is a commonly used method for the formylation of phenols and phenolethers by treatment with HCN and HCl in the presence of aluminum chloride\ or more commonly\in a modi_ed procedure using HCl and zinc cyanide ð46OR"8#26Ł[ Formylation generally occurs parato an activating substituent[ For examples\ see Equation "13# ð68JHC688Ł and also ð37JCS1072\75OPP098Ł[

OHO

OMe

OHO

OMe

OHC

(24)Zn(CN)2, HCl, Et2O

87%

2[92[0[3[5 Dichloromethyl methyl ether as formylation reagent

Perhaps the most general formylation procedure for arenes\ and certainly the most popular inrecent times\ is formylation using dichloromethyl methyl ether in the presence of SnCl3\ or moreusually TiCl3 in CH1Cl1 ð52CB297\ 67OPP190Ł[ The procedure is practically very simple\ gives highyields and is normally complete within an hour at room temperature or below[ Formylations occurortho or para to an activating substituent\ but nonactivated arenes also react[ Yields are normallygood\ and a wide variety of substituents are tolerated including halo\ alkoxy\ amido and carboxylicacid groups[ Many examples have been reported\ for example\ Equation "14# ð80JOC0581Ł^ for moreexamples see ð67AJC0422\ 70JCS"PI#0326\ 76TL1362\ 89SC1454Ł[

NBr

MeO

OOMe

NBr

MeO

OOMe

OHC

Cl OMe

(25)Cl

82%

, CH2Cl2, SnCl4

82Benzaldehyde and Substituted Benzaldehydes

2[92[0[3[6 Miscellaneous formylations

Various miscellaneous formylations of arenes are known[ Of these\ among the more importantare the formylations of simple nonactivated arenes with formyl ~uoride ð59JA1279\ 76CRV560Ł in aFriedelÐCrafts type reaction[ Similar\ simple arenes have also been formylated with CO\ catalysedby super acids\ where yields are moderate ð76CRV560\ 80CC0440\ 81JOC1566Ł[ For a detailed discussionof formylation reactions in general\ see ðB!53MI 292!90Ł[

The formation of benzaldehydes directly by pericyclic reactions is rare and is not discussed in thischapter[

2[92[1 BENZALDEHYDE AND SUBSTITUTED BENZALDEHYDES

2[92[1[0 Benzaldehyde

Although\ virtually all of the reductive\ oxidative and organometallic routes mentioned in Section2[92[0 give good yields of benzaldehyde\ not all of the formylation methods are generally applicablesince most require activating electron!donating substituents on the substrate[ The RiemerÐTiemannreaction is not applicable and the VilsmeierÐHaack reaction also fails for benzene[ The Gattermannreaction\ Du} reaction and reaction of benzene with dichloromethyl methyl ether:AlCl2 all givepoor yields of benzaldehyde[ Formylation of benzene using formyl ~uoride with boron tri~uoride ascatalyst proceeds in modest yield "45)# ð76CRV560Ł[ Best results are obtained using the GattermannÐKoch procedure with AlBr2 as catalyst "89) yield of benzaldehyde# ðB!53MI 292!90Ł[

An industrially viable route to benzaldehyde involves the oxidation of toluene using chlorinefollowed by hydrolysis of the benzal chloride intermediate\ although some ring chlorination productsare also observed[ An alternative\ cleaner method is oxidation of toluene using manganese dioxidein the presence of acetic anhydride[ In this case the intermediate is benzal diacetate which is alsoreadily hydrolysed to benzaldehyde ðB!78MI 292!91Ł[

2[92[1[1 Alkyl Benzaldehydes

Because alkyl substituents are inert to most conditions\ the majority of general methods are alsoapplicable to the synthesis of alkyl benzaldehydes[ For reductive procedures\ the carbon that willbecome the formyl carbon is already in place so only one positional isomer is possible\ and electronice}ects of alkyl substituents have little e}ect[ Such reactions therefore appear applicable to mono!\di!\ or polyalkyl benzoic acids and their derivatives\ assuming the starting materials are available\although relatively few examples containing more than one alkyl group have been reported[3!Methylbenzoic acid derivatives have often been used as model compounds[ Some of the best yieldsof aldehyde are from reduction of 3!methylbenzoyl chloride with sodium tri"t!butoxy# aluminumhydride "76)#\ ð82JOC3621Ł\ or cadmium moderated borohydride "78)# ð79JCS"P0#16Ł\ or byreduction of 3!methylbenzonitrile with potassium 8!sec!amyl!8!boratabicycloð2[2[0Łnonane "72)#ð78TL2566Ł[ Steric hindrance may be an important consideration when making 1!alkylbenzaldehydesby reductions of their acid derivatives[ Of the few examples where comparisons have been madebetween 1!\ 2! and 3!alkyl substituted compounds\ 1!substituted benzaldehydes tend to be producedin lower yield[ Simple 1!methyl benzaldehydes can nevertheless be produced in good yield\ forexample\ Equation "15# ð53JOC0974Ł[

CN CHO

(26)Li(OEt)3AlH, Et2O

87%

Oxidations of polyalkyl benzenes to alkyl benzaldehydes might be expected to be problematicsince more than one benzylic C0H bond exists[ However\ various selective oxidations have shownthis to be a synthetically viable method[ For instance\ can will oxidise 0\1!\ 0\2!\ and 0\3!dimethylbenzenes selectively at just one carbon to produce 1!\ 2!\ and 3!methylbenzaldehydes respectively\all in quantitative yield "Equation "16## ð55TL3382Ł[


R1

CHO

R1R3

R2

R3

R2

(27)can, 100 °C, 50% AcOH

R1 = Me; R2, R3 = H, 100%R2 = Me; R1, R3 = H, 100%R3 = Me; R1, R2 = H, 100%

Virtually all of the methods listed for the oxidations of benzyl alcohols\ halides and amines tobenzaldehydes appear to tolerate alkyl substituents on the benzene ring\ and they are used exten!sively[ The same applies to the organometallic methods[ The palladium!catalysed formylation ofaryl iodides is reported to give lower yields for the formation of 1!substituted benzaldehydes thanfor 2! or 3!substituted analogues\ presumably due to steric hindrance ð75JA341Ł[ This may be truefor other methods\ but few comparative studies have been reported[

Alkyl benzenes are signi_cantly more reactive towards formylation than benzene itself[ Of theformylation methods\ the GattermannÐKoch reaction of alkyl benzenes is suitable for the formationof para!substituted benzaldehydes ðB!53MI 292!90Ł[ Only modest yields result\ but the reaction doesgive almost exclusively the one isomer[ Formyl ~uoride formylations also give high paraÐorthoratios and better yields "×69)# for alkyl and polyalkyl benzenes\ for example\ Equation "17#ð76CRV560Ł[

(28)

CHO

HCOF, BF3

72%

The modi_ed Du} reaction gives moderate yields of alkyl benzaldehydes\ although mixtures ofortho! and para! products are generally observed[ However\ in some cases where steric hindranceplays a role\ good yields of a single product may be achieved\ for example\ t!butyl benzene gives a64) yield of 3!t!butyl benzaldehyde ð61JOC2861Ł[ The Gattermann synthesis works best for veryactivated aryls but also works for alkylbenzenes at elevated temperatures[ Yields are often good[An example by a modi_ed procedure using s!triazine instead of zinc cyanide is shown in Equation"18# ð58AP"291#717\ 60AP"293#251Ł^ para! or ortho!substitution is observed[

(29)

CHO

N N , HCl

N

89%

Dichloromethyl alkyl ethers may also be used for the synthesis of alkyl benzaldehydes\ althoughthe regioselectivity is not as good as for many other formylations\ so this method is most useful ifone position is blocked[

2[92[1[2 Halobenzaldehydes

The hydrogenolysis of organic halides\ including aryl halides is a well!documented reactionð79S314Ł\ and hence caution should be exercised when synthesising halobenzaldehydes by reductionsof corresponding halo benzoic acid derivatives\ especially since the presence of the electron!with!drawing acyl group makes this process more facile[ Nevertheless\ many of the reductive methodsare applicable\ notably those using borane reagents and certain aluminum hydrides[ Some examplesgiving good yields of halobenzaldehydes are the reduction of halobenzoic acids with NaAlH"ButO#2ð82JOC3621Ł and t!thexylbromoborane!DMS complex ð76JOC4929Ł\ reduction of halo!substitutedbenzoyl chlorides with complex borohydrides ð67TL1362Ł\ and the reduction of halobenzonitrileswith LiAlH"EtO#2 "Equation "29## ð53JA0974Ł[


(30)

Cl

CN

Cl

CHOLiAlH(OEt)3

84%

Palladium!catalysed reactions of tributylstannane with 3!bromobenzoyl chloride give very little"³4)# hydrogenolysis of the C0Br bond\ and 67) of the desired aldehyde ð70JOC3328Ł[ Goodresults are also obtained using tributylgermane:Pd"PPh2#3 "Equation "20## ð78JOM"265#30Ł[

(31)

Cl Cl

COCl

Cl Cl

CHOBu3GeH, Pd(PPh3)4, HMPA, 80–100 °C

85%

Fluorine!substituted benzaldehydes have been obtained by the reduction of the correspondingacids with hypervalent silicon species "Equation "21## ð76TL2830Ł[

(32)

CO2H

F

CHO

F

SiH2Ph

NMe2

96%

A halo!substituent appears to be inert to virtually all the methods of oxidising benzyl alcohols\halides and amines\ thus making it an excellent method for the synthesis of halobenzaldehydes[Furthermore\ the slight electron!withdrawing e}ect exhibited by these substituents helps preventover!oxidation[ Similarly\ halotoluenes can be oxidised e.ciently to benzaldehydes by the methodsdescribed in Section 2[92[0[1[0[ For examples see Equation "22# ð89BSB234Ł\ Equation "23# ð78S182Łand Equation "24# ð63SC34Ł[

(33)Cl

NH2•HBr

Cl

CHOMe2SO, 100 °C

87%

(34)Cl Cl

CHO i, KMnO4, Et3N, CHCl3, H2Oii, H2SO4

89%

(35)Br

Br

CHO

Br

i, Hg2(ONO2)2, DME

ii, NaOH

Of the organometallic!based methods for the synthesis of benzaldehydes\ many utilise haloarenesas starting materials[ The e.ciency of metalÐhalogen exchange varies in the order I×Br×Cl×F\and thus selective formylations of dihaloarenes are possible[ This strategy has been utilised suc!cessfully for the synthesis of Br!\ Cl! and F!substituted benzaldehydes[ Methods which have beenused include Grignard reagent additions to imidazolidinium salts "Equation "25## ð68CC006Ł\ pal!ladium!catalysed formylations with CO and either Bu2SnH "Equation "26## ð75JA341Ł or poly"methylhydrosiloxane# "PMHS# "Equation "27## ð73JOC3998Ł[

Cl

MgBr

Cl

CHO

i,

ii, H2O

90%

NN

Me

Ac

(36)

I–

+

(37)

CHO

Cl

CO (3 atm), Bu3SnH, Pd(PPh3)4, THF

78%

I

Cl


(38)

CHOI

Br Br

CO (50 atm), PMHS, Pd(PPh3)4

95%

1!Fluorobenzaldehydes may be synthesised selectively from ~uoroarenes by an ortho!lithiationprocedure using ~uoride as an ortho!directing group[ 1!Fluorobenzaldehydes with a variety of othersubstituents have been prepared in this manner\ for example\ Equation "28# ð81TL6388Ł[

(39)

Cl

I

F

Cl

I

F

CHO i, LDAii, DMF

97%

Classical formylations of simple haloarenes to give halobenzaldehydes are not widely used sincehalo substituents deactivate the ring towards electrophilic substitution[ However\ if other activatinggroups are present\ halo groups are tolerated in many cases[

2[92[1[3 Oxygen!substituted Benzaldehydes

There are many hundreds of syntheses of benzaldehydes containing either hydroxy or ethersubstituents directly attached to the aromatic ring[ Of those papers reporting general routes tobenzaldehydes by reduction of carboxylic acid derivatives\ almost all have examples containing analkoxy substituent or occasionally more than one "see Section 2[92[0[0#[ Yields range from moderateto excellent^ for an example see Equation "39# ð67TL0326Ł[

(40)MeO

OMe

COCl

MeO

OMe

CHO

(Ph3P)2CuBH4, PPh3, Me2CO

86%

By contrast\ hardly any examples have been reported for reductions of benzoic acids containinga free hydroxy group[ One method that has been used\ however\ is reduction by sodium amalgam"Equation "30## ð35JA1491Ł[

(41)

CO2H

OH

F

CHO

OH

F

Na-Hg

57%

Most oxidative methods also tolerate alkoxy groups\ and more examples containing free hydroxygroups are found using these reactions^ see Equation "31# ð68S033Ł\ Equation "32# ð82TL2408Ł andEquation "33# ð73S636Ł[

(42)O O

OHCddq, dioxan

70%

OMe

OMe

O

O

O

Ph

Br

OMe

OMe

CHOO

O

O

Ph

Ag2CO3, DMSO, 90 °C

80%(43)


(44)

OH

OH

OH

CHO

OH

CHO

Me2SeO, PhH, 80 °C

92%

Aryl Grignard reagents containing alkoxy substituents have been formylated using reagentssuch as DMF "Equation "34## ð66JOC2297Ł\ lithium formate ð73TL0732Ł and N!3\3!trimethyl!1!oxazolinium iodide ð69JA5565\ 63OS"43#31Ł\ and Stille!type formylations of methoxy!substituted iodo!benzenes have also been accomplished ð75JA341Ł[

(45)

MeO

Br

MeO

CHO i, Mg

ii, DMF

Oxygen is one of the most widely used atoms for directed ortho!metallations[ This method hasbeen utilised extensively for the selective conversion of oxygen substituted arenes into ortho!oxygensubstituted benzaldehydes[ Some examples are shown in Equation "35# ð82T0310Ł and Equation "36#ð80SC056Ł[ Selective ortho!formylations of phenols may be realised by reaction of the correspondingaryloxymagnesium halides with formaldehyde in the presence of HMPA "Equation "37##ð67JCS"P0#207Ł[ For other less direct methods for overall exclusive ortho!formylation of phenols\see ð63TL2352Ł[ RiemerÐTiemann\ Vilsmeier\ Gattermann and Lewis acid mediated reactions ofdichloromethyl ethers are all particularly well suited to substrates containing electron!donatingsubstituents such as hydroxyl and alkoxy groups\ and they have been used extensively "see Section2[92[0[3#[ Some further examples containing various other functional groups are shown in Equation"38# ð89SC598Ł\ Equation "49# ð76TL1362Ł and Equation "40# ð72CPB0640Ł[

(46)

O

O

O-THPO

O

O-THP

CHO

i, BunLi ii, DMFiii, H+

72%

(47)

MeO

OMe

O-TIPS MeO

OMe

OH

OHC

i, BunLi ii, DMFiii, H+

85%

(48)OHC

OHOMgBr i, HMPA, PhH, para HCO2Hii, 10% HCl

90%

(49)

OH

Cl

OH

Cl CHO

NaOH, CHCl3, H2O, ultrasound

84%

MeO

MeO

N

O

O

MeO

MeO

N

O

OCHO

TiCl4, CH2Cl2

OMeCl

Cl

(50)

(51)

OH

Cl

MeO2C

OH

Cl

MeO2C CHOHMT, MeSO3H, HCl, H2O

77%


An alternative formylation procedure for arenes containing oxygen substituents is by reactionwith tris"phenylthio#methane in the presence of dimethyl"methylthio#sulfonium tetra~uoroborate"dmtsf#[ The intermediate dithioacetals formed in these reactions are readily hydrolysed to producethe corresponding benzaldehydes\ for example\ Scheme 2 ð73S055Ł[

OMe

OMe

OMe

OMe

PhS SPh

OMe

OMe

CHO

Scheme 3

DMTSF, (PhS)3CH DMTSF, H2O

70%

2[92[1[4 Sulfur!substituted Benzaldehydes

There are fewer examples of benzaldehydes containing sulfur substituents than those containingoxygen substituents[ This may re~ect the fact that the sulfur centre itself may react under certainreducing and:or oxidising conditions[ Nevertheless\ some examples have been reported^ for instance\a benzyl bromide containing a thioether may be oxidised selectively at the benzylic position withdimethylselenoxide "Equation "41## ð73S636Ł\ and under certain conditions manganese dioxideoxidises benzylic alcohols to benzaldehydes in the presence of a thioether ð66JOC2403Ł[

(52)SMe

Br

SMe

CHO

Me2SeO, ClCH2CH2Cl, KHPO4

97%

Sulfur substituents in general tend to be excellent at directing ortho!metallations[ Quenching withDMF is then an excellent route to ortho!S!substituted benzaldehydes\ for example\ Equation "42#ð78JOC13Ł and Equation "43# ð75JOC1722Ł[

(53)SO2But SO2But

CHO

i, BunLiii, DMF

90%

(54)

SO3Et SO3Et

CHO

i, BunLiii, DMF

74%

Very few methods have been reported for the formylation of aryl alkyl thioethers by classicalformylation techniques[ Vilsmeier reaction of methyl phenyl sul_de does give 3!methyl!thiobenzaldehyde but the yield is reported to be poor ð44BSF0483Ł[

2[92[1[5 Nitrogen!substituted Benzaldehydes

Many reagents will reduce benzoic acids and their derivatives containing a nitro substituent andyields are very often high "×79)#[ A notable exception is the reaction of p!nitrobenzoyl chloridewith hydridoiron tetracarbonyl anion which fails because the nitro group is reduced simultaneouslyunder the conditions[

A selection of methods giving excellent yields of simple nitrobenzaldehydes are reductions of theacyl chlorides with either sodium tri"t!butoxy# aluminum hydride "Equation "44## ð82JOC3621Ł\hypervalent silicon hydrides ð77TL0160Ł\ tributylstannane under palladium catalysis ð70JOC3328Ł or0\2!dimethyl!1!phenylbenzimidazole ð75JOC4399Ł[

88Polyaromatic Aldehydes

(55)

COCl CHO

O2N O2N

NaAlH(OBut)3

89%

Fewer examples of reductive approaches to amino benzaldehydes are reported\ although goodyields have been found for the reductions of nitrobenzoic acids by t!thexylbromoborane!DMScomplex ð76JOC4929Ł\ or ButLi:8!BBN!H ð76TL5120Ł[

The nitro substituent appears to tolerate most oxidation procedures\ with excellent yields beingobtained for the oxidation of 3!nitrobenzyl bromide with dimethyl selenoxide "099)# ð73S636Ł\ orthe oxidation of 3!nitrobenzyl alcohol with tetrakis"pyridino# cobalt"II# dichromate "84)#ð81SC0380Ł^ see also ð89BCJ1322Ł[ Free amino substituents do not appear to tolerate many oxidants\although amino toluenes have been oxidised by 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#if the amino group is sterically hindered "Equation "45## ð73TL1890Ł[

(56)H2N

CHO

H2N

ddq, dioxan

49%

1! and 3!Methyl!N!acetylanilines have been oxidised successfully to 1! and 3!N!acetylaminobenzaldehydes respectively\ in ×89) yield using can ð55TL3382Ł[

Of the organometallic routes to benzaldehydes\ few examples have been reported for N!substitutedderivatives[ The synthesis of p!nitrobenzaldehyde has been reported by the Stille procedure\ but inpoor yield[

Formylations of nitroarenes by electrophilic aromatic substitution are not very viable since thereactions are disfavoured by the electron!withdrawing nature of the nitro group[ A few examplesare known however\ where other activating groups are present to counteract this e}ect\ for example\Equation "46# ð59CB77Ł[

(57)AlCl3, Cl2CHOMe

62%

O2N

OMe

O2N

OMe

CHO

The strong electron!withdrawing nature of the nitro group actually makes nitroarenes susceptibleto nucleophilic substitution\ and direct formylations have been achieved by reactions with the CCl2−

anion followed by hydrolysis of the intermediate "Scheme 3# ð76TL2910Ł[

Cl

NO2

Cl

NO2

CHOCl

NO2

Cl

Cl

Scheme 4

ButOK, CHCl3

94%

H+, H2O

66%

Formylations of N!alkyl and N\N!dialkyl amines are best achieved using the Vilsmeier reaction\although yields are very variable^ the formylations occur para to the amine substituent ð52OSC"3#220\B!53MI 292!90\ 82T3904Ł[

Finally a simple direct route to 3!aminobenzaldehydes has been achieved by reaction of simpleanilines with the DMSO!HCl reagent in the presence of copper"II# chloride\ where yields are goodto excellent\ for example\ Equation "47# ð81JCS"P0#1124Ł[

Br

H2N

Br

Br

H2N

Br

CHO(58)

DMSO-HCl, CuCl2

84%

2[92[2 POLYAROMATIC ALDEHYDES

Just as benzaldehyde has been extensively used as the model product for methodology towardssimple aryl aldehydes\ naphthaldehyde has correspondingly been used for routes to polycyclic aryl


aldehydes[ Both 0! and 1!naphthaldehydes have been made by numerous reductive methods fromvarious naphthoic acid derivatives[ Yields in many cases are excellent[ High yielding syntheses of1!naphthaldehyde include reduction of 1!naphthoyl chloride either by Rosenmund reaction "70)#ð44OSC"2#516Ł\ or with NaAlH"ButO#2 "70)# ð82JOC3621Ł\ reduction of 1!N\N!dimethylnaphthamidewith LiAlH"EtO2# "70)# ð53JA0978Ł\ or reduction of the corresponding nitrile by Stephen|s method"80)# ð28JA1137Ł[ Good yields of 0!naphthaldehyde are also reported from the reduction of thecorresponding acid with bis"N!methylpiperazinyl# aluminum hydride "84)# ð73JOC1168Ł\ and thenitrile via reduction of its nitrilium ion with triethylsilane "73)# ð63CC34Ł\ amongst others "seeSection 2[92[0[0#^ interestingly the Stephen reaction gives very poor yields in this case[

Few examples of multifunctionalised naphthaldehydes or aldehydes of other polyaromatic systemshave been made by the newer reductive methods\ although they have much potential[ For oldermethods such as the McFadyenÐStevens procedure some more interesting examples have beendocumented\ for example\ Equation "48# ð36JA0887Ł[

O

NN

PhSO2

OMe

OMe OMe

OMe (59)Na2CO3

79%

OHC

A greater variety of polyaromatic aldehydes have been made by oxidative routes[ Oxidantsthat have been used include barium manganate "Equation "59## ð67TL728Ł\ ddq "Equation "50##ð77JOC3476Ł and N!cyclohexylbenzene sul_namide "Equation "51## ð70JOC3506Ł[

(60)OH

OH

CHO

CHO

BaMnO4, CH2Cl2

87%

(61)

CHO

ddq, AcOH, H2O

90%

Br

Br

Br

CHONaH

NH

S Ph

O(62)

Reaction of 4!bromo methyl!0\ 0H!benzo"a#~uoren!0\0!one with silver nitrate followed by basedecomposition of the intermediate\ the nitrate ester\ gave the corresponding aldehyde in 75) yield"Equation "52## ð50JA082Ł[

(63)

OO

CHO

i, AgNO3ii, KOH

86%

Br

Certain polyaromatic compounds on treatment with strong oxidants can be cleaved selectively atone position to give aldehyde products\ for example\ Equation "53# ð59JOC0785Ł[

(64)

CHOCHO

i, OsO4ii, NaIO4

78%

090Polyaromatic Aldehydes

Naphthyl lithium and naphthyl magnesium halide reagents can be formylated by dialkyl!formamides\ or by other formylating agents mentioned in Section 2[92[0[2^ see for example ð67S392\70AG"E#767\ 73S117\ 73TL0732Ł^ yields are generally high[

Many polyaromatic aldehydes have been made by classical electrophilic!substitution reactions ofactivated arenes with formyl cation equivalents[ In these reactions regioselectivity is an importantfactor[ Formylation of naphthalene generally occurs at the 0!position\ as is the case using dichloro!methyl methyl ether:SnCl3[ The yield in this case is 79) ð59CB77Ł[ Anthracene gives an 73) yieldof 8!formyl anthracene in the Vilsmeier reaction "Equation "54## ð44OSC"2#87Ł[

(65)

CHO

PhMeNCHO, POCl3

84%

Anthracene itself has also been formylated in nearly quantitative yield by a modi_ed Vilsmeierreaction using the formylation complex derived from tri~uoromethane sulfonic anhydride and DMFð89CC0460Ł[ Naphthalenes with electron!donating substituents in the 1!position formylate in the0!position of the same ring as the activating substituent "Equation "55# ð61JCS"P0#781Ł and Equation"56# ð52CB297Ł#^ similar substituents on anthracenes alter the position of formylation "Equation"57## ð45MI 292!90\ 63BCJ0576Ł[

(66)

CHO

Zn(CN)2, AlCl3, HCl

89%

(67)

OHOH

CHOOMe, TiCl4

Cl

Cl

82%

(68)

OHOH

CHO

Zn(CN)2, HCl, Et2O, H2O

The formylation of naphthalenes with various combinations of alkoxy substituents by malonicacid in the presence of manganese"III# gives modest yields of the corresponding aldehydesð78BCJ434Ł[ Reactions of 0! and 1!methoxynaphthalenes with DMF and pyro!phosphoryl chloridelead to formylation at the 3! and 0!positions respectively\ in yields over 85) ð82T3904Ł[ Equation"58# shows an example where the Du} formylation has been used in a synthesis of 0\3\7!trimethoxy!1!naphthaldehyde[ Interestingly\ attempted reaction under Vilsmeier conditions gave mainlyO!formylation[ Treatment of the trimethoxy derivative under the same conditions gave the 4!formylproduct "00# ð78BCJ1625Ł[

OMe OH

OMe

OMe OH

OMe

CHO

(69)HMT, AcOH, TsOH

61%

OMe OMe

OMe

(11)

CHO


2[92[3 HETEROCYCLIC ARYL ALDEHYDES

2[92[3[0 O!Heterocyclic Aldehydes

2[92[3[0[0 Furan and benzofuran carboxaldehydes

Both 1! and 2!furoic acids and various derivatives have been reduced to the correspondingfuran carboxaldehydes using numerous reducing agents[ 1!Furoic acid itself may be reduced withhypervalent silicon hydrides ð76TL2830Ł\ or reaction with N\N!dimethyl chloromethyleniminiumchloride followed by reduction of the intermediate with LiAlH"ButO#2 ð72TL0432Ł\ to give thealdehyde in 65) and 69) yields respectively[ Better yields are obtained by reduction of thecorresponding acyl chloride with complex borohydrides "71)# ð67TL1362Ł\ hypervalent silanes"76)# ð77TL0160Ł\ or the hydridoiron tetracarbonyl anion "89)# ð66TL670Ł[

Furan 2!carboxaldehyde has been produced in 51) yield from 2!furoic acid by reduction usingbis"N!methylpiperazinyl# aluminum hydride ð73JOC1168Ł[

Reductions of cyano furans with dibal!H has been used to make various substituted furancarboxyaldehydes\ for example\ Equation "69#\ as well as all the possible regioisomeric furandicarboxyaldehydes "from the dicyano derivatives# in good yield ð69BSF0334Ł^ see also ð53JOC2935Ł[

(70)

O

CN

CN O

CHO

CHO

dibal-H (2 equiv.), PhH

65%

Furans and benzofurans appear to tolerate many oxidative conditions and these methods haveproved popular for the synthesis of a variety of O!hetaryl aldehydes[ Oxidants that have been usedinclude MnO1 "Equation "60## ð60AJC0772Ł\ silver carbonate "Equation "61## ð65JHC414Ł\ or bariumferrate "Equation "62## ð77BCJ1074Ł for the oxidation of hydroxymethyl furans[ Oxidations underSwern conditions have been carried out in the presence of a phenythio methyl group in good yield"Equation "63## ð81JA2809Ł[

(71)

O

OMe

OH

O

OMe

CHO

MnO2, CCl4

87%

(72)O

OH

O CHO

Ag2CO3, PhH

80%

O Ph

OHHO

Ph

(73)

O Ph

CHOOHC

Ph

BaFeO4, H2O, PhH

80%

O

CO2Me

HO SPh (74)

O

CO2Me

OHCSPh

i, (COCl)2, DMSO

ii, Et3N

Furans containing halomethyl substituents have been oxidised to the corresponding aldehydesby\ amongst others\ the Sommelet reaction\ for example\ Equation "64# ð69BSF0334Ł\ or by oxidationwith the sodium salt of 1!nitropropane\ for example\ Equation "65# ð57JHC84Ł[

(75)

O CO2Me

Br

O CO2Me

CHO i, HMT, CHCl3ii, H2O

54%

O CF3

CO2Et

Br (76)

O CF3

CO2Et

OHC

NaOEt, PriNO2, EtOH

71%

092Heterocyclic Aryl Aldehydes

Other oxidative methods leading to furan carboxaldehydes include oxidative decarboxylation ofa benzofuran!2!acetic acid using pyridine N!oxide "Equation "66## ð81IJC"B#415Ł\ and a!sulfurationof a phenylthiomethyl group followed by silver perchlorate promoted hydrolysis of the intermediatedithioacetal "Equation "67## ð81JA2809Ł[ This latter example has been used in studies towards thetotal synthesis of furanocembranolides[ A _nal oxidative procedure involves cleavage of a diol usingan oxidant such as NaIO3\ for example\ Equation "68#[ The substrate in this case is readily availableby condensation of glucose with acetylacetone ð34JCS005Ł[

(77)

O

CO2H

O

CHON O–

+

Ac2O, PhH

90%

O

OSiButPh2O

O

H

CO2Me

SPh

O

OSiButPh2O

O

H

CO2Me

CHO

(78) i, KHMDS, then PhSO2SPh

ii, AgClO4, H2O, PhH

HO

OH

OH

OH

O

O

O

O

OHC

(79)NaIO4

Lithiations of furans and benzofurans occur preferentially at the 1!position[ This strategy hasbeen used in the synthesis of the corresponding 1!formyl derivatives by quenching the anionswith DMF\ for example\ Equation "79# ð66BSF031Ł^ see also ð67HCA329\ 72TL0666Ł[ MetalÐhalogenexchange reactions followed by quenching with DMF have also been used for the synthesis ofboth 1! and 2!furan carboxaldehydes\ for example\ ð69BSF0727Ł[ Preferential metallation of1\2!dibromofuran occurs at the 1!position "Equation "70##[

(80)O O

CHOBunLi, DMF

70%

(81)

O

Br

Br O

Br

CHO

BunLi, DMF

Palladium!catalysed formylation of 2!iodofuran with CO and Bu2SnH occurs under Stille con!ditions in 59) yield ð75JA341Ł[ Classical formylations of furans and benzofurans have beenaccomplished using either Lewis acid mediated reactions with dichloromethyl methyl ether or byGattermann reactions[ The most popular method however is by use of the Vilsmeier reactionðB!53MI 292!90Ł[

Furans undergo formylation at the 1! or 4!positions\ and benzofurans at the 1!position pref!erentially[ Formylation at other positions may occur if the favoured positions are blocked however\although yields tend to be lower[ For benzofurans where the 1!position is blocked formylation inthe benzene ring may compete\ particularly if electron!donating substituents are present[ Selectedexamples are presented in Equation "71# ð73JOC1404Ł\ Equation "72# ð42JIC092Ł and Equation "73#ð81T0928Ł[ In the last example\ concomitant removal of the acetate function has been observed[

(82)

O O CHO

POCl3, DMF

96%


(83)

OMeO OMeO

CHO

ZnCl2, HCN, HCl, Et2O

85%

O

O

O

O

HO

CHO

(84)

OMe OMe

Zn(CN)2, HCl, KCl, Et2O

50%

Lastly\ 2!formyl benzofuran has been synthesised by an intramolecular cyclisation reaction of anaryl radical onto a pendant propargyloxy group followed by a radical trapping reaction withTEMPO[ Acid!catalysed elimination of amine from the initially formed O!vinylhydroxylamine thenfurnishes the aldehyde "Scheme 4# ð70CC484Ł[

N O•

Me2CO

N2

O

+

BF4–

OH

O

NR2H+

O

CHO

Scheme 5

H+

2[92[3[1 S\ Se and Te Heterocyclic Aldehydes

2[92[3[1[0 Thiophene and benzothiophene carboxaldehydes

Thiophene is classed as a relatively electron!rich aromatic compound with a resonance energylarger than furan and about half that of benzene ðB!74MI 292!90Ł[ Its similarity to benzene ishighlighted by the fact that many of the methods used for the synthesis of formyl thiophenes parallelthose for benzaldehydes\ and most start with the thiophene ring already in place[ Like furan\classical formylations using the Vilsmeier reaction or similar procedures occur preferentially at the1! or 4!position of thiophene[ Deprotonation with strong bases occurs at the same position\ thusmaking the synthesis of 2! and 3!substituted derivatives more di.cult[ Both 1! and 2!formylthiophene derivatives have\ however\ been synthesised by reduction of the corresponding cyanocompounds ð58BSF1400Ł[ Thiophene!1!carboxylic acid and its acyl chloride have also been reducedto 1!formyl thiophene by hypervalent silicon hydrides ð76TL2830\ 77TL0160Ł in 77) and 79)yields respectively[ The Sommelet oxidation of 1! and 2!halomethylthiophenes has produced 1! and2!formylthiophenes in 63) and 61) yields respectively\ for example\ Equation "74# ð42JCS0631\52OSC"3#807Ł[

(85)S

Cl

S CHO

i, HMT, 50% AcOHii, conc. HCl

74%

An interesting route to certain 2!formylthiophenes involves dibromination of 2!methylthiophenesfollowed by hydrolysis "Scheme 5# ð64TL3694Ł[ Slow addition of bromine to a light!irradiated


solution of the substrate in the presence of AIBN promotes this reaction and suppresses the normalrapid ring bromination of thiophenes[

S ClS Cl

Br

Br

S

CHO

Cl

Scheme 6

Br2, AIBN, hν, CCl4

85%

Na2CO3, py

70%

Probably the most popular method for the synthesis of formyl thiophenes is by treatment of anappropriate lithiated thiophene with a dialkyl formamide[ 1!Lithio thiophenes can be formed directlyfrom deprotonation of the parent thiophene or by haloÐlithium exchange from a 1!halothiophene\for example\ ð42JA2586\ 65BSF154\ 77S205Ł[ The selective formation of 2!formyl thiophenes has alsobeen accomplished by haloÐlithium exchange of 2!bromothiophenes\ followed by addition of DMF\for example\ Equation "75# ð56BSF1384\ 75CB2087Ł[

i, BunLiii, DMF

99%S

Br S

S

CHO S

(86)

Treatment of 2!bromothiophene with two equivalents of butyllithium leads to 1\2!dilithio!thiophene by simultaneous haloÐmetal exchange and deprotonation[ Addition of DMF then a}ordsthe corresponding dialdehyde in moderate yield\ "Equation "76## ð56BSF1384Ł^ see also ð58BSF1400Łfor the synthesis of di! and triformyl thiophenes[

(87)

S

Br

S

OHC

OHC

i, BuLi (2 equiv.)ii, DMF

40%

Thiophene\ like furan is more reactive towards electrophiles than benzene[ Because of itsrelatively high aromatic character\ substitution products predominate over addition products^ thusthiophene is an excellent candidate for formylation by the Vilsmeier reaction ð49JA0311\ 52OSC"3#804\B!53MI 292!90\ 79S022Ł[ Finally\ 1!nitrothiophene undergoes nucleophilic substitution with CCl2−

anion to give\ after hydrolysis\ the 2!formyl derivative ð76TL2910Ł[The preparations of formyl benzothiophenes may be accomplished in many cases by analogous

procedures to those used for formyl thiophenes[ Lithiation occurs preferentially at the 1!positionand 2!formyl derivatives may be made by lithiation of the corresponding bromides\ for example\Equation "77# ð60JCS"C#071Ł[ It should be noted however that 2!lithio benzofurans need to be keptat low temperature to avoid ring cleavage occurring[

(88)

S

Br

S

CHO i, BuLi, –70 °Cii, DMF

85%

Benzothiophene is slightly less reactive towards electrophiles than thiophene itself\ but stillundergoes Vilsmeier formylation[ The 2!position is more activated than the 1!position\ unlikethiophene and benzofuran\ although mixtures are often produced[ If one position is blocked singleproducts can be obtained\ for example\ Equation "78# ð56JCS"C#668Ł[ If the benzene ring containselectron!donating substituents "or the heterocyclic ring contains electron!withdrawing substituents#\then formylation may occur preferentially in the six!membered ring\ for example\ Equation "89#ð56JCS668Ł[

(89)MFA, POCl3

50%S

OMe

S

OMe

CHO


(90)

S

OMe

S

OMe

CHO

MFA, POCl3

70%

2[92[3[1[1 Se and Te heterocyclic aldehydes

Various formyl selenophenes and tellurophenes have been made\ normally by analogous methodsto those used for the preparation of formyl thiophenes[ Tellurophene is more reactive to electrophilicattack than selenophene\ which is more reactive than thiophene[ All are less reactive than furan[For a comparison of the formylation reactions of these heterocycles see ð60CC0330Ł[ For otherexamples of formyl selenophenes see ð58BSF1400\ 65BSF154Ł[

2[92[3[2 N!Heterocyclic Aldehydes

2[92[3[2[0 Pyrrole and indole carboxaldehydes

Many of the general procedures used for the synthesis of benzaldehydes may be applied to thesynthesis of pyrrole and indole carboxaldehydes\ and due to their importance in the nature of thepyrrole subunit "for instance in porphyrins# many examples are to be found in the literature[Conversions of acyl pyrroles into the corresponding aldehydes have been accomplished by Raneynickel reduction of a corresponding 2!"thiolester# pyrrole in good yield "Equation "80## ð55CJC0996Ł[The most common method for converting 1!acyl pyrroles into 1!formyl pyrroles appears to betreatment of the carboxylic acid with trimethylorthoformate and tri~uoroacetic acid ð61AJC0868Ł[This reaction is actually a decarboxylation formylation sequence but gives the same overall trans!formation as reduction[ Battersby and co!workers have used such a procedure\ for example\ in asynthesis of an isobacteriochlorin macrocycle "Equation "81## ð70CC686Ł[

NH

O

SEtEtO2C

EtO2C NH

CHOEtO2C

EtO2C(91)

Raney Ni, Me2CO, MeOH

85%

NH

MeO2CCO2Me

CO2But

NH

O

NH

MeO2CCO2Me

CHO

NH

O

(92)(MeO)3CH, TFA

86%

Pyrrole and indole carboxaldehydes have been made from oxidations of their methyl analogues\for example\ N!protected 2!methylindoles have been oxidised to the 2!carboxaldehydes by seleniumdioxide ð72TL3462Ł\ and 1!methylpyrroles have been oxidised by sulfuryl chloride ð63JOC1761Ł[ Forexamples of the oxidation of 1!hydroxymethyl indoles to aldehydes by MnO1\ see ð73JOC2084\76JCS"P0#820Ł^ the same reagent has also been used for the partial oxidation of 3!hydroxymethylindole ð79JOC2249Ł[ The Sommelet oxidation can be applied to indole systems ð41JA4009Ł\ andN!protected pyrroles and indoles both metallate preferentially at the 1!position^ the anions maythen be quenched by DMF to give the aldehyde products ð71SC120\ 81H"23#0184Ł[

Probably the most frequently used way of making pyrrole or indole carboxaldehydes is by classicalformylation procedures[ The Vilsmeier reaction of pyrrole is a very important reaction and occursat the 1!position in good yield ð52OSC"3#720Ł[ If both of the 1! and 4!positions are blocked\ the otherpositions often still undergo formylation ð52JOC2941Ł[ With electron!withdrawing groups in the


1!position\ formylation tends to occur at the 3!position[ However\ di}erent methods may givedi}erent selectivities[ For the reaction shown in Equation "82#\ the Vilsmeier procedure gave amixture of isomers in moderate yield\ whereas formylation with dichloromethyl methyl ether provedfar superior ð67JOC3738Ł[ If electron!donating groups are present in the 1!position 4!formyl deriva!tives are generally observed[

N

OMe

OMeN

OMe

OMe

OHC

(93)AlCl3, Cl2CHOMe

89%

Indole\ unlike pyrrole\ but similar to benzothiophene undergoes preferential formylation at the2!position[ Under Vilsmeier conditions 2!indole aldehyde itself is produced in 86) yield from indoleð52OSC"3#428Ł[ If the 2!position is blocked\ 1!formylation is sometimes successful as shown inEquation "83# ð74TL1044Ł[ If the nitrogen centre is not protected N!formylation tends to occur[

N

F

Me

N

F

Me

CHO

(94)POCl3, DMF

86%

When positions 1 and 2 are both blocked\ formylation can occur in the six!membered ring[ Avery elegant example of this is shown in Equation "84# where the Du} reaction proved to be themethod of choice for the regioselective formylation of ellipticine ð81S0110Ł[

(95)N

NH

N

NH

OHC

HMT, TFA

97%

2[92[3[2[1 Pyridine and quinoline carboxaldehydes

Pyridine is very deactivated towards electrophilic substitution with respect to benzene[ For thisreason classical formylation\ using methods such as the Gattermann or Vilsmeier reactions\ are notgenerally successful[ The best ways of making substituted pyridines tend to be by ring synthesisusing a suitably functionalised precursor ðB!74MI 292!90Ł\ however few methods give formyl pyridinesdirectly[ It is therefore important to be able to transform other functional groups on the pyridinering into aldehyde groups[

Reductions of pyridines containing carboxylic acid substituents or their derivatives are commonlyused procedures for the synthesis of pyridine carboxaldehydes[ This feature is demonstrated by thefollowing examples] "i# 1!formyl pyridines have been made by reduction of the corresponding acylchlorides with sodium diethyldihydroaluminate ð82SC0664Ł\ or with hypervalent silicon hydridesð76TL2830\ 77TL0160Ł^ "ii# 2!formyl derivatives have been produced from the cyano pyridines usingtriethoxy aluminum hydride ð45AG327Ł\ or by a modi_ed Stephen reduction ð40JOC0010Ł "in thelatter the semithiocarbazone was isolated#\ from the acyl chloride by palladium!catalysed reductionwith tributylstannane ð70JOC3328Ł\ or reduction of the acid using dimethylchloro methyleneiminiumchloride:lithium tri"t!butoxy# aluminum hydride ð72TL0432Ł\ or bis"3!methylpiperazinyl# aluminumhydride "Equation "85## ð63CL0336Ł[ The latter reagent has also been used for 3!formyl pyridinesynthesis by reduction of the corresponding methyl ester ð64CL104Ł[ For ester reduction usingdibal!H\ see ð57BSF3006Ł[ Electrochemical reduction of acid derivatives has also been achievedð52ACS1214Ł[


N

CO2H

N

CHOHAl N N Me

(96)2

(2 equiv.)

75%

The synthesis of formyl pyridines from oxidation of a methyl substituent has been achieved usingselenium dioxide "Equation "86## ð57CPB786\ 73CPB3803Ł or iodine:DMSO ð69JOC730Ł[ The mostpopular method for oxidation of hydroxymethyl pyridines is by use of manganese dioxide\ forexample\ Equation "87# ð73JA529Ł[

N N

O

EtOOEt

O

N N

O

EtO

OHC

OEt

O

(97)SeO2

69%

NHO N

NH

O

NOHCN

NH

O

(98)MnO2, CH2Cl2

75%

For an example where MnO1 selectively oxidises a 3!hydroxymethyl substituent over a2!hydroxymethyl substituent\ see ð37JA2323Ł[ Silver carbonate has been used to oxidise 1!\ 2! and3!hydroxymethylpyridines to the aldehydes ð65JHC414Ł[ The Sommelet reaction ð42JCS0639Ł and theKornblum oxidation ð73S636Ł have also been employed for the synthesis of pyridine carbox!aldehydes[ For a comparison of methods that have been used to synthesise 2!formyl pyridines\ seeð65HCA100Ł[ Various routes proceeding via pyridyl organometallic reagents are known\ for example\2!formyl pyridine has been made from the 2!bromo derivative by palladium!catalysed formylationunder pressure of CO[

Probably the most popular method used for the preparation of substituted formyl pyridines is byreaction of a metallated pyridine with a dialkylformamide[ Metallation is not always easy sincealkyllithium reagents sometimes undergo nucleophilic addition to pyridines[ Lithiation is\ however\often successful if directed metallation groups are present or if hindered bases such as LDA areused[ For selected examples see Equation "88# ð72TL2180Ł\ Equation "099# ð71CPB0146Ł\ Equation"090# ð67TL116Ł and Equation "091# ð74CL0792Ł[

(99)

NBrNBr

CHO i, LDAii, DMF

73%

N

MeO NH

ButO

N

MeO NH

ButOOHC

(100)

i, BunLiii, DMF

73%

N

NO

N

NO

CHO

(101)

i, MeLiii, DMF

52%

(102)

NO Br NO CHO

i, Mg, EtMgBrii, DMF

94%


Many of the methods which have been used for the preparation of pyridine carboxaldehydes areequally applicable to the synthesis of quinoline carboxaldehydes[ For example\ methyl quinolineshave been oxidised to the corresponding aldehydes using selenium dioxide ð30JA1543\ 65BSF678Ł\quinoline esters have been reduced to aldehydes using dibal!H ð65BSF678Ł\ and certain quinolineshave been metallated and reacted with DMF or MFA to produce the formyl derivatives\ forexample\ Equation "092# ð63T3042Ł[

N

OMe

OMe N

OMe

OMe

CHO(103)

i, BunLiii, MFA

68%

2[92[3[3 Miscellaneous Heterocycles] Oxazoles\ Thiazoles and Imidazoles

Oxazoles\ thiazoles and imidazoles all react preferentially at the 1!position with strong lithiumbases[ The standard method of synthesis of 1!formyl derivatives is therefore by metallation at thiscentre\ by deprotonation or haloÐmetal exchange\ followed by quenching the resulting anion witha suitable electrophile\ such as DMF[ For an example of this strategy applied to 1!formyloxazole\see ð80JOC338Ł[ In fact\ the same organometallic reagent\ 1!lithiooxazole\ can be used for thesynthesis of the 3!formyl derivative\ since it is an ambident nucleophile and reacts with aldehydesat the 3!position[ Choice of a suitable aldehyde\ such as "01#\ a}ords the alcohol "02# which may bedeprotected and the resulting triol then cleaved oxidatively to produce 3!formyl oxazole "Scheme6# ð80JOC338Ł[

O

NLi

O

N

OH

O

OO

NOHCO

O

O

Scheme 7

(12)

i, DOWEX

ii, NaIO4

(13)

In the case of thiazoles all three isomeric formyl derivatives have been produced using selectivelithiation procedures\ and quenching the resulting anions with a formamide ð76S887Ł[ Likewise\formyl imidazoles may be made using analogous metallation reactions ð77TL2396\ 80JOC3185Ł[ Classi!cal formylations of these heterocycles are di.cult\ and therefore not generally applicable[ Oxidativemethods appear to be applicable if the required starting materials are available[ For instance\ both1!formylimidazoles and 1!formylthiazoles have been produced from selenium dioxide oxidation ofthe corresponding alcohols ð55ACS1538Ł[


3.04Ketones: Dialkyl KetonesKEVIN E. B. PARKESRoche Products Ltd., Welwyn Garden City, UK

and

STEWART K. RICHARDSONUniversity of Notre Dame, IN, USA

2[93[0 SATURATED UNSUBSTITUTED KETONES 001

2[93[0[0 From Alkanes 0012[93[0[1 From Alkenes 0022[93[0[2 From Alkynes 0032[93[0[3 From Halides 0032[93[0[4 From Alcohols and Their Derivatives 003

2[93[0[4[0 By oxidation of secondary alcohols 0032[93[0[4[1 From diols 0102[93[0[4[2 By oxidation of derivatives of alcohols 0102[93[0[4[3 Rearranèment of allylic alcohols 011

2[93[0[5 From Epoxides 0112[93[0[6 From Acetals\ Enol Ethers and Enol Esters 0122[93[0[7 From Aldehydes or Ketones 012

2[93[0[7[0 From saturated aldehydes or ketones 0122[93[0[7[1 From unsaturated ketones 0162[93[0[7[2 From a!functionalized ketones 017

2[93[0[8 From Carboxylic Acids and Their Derivatives 0182[93[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives 0182[93[0[8[1 Other preparations from acids and acid derivatives 020

2[93[0[09 From Sulfur or Other Lower Chalcoèn!containin` Precursors 0202[93[0[00 From Nitroèn!containin` Precursors 021

2[93[0[00[0 From amines 0212[93[0[00[1 From oximes\ hydrazones and their derivatives 0222[93[0[00[2 From nitroalkanes 0232[93[0[00[3 From nitriles 023

2[93[0[01 From Orànosilanes 0232[93[0[02 From Orànoboranes 0232[93[0[03 Methods Involvin` Umpolun` 024

2[93[0[03[0 Acyl anions and their equivalents 0252[93[0[03[1 Other anion equivalents 026

2[93[1 BETA!UNSATURATED AND MORE REMOTELY UNSATURATED KETONES 027

2[93[1[0 Dialkyl Ketones with One Double Bond 0272[93[1[0[0 From ketones 0272[93[1[0[1 From carboxylic acid and carboxylic acid derivatives 0392[93[1[0[2 Preparations involvin` rearranèments 0302[93[1[0[3 Miscellaneous preparations 031

2[93[1[1 Dialkyl Ketones with More Than One Double Bond 0332[93[1[2 Dialkyl Ketones with Aryl or Heteroaryl Substituents 033

2[93[1[2[0 From ketones 0332[93[1[2[1 From carboxylic acids and carboxylic acid derivatives 035

000

001 Dialkyl Ketones

2[93[1[2[2 Other preparations 0352[93[1[3 Alkynyl!substituted Dialkyl Ketones 035

2[93[1[3[0 From ketones 0352[93[1[3[1 Fra`mentation reactions 036

2[93[2 HALO!SUBSTITUTED DIALKYL KETONES "a!\ b! AND MORE REMOTE HALOGENS# 037

2[93[2[0 Introduction 0372[93[2[1 Fluoroaliphatic Ketones 037

2[93[2[1[0 a!Fluoroaliphatic ketones 0372[93[2[1[1 b!Fluoroaliphatic ketones 049

2[93[2[2 Chloroaliphatic Ketones 0402[93[2[2[0 a!Chloroaliphatic ketones 0402[93[2[2[1 b!Chloroaliphatic Ketones 042

2[93[2[3 Bromoaliphatic Ketones 0422[93[2[3[0 a!Bromoaliphatic ketones 042

2[93[2[4 Iodoaliphatic Ketones 0442[93[2[4[0 a!Iodoaliphatic ketones 0442[93[2[4[1 b!Iodoaliphatic ketones 045

2[93[3 KETONES BEARING AN OXYGEN FUNCTION 045

2[93[3[0 OH!functionalized Ketones 0452[93[3[0[0 a!OH!functionalized ketones 0452[93[3[0[1 b!OH!functionalized ketones 0482[93[3[0[2 g!Functionalized and more remotely OH!functionalized ketones 050

2[93[3[1 OR!functionalized Ketones 0512[93[3[2 OX!functionalized Ketones 052

2[93[4 KETONES BEARING A SULFUR FUNCTION 053

2[93[4[0 SH! and SR!functionalized Ketones 0532[93[4[0[0 a!SH! and SR!functionalized ketones 0532[93[4[0[1 b!Functionalized and more remotely substituted SH! and SR!functionalized ketones 057

2[93[4[1 Hi`her!coordinated Sulfur!functionalized Ketones 069

2[93[5 KETONES BEARING A Se or Te FUNCTION 062

2[93[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Ketones 0622[93[5[1 Hi`her!coordinated Se! or Te!functionalized Ketones 066

2[93[6 KETONES BEARING A NITROGEN FUNCTION 067

2[93[6[0 NH1\ NHR and NR1!functionalized Ketones 0672[93[6[0[0 a!NH1\ NHR and NR1!functionalized ketones 0672[93[6[0[1 b!Functionalized and more remotely NH1\ NHR and NR1!functionalized ketones 073

2[93[6[1 NHX and NX1!functionalized Ketones 0782[93[6[2 NY!functionalized Ketones 0892[93[6[3 NZ!functionalized Ketones 083

2[93[7 KETONES BEARING A P\ As\ Sb OR Bi FUNCTION 084

2[93[7[0 XR1 and X¦R2!functionalized Ketones 0842[93[7[1 Hi`her!coordinated P\ As\ Sb or Bi!functionalized Ketones 085

2[93[7[1[0 a!Hi`her!coordinated P\ As\ Sb or Bi!functionalized ketones 0852[93[7[1[1 g!Coordinated and more remotely hi`her coordinated P\ As\ Sb or Bi!functionalized ketones 199

2[93[8 KETONES BEARING A METALLOID FUNCTION 191

2[93[8[0 Silicon!functionalized Ketones 1912[93[8[0[0 a!Silyl ketones 1912[93[8[0[1 b!Silyl ketones 192

2[93[8[1 Germanium!functionalized Ketones 1922[93[8[2 Boron!functionalized Ketones 192

2[93[09 KETONES BEARING A METAL FUNCTION 193

2[93[09[0 Tin!functionalized Ketones 193

2[93[0 SATURATED UNSUBSTITUTED KETONES

2[93[0[0 From Alkanes

Although the oxidation of activated methylene groups next to unsaturated or aromatic groups isa well established method for the synthesis of unsaturated and aromatic carbonyl compounds\ no


equivalent methodology exists for the oxidation of unactivated methylene groups[ The area is\however\ one of active interest in a number of groups\ notably those of Barton ðB!80MI 293!90Ł\Sawyer ð89JA0825Ł and Murahashi ð82TL0188Ł[ So far the most promising results have been obtainedin the metal!mediated peroxide oxidations of highly symmetrical alkanes\ which can give modestyields of ketones at partial completion[

A somewhat unusual methylene activating group is the cyclopropyl ring\ and oxidations ofcyclopropylmethyl groups with ruthenium tetroxide\ generated in a catalytic ruthenium trichlorideÐsodium periodate system ð74CL0274Ł\ with the complex of chromium trioxide with 2\4!dimethyl!pyrazole "Equation "0## ð82CC843Ł\ or with ozone adsorbed onto silica gel ð65AG"E#650Ł give goodyields of cyclopropyl ketones\ particularly for doubly activated examples[

O

(1)80%

2[93[0[1 From Alkenes

The Wacker oxidation of ethylene to acetaldehyde by oxygen in the presence of a palladium"II#catalyst and a copper salt as cooxidant has been an important industrial process since it was _rstdeveloped in 0847[ The reaction was slow to be adopted as a synthetic method because of theaqueous hydrochloric acid!containing medium used and the chlorinated by!products seen withhigher alkenes[ However\ it is now known that an appropriate choice of solvent "particularly2!methylsulfolane or N!methyl!1!pyrrolidone# and cooxidant allows a wide variety of terminalalkenes to be oxidized in high yield to the corresponding methyl ketones[ Tsuji has discussed theorganic synthetic potential of the reaction in a useful review which also includes some unpublishedmaterial from the author|s own laboratory ð73S258Ł[ Recent publications have extended the methodto use electrochemistry to regenerate the oxidant ð76TL2572Ł\ and a palladium"II#\ hydroquinone\iron phthalocyanine catalyst system which\ being chloride free\ avoids the problem of chlorinatedby!products ð77TL1774Ł[ The same transformation can also be achieved using the Jones reagent inthe presence of mercury"II# salts as catalyst ð64JOC2466Ł[ The oxidation of disubstituted alkenes toa!diketones has been reported with potassium permanganate in the presence of copper sulfateð78JOC4071Ł[

Although a number of oxidants will cleave alkenes\ relatively few do so cleanly or in high yield\the most important and well established exception being ozone ðB!58MI 293!90Ł[ In cases where ozoneis not employed\ the conversion is generally achieved via the corresponding 0\1!diol by osmium"VIII#oxide!mediated hydroxylation\ followed by periodate or lead"IV# acetate cleavage[ Isolation of thediol intermediate is not necessary and hydroxylation and cleavage can be achieved in a single potby a mixture of osmium"VIII# oxide and sodium periodate ð45JOC367Ł[ Cleavage of alkenes canalso be achieved by oxygen in the presence of rhodium catalysts ð72HCA066Ł\ and by catalytictriphenylbismuth and N!bromosuccinimide "NBS# in bu}ered aqueous acetonitrile ð75T4516Ł[

Despite the importance of hydroformylation as a route to aldehydes\ the analagous hydro!acylation transformation is virtually unknown\ although both the silver!catalysed addition of analdehyde ð68TL2Ł\ and rhodium"I#!catalysed addition of an aldimine ð68JA378Ł to an alkene havebeen reported[ The intramolecular version of this transformation is slightly better studied\ and3!pentenals are known to give cyclopentanones both on treatment with tin"IV# chloride ð68CC034Ł\and with rhodium"I# catalysts ð73TL850Ł[ The latter reaction clearly has considerable potential since2!substituted cyclopentanones of high optical purity can be prepared using chiral rhodium catalysts"Equation "1## ð81TL5220Ł[

O

But

O

But

(2)Rh[(S)-BINAP]ClO4

87%, 99% ee

(S)-BINAP = (S)-2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl

003 Dialkyl Ketones

2[93[0[2 From Alkynes

Mercury"II#!catalysed acid hydration of terminal alkynes is a well established method for thesynthesis of methyl ketones[ The transformation has also been reported using a gold"II# catalyst\which has the advantage of requiring neutral conditions and can be performed on substratescontaining an alkene\ hydroxy or acetate functionality ð80JOC2618Ł[ Variants using mercury!impreg!nated Na_on!H ð67S560Ł\ phenylmercuric hydroxide ð71JOC2220Ł\ or p!methoxybenzenetellurinicanhydride have also been reported ð75TL5988Ł[

Alkynes may also be converted into ketones by hydroboration and oxidation of the intermediatevinylborane[ Diborane and simple mono! and dialkylboranes give very poor regioselectivity in thehydroboration^ however\ excellent results can be obtained either with dimesitylborane ð72TL0322Łor with thexyliodoboraneÐdimethylsul_de complex ð82TL4002Ł\ followed by a conventional basichydrogen peroxide workup "Equation "2##[

PrnPrn

PrnO

O(3)+

1.0% 99.0%

The cobalt!catalysed combination of an alkene\ an alkyne and carbon monoxide is known as thePausonÐKhand reaction\ and normally gives a cyclopentenone product[ However\ it has recentlybeen found that if the reaction is performed under nitrogen with the reagents adsorbed on silica inthe absence of solvent\ the saturated cyclopentanone is formed instead "Scheme 0# ð82TL1976Ł[

Scheme 1

AcN

Co2(CO)6

AcN AcN OCo2(CO)8

76%

∆

94%

2[93[0[3 From Halides

The Kornblum oxidation\ in which a primary alkyl halide is heated with an N!oxide or sulfoxide\is most often used for the preparation of aldehydes\ but can also be used for the preparation ofketones from secondary halides[ Most recent work has been aimed at developing modi_ed conditionsand reagents which allow the reaction to be performed under less vigorous conditions[ New reagentsinclude 3!dimethylaminopyridine N!oxide in the presence of diazobicycloundecane ð70BCJ1110Ł\ avariety of pyridone N!oxide reagents ð68JCS"P0#1382Ł\ and DMSO in the presence of sodium hydrogencarbonate and sodium iodide ð75SC0232Ł[ The conversion may also be achieved with moreconventional oxidizing agents\ including tetrabutylammonium periodate ð75SC32Ł\ tetra!butylammonium dichromate ð68CI"L#102Ł\ and iodine penta~uoride ð66S308Ł[

The dehydrohalogenation of halohydrins can be achieved with potassium carbonate in thepresence of catalytic palladium"II# acetate ð71TL2974Ł[ A slightly less general reaction is catalysedby the cobalt complex chlorotris"triphenylphosphine#cobalt"I# ""Ph2P#2CoCl#\ which\ in the presenceof a tertiary amine as hydrogen bromide scavenger\ e}ects the dehydrobromination of bromohydrinsto give ketones[ The reaction is suggested to involve a b!hydroxyalkylcobalt intermediateð66BSF0830Ł[ In the special cases of halohydrins derived from terminal alkenes\ or some cyclicalkenes\ dehydrohalogenation can be achieved photochemically ð81TL1348Ł[

Vinyl halides may be hydrolysed to ketones using mercury"II# acetate either in tri~uoroacetic acidor in acetic acid containing boron tri~uoride etherate ð67TL0832Ł[

2[93[0[4 From Alcohols and Their Derivatives

2[93[0[4[0 By oxidation of secondary alcohols

Although the greater oxidative stability of ketones compared to aldehydes makes the preparationof ketones by oxidation of secondary alcohols a relatively easier process\ the same or similar reagents


are generally used for both oxidations[ As with aldehydes "Chapter 2[90#\ the reagents may beconveniently discussed in six classes] "i# metal!based oxidants\ particularly chromium\ magnesium\and ruthenium salts^ "ii# activated dimethyl sulfoxide reagents^ "iii# halogen!based oxidants^ "iv#Oppenauer and related oxidations^ "v# electrochemical and photochemical oxidations^ and "vi#miscellaneous[

Recent research in oxidation methods has often been directed towards developing low!costmethods with increased environmental acceptability[ Thus\ catalytic methods\ particularly thoseusing hydrogen peroxide or t!butyl hydroperoxide as ultimate oxidant\ have received considerableattention[ Also of interest from this point of view are solid!supported oxidants\ which allow asimpli_ed workup by _ltration[ Such oxidants\ which also often vary in selectivity and reactivitywhen compared with the unsupported parent reagent\ have been the subject of a review ð68S390Ł[

"i# Usin` metal!based oxidants

"a# Chromium rea`ents[ High!valent chromium reagents are probably the most important groupof oxidants for alcohol oxidation[ However\ as evidenced by its use for cleaning glassware\ chromicacid is a very powerful oxidant and the challenge is to develop reagents that have improvedselectivity\ work under near!neutral conditions\ and allow a simple workup[ The earliest reagentsto achieve some success were the Jones "chromic acidÐacetone# and Collins "chromium trioxideÐpyridine# reagents[ Although not without their drawbacks\ they are still used today\ with the Collinsreagent in particular showing advantages for some sensitive substrates such as b!hydroxyketonesð70S456Ł[

A number of other reagents based on chromium trioxide are now known[ These include severalmodi_ed versions of the Collins reagent in which the pyridine is replaced by phenanthrolineð79TL0472Ł or benzatriazole ð89SC2248Ł[ Although these amines have the advantage of giving stable\isolable complexes\ the actual oxidation chemistry seems very similar[ A rather di}erent way ofmodulating the reactivity of chromium trioxide is by suspending it on celite ð68S704Ł\ or on {wet|aluminum oxide ð80BCJ1746Ł^ such reagents have the distinct advantage of greatly simplifying theworkup\ which is by _ltration[

The Jones reagent was the _rst of an enormous range of chromate! or dichromate!based oxidants\of which the most important is pyridinium chlorochromate "pcc#[ This is probably the most suc!cessful and versatile chromium oxidant\ and certainly the single most popular oxidant for alcoholstoday ð71S134Ł[ Despite the established position of the reagent\ modi_cations and improvements ofthe original method are still being published\ the most important of which is an improved and saferprocedure for its preparation ð89T3306Ł[ An important group of modi_cations is aimed at simplifyingthe workup\ which can be complicated by di.culties in separating the product from tarry chromium!containing residues[ These include poly"vinylpyridinium# "chlorochromate#\ a polymeric analogueof pcc ð67JOC1507\ 70JOC0617Ł\ a variety of polymer!bound quaternary ammonium chlorochromatesð75JOC3905Ł\ and 1\1?!bipyridinium chlorochromate\ which apparently gives more tractable residuesð79S580Ł[

One of the few disadvantages of pcc is its mildly acidic character\ which makes it unsuitable forthe oxidation of some sensitive substrates[ Several modi_ed reagents which reduce or overcome thisproblem have been reported\ including pyridinium ~uorochromate ð71S477Ł\ pcc adsorbed ontoalumina ð79S112Ł\ and trimethylsilyl chlorochromate\ which is prepared in situ from chromiumtrioxide and chlorotrimethylsilane and allows oxidations to be performed under strictly neutral andanhydrous conditions ð72TL3256\ 74T1892Ł[ In addition\ the use of ultrasound in oxidations withsilica!gel!supported pcc\ leading to a signi_cant reduction in the length of time and the amount ofreagent required\ has been described ð78JOC4276Ł\ and molecular sieves have been found to assistthe oxidations of a variety of alcohols including carbohydrate and nucleoside derivativesð71JCS"P0#0856Ł[

A wide range of other supported forms of chromic acid have been described\ testifying to theconsiderable interest there is in simplifying the workup of chromium oxidations[ Examples includechromic acid adsorbed on silica gel ð67S423\ 68T0678Ł\ and chromate ion bound to an anion exchangeresin ð65JA5626Ł or to a poly"vinylpyridine# resin ð67JOC1507Ł[ High yields of ketones can also beobtained in oxidations with preformed quaternary ammonium chromates ð68S245Ł[

After pcc the most widely used chromate oxidant for alcohols is pyridinium dichromate indichloromethane\ which has the advantage of being appreciably less acidic ð68TL288Ł and\ like pcc\of being available in a resin supported form ð68TL0390Ł[ Several other neutral\ organic!soluble\

005 Dialkyl Ketones

dichromate oxidants have been developed and o}er a number of advantages\ in particular allowingthe oxidation of very sensitive substrates and short reaction times[ These include the 1! and3!benzylpyridinium dichromates ð80SC308Ł\ bis"benzyltriethylammonium# dichromate ð71S0980Ł\and tetrakis"pyridino#cobalt"II# dichromate ð81SC0380Ł[ Bis"phosphonium#dichromate ð75TL0664Łand 2!carboxypyridine dichromate "sometimes referred to as nicotinium dichromate\ ndc# ð76T2852Łhave also been found to have advantages for some oxidations[ The use of potassium dichromateunder phase transfer conditions is also very e}ective and has the advantage of simplifying theworkup and product isolation\ although the method is unfortunately only applicable to acid!stablesubstrates ð67TL0590Ł[

One of the most interesting recent developments is the use of the chromate ester "0# as a catalyticoxidant for alcohols[ The reagent is used with a peracid as co!oxidant\ is compatible with acid!sensitive functionalities like tetrahydropyranyl ethers\ and oxidizes primary alcohols only veryslowly\ allowing selective oxidations to be performed ð74TL4744Ł[ Other catalytic chromium systemsinclude chromia!pillared montmorillonite clay ð89TL4674Ł\ or chromium"III# bound to a per!~uorinated resin sulfonic acid support ð73TL2206Ł\ both used with t!butyl hydroperoxide ascooxidant[

OCr

O

O O

(1)

Peroxychromium species such as CrO4 =C4H4N ð66TL2638Ł\ and CrO6 ð75T608Ł and a number ofchromium"V# complexes ð79TL0472Ł have been used as reagents for secondary alcohol oxidation[Although they do have advantages in some situations\ in particular in being neutral\ they have notachieved widespread use[

"b# Manànese reaènts[ Simple manganate"VI# or manganate"VII# reagents are very powerfuland unselective oxidants with little application in organic synthesis\ although a variety of modi_edand more useful reagents are now available[ Probably the most important of these reagents for thepreparation of saturated ketones is copper manganate"VII# ð71JOC1689Ł\ which is generally used inthe form of a solid mixture of potassium manganate"VII# and copper sulfate ð68JOC2335Ł[ Thisreagent appears to be a very mild as well as high!yielding oxidant and is compatible with functionalityas sensitive as an N!nitroso group "Equation "3## ð78SC104Ł\ although the reaction is inhibited byremote unsaturation in the substrate ð72JA2077Ł[ Barium manganate"VII# has also been reported tobe an e}ective oxidant for secondary alcohols and a!hydroxyketones\ and has the advantage of notonly being more selective but also of having greater heat and light stability than earlier manga!nate"VII#!based reagents[ Other potentially useful reagents include benzyltriethylammoniummanganate"VII# ð70AG"E#093Ł and solid potassium manganate"VII#\ which gives much improvedresults under the in~uence of ultrasonic irradiation ð72CL268Ł[

N

NOOH

N

NOO(4)

92%

Less work has been done with manganate"VI# reagents^ however\ a mixture of potassium manga!nate"VI#\ copper sulfate and alumina has been reported to selectively oxidize secondary and benzylicalcohols in the presence of primary of allylic alcohols "Equation "4## ð78TL1448Ł[

OHOH OHO(5)

65%

"c# Ruthenium reaènts[ As with chromium and manganese reagents\ the challenge for chemistswanting to develop oxidants of this class has been to moderate the reactivity and improve theselectivity of simple ruthenium reagents[ In an interesting contrast to the other metal oxidants\where modi_ed stoichiometric reagents have been developed\ the most successful approach towards


ruthenium!based oxidants has been the development of catalytic systems\ and three distinct systemshave been found to be useful[

Although not very widely used\ bis"triphenylphosphine#ruthenium"II# chloride appears to havesome potential as a catalytic oxidant of secondary alcohols[ It was _rst reported in combinationwith N!methylmorpholine!N!oxide ð65TL1492Ł\ although more recent publications have usedbis"trimethylsilyl#peroxide ð77BCJ2596Ł\ or iodosylbenzene ð70TL1250Ł\ as cooxidant[

Rather more valuable are the oxidations in which the active species is ruthenium tetroxide[ Theseare generally performed in a two!phase system with the substrate in an organic phase\ normally tri!or tetrachloromethane\ and an aqueous cooxidant phase[ A careful study with octan!1!ol as substrateand sodium bromate as cooxidant has de_ned the optimal conditions to be a pH of between 4 and7 and a stirrer speed su.cient to break up the boundary between the phases ð77JOC0092Ł[ Theauthors also emphasize that it is important to use the {hydrated| form of the oxide\ which actuallyhas a hydroxide structure\ since the anhydrous oxide is very insoluble and does not form the activetetroxide under the reaction conditions[ Variants on this procedure use sodium bromate in aphosphate bu}er with ruthenium trichloride as precursor of the tetroxide ð74TL1096Ł\ or use sodiumperiodate ð76JOC0038Ł or hydrogen peroxide with didecyldimethylammonium bromide phase trans!fer catalyst ð77JOC2442Ł as cooxidant[

Unquestionably the most important ruthenium oxidants\ and one of the most important recentdevelopments in oxidation methodology generally\ are the tetraalkylammonium perruthenatesdeveloped by Gri.th and by Ley[ These use a catalytic tetraalkylammonium perruthenate\ generallytetrapropylammonium perruthenate "TPAP#\ in the presence of 9[3 nm "3 Aý# molecular sieves withN!methylmorpholine!N!oxide as regenerating oxidant to achieve the oxidation under very mild\neutral conditions[ The reagent is notable for the wide range of functionality tolerated\ includingTHP and silyl ethers\ alkenes\ epoxides and esters "Equation "5##\ and the fact that chiral centres ato the newly formed carbonyl group are not epimerized ð76CC0514Ł[ The reagent has been the subjectof a review ð89MI 293!90Ł[

73%

O

OH

O

O

(6)

"d# Miscellaneous metal oxidants[ Despite their importance in epoxidation chemistry\ vanadylspecies have seen very little use in alcohol oxidation reactions\ although they are known to o}er ahigh degree of selectivity for secondary over primary alcohols ð72TL4998Ł[

A wide range of molybdenum and tungsten salts can catalyse the oxidation of alcohols byhydrogen peroxide or t!butyl hydroperoxide[ The research group of Ishii has been particularly activein this area\ publishing a series of papers on a number of variants of which the tris"cetylpyridinium#01!tungstophosphateÐhydrogen peroxide system appears to be optimal ð77JOC2476\ 77SC758Ł\although Venturello et al[ recommend the related trioctylmethylammonium tungstophosphateÐhydrogen peroxide system ð80JOC4813Ł[ Benzyltrimethylammonium tetrabromooxomolybdate"BnMe2N¦ MoOBr3

−# ð73TL3306Ł\ and ammonium molybdate ð73TL062Ł\ are also known to catalysethe hydrogen peroxide oxidation of alcohols[ Two molybdenum peroxy complexes\ "1# ð79TL3732Łand "2# ð76JOC4356Ł\ have also been reported as stoichiometric oxidants for alcohols\ although "2#can also be used catalytically with hydrogen peroxide as cooxidant ð68JOC810Ł[

N

OMo

O

O

OOPh

Ph N

O

Mo

O

O

O

OO

O

O

(3)(2)

A number of ferrates have been examined as potential oxidants for alcohols[ In one valuablecomparative study\ barium ferrate was found to show a very similar reactivity to barium manganate

007 Dialkyl Ketones

ð75SC612Ł[ Silver ferrate ð75SC100Ł\ and a mixture of potassium ferrate\ alumina\ and copper sulfateð75TL1764Ł\ have also been found to be potentially useful oxidants[

Iridium pentahydride catalyses the dehydrogenation of alcohols in a remarkable reaction thatrequires no cooxidant or hydrogen acceptor but actually evolves gaseous hydrogen ð76TL2004Ł[Raney nickel can also be used to dehydrogenate secondary alcohols\ although in this case 0!octeneis required as a hydrogen acceptor ð75JOC4371Ł[

A number of catalytic palladium systems for alcohol oxidation are known\ and the scope of themethod has been examined ð72JOC0175Ł[ The optimal conditions found employ 0Ð2 mol) of eithera palladium"9# or palladium"II# catalyst with bromobenzene as reoxidant[ The oxidation can alsobe performed with tetrachloromethane or bromotrichloromethane as reoxidant ð74T4534Ł\ andunder phase transfer conditions with iodobenzene as reoxidant ð74TL5146Ł[

Copper"II# or zinc"II# nitrate supported on silica gel ð78JOC0420Ł\ and iron"III# nitrate supportedon clay ð79S738Ł\ have all been reported to oxidize secondary alcohols to ketones in good yield[Primary and secondary benzylic alcohols are also oxidized\ although unactivated primary alcoholsare una}ected[ The complex of copper"II# bromide and lithium t!butoxide oxidizes secondaryalcohols in high yield ð81CL0074Ł[

Barton|s group have examined a range of pentavalent bismuth reagents for oxidizing secondaryalcohols and recommend triphenylbismuth carbonate ð68CC694Ł[ The reagent is of interest sincesome normally sensitive functionalities\ such as pyrroles and indoles\ are una}ected[

Lanthanide reagents have received relatively little attention as potential oxidants for alcohols[The most important exception is the cerium"IV#!catalysed oxidation of alcohols by sodium bromateð71TL428Ł\ which may also be performed with a polymer!supported catalyst using cerium"IV#impregnated on Na_on resin ð78BCJ408Ł[ Ytterbium"III# nitrate is also known to catalyse theoxidation of alcohols by iodosobenzene and has the unusual selectivity of oxidizing primary inpreference to secondary alcohols\ although good yields of ketones can be obtained with longerreaction times ð82CL460Ł[

"ii# Usin` dimethylsulfoxide reaènts

Since P_tzner and Mo}at|s serendipitous discovery in 0852 that alcohols were oxidized at roomtemperature by dimethyl sulfoxide in the presence of dicyclohexylcarbodiimide and phosphoric acidð52JA2916Ł\ oxidations by activated DMSO have become established as one of the mildest and mostgeneral methods for the oxidation of alcohols[ Today the most commonly used variant is thatdeveloped by Swern and co!workers\ which uses oxalyl chloride to activate the DMSO ð67JOC1379\67T0540Ł[

The area is well served by several good reviews[ Literature up to 0879 is covered in a classic reviewby Mancuso and Swern ð70S054Ł\ which has been updated to the end of 0878 by Tidwell ð89S746Ł[Tidwell has also published an Orànic Reactions chapter on the subject which includes extensivetabulations of examples\ and a good discussion of the scope of the oxidation and of potential sidereactions ð89OR"28#186Ł[ Relatively little can be added to the coverage provided by these reviews[However\ bis"trichloromethyl# carbonate "triphosgene# has recently been reported to be a goodactivating reagent and\ being a crystalline solid\ avoids the handling and scale!up problems associ!ated with the relatively toxic and corrosive reagents generally used ð80JOC4837Ł[

Alcohols can also be oxidized by a mixture of N!chlorosuccinimide and diisopropyl sul_deð73CC651Ł[ The reaction is probably mechanistically closely related to the SwernÐMo}att oxidationand shows the curious and unexplained feature that at 9>C primary alcohols are oxidized inpreference to secondary\ while at −67>C the opposite selectivity is found[

"iii# Usin` haloèn!based oxidants

Although clearly the reactions are of limited generality\ under suitable conditions both elementalchlorine and bromine may be used for the oxidation of alcohols to ketones[ For example\ chlorinein hexamethylphosphoramide ð65S700Ł and bromine in the presence of nickel"II# benzoate ð79SC770Ł\or a hexaalkyldistannoxane ð65BCJ0545\ 65TL3486Ł\ have been used to prepare ketones from alcohols[In fact these elemental halogen oxidations are merely examples of a much larger class of electrophilichalogen"I# reagents which can oxidize secondary alcohols to ketones\ and of which the mostimportant members are the hypohalites[ Good results have been reported with sodium hypochlorite


under phase transfer conditions ð65TL0530\ 77S757Ł\ and with the easily stored calcium hypochloriteð71TL24Ł[ Calcium hypochlorite can also be used in a nonaqueous system which uses the hypochloriteform of the ion exchange resin IRA 899 as catalyst and permits a simple workup by _ltrationð71JOC253Ł[ In acetic acid solution\ sodium hypochlorite oxidations are selective for secondary overprimary alcohols\ and appear not to be prone to epimerizing sensitive ketone products ð79JOC1929\71TL3536Ł[ The reaction may well involve an acetyl hypohalite as the actual oxidant\ as is the mostlikely case in oxidations using peracetic acid and sodium bromide ð76BCJ3032Ł or benzyltrimethyl!ammonium tribromide ð78BCJ1474Ł[ Other electrophilic halogen reagents reported as oxidants foralcohols include trichloroisocyanuric acid ð81SC0478Ł\ bisquinuclidine bromine ð81JOC0599Ł\ andN!iodosuccinimide ð70S283Ł[

A number of higher oxidation state halogen reagents are important oxidants for alcohols\ inparticular periodinane "3#\ which was _rst reported as an oxidant for alcohols by Dess and Martin in0872 ð72JOC3044Ł[ An improved preparation has recently been described ð82JOC1788Ł[ The oxidationoccurs under very mild conditions and is compatible with a wide range of other functionalities\including secondary amides\ sul_des\ alkenes\ furans and vinyl ethers ð80JA6166Ł[ The relatedalkoxyaryltri~uoroperiodinane "4# has also been reported to oxidize alcohols to ketones in moderateto high yields ð68JA4183Ł[ Lastly in this section\ sodium bromite in acetic acid ð72S704Ł\ or in thepresence of aluminum oxide ð77JCS"P0#1312Ł\ is known to be an e}ective oxidant for alcohols[

OI OAc

AcO OAc

OI F

F F

(5)

O

(4)

"iv# Oppenauer and related oxidations

The oxidation of secondary alcohols by an aluminum alkoxide!catalysed hydrogen transfer to anacceptor ketone\ present in excess to drive the equilibrium in the desired direction\ was _rst reportedby Oppenauer ð26RTC026Ł[ The method was quite widely used in the older literature\ particularlyfor the oxidation of steroidal alcohols\ and was the subject of a review ð40OR"5#196Ł[ Very recentlythere has been a resurgence of interest in the method\ mainly centred on the development of newcatalysts which can be used for the oxidation of primary alcohols to aldehydes\ althoughruthenium"II# halides ð81CC226Ł and lanthanide alkoxides ð73JOC1934Ł have been found to be usefulalternative catalysts for the oxidation of secondary alcohols[

An interesting extension of the reaction couples carbon!to!carbon bond formation with theoxidation[ Thus\ addition of a solution of a Grignard reagent in an acyclic ether to an aldehydeforms a new carbon!to!carbon bond\ and the resulting halomagnesium alkoxide can be oxidized\ inthe same pot\ by addition of benzaldehyde as hydrogen acceptor[ Alternatively\ the halomagnesiumalkoxide can be prepared directly from an alcohol and ethylmagnesium bromide\ although inboth cases the majority of reported examples are preparations of unsaturated ketones "Scheme 1#ð76TL658Ł[ Snider et al[ have also coupled the diethylaluminum chloride!catalysed sequential enereactions of exocyclic alkenes with acrolein "which lead to cyclohexanols# with an Oppenaueroxidation which occurs in the presence of excess acrolein\ to give an attractive one!pot cyclohexanonering annelation "Scheme 2# ð75T1840Ł[

Scheme 2

MgBr +O

OOMgBr

PhCHO

69%

Possibly related to the Oppenauer oxidation is the highly selective oxidation of secondary alcoholson alumina using trichloroacetaldehyde as oxidant ð65TL2388Ł[ The method has been particularlyrecommended for cyclobutanone preparations ð66S444Ł[

019 Dialkyl Ketones

O+

AlMe2ClHO

AlMe2Cl

–

Scheme 3

acrolein, AlMe2Cl

acrolein

OOAlMeCl

+–

"v# Electrochemical and photochemical oxidations

Since an alcohol will not lose an electron at experimentally achievable electrode potentials\the direct electrochemical oxidation of alcohols is impossible[ However a number of systems areknown which use an intermediary species\ often referred to as an {electron carrier|\ which can oxidizethe alcohol chemically\ the resulting reduced form of the electron carrier being reoxidized at theanode to complete the process[ These include several traditional electron carriers such as iodoniumreagents ð68TL054Ł\ sulfur species ð68TL2750\ 79TL0756Ł\ molecular oxygen ð78S392Ł\ nitrateð79TL3584Ł\ and hydroxyphthalimide ð72CC368Ł\ as well as established oxidants for alcohols likeruthenium salts ð75JOC044\ 89SC288Ł\ in what are e}ectively electrocatalytic versions of the oxidations[Two!stage systems in which the oxidant is not reoxidized directly at the anode but via an electroncarrier are also possible ð80BCJ685Ł[

Photochemical oxidations of alcohols to form ketones is a largely unexplored area\ although it isknown that irradiation of an alcohol in the presence of a copper"II#\ iron"III# or silver"I# saltð68JOC027Ł or platinum on titanium dioxide ð73TL2252Ł can give high yields of ketones[

"vi# Miscellaneous other oxidations

Dimesityl diselenide catalyses the oxidation of alcohols to ketones by t!butylhydroperoxide[ Themethod is extremely mild and is even compatible with the presence of phenylthio or phenylselenogroups ð71JOC726Ł[ Under suitable conditions many peroxy reagents\ including mcpba in the pres!ence of dry hydrogen chloride ð89SC526Ł\ and Oxone "a mixed persulfate reagent# in the presence ofhydrated aluminum oxide ð80BCJ0935Ł\ are capable of oxidizing alcohols to ketones[ Perhaps moreuseful is methyl"tri~uoromethyl#dioxirane\ which not only achieves the conversion remarkablyrapidly "1Ð19 min#\ but is also compatible with acid!labile functionalities such as epoxides "Equation"6## ð80JA1194Ł[ Good results have also been reported with the per~uorodialkyloxaziridine "5#ð81TL6134Ł[

OH

OH

OH

O

H3C

F3C

OO

(7)94%

(6)

N

O

F

C3F7C4F9

Other miscellaneous oxidants include trityl tetra~uoroborate ð67TL1660Ł\ and 0\0?!azo!dicarbonylpiperidine\ which provides an attractive method of oxidizing alcohols via their bromo!magnesium salts ð66CL646Ł[


2[93[0[4[1 From diols

Probably the most important route to ketones from 0\1!diols is by oxidative cleavage[ Manyalcohol oxidants\ particularly metal!based oxidants\ will cleave vicinal diols\ and this can be aserious side reaction in attempts to prepare 0\1!diones[ However\ since few of these reagents giveconsistently high yields of ketones\ the majority of glycol cleavages are performed with eitherperiodate\ lead"IV# acetate\ or occasionally bismuth reagents ðB!54MI 293!90\ B!58MI 293!91\ 70CC0121Ł[In all three cases the mechanism appears to involve cyclic species\ explaining why the cleavage ofrigid trans diols is generally unsuccessful[ Diols protected as their dibutylstannylene derivatives canalso be cleaved with either periodate or lead"IV# acetate ð70TL1774Ł[

The preparation of ketones from 0\1!diols by pinacol rearrangement ð59QR246Ł\ and by rho!dium"III#!catalysed dehydration of 0\2!diols ð65CL120Ł is possible\ although problems of regio!control limit the application of both these reactions in syntheses where no additional directingfunctionality is present[

2[93[0[4[2 By oxidation of derivatives of alcohols

"i# Ethers

A wide range of alkyl and silyl ethers react with hydride!abstracting reagents to give an oxoniumion which hydrolyses to a ketone on workup[ Thus methyl ethers of secondary alcohols are oxi!datively cleaved by nitronium tetra~uoroborate ð66JOC2986Ł\ or uranium"VI# ~uoride ð67JA4285Ł\and O!trimethylsilyl derivatives can be oxidized with trityl tetra~uoroborate ð65JOC0368Ł or withnitrosonium tetra~uoroborate\ which will also oxidized stannyl ethers ð65S598Ł[ Sodium bromate\in the presence of cerium"IV# ammonium nitrate ð79S786Ł or polymer!supported cerium"IV# orchromium"III# catalysts ð78BCJ408Ł will oxidize a wide range of ether derivatives including methyl\benzyl\ trimethylsilyl and t!butyldimethylsilyl\ with selectivity for secondary over primary deriva!tives[ Alkyl ethers can be oxidized by copper"II# or zinc"II# nitrates suspended on silica ð78JOC2990Ł[

Silyl ethers can also be oxidized under rather milder conditions[ For example\ trimethylsilyl ethersare oxidized using dimethyl sulfoxideÐoxalyl chloride\ although the conditions "−29>C for 29Ð34min# are appreciably more vigorous than are normally required for alcohol oxidationsð76JCS"P0#0110Ł[ t!Butyldimethylsilyl ethers are inert to the reaction conditions and hinderedtrimethylsilyl ethers react appreciably less rapidly\ allowing some interesting selective oxidations tobe achieved "Equation "7##[ The Jones reagent will also oxidize trimethylsilyl ethers ð72S461Ł and\in the presence of potassium ~uoride\ t!butyldimethylsilyl ethers to ketones in yields that comparewell with a conventional two!pot deprotectionÐoxidation sequence ð74SC648Ł[ t!Butyldiphenylsilylethers are una}ected\ again allowing some interesting selective transformations to be achieved"Equation "8##[ The oxidative deprotection and stability under alcohol oxidative conditions of silylethers has been the subject of a very comprehensive review\ which includes extensive tabulations ofthe reactivities observed ð82S00Ł[ Lastly in this section\ tributylstannyl ethers can be oxidized toketones by a combination of lithium bromide and copper"II# bromide ð81CL312Ł[

TMS-O

TMS-OO

O

HOO

(8)74%

TBDMS-O OSiPh2But O OSiPh2But(9)

90%


"ii# Esters

Ketones may be prepared under strictly neutral conditions by the photolysis of the pyruvateesters of alcohols ð65JOC2929\ 65SC170Ł\ and the reaction has been applied to good e}ect in the

011 Dialkyl Ketones

preparation of a number of delicate carbohydrate ketones ð66JOC0105Ł[ Nitrite esters are oxidizedto ketones by dimethyl sulfoxide ð75T3022Ł\ and alcohols may be oxidized via their aci!nitro estersð68CC292\ 70TL1184Ł[ Both reactions can be regarded as variants of the Kornblum oxidation[

"iii# Carbonates

Treatment of alkyl allyl carbonates with palladium catalysts in the absence of phosphine ligandsgives good yields of ketones "Equation "09## ð73TL1680Ł[

O O

OO

(10)PdII

77%

2[93[0[4[3 Rearrangement of allylic alcohols

Allylic alcohols can be isomerized to ketones by treatment with rhodium"I# ð79JOC1158Ł orruthenium"II# catalysts ð80TL2928\ 82TL4348Ł[ Although the optimal conditions are substrate depen!dent\ good yields are frequently attainable\ and isolated double bonds and alcohols are una}ected[In the special case of 3!keto allylic alcohols\ acid!catalysed rearrangement to the 0\3!dione is possible"Equation "00## ð74JOC1549Ł[

O

OH

O

O

(11)

H

HBr

93%

2[93[0[5 From Epoxides

Treatment of epoxides with Lewis acids can give respectable yields of carbonyl compounds\although the identity of the product formed appears to depend on both the direction of ring openingand the migratory aptitude of the substituents[ Thus mono! and 0\0!disubstituted epoxides generallygive aldehydes\ but with 0\1!disubstituted and trisubstituted epoxides both the exact structure ofthe substrate and the conditions used are important[ For instance\ treatment of trisubstitutedepoxides with antimony"V# ~uoride ð80SL380Ł gives ketones selectively[ However\ even in 0\0!disubstituted epoxides\ the selectivity can be a}ected by small changes in the substrate\ as is the casein the lithium bromide!mediated rearrangement of the epoxide "6#\ which normally gives "7#\ theelectronically preferred product\ but when R is an oxygen functional group a chelation!controlledmigration leads to the formation of "8# as the sole product "Equation "01## ð74CL0326Ł[ This areahas been discussed in rather greater depth in a review of epoxide chemistry ð73S518Ł[

H

R O

H

R O

H

RO

(12)

(7) (9) (8)

+LiBr, HMPA

HMPA = hexamethylphosphoramide


2[93[0[6 From Acetals\ Enol Ethers and Enol Esters

The chief importance of acetals in organic synthesis is as protecting groups for carbonylcompounds[ As well as simple dialkylacetals\ 0\2!dioxanes\ and 0\2!dioxolanes\ many more complexacetals have been used as protecting groups and allow the preparation and deprotection of ketonesunder a remarkably wide range of conditions[ Readers interested in these aspects should refer toone of the specialist works on protecting groups such as that by Greene and Wuts ðB!80MI 293!91Ł\since the following discussion is only intended to highlight some of the more important approachesto preparing ketones from simple acetals[

Traditional methods of ketone preparation from acetals are variants on the theme of acid!catalysed hydrolysis\ and these have now been extended to use supported or heterogeneous acidssuch as Amberlyst!04 ð73S0910Ł or wet silica gel ð67S52Ł\ which permit a much simpler reactionworkup[ However\ a more important objective of research in this area has been to develop lessstrongly acidic conditions for acetal hydrolysis and to _nd methods that allow highly selectivedeprotections to be performed[ One approach to the former goal is to use transacetalizationswhich are catalysed by very mild reagents such as pyridinium tosylate ð68S613Ł\ and palladium"II#bis"acetonitrile# dichloride ð74TL694Ł\ although hydrolyses with neutral reagents\ such as aqueousDMSO ð78CL890Ł\ are also possible[ The use of aqueous DMSO is of particular note since it allowsdimethyl acetals to be hydrolysed in the presence of other\ more sensitive\ functionalities\ includingacetal!based alcohol protection such as methoxymethyl "MOM# or THP[ A number of procedures\including silica!supported iron"III# chloride ð76S26Ł and samarium"III# chloride in the presence ofchlorotrimethylsilane ð78CL0512Ł\ allow acetals derived from ketones to be cleaved preferentially inthe presence of those derived from aldehydes[

A relatively recent discovery is the ability of a number of reagents to e}ect the {hydrolysis| ofacetals under strictly nonaqueous conditions[ These methods appear to involve an electrophilicattack on one of the acetal oxygens leading to an oxonium ion which is cleaved to the ketone bynucleophilic attack on the alkyl group[ The mechanism is illustrated in Scheme 3 for the case ofiodotrimethylsilane ð66TL3064Ł[ Other reagents which work in this way include diiododimethylsilaneð89JOC1816Ł and phenyldichlorophosphate in the presence of sodium iodide ð75SC0246Ł[

O O

R1 R2

TMS

R1 R2

+OO-TMS

O O

R1 R2

R1 R2

O

I–

Scheme 4

+

+ IO-TMS

TMS-I

I–

Enol esters and silyl enol ethers are most often prepared from ketones as intermediates in otherreactions[ They are\ in general\ hydrolytically labile compounds\ making their transformation backto ketones relatively straightforward should it be required[ Tributyltin ~uoride with palladiumcatalysis has been recommended for the hydrolysis of more stable silyl enol ethers ð72JA4692Ł[

2[93[0[7 From Aldehydes or Ketones

2[93[0[7[0 From saturated aldehydes or ketones

"i# Alkylation

Although in principle ketone alkylations provide a powerful way of elaborating ketones\ simplebase!catalysed alkylations su}er from a number of drawbacks which limit their use[ These includepoor or no regio!\ diastereo! or enantiocontrol\ the occurrence of O! as well as C!alkylation\ and apropensity to give over!alkylated and aldol products[ Methods which o}er solutions to all theseproblems are now available and are described in this section\ although the coverage is necessarilybrief[

013 Dialkyl Ketones

The fundamental problem underlying the problems of both poor regioselectivity and poly!alkylation of sodium and potassium enolates is the fact that alkylation and proton transfer fromalkylated product to unreacted enolate proceed at similar rates\ although\ for reasons that areunclear\ tri~ate alkylating agents appear to be an exception and give good yields of monoalkylatedproducts with potassium enolates ð82JOC3358Ł[ Probably the earliest approach to controlling ketonealkylation involved the introduction of a directing group such as an ester\ thiolester or arylsulfonylgroup which is removed after alkylation[ The decarboxyalkylation of keto!ester intermediates canbe achieved by basic hydrolysis and acidi_cation\ and more conveniently with hot DMSO ð71S794Ł[Allyl esters can also be removed by treatment with palladium"9# ð74JOC2305Ł and thiol esters withRaney nickel ð68TL3010Ł[ Today\ however\ alkylations of metal enolates are more likely to beperformed with the lithium species which\ because of the greater covalent character of the lithiumoxygen bond\ undergo proton transfer far less rapidly and allow regioselective monoalkylation[Particularly low levels of polyalkylation have been reported to occur with manganese enolatesð82TL6284Ł[ The alkylation of metal enolates\ in particular those involving preformed metal enolateswhich avoid the aldol by!products often obtained under base!catalysed conditions\ has been wellreviewed by Caine ðB!68MI 293!90Ł\ and the speci_c topics of regiospeci_c enolate generation byd|Angelo ð65T1868Ł and of stereoselective alkylation of chiral enolates by Evans ðB!73MI 293!90Ł[

The poor diastereo! and enantiocontrol of the alkylation of metal enolates is less easily overcome\although the sense of any diastereoselection can be predicted using Houk|s rule\ an electrophilicanalogue of Cram|s rule which predicts the transition state depicted as "09# to be favoured[ This hasbeen tested quite extensively for the methylation and protonation of enolates and found to hold inthe vast majority of cases\ although the diastereoselectivity is frequently quite modest ð74CC038Ł[Enantioselective alkylations of ketone enolates are proving to be a particularly challenging objective\and are receiving quite extensive attention\ as are the enantioselective protonations of enolates\ aprocess that provides a complementary approach to a!chiral ketones ð80TA0Ł[

(10)

S

M

L

E+

Several important methods of ketone alkylation involve nitrogen derivatives of the ketone\ ofwhich the _rst to be introduced were enamines ð43JA1918Ł\ followed by metallated imines ð52JA1067Ł\and lastly metallated hydrazones ð65TL2Ł[ The alkylation of ketones via their nitrogen derivativeshas been the subject of a Synthesis review ð72S406Ł[ One particularly important application ofthese methods is for the enantioselective alkylation of ketones ð70JA2970\ 68CPB1659\ B!72MI 293!90Ł[Probably the best established of these methods is that developed by Enders\ which employs hydra!zones derived from "S#!"−#! or "R#!"¦#!0!amino!1!methoxymethylpyrrolidine "abbreviated toSAMP and RAMP\ respectively# and gives reliably high enantioselectivities of predictable sense"Scheme 4# ðB!73MI 293!91Ł[

Some stable enolate species\ such as silyl enol ethers\ will react with alkylating agents and\ afterworkup\ allow the isolation of good yields of alkylated ketones[ In the case of silyl enol ethers thereaction is Lewis acid!catalysed and involves the electrophilic attack of a carbocation on the enolether[ This mechanistic pathway also rationalizes the major limitation of the method\ which isrestricted to tertiary alkylating agents and is thus complementary to metal enolate methods whichdo not allow alkylations with tertiary halides[ The other major advantage of the method is thatit allows one to harness the well!developed techniques for preparing either the kinetic or thethermodynamic silyl enol ether with high speci_city to be used to control the regioselectivity of thealkylation[ Early work in the area has been reviewed ð71AG"E#85Ł[ Further research has been directedto trying to extend the bene_ts of this good regiocontrol to a wider variety of alkylating agents[One approach has been to use an a!phenylthio halide to introduce an a!phenylthio alkyl group fromwhich the phenylthio substituent is removed in a subsequent reduction "Scheme 5# ð77T3196Ł[Silver"I# tri~uoroacetate has been found to activate primary alkyl halides to nucleophilic attack bysilyl enol ethers\ although primary alkyl bromides and secondary alkyl iodides are unreactiveð81TL0744Ł[ Lastly\ intramolecular alkylations are an important route to cyclohexanones and cyclo!heptanones ð67JOC699Ł\ but not cyclopentanones\ in accord with Baldwin|s rules ð66CC122Ł[


O

NN

OMe

NN

OMe

O

O

Scheme 5

>95% ee

>95% ee

i–iv

70%SAMP

87%

RAMP

87%

LDA = lithium diisopropylamideSAMP = (S)-(–)-1-amino-2-methoxymethylpyrrolidineRAMP = (R)-(+)-1-amino-2-methoxymethylpyrrolidine

i–iv

70%

i, LDA; ii, ; iii, MeI; iv, HClBr

O

O-TMS

O-TMS

O

SPh

O

PhS

O

O

Raney Ni

99%

Scheme 6

Raney Ni

98%

i, TiCl4ii, PhSCH2Cl

87%

i, TiCl4ii, PhSCH2Cl

71%

LDA, TMS-Cl97%

Et3N, TMS-Cl83%

LDA = lithium diisopropylamide

"ii# Homologation

Although any preparation of functionalized ketones involving carbon!to!carbon bond formationand starting from a ketone can be thought of as a homologation\ this section will deal only withthose reactions which increase the number of carbon atoms without any increase in the functionalcomplexity of the molecule[ Homologations of this sort\ particularly by one carbon atom\ haveproved particularly important for the synthesis of medium!ring ketones by the ring expansion ofmore accessible\ normal ring ketones[

One important and well established reagent for ketone homologation is diazomethaneð43OR"7#253Ł\ although trimethylsilyldiazomethane has been recommended as a safer alternativeð71CPB008\ 71CPB2279Ł[ Epoxide formation can be a signi_cant\ or even dominant\ side reactionalthough good results are generally obtained with cyclic ketones[ One alternative which doesnot appear to share this drawback is dibromomethyllithium\ which adds to a ketone to give adibromomethylcarbinol[ This rearranges to the homologated ketone on further treatment withbutyllithium in a reaction which is proposed to proceed by a carbenoid mechanism and which allowsthe regioselective homologation of unsymmetrical ketones "Scheme 6# ð66BCJ0481Ł[ The reaction ofa ketone with phenylselenoalkyllithium gives a hydroxyselenide which may also be rearranged tothe homologated ketone "Scheme 7# ð89BSF570Ł[ Both the selenium and dibromomethyllithiumchemistry have been extended to allow the introduction of an RCH unit ð68S857Ł[

Dowd et al[ have developed a very versatile\ free!radical!mediated ring expansion of b!keto esters[

015 Dialkyl Ketones

OOHBr

Br O

Scheme 7

LiCHBr2

78%

BunLi

79%

O

+ SePh

Li

HO

PhSe O

Scheme 8

70%

AgBF4

85%

The method allows homologation by one ð80TL454Ł\ three or four carbons "Equation "02## ð78T66Ł\and appears to be quite tolerant of other functionality[

+

71%

I

CO2EtO

O

CO2Et

CO2EtO

(13)

25%

Bu3SnH, AIBN

AIBN = 2,2'-azobisisobutyronitrile

"iii# Transposition

0\1!Carbonyl transpositions regularly prove to be valuable in organic synthesis and\ fortunately\are the subject of a very comprehensive review ð72T234Ł[ Three chief groups of methods\ involvingsulfur\ silicon or boron chemistry\ can be distinguished\ all of which have variants allowing for theintroduction of an alkyl group at the original ketonic carbon[

The sulfur methods generally involve the preparation of an a!thioketone\ which is subsequentlyconverted into a vinyl sul_de and hydrolysed to give the transposed ketone "Scheme 8# ð68TL420Ł[Transpositions during which an additional alkyl group is introduced are also possible ð73BCJ097Ł[

The boron!based transpositions involve the addition of a Grignard reagent to the ketone anddehydration of the resulting carbinol to give an alkene which is then hydroborated and oxidized togive the transposed\ alkylated ketone "Scheme 09# ð50JA1840Ł[

The silicon!based methods involve the initial preparation of a vinylsilane followed by transpositionvia an a!silyl epoxide "Scheme 00# ð79JOC2917Ł[

O NNHTs

NNHTs

SMe i, BunLi, TMEDA

ii, MeSSMe

BunLi

Scheme 9

HgCl2, MeCN, H2OSMe O

TsNHNH2


O

O

Scheme 10

R ROHRRMgX i, B2H6

ii, chromic acid

–H2O

Scheme 11

O TMS TMSO i, PhSO2NHNH2

ii, BunLi, TMEDA

iii, TMS-Cl

mcpba LAH

OTMS

OH chromic acid

"iv# Oxidative addition to aldehydes

Although the addition of an organometallic reagent to an aldehyde followed by oxidation of theresulting secondary alcohol is a standard method for the two!step preparation of ketones\ theircombination in a single pot is uncommon[ However\ organovanadium dichlorides\ which areprepared by the reaction of vanadium"III# chloride with a Grignard or an organolithium reagentð74JA6068Ł\ and boronÐWittig reagents ð78TL4532Ł do react chemoselectively with aldehydes to givesaturated ketones in a high!yielding\ one!pot process[ The less general conversion of an aldehyde toa methyl ketone can also be achieved with "1\5!di!t!butoxy!3!methylphenoxy#dimethylaluminumð89TL212Ł[

2[93[0[7[1 From unsaturated ketones

"i# Conju`ate reduction

The conjugate reduction of enones to saturated ketones has traditionally been achieved withdissolving metal reagents\ particularly lithium in liquid ammonia ð65OR"12#0Ł[ Variants whichemploy ultrasound to promote the reduction by nickel"II# chloride activated zinc dust ð76TL1236Łor use aluminum powder in the presence of nickel"II# chloride have also been reported ð80T7476Ł[

Catalytic hydrogenation is also a well established method for the reduction of the carbonÐcarbondouble bond of enones[ The reduction can be achieved both by transfer hydrogenation ð67JOC2874Łand using homogeneous catalysts ð78SC562Ł[ The latter technique has been extended by the use ofBINAPÐRu"II# catalysts to allow the enantioselective reduction of 1!alkylidinecyclopentanoneswith high enantiomeric excess ð81TL524Ł[

Recent research on conjugate reduction has mainly been devoted to developing modi_ed hydridereducing agents with improved 0\3! versus 0\1!selectivity[ Aluminum!based reagents have generallyproved less satisfactory\ although good results have been reported for diisobutylaluminum hydride"dibal!H# in the presence of the hindered Lewis acid methylaluminum bis"1\5!di!t!butyl!3!methyl!phenoxide# ð77BCJ1130Ł\ for a variety of aluminum hydride reagents in the presence of copper"I#salts ð65JOC0828\ 66JOC2079Ł\ and for bis"diisopropylamino#aluminum hydride ð65TL2754Ł[

The development of conjugate reducing agents based on borane or borohydride derivatives hasbeen rather more successful[ Probably the best!established reagent of this class is potassium tri!s!butylborohydride "K!Selectride#\ although reasonable selectivity is only observed with cyclic ketonesð65JOC1083Ł[ This limitation is not shared by the softer potassium triphenylborohydride which\ in arecent and careful study\ has been shown to be generally the superior reagent for this applicationð77SC78Ł[ Catchecol borane has also been found to give very high 0\3!selectivity and is notable forbeing equally successful in the conjugate reduction of b\b!disubstituted enones ð89JOC4567Ł[ Becauseof the requirement that the enone must adopt an s!cis conformation\ the reaction fails for cyclic

017 Dialkyl Ketones

ketones\ a limitation that is shared by the otherwise very successful molybdenum carbonyl!catalysedconjugate reduction with phenylsilane ð76JOC1465Ł[

Other attractive metal hydride reagents for the conjugate reduction of a\b!unsaturated ketonesinclude the copper hydride cluster ð"PPh2#CuHŁ5\ all six hydrides of which are transferable ð77JA180\77TL2638Ł\ triphenylsilane in the presence of catalytic triethylborane ð80BCJ1474Ł\ and a mixture ofCollman|s reagent "Na1Fe"CO#3# and iron pentacarbonyl\ conditions which have the advantage ofbeing compatible with a wide range of other functionalities including epoxides\ aldehydes\ halidesand isolated double bonds ð64ACR231Ł[ Alternatively organic hydride donors\ such as 0\2!dimethyl!1!phenylbenzimidazole "00#\ which can also be used to introduce deuterium speci_cally at either thea or b position may be used ð75BCJ0636Ł[ Sodium dithionite under phase transfer conditions willalso selectively reduce the carbon!to!carbon double bond ð75T3592Ł[

N

N

Me

Me

Ph

(11)

"ii# Conju`ate additions of carbon nucleophiles

a\b!Unsaturated ketones are ambident electrophiles which can react with carbon nucleophiles inboth a 0\1! and a 0\3! fashion[ The outcome is largely determined by the electronic nature of thereagent\ with soft\ polarizable species tending to give predominantly the 0\3!product\ although stericfactors do play a role and make conjugate addition to b\b!disubstituted enones appreciably moredi.cult[

Easily the best!established class of reagents for conjugate additions are the organocuprates which\since they have been the subject of a considerable number of reviews\ will not be discussed in detailhere[ The early literature has been described by Posner\ one of the pioneers in the area\ ð61OR"08#0Ł\and the coverage has recently been updated by Lipshutz et al[\ whose group has also made majorcontributions to cuprate chemistry ð81OR"30#024Ł[ Speci_c aspects of organocuprate chemistry suchas higher!order cuprate chemistry ð73T4994Ł\ copper!catalysed reactions of Grignard and organo!lithium reagents ð73T530Ł and organocopper conjugate additionÐenolate trapping reactions ð74S253Łhave also been the subject of reviews[

The conjugate addition of cuprate reagents to enones is still a very active area of research\ withone important objective being the development of reagents which add enantioselectively[ At presentthe enantiomeric excesses being reported are quite variable\ although some results reported foramidocuprates\ which contain a chiral amine ligand\ appear very promising ð89TL3094\ 82T854Ł\ asdo the results of Grignard additions catalysed by chiral copper"I# thiolate complexes ð82TL6614Ł[Another interesting development is the preparation of organocopper reagents directly from an alkylhalide by reaction with a zero!valent copper species formed by the lithium naphthalenide reductionof "thienyl#Cu"CN#Li[ The method has the considerable advantage of permitting the preparationof organocopper reagents containing functional groups such as ester or chloro which would beincompatible with a Grignard or organolithium intermediate\ and should signi_cantly increase thescope of the chemistry ð81JOC1382Ł[

Although the majority of conjugate additions of alkyl groups are achieved by copper!basedmethods\ some alternatives are available[ Triorganozincates are one such option and appear to besuperior with respect to solubility and thermal stability[ They can be prepared by the reaction ofGrignard ð75JOC2882Ł or lithium ð75TL0326Ł reagents with zinc chloride\ or from Grignard reagentsand dimethylzinc[ The latter method gives a mixed triorganozincate in which methyl acts as a{dummy| ligand and is not transferred ð77JOC3022Ł[ Dialkylzinc reagents in the presence of catalyticNi"acac#1 have been found to be particularly useful for conjugate additions to b\b!disubstitutedenones ð74JOC4650Ł[

2[93[0[7[2 From a!functionalized ketones

Although a wide range of reducing agents is capable of e}ecting the reductive a!defunc!tionalization of particular classes of a!functionalized ketones\ samarium"II# iodide has attracted


considerable popularity because of the very good results obtained with many of these substrates\including a!halo\ a!acetoxy\ a!silyloxy\ a!tosyloxy\ a!phenylthio and a!phenylsulfonyl ketones[ How!ever a!hydroxyketones are not reduced and poor results can be obtained with substrates withhindered a!centres ð75JOC0024Ł[

a!Haloketones are probably the most frequently studied substrates for reductive a!cleavage\ andmany classes of reducing agent are known to e}ect the transformation[ Thus\ a number of one!electron reductants including samarium"II# or cerium"III# iodides may be used ð68SC130Ł\ as maysome mild hydride donors such as 0\2!dimethyl!1!phenylbenzimidazole "00# ð75JOC4399Ł or phenyl!silane in the presence of a molybdenum"9# catalyst and triphenylphosphine ð76JOC4469Ł[ Dehalo!genation with soft nucleophilic reagents such as sodium iodide ð75S469Ł\ sodium hydrogen tellurideð75S469Ł and sodium formaldehyde sulfoxylate "HOCH1SO1

−Na¦# ð76SC0476Ł\ or with some metalcarbonyls ð68JOC1457\ 68JOC530Ł\ is also possible[

a\a?!Dihaloketones give oxyallyl species on dehalogenation with low!valent metal reagents whichwill react with alkenes or dienes in a ð2¦1Ł or ð2¦3Ł sense to give cyclopentanones or cyclo!heptanones[ The reaction provides a very ~exible route to odd!membered ring systems of importancein natural product chemistry "Equation "03## ð74T4768Ł[ This chemistry has been reviewed as partof a much more general chapter on the reductive dehalogenation of polyhaloketones in Or`anicReviews ð72OR"18#052Ł[

Br Br

O

Br Br

+O

O

O(14)

i, Fe2(CO)4ii, Zn/Cu

63%

Hydroxide is a relatively poor leaving group and consequently many of the single!electronreductants that are very e}ective for a!dehalogenation work poorly on a!hydroxyketones[ It istherefore often preferable to activate the acyloin _rst\ by acylation or sulfonation\ and then reducewith samarium"II# iodide ð75JOC0024Ł or the vanadium"II#ÐTHF complex ðV1Cl2"THF#5ŁðZn1Cl5Łð81CL0784Ł[ However\ a!hydroxyketones can be reduced directly with lithium diphenylphosphide\which presumably adds 0\1! to the ketone and then undergoes a Wittig type reaction ð75JOC1267Ł\and with trimethylsilyl iodide ð68SC554Ł\ in which it is most likely the a!trimethylsilyloxy derivativewhich undergoes the reduction[

Relatively few alternatives to the standard reductive desulfonation of a!sulfonylketones withaluminum amalgam are available ð53JA0528Ł[ However\ the reduction can be achieved with sam!arium"II# iodide ð75JOC0024Ł and photochemically in the presence of a rhodium"II# sensitizer and aHantzch ester as ultimate reducing agent ð75CL76Ł[

a!Diazoketones are very versatile intermediates from which a wide range of derivatives may beprepared[ The two most important reactions from the point of view of this chapter are cyclo!propanation and the intramolecular insertion into C0H bonds\ generally to give cyclopentanones[Both processes are mediated by copper"II# and rhodium"II# catalysts and have been the subject ofa review ð80T0654Ł[ The insertion reaction can occasionally provide a very elegant cyclopentanonering synthesis\ the major drawback being the poor regiospeci_city[ Several strategies for improvingthe selectivity are known\ including suitable placement of electron!withdrawing groups\ such asesters\ which protect C0H bonds a and b to them from attack ð77TL1172Ł\ using rhodium catalystswith bulky ligands to favour methylene insertion over methine insertion ð81TL1698Ł\ or placingdouble bonds to harness the preference for allylic over nonallylic insertion ð80T6392Ł[ Enantio!selective versions of the reaction are also known ð72JA4824Ł[

2[93[0[8 From Carboxylic Acids and Their Derivatives

2[93[0[8[0 Reaction of carbon nucleophiles with acids and their derivatives

The preparation of ketones by the reaction of an acid chloride with an organometallic reagent hasbeen attempted with an enormous range of organometallic reagents[ Unfortunately\ few alkylmetalspecies show su.cient selectivity for reaction with the starting acid chloride over reaction with theproduct ketone to make the reaction synthetically viable[ Probably the _rst successful approachused Grignard reagents\ although an inverse addition of the Grignard reagent to an excess of acidchloride at low temperature is required if reasonable yields are to be obtained ð43OR"7#17Ł[ Improved

029 Dialkyl Ketones

results are obtained if THF rather than ether is used as solvent ð68TL3292Ł or if the reaction isperformed in the presence of tris"acetylacetonato#iron"III# ð76TL1942Ł[ The latter conditions areinteresting in being compatible with a wide range of other functional groups including ester andnitrile[ The other two reagents traditionally used for converting acid halides into ketones areorganozinc and organocadmium halides ð43OR"7#17Ł[ The latter\ which are prepared from an alkyl!lithium or Grignard reagent and cadmium"II# chloride\ are now little used\ for toxicological andenvironmental reasons[

Today the transformation is most often undertaken with an organocuprate\ an organozinc halideor an organomanganese halide[ The disadvantages of the organozinc halides are their relatively lowreactivity\ even with acid chlorides\ and di.culty of preparation[ However\ the reaction has beenfound to be greatly facilitated both by palladium catalysis ð72TL4070Ł and by copper"I# saltsð80JOC0334Ł and\ with the improved methods of preparation available ð74TL4418Ł\ must now con!stitute a very attractive preparation of ketones\ particularly in view of the toleration of sensitivefunctionality like "8!~uorenyl#methoxycarbonyl "Fmoc# and phthalimide "Equation "04## ð89SL624Ł[

INH-t-BOC

CO2Me

NH-t-BOC

CO2Me

AcO

O(15)

i, Zn/Cu, ultrasoundii, PdII, AcOCH2COCl

64%

t-BOC = t-butoxycarbonyl

As well as the zinc!derived cuprates\ a wide range of other organocopper species have been usedto prepare ketones from acid chlorides[ When an unfunctionalized primary alkyl group is to becoupled\ simple lower!order cuprates work well and are compatible with acid chlorides containingester\ nitrile and iodo groups ð61JA4095Ł\ although for more hindered cases higher!order cupratesgive better results ð77OSC"5#137Ł[ It is even possible to prepare suitable organocopper species directfrom the alkyl halides containing ester\ nitrile and chloro groups by reaction with the copper"9#complex obtained by treating lithium 1!thienyl cyanocuprate with lithium naphthalenide ð78SC0722Ł[The acylation of organomanganese halides\ which are prepared from a Grignard or alkyllithiumreagent and manganese"II# halide\ has been the subject of a detailed study ð73T572Ł[ Organo!manganese couplings can also be performed catalytically by adding a Grignard reagent to a solutionof the acid halide and 2 mol) of MnCl3Li1 ð81TL3328Ł[ Other reagents that\ although less widelyused or studied\ appear to have considerable potential for preparing ketones from acid chloridesinclude organothallium ð89JOC2257Ł\ and organovanadium ð75TL818Ł reagents[

Although many of the methods described above for preparing ketones from acid halides alsowork with acid anhydrides\ the reaction is somewhat limited by the fact that only half of the acid isincorporated into the product[ This drawback can be avoided if mixed anhydrides are used and theidea has been shown to be practical for both Grignard reagents ð67SC48Ł\ and organomanganesereagents ð68SC528Ł\ although few applications have been reported[

The preparation of a ketone by the reaction of a simple ester with an organometallic reagentappears to be a particularly di.cult transformation which is only successful if special precautionsare taken to prevent further reaction of the ketone product[ This can be achieved by performing thereaction with an alkyllithium reagent at low temperature "−009>C# in the presence of chloro!trimethylsilane\ which presumably traps the tetrahedral intermediate ð75JOC840Ł\ or with a Grignardreagent in the presence of triethylamine ð79S766Ł or lithium diisopropylamide ð76HCA0634Ł\ whichprotects the ketone by enolization[ The introduction of a bulky silyl substituent at the a position ofthe ester also very e}ectively prevents the reaction proceeding beyond the ketone stage ð74JOC4159Ł\and cyclic ketones can be prepared in high yields by the samarium"II# iodide!mediated cyclizationof v!iodo esters\ a reaction which appears to involve the addition of an alkylsamarium nucleophileto the ester "Equation "05## ð82JOC6105Ł[

(16)I

MeO2C

OSmI2, THF

93%

A number of ketone preparations from activated esters have been reported which\ despite therequirement to prepare the particular ester\ do appear to have some advantages[ For example\ bothselenoesters ð72TL3244Ł and 1!pyridyl esters ð72JOC1597Ł react with organocuprates to give high


yields of ketones[ The latter reaction has the distinct advantage over the analogous reaction of anacid chloride with a dialkylcuprate of using both alkyl groups from the organometallic reagent[

Perhaps surprisingly\ tertiary amides can be converted directly into ketones by reaction with analkyllanthanum tri~ate ð76TL3280Ł[ However\ most ketone preparations from amides use particularlyreactive derivatives\ such as acyl imidazoles ð89SC1572Ł\ or acyl aziridines ð73TL700Ł\ and N!methoxy!N!methyl "Weinreb# amides[ The latter\ in which internal chelation stabilizes the tetrahedral inter!mediate and prevents overreaction\ are rapidly becoming one of the preferred acid derivatives forketone preparation[ The idea has been generalized to N\N?!dimethoxy!N\N?!dimethylurea\ whichhas been found to react with a wide range of organometallic reagents to give N!methoxy!N!methylamides\ which can then be coupled with a second organometallic reagent to give an unsymmetricalketone ð80JOC1800Ł[

The preparation of ketones by the reaction of Grignard reagents with nitriles has a long history\although the conditions are quite critical\ with aromatic solvents being required for good resultsð79TL044Ł[ The reaction is also catalysed by the addition of copper"I# salts\ which allow the reactionto be used for the preparation of quite hindered ketones ð76JOC2890Ł[

The reaction of a carboxylic acid with two equivalents of an alkyllithium reagent is a wellestablished preparation of ketones which works because the dianionic tetrahedral intermediate doesnot break down under the reaction conditions to liberate the ketone\ which is therefore unavailablefor overreaction to the tertiary alcohol[ In practice\ obtaining good yields of ketone\ free fromcarbinol\ depends heavily on good experimental technique\ both in the addition of the alkyllithiumand in the hydrolysis of the tetrahedral intermediate ð69OR"07#0Ł[ Improved workups in which thereaction is quenched with aniline ð70JOC2817Ł\ gaseous formaldehyde ð70JOC2817Ł or\ for the speci_ccase of methyl ketone preparation\ with chlorotrimethylsilane ð72JOC0449Ł have been described\ andthe addition of cerium"III# chloride to the reaction mixture has been found to be highly bene_cialð83TL192Ł[ It is also possible to generate the lithium salt of the carboxylic acid from an alkyllithiumand carbon dioxide and react it in situ with a second equivalent of a di}erent alkyllithium to givean unsymmetrical ketone ð81AG"E#0924Ł[

2[93[0[8[1 Other preparations from acids and acid derivatives

The ready accessibility of b!keto esters by Claisen and Dieckmann condensations makes themimportant precursors of ketones[ Although the preparation of a ketone from a b!keto ester wastraditionally achieved by basic hydrolysis followed by acidi_cation and decarboxylation\ the reactionis frequently performed today with the salt:DMSO conditions _rst developed by Krapcho ð71S794Ł[The initial condensation can also be combined with the decarboxylation by using either acid dianionsð66JOC0078Ł or silyl ester enolates ð67TL2602Ł as one partner in the initial condensation[ In bothcases the aqueous workup gives a b!keto acid which decarboxylates in situ[ a!Hydroxy acids can becleaved by a variety of reagents\ including N!iodosuccinimide ð71JOC2995Ł\ and the benzoazoliumsalt "01# ð67CL38Ł\ to carbon dioxide and a ketone[

O

N

Et

Cl BF4–

+

(12)

2[93[0[09 From Sulfur or Other Lower Chalcogen!containing Precursors

The hydrolyses of thioacetals and vinyl sul_des are closely related processes which involve acommon sulfenium ion intermediate "Scheme 01#[ The mechanism is analagous to that of the closelyrelated hydrolysis of acetals and vinyl ethers\ although it di}ers in the important respect that theequilibrium is strongly towards the thioacetal rather than the carbonyl compound[ For this reasonit is necessary to drive the hydrolysis to completion by removing the thiol produced\ and a numberof methods have been developed for doing so\ the most important of which are the formation of aninsoluble transition metal thiolate\ alkylation of the thiol\ and oxidation of the thiol to a higheroxidation state of sulfur[ References to a selection of methods are contained in Table 0\ and the

021 Dialkyl Ketones

subject has been discussed in rather more detail by Gro�bel and Seebach ð66S246Ł[ Thioacetals havean important application as protecting groups and a useful discussion of this aspect may be foundin Greene and Wuts ðB!80MI 293!91Ł[ The cleavage of selenoacetals has been the subject of asystematic study which found that mercury"II# chloride in wet acetonitrile\ basic copper"II# chloridein aqueous acetone\ and hydrogen peroxide or benzeneseleninic anhydride in THF all gave goodresults ð68S766Ł[

R1

R2

SR3+

R1

R2

O

Scheme 12

–R3S–

+H+

H2O

R1

R2

SR3

SR3

R1

R2

SR3

Table 0 Preparation of ketones from thioacetals[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐRea`ent Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐTransition metal reagents

HgO\ HBF3 70S40PbO1\ BF2 = Et1O 71S479

Alkylating reagentsMeOSO1F 61S450Et2O = BF3 70S024

Oxidizing reagentsTl"NO2#2 68SC290Electrochemical 89TL1488Ceric ammonium nitrate 70SC312"PhSeO#1O 79JCS"P0#0543PhIO 71TL846mcpba 76S0002

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

Anions of sulfones can be oxidized to ketones by either bis"trimethylsilyl#peroxide ð72JOC3321Łor the molybdenum peroxide reagent MoO4 =pyridine =HMPA "MoOPH# ð79TL2228Ł[ In both casesan a!hydroxy sulfone is the presumed intermediate[

2[93[0[00 From Nitrogen!containing Precursors

2[93[0[00[0 From amines

Although the conversion of an amine into a carbonyl compound is a relatively common biologicaltransformation\ which can occur by ~avin!\ NADP! or pyridoxyl!mediated processes\ it is onlyrarely performed chemically[ Despite this there is a range of methods for achieving the trans!formation\ including some involving a pyridoxal!like prototropic rearrangement of an imine"Scheme 02# ð71JA3335Ł[

Direct oxidation of an amine to an imine is possible using an arylsulfonyl peroxide under stronglybasic conditions\ followed by hydrolysis to the ketone ð73JOC3900Ł[ Alternatively the oxidation andhydrolysis can be achieved in a single pot by nitroxyl!mediated electro!oxidation ð72JA5621Ł[ Anodicmethoxylation of carbamates also provides a simple route to ketones via their dimethylacetalsð72JOC2227Ł[

Although the ease of hydrolysis of imines makes them a particularly attractive intermediate in anamine!to!ketone conversion\ a recent method which involves the oxidation of a metallated silylaminewith dry air to give an oxime also appears attractive[ The oxime intermediate is hydrolysed to therequired ketone during ~ash chromatographic puri_cation\ and the conditions are compatible withphosphine\ thioether and tertiary amine functionality "Scheme 03# ð77TL5690Ł[


NH2

NMe CHONMe

N

dbu

O

+

H3O+

91%

NMe

+

Scheme 13

+

N

+


HNTMS

NOTMS

OLi

NO

i, BunLi

ii, dry air

NOH O

Scheme 14

SiO2, H2O

87%

2[93[0[00[1 From oximes\ hydrazones and their derivatives

Probably because they are relatively stable derivatives of ketones\ and have the reputation of onlybeing hydrolysed under fairly vigorous conditions\ oximes and hydrazones are relatively infrequentlyconsidered as potential precursors or protecting groups\ despite the very sizeable body of literaturedescribing methods of achieving this sort of transformation[

Classical oxime and hydrazone hydrolyses use fairly vigorous acidic conditions[ However\ thetransformation can be achieved with milder heterogeneous acid catalysts such as Amberlyst!04 resinfor tosylhydrazones\ dinitrophenylhydrazones and semicarbazones ð77JCS"P0#1452Ł\ or Dowex!49resin for oximes and semicarbazones ð77JOC767Ł[ Dowex!49 is particularly useful since it will allowthe selective hydrolysis of semicarbazones derived from ketones in the presence of those derivedfrom aldehydes[ Dimethylhydrazones may also be hydrolysed by a Lewis acid!catalysed transfer ofthe hydrazine to acetone ð65S345Ł\ or by addition of water to the complex of the hydrazone withboron tri~uoride etherate ð71SC04Ł[ A milder approach to the hydrolysis of hydrazones uses metalcomplexation of nitrogen to help polarize the carbonÐnitrogen double bond and facilitate attack bywater[ The metal ion most commonly used for this purpose is copper"II#\ which has the advantage ofalso driving the reaction to completion by scavenging the liberated hydrazine derivative ð65TL2556Ł[

Probably the largest group of methods for preparing carbonyl compounds from C1N derivativescomprises those employing oxidizing agents[ These include a number of nitrosating reagents which\like copper"II# complexation\ activate the carbon atom to attack by water by electrophilic attack atthe nitrogen atom[ Examples of this type of method include the hydrolysis of oximes by nitrosylchloride ð66CI"L#343Ł or a mixture of sodium nitrite and chlorotrimethylsilane which provides an insitu source of nitrosyl chloride ð89TL5566Ł^ the hydrolysis of tosyl hydrazones mediated by sodiumnitrite in tri~uoroacetic acid ð68S196Ł^ and hydrolysis of both oximes and N\N!dimethylhydrazoneswith either nitronium or nitrosonium tetra~uoroborate ð65S509Ł[ Active oxygen reagents can alsobe used[ For instance\ aryl hydrazones can be cleaved with basic hydrogen peroxide ð67S808Ł\ oximeswith dimethyldioxirane ð82SL316Ł\ tosylhydrazones with sodium percarbonate ð81SC1476Ł\ anddimethylhydrazones with sodium periodate ð65TL2Ł[ The recently introduced magnesium mono!peroxyphthalate has been found to be particularly valuable in cleaving hydrazones without a}ect!

023 Dialkyl Ketones

ing the stereochemical integrity of a chiral centre a to the ketone product ð89SL614Ł\ an advantagealso o}ered by the N!bromosuccinimide!mediated cleavage of tosyl hydrazones ð66JOC2194Ł[

Conventional high!valency metal oxidants can also be employed for preparing ketones fromoximes or hydrazones[ Thus\ bis"trimethylsilyl# chromate ð81SC1314Ł\ and pcc in the presence ofhydrogen peroxide ð79S014Ł\ have both been found valuable for the preparation of ketones fromoximes^ thallium"III# acetate can be used to regenerate ketone tosylhydrazones ð68TL3472Ł^ andcetyltrimethylammonium permanganate will convert arylhydrazones to ketones ð75JOC2952Ł[ Ben!zeneseleninic anhydride will also cleave a range of C1N derivatives\ including oximes\ aryl! andtosylhydrazones and semicarbazones\ but not N\N!dimethylhydrazones or O!methyl oximes[ Thereagent appears to be particularly e}ective for the regeneration of hindered ketones ð79JCS"P0#0101Ł[

Although the majority of new methods involve the use of oxidative reagents\ it is also possible toachieve the transformation under reducing conditions[ For example\ both Raney nickelÐsodiumhypophosphite ð75SC792Ł and vanadium"II# chloride ð79S119Ł can be used for deoximation\ andtitanium"III# chloride can be used to liberate ketones from tosylhydrazones\ oximes\ semicarbazones\and thiosemicarbazones ð66CI"L#631Ł[ Despite the variety in the types of reducing agent used\ theyall appear to involve an initial reduction to an imine\ which is hydrolysed under either the reactionor workup conditions[

Lastly\ it has recently been reported that both oximes ð80JCS"P0#1945Ł and hydrazones ð80TL1546Łcan be cleaved enzymatically with baker|s yeast[ The hydrolysis\ which is greatly aided by sonication\gives near quantitative yields of the ketone[

2[93[0[00[2 From nitroalkanes

The preparation of a carbonyl compound from a primary or secondary nitroalkane is usuallyknown as the Nef reaction[ The conversion was originally achieved by treatment of the nitronatesalt of a nitroalkane with strong acid\ but the extremely vigorous nature of these conditions\ andthe occurrence of a number of side reactions\ has lead to the development of a wide range ofalternative conditions[ These methods have been reviewed comprehensively in a recent volume ofOr`anic Reactions ð89OR"27#544Ł[

2[93[0[00[3 From nitriles

A study of a number of methods for achieving the oxidative decyanation of secondary nitrilesfound that the best results were obtained by preparing the a!hydroperoxy nitriles by direct oxy!genation of the anion and subsequent reductive hydrolysis with tin"II# chloride followed by sodiumhydroxide ð72JOC3976Ł[

2[93[0[01 From Organosilanes

Probably the most important organosilane precursors of unsubstituted ketones are vinylsilanes\which can be oxidized directly to the corresponding ketone with molecular oxygen ð78CL1122Ł\although the conversion is most often achieved by epoxidation followed by acid!catalysed rearrange!ment ð63JA2572Ł[ Both methods result in formation of the ketone at the silicon!bearing carbon atom[

2[93[0[02 From Organoboranes

Hydroboration reactions are most often worked up with alkaline hydrogen peroxide to give analcohol[ In cases where a ketone is required\ it is generally obtained by oxidation of the alcohol ina second step\ although it is also possible to achieve the transformation in a single pot by usingpyridinium chlorochromate rather than alkaline hydrogen peroxide to oxidize the borane inter!mediate ð89SC2154Ł[

Organoboranes are valuable precursors of ketones\ particularly symmetrical ones\ through anumber of carbon!to!carbon bond forming reactions in which alkyl groups on boron become boundto the ketone carbon atom[ The earliest examples of this involved the reaction of a thexyl!dialkylborane with either carbon monoxide or cyanide and have recently been combined with


enantioselective hydroboration methodology to give quite complex ketones of very high opticalpurity ð77JA0418Ł[ The thexyl group is important since\ being nonmigrating\ overreaction to give atertiary carbinol is not possible[

Ketones can also be prepared by reaction of an organoborane with a carbanion bearing threeleaving groups and\ for reasons of both reaction selectivity and reagent toxicity\ this chemistry isnow normally preferred[ Thus\ good yields of ketones can be obtained by treatment of tri!alkylboranes with the anion derived from 3\3!dimethyl!1!oxazoline ð72SC256Ł or tris"phenyl!thio#methane ð70CC0038Ł\ in which tertiary carbinol formation is apparently not a problem[Overreaction can also be prevented by using an alkoxyborane\ the alkoxy group\ like thexyl\ beingnonmigrating[ Such boranes have been used in a number of recent approaches to homochiralketones by the reaction of lithium dichloromethyl methyl ether with the products of enantioselectivehydroborations "Scheme 04# ð71JA5733\ 73T0214\ 76JA4319Ł[ An ingenious variation on this theme uses"phenyldimethylsilyl#dichloromethyllithium to give an a!hydroxy silane which can be oxidized tothe required ketone with the Jones reagent "Scheme 05# ð79SC702Ł[

BH2B i, trans-2-butene

ii, 1-pentene

MeCHO

BEtO O

Scheme 15

i, Cl2CHOMe, ButOLiii, H2O2, HO–

66%, 70% ee

Bn-C8H17 i, thexylborane

ii, 1-octene

i, PhMe2SiCCl2Li

ii, H2O2, HO–

n-C8H17

O

Scheme 16

PhMe2Si n-C8H17OH

Jones

51%

A number of attractive boron!based routes to ketones involve the preparation of an alkenylboranewhich\ on treatment with basic hydrogen peroxide\ gives the ketone directly[ These preparationsbene_t from the impressive range of methods which are now available for the synthesis of alken!ylboranes and which complement the simple hydroboration of alkynes[ These include an alkylativehydration of an alkyne in which chlorotributyltin is used to induce the migration of a primary alkylgroup to the adjacent acetylenic carbon of a lithiumÐ0!alkynyltrialkylborate complex "Scheme 06#ð73JOC4064Ł[ A similar borane!based transformation of a 0!bromoalkyne is also known ð71JOC643\71JOC2797Ł\ as are sequences involving 0\1!dimethoxyethenylborates "Scheme 07# ð70CL0948Ł[

2[93[0[03 Methods Involving Umpolung

Although reactions involving polarity reversal\ such as the benzoin condensation\ have beenknown since the earliest days of organic chemistry\ it is only over the last 29 years that the concepthas really played an important role in synthetic chemistry[ Much of the early development of thearea and the nomenclature used in this section are due to Seebach ð68AG"E#128Ł[ A vast range ofumpolung synthons are now available\ with by far the most important for ketone preparation beingthe d0 "formyl dianion and acyl anion# reagents\ and the d2 "homoenolate# equivalents[

025 Dialkyl Ketones

n-C6H13 BB

n-C6H13

Bun

Li Bun

Scheme 17

Bu3SnCl

H2O2, HO–

62%B

n-C6H13 Bun

SnBu3 n-C6H13 n-C5H11

O

MeO

Br

OMe MeO

Bu3B

OMe

–

BuEt

O

Scheme 18

i, BunLi

ii, Bu3B

i, EtOSO2F

ii, H3O+

2[93[0[03[0 Acyl anions and their equivalents

Although their synthetic value is perhaps rather limited\ a number of acylmetal reagents can beprepared\ and some reports\ most notably from the group of Seyferth\ of their use in preparativechemistry have appeared[ Acyllithium reagents can be prepared by the addition of an alkyllithiumto a saturated solution of carbon monoxide in a tetrahydrofuranÐetherÐpentane solvent mixture at−009>C ð74JOC0874Ł or more conveniently\ in cases where the method is applicable\ by lithiumÐtellurium exchange of a telluroester having no acidic a!protons ð89JA344Ł[ Although the extremebasicity and low stability of these reagents limits their synthetic applications\ acylcuprates\ whichare prepared in an analogous way from carbon monoxide and a dialkylcyanocuprate\ appear to bemore useful and will add to both cyclic and acyclic enones and to enals in very respectable yieldsð75TL0362Ł[

Acyl radicals have received a considerable amount of attention over the last few years and\ likethe acyl anion species\ o}er the possibility of achieving transformations that would be impossibleaccording to {normal| criteria of reactivity[ Acyl radicals are usually generated by treatment of anacyl selenide with tributyltin hydride and have been trapped with alkenes\ either intermolecularlyð78JOC066Ł or intramolecularly to give cyclohexanes ð89JCS"P0#1764Ł or large ring systems ð89JA3997Ł[Interestingly\ 05!membered ring lactones are formed even when competing 5!exo or 6!endo!tri`cyclization modes are also possible\ although macrocyclization and 4!exo!tri` cyclization occur atsimilar rates "Equation "06##[ The generation of acyl radicals from acylgermanes ð89JOC4451Ł\ from"S#!acylxanthates ð77CC297Ł\ and from acylcobalt precursors ð89JCS"P0#1610Ł has also been reported[

O

O

SePh

O

O

O

O (17)Bu3SnH, AIBN

70%


Many d0 synthons that have been described and can be classi_ed either as formyl dianionequivalents\ in which the two carbonyl substituents are introduced in successive alkylating steps\ oras acyl anion equivalents\ in which one of these substituents is already present[ A compilation ofacyl anion equivalents reported up to the early 0879s is available and includes details of theelectrophiles used ð71MI 293!90Ł[ The general topic of nucleophilic acylation has been the subject ofa review ð65T0832Ł\ as has the chemistry of silicon!containing carbonyl equivalents ð71CSR382Ł[


It should also be noted that many of the formyl anion equivalents discussed in Chapter 2[90[0[03[0can be doubly alkylated and are thus also formyl dianion equivalents[

A large proportion of formyl anion and dianion equivalents are based on sulfur[ This groupincludes one of the earliest and still one of the most important synthons\ 1!lithio!0\2!dithiane\which has been the subject of several reviews ð66S246\ 78T6532Ł[ Formyl anion synthons containingsulfur"VI#\ such as "02# ð73CC375Ł\ are also known[

(13)

PhSO2 TMS–

d0!Formyl anion and dianion synthons based on nucleophilic metal carbonyl derivatives can bevery useful reagents for ketone synthesis[ The best!known example is the Collman reagent\Na1Fe"CO#3\ which reacts with primary and secondary halides and sulfonates to give an alkyl ironcomplex which can be alkylated a second time to liberate the required ketone "Equation "07##[ Thereagent tolerates ketone\ ester or nitrile functionality\ but has the drawback of being somewhatbasic\ causing elimination of some substrates\ in particular of tertiary halides and sulfonates\ andbeing restricted to quite reactive alkylating agents "generally primary iodides# in the second stepð64ACR231Ł[ A number of related ionic iron carbonyl complexes ð68CL210\ 78BCJ1617Ł have also beenused[

(18)

i, Na2Fe(CO)4ii, EtI

74%

BrCO2Et

CO2Et

O

Acyl anion equivalents\ which already contain one of the carbonyl substituents\ are also importantketone precursors[ Two principal groups can be identi_ed] those based on vinyl anions\ and thoseusing protected cyanohydrins or related species[ The latter\ which are extensions of the benzoincondensation\ have been the subject of a review ð72T2196Ł[ One particularly important class of thesesynthons is the dialkylaminonitriles which\ since they are prepared by the Strecker reaction of analdehyde\ allow a fairly direct preparation of ketones from aldehydes[ Lastly\ a wide variety ofmetallated vinyl compounds have been prepared and used as acyl anion equivalents[ Examplesinclude lithium and Grignard derivatives of vinyl silanes ð71CSR382Ł\ and lithiated derivativesof vinyl sul_des ð73BCJ0752Ł\ vinyl esters ð70T2886Ł\ vinyl carbamates ð89JOC4579Ł and enaminesð70CC0010Ł[

2[93[0[03[1 Other anion equivalents

Although homoenolates of nonenolizable ketones can be formed with very strong bases\ thechemistry is of limited synthetic generality and d2 synthons are generally preferred[ The majority ofhomoenolate equivalents are substituted allyl anion species and consequently have the limitationthat the selectivity for alkylation at the required g!position can be modest[ A useful introduction tothe chemistry of both homoenolates and their equivalents has been provided by Wertiuk ð72T194Ł[

b!Functionalization of ketones can also be achieved via b!keto radical intermediates[ These areavailable by the manganese"III# oxidation of cyclopropanols and allow the rapid elaboration ofsubstituted medium!ring ketone systems "Equation "08## ð82CL434Ł[

(19)

HOO

H

H

MnIII, Bu3SnH

75%

027 Dialkyl Ketones

Lastly\ a number of a1 synthons are known\ although they have most often been reported reactingwith fairly stabilized anions such as enolates or keto esters[ However\ the sulfur!substituted allylacetate "03# will couple with a lithium dialkylcuprate and thus acts as an a!keto cation equivalent"Scheme 08# ð68JA3302Ł[

SPh

OAc

SPh

Bun

O

Bun

Scheme 19

Bu2CuLi

89%

HgCl2

(14)

2[93[1 BETA!UNSATURATED AND MORE REMOTELY UNSATURATED KETONES

The unconjugated alkene functionality is relatively unreactive and many of the methods describedin Section 2[93[0 can therefore be used for the preparation of remotely unsaturated ketones simply byusing an appropriately unsaturated precursor[ One very signi_cant restriction to this generalizationconcerns b\g!unsaturated ketones where the ease with which the double bond can migrate intoconjugation can restrict the choice of reagents[

This section describes methods in which the unsaturation is a necessary\ or integral\ part of thechemistry[ The reactions consequently have no direct analogues for the preparation of saturatedketones^ indeed some of the methods\ with the addition of a _nal hydrogenation step\ can formpowerful approaches to saturated ketones[

2[93[1[0 Dialkyl Ketones with One Double Bond

2[93[1[0[0 From ketones

"i# Vinylation of saturated ketones

Although the direct base!catalysed vinylation of a ketone with a 0!bromoalkene is not possible\the transformation can be achieved using one of a number of vinyl cation equivalents[ Most of thesereagents employ transition metal chemistry\ as in the palladium!catalysed vinylation of lithiumenolates with alkenes ð79JA3862Ł and of tin enolates by 0!bromoalkenes ð72CL728Ł[ Lithium enolatescan also be vinylated with h1!ethoxyethene complexes of iron ð79JA4829Ł[ This chemistry has beenextended both to allow isopropenylation of enolates ð70JOC3092Ł and\ with 0\1!dimethoxyethenecomplexes\ to give a 0\1!ethene dication equivalent[ By variation of the reaction conditions\ thelatter complex allows the preparation of both "E#! and "Z#! alkenylated ketones "Scheme 19#ð73JA6153Ł[ Enol silanes can be ethenylated intramolecularly by alkynes with mercury"II# catalysis\via a postulated transient a!mercury ketone intermediate[ The initially formed vinylmercury productis normally protonated "or deuterated# in the workup\ but can also be trapped with other elec!trophiles "Equation "19## ð74JA0615Ł[ Ethenylation of zinc enolates can also be achieved withphenylselenoacetaldehyde "Scheme 10# ð71JOC0521Ł[

Fe+

COCO

OMeMeO

Fe+

COCO

OMe

Fe+

COCO

OMe

OLiOLi

FeCO

COO

FeCO

CO

i, Me2CuLi

ii, HBF4

Scheme 20

O

RT, 30 min

O∆

52%

O∆

38%

028b! and More Remotely Unsaturated

(20)

O-TMS O i, HgCl2ii, HCl

83%

O(1/2Zn) O

Scheme 21

O OH

SePh

PhSeCH2CHO

95%

MsCl, Et3N

82%

"ii# Allylation of saturated ketones

Since allyl halides are highly reactive alkylating agents\ conventional base!catalysed and metalenolate!based alkylation methods may be employed for the allylation of ketones\ although with theusual attendant problems of polyalkylation and poor regiocontrol "Section 2[93[0[7[0#[

The palladium!catalysed allylation of stabilized anions\ such as those derived from b!ketoesters\with allyl acetates is\ by now\ a well established reaction which has been studied in considerabledetail ð66T1504Ł[ More recent work has shown the reaction to be successful with nucleophiles suchas enol stannanes ð79TL1480Ł\ enol silanes ð72CL0214\ 75CL0998Ł\ enol acetates ð72TL3602Ł and evenlithium ð70CC0048Ł or zinc ð72JOC3987Ł enolates\ thus allowing the preparation of a variety of simpleunsaturated ketones[ The allylation is also reported to be catalysed by rhodium"I# to give productswith inversion rather than retention of allyl con_guration ð73TL4046Ł\ and by cobalt"II# underneutral rather than mildly basic conditions ð82TL5290Ł[ Considerable variation is also possible inthe allyl component of the reaction^ for example\ allyl isoureas ð73CL0116Ł or allyl carbonatesð74JOC0412Ł can be substituted for the more usual allylic acetate[

One particularly interesting development of the palladium!catalysed allylation chemistry is thedecarboxylative allylation where an allyl b!ketoester undergoes a formal extrusion of carbon dioxideon treatment with either a palladium"9# ð79JA5270Ł or a palladium"II# ð79TL2088\ 72TL0682Ł catalyst"Equation "10##[ Decarboxylative allylations of b!ketoacids with allylic acetates are also possibleð75JOC310Ł[ Considerable e}ort is also being devoted to the development of enantioselective versionsof the reaction\ although largely with ketoester and malonate nucleophiles[ However thepalladium"9#!catalysed intramolecular allylation of proline!derived enamines has been shown toproceed with very high enantiomeric excess\ although the chemical yields are quite modest "Equation"11## ð75CC358Ł[

O

O

OO

(21)Pd0

96%

OH

(22)Pd0

47%, 100% ee

NO

O

H

Allyl halides\ because of their high SN0 reactivity\ are e}ective electrophiles in the Lewis acid!catalysed alkylation of silyl enol ethers ð68TL0408\ 68TL3860Ł[ The reaction is discussed in more detailin Section 2[93[0[7[0[

039 Dialkyl Ketones

"iii# Conju`ate addition of unsaturated nucleophiles to a\b!unsaturated ketones

Although the methodology used for the conjugate addition of carbon nucleophiles is broadlysimilar\ irrespective of whether or not the nucleophile contains carbonÐcarbon double bonds\ therather di}erent character and generation of vinyl! and allylmetal reagents justi_es some additionaldiscussion beyond that of Section 2[93[0[7[1[

Hydrometallation of alkynes is an attractive way of preparing alkenylmetal reagents[ For example\hydroalumination of an alkyne gives an alkenylaluminum reagent which can either be used as aprecursor of a cuprate ð89JOC0314Ł or treated with methyllithium to form an ate complex which willadd 0\3! to an enone ð68JOC0327Ł[ Alkenylzirconium reagents\ prepared analogously by hydro!zirconation of an alkyne\ can also be used as cuprate precursors ð89JA6339\ 89JA6330Ł or alternativelycan be activated towards conjugate addition\ even to hindered enones\ by Ni"acac#1\ or Ni"acac#1prereduced with dibal!H ð79JA0222Ł[ Alkenylboranes\ prepared by the reaction of an alkyne with 8!borabicycloð2[2[0Łnonane "8!BBN!H#\ also undergo e.cient conjugate addition to acyclic enonesð65JA6721Ł[

Allylsilanes add 0\3 to enones in the presence of titanium"IV# chloride ð66JA0562Ł\ or tritylperchlorate ð76CL178Ł catalysts[ Impressively\ the reaction is equally successful with b\b!dis!ubstituted enones "Equation "12##\ and the resulting enolate intermediate can be trapped withcarbon electrophiles ð68CL134Ł[ Allylstannanes undergo 0\3!addition to enones in the presence oftrimethylsilyl tri~ate\ to give the product in which the allylstannane has coupled at its more hinderedposition "Equation "13## ð80SC14Ł[ Allylsilanes do not react under these conditions and the reactionfails for b\b!disubstituted enones[ The reaction can also be performed photochemically^ under theseconditions couplings with b\b!disubstituted enones are successful\ although products from both a!and g!attack are also seen ð80CL0902Ł[

OO

H

TMS (23)+TiCl4

85%

(24)

O O-TBDMS

+ Bu3SnTBDMS-OTf

88%

2[93[1[0[1 From carboxylic acid and carboxylic acid derivatives

b\g!Unsaturated ketones can be prepared by the aluminum chloride!catalysed electrophilic acyl!ation of allylsilanes ð68JOC2286Ł\ or by the reaction of allylmercury"II# iodides with acid chloridesð82JOC1736Ł[ The Lewis acid!catalysed reactions can also be performed with allylstannanesð80CL0070Ł\ which also react with transition metal catalysis ð66JOM"018#25Ł[ In all three systems thereaction proceeds by an E1? mechanism with allylic rearrangement[ A related reaction is thealuminum chloride!catalysed acylation of 0!trimethylsilyl!1!methylcyclopropane\ which providesb\g!unsaturated ketones in a regio! and stereospeci_c manner "Equation "14## ð70TL1772Ł[ b\g!Unsaturated ketones have also been prepared by the acylation of h2!allylnickel complexes withpyridine!1!carboxylates ð68CL0372Ł\ and by the zincÐsilver couple!mediated reaction of allyl halideswith nitriles ð70TL538Ł[

(25)TMS

OPriCOCl, AlCl3

75%


2[93[1[0[2 Preparations involving rearrangements

"i# Claisen rearran`ements

The Claisen rearrangement\ the ð2\2Ł sigmatropic rearrangement of an allyl vinyl ether\ can be auseful route to g\d!unsaturated ketones ð64OR"11#0\ 66S478Ł[ The chief di.culty with the reaction liesin the preparation of the allyl vinyl ether substrate[ This is normally achieved by a mercury"II#!catalysed vinyl ether exchange reaction "Equation "15##\ although a number of alternatives havebeen reported\ including the Bro�nsted acid!catalysed reaction of an allylic alcohol with a ketoneacetal ð71JOC632Ł and the reaction of an allylic alcohol with a b!chloroacrylic acid to give ab!allyloxyacrylic acid which rearranges and decarboxylates in situ "Scheme 11# ð74JOC3553Ł[ An azaanalogue of the Claisen rearrangement is also known and o}ers some advantages in terms of easeof preparation of the precursors ð77JOC3378Ł[ Finally\ Claisen rearrangements of allyloxyketone!derived enol silanes have been used to prepare b\g!unsaturated ketones "Scheme 12# ð75JOC0282Ł[

(26)

HO

O

Hg(OAc)2, ethyl vinyl ether

85%

OH+

OH

Cl O OO

OH

O

Scheme 22

i, NaH (2 equiv.)

ii, H3O+

i, NaHii, 200–215 °C

78%

O

OO-TMS

OO

Scheme 23

TMS-Cl, Et3N

84%

HIO4

72%

"ii# Oxy!Cope rearran`ements

The oxy!Cope rearrangement is a ð2\2Ł sigmatropic rearrangement of a hexa!0\4!dien!2!ol systemto form a d\o!unsaturated ketone[ Early studies of the rearrangement were performed using thermalconditions which\ because of the temperatures required "×199>C#\ are of limited synthetic utilityð64OR"11#0Ł[ However\ formation of the potassium salt of the starting dienol has been found to leadto an enormous increase in the rate of the reaction\ allowing it to be run at room temperature[ Thisdiscovery has greatly extended the scope of the reaction by permitting the use of substrates containingmore sensitive functionality and allowing further elaboration of the product by trapping of thepotassium enolate in situ ð89AG"E#598Ł[ One of the few drawbacks of the anionic conditions is thatthe yields can vary considerably depending on the batch of potassium hydride used\ although theproblem can be avoided by pretreatment of the hydride with 09 mol) of iodine ð75JOC0013Ł[ Therearrangement can also be promoted by catalytic mercury"II# tri~uoroacetate ð71TL3152Ł or byformation of a trimethylsilyl ether derivative ð71CC717Ł[ The reaction has proved to be particularlyvaluable for the preparation of macrocyclic ketones by four!carbon ring expansion of more accessible

031 Dialkyl Ketones

cyclic ketones[ Such a strategy requires the a!ethenylation of the starting ketone\ a far from simpletransformation for which a number of elegant solutions have been developed "Scheme 13# ð79BCJ1847\71JOC1157Ł[

O

Cl ClOMgCl OMgCl

Scheme 24

MgCl

200 °C

OOH

70 °C

"iii# Other rearran`ements

Since the migratory aptitude of vinyl groups is greater than that of alkyl or hydrogen groups ina pinacol rearrangement\ the reaction has considerable potential for the preparation of b\g!unsatu!rated ketones[ This has been nicely illustrated by an asymmetric synthesis of a!vinyl ketones by thetriethylaluminum!promoted rearrangement of homochiral vicinal hydroxymesylates "Equation "16##ð72TL3886Ł[ Vinyl cycloalkanones can be prepared from cycloalkenes in a four!step sequence whichinvolves the alkoxide!induced rearrangement of an a\a!dichlorocyclobutanone formed by additionof dichloroketene to the alkene "Scheme 14# ð82TL7046Ł[

OHR

MsO H H R(27)

O

Et3Al

R = Ph, 86%, >99% eeR = vinyl, 75%, >99% ee

Cl

Cl

O OMe

CO2Me

• OCl

Cl

Scheme 25

NaOMe

75%

dibal-H

83%

i, MsCl, pyridineii, HClO4

63%OMe

OH

O

2[93[1[0[3 Miscellaneous preparations

The reaction of nitrile oxides with allylsilanes has been used to prepare b\g!unsaturated ketonesin a sequence which uses a Peterson elimination to form the double bond "Scheme 15# ð75S201Ł[b\g!Unsaturated ketones can also be prepared from allyl halides by reaction with acyl stannanesð76CL0260Ł[ One remarkable approach to b\g!unsaturated ketones involves the fragmentation ofbis"homoallylic# potassium alkoxides[ Thus addition of an excess of an allylic Grignard reagent toa carboxylic ester gives the corresponding tertiary alcohol\ which on warming with potassium


hydride looses one allyl group to form the unsaturated ketone\ often in high yield and with relativelylittle migration of the double bond into conjugation "Scheme 16# ð76HCA0747Ł[

But N O– TMSTMS

ON

But

BF3•Et2O

77%ButTMS

OHO

++

Scheme 26

But

O

H2, Raney Ni

85%81%

MgCl OHBun

Bun

O

Scheme 27

Bun

O

BunCO2Me + i, KH, HMPA

ii, NH4Cl (aq.)

+

5 : 1


g\d!Unsaturated ketones can be prepared by the aluminum chloride!catalysed reaction of anallylsilane with a nitroalkene to give a nitronate which is readily converted into the unsaturatedketone with a Nef reaction "Equation "17## ð70TL0004Ł^ d\o!unsaturated ketones can be prepared bythe silver ~uoride!mediated reaction of allyl chlorides with trimethylsiloxycyclopropanes\ a reactionin which a b!silver ketone species is the postulated intermediate "Equation "18## ð77TL5026Ł[

TMS + n-C10H21NO2

n-C10H21O (28)

i, AlCl3ii, TiCl3

74%

(29)Cl + TMS-O

OAgF

53%

The free!radical fragmentation of b!trialkylstannyl alkoxy radicals has been employed in severalpreparations of remotely unsaturated ketones[ In the most direct approach\ the alkoxy radical isgenerated by treatment of the corresponding alcohol with lead"IV# acetate ð73TL4224Ł or withiodosobenzene boron tri~uoride etherate and dicyclohexylcarbodiimide ð73CC0996Ł and gives aproduct whose double!bond geometry is determined by the stereochemistry of the starting material[Alternatively\ the required oxygen radical can be produced by the intramolecular addition to aketone of an alkyl radical generated by tin hydride reduction of a halide\ providing a ~exible andelegant ring expansion methodology "Equation "29## ð77CC0393Ł[ Similar products have also beenprepared via the Wharton fragmentation of monosulfonates of 0\2!diols ð74JOC064Ł[

SePh

O

SnBu3

O

(30)Bu3SnH (cat.), AIBN

89%


033 Dialkyl Ketones

2[93[1[1 Dialkyl Ketones with More Than One Double Bond

Ketones containing more than one nonconjugated double bond are generally prepared by methodsthat are directly analogous to those used for the preparation of saturated ketones "Section 2[93[0#or ketones with a single nonconjugated double bond "Section 2[93[1[0#[

The oxy!Cope rearrangement\ a powerful approach to d\o!unsaturated ketones "Section2[93[1[0[1#\ has been extended by several workers to give multiply unsaturated ketones[ For example\2\4!hexadienones can be prepared by replacing one of the double bonds in the 0\4!hexadiene unitwith an alkyne "Equation "20## ð73S0909Ł or an allene "Equation "21## ð82JOC4371Ł[ In both casesthe rearrangement products contain additional b\g unsaturation but di}er in placing the doublebond endo or exo to the ring[ The acetylenic rearrangement is also catalysed by silver"I# saltsð75T0222Ł[

CO2Et

OH

CO2Et

O

(31)NaH

45%

CO2Et

O

(32)

CO2Et

OH

NaOEt

80%•

Wender|s group has developed a double oxy!Cope rearrangement which allows the preparationof triply unsaturated cyclic ketones\ which are ring!expanded by eight carbon atoms[ One of thechallenges of this chemistry has been the preparation of the a!butadienyl ketone precursors required\and several approaches which are of general interest for unsaturated ketone preparation have beendeveloped "Scheme 17# ð70T2856\ 70TL1360\ 73CC423Ł[

O

OAc

O

Scheme 28

MeS SMe i,

ii, Ac2Oiii, HgCl2

73%

i, Ph3P=CH2 ii, LAHiii, CrO3•pyridine

64%

Li

Li

70%

KH

90%

OH OO

2[93[1[2 Dialkyl Ketones with Aryl or Heteroaryl Substituents


"i# Arylation of saturated ketones

The a!arylation of ketones\ although infrequently used\ can be a very e.cient reaction andprovide rapid access to an otherwise inaccessible molecule[ Two e}ective\ and related\ ketonearylation procedures involve the dichlorobis"tri!o!tolylphosphine#palladium"II#!catalysed reactionof an a!stannyl ketone or enol stannane intermediate with an aryl bromide[ The reactive tin speciescan be generated either from an enol acetate with trimethyltin methoxide ð71CL828\ 73BCJ131Ł orfrom an enol silane with tributylstannyl ~uoride ð71JA5720Ł[ Both reactions give respectable resultswith a wide range of substrates[ The photochemical arylation of ketone enolates also appears tohave quite a wide scope ð65JOC0691Ł and has recently been extended to the intramolecular arylation ofenol silanes "Equation "22## ð82TL5520Ł[ A photosensitized electron transfer mechanism is suggested[Other useful arylation procedures include the electrophilic arylation of enol silanes with arene


diazonium salts ð74CC0434Ł\ the nickel"II#!catalysed coupling of a!bromoenol silanes with arylGrignard reagents ð65CL0128Ł\ and the reaction of cyclic a\a?!dibromoketones with diphenylcopperlithium which\ surprisingly\ gives monophenylated products "Equation "23## ð75TL3560Ł[ Ketonescan be perphenylated by reaction of their enolates with triphenylbismuth carbonate ð74JCS"P0#1556Ł[

MeO

MeO

O-TBDMS MeO

MeOO

(33)hν

74%

Br

Br

O

Ph

O

(34)Ph2CuLi

81%

"ii# Benzylation of saturated ketones

Because of their high reactivity\ benzyl halides can be used successfully for the benzylation ofketones using conventional enolate\ imine anion\ or enamine chemistry[ In addition\ secondarybenzylic halides react under Lewis acid!catalysed conditions with enol silanes to give mono!benzylated products regiospeci_cally and in high yield ð68TL0408\ 68TL3860Ł[ Silver tri~ate has alsobeen found to catalyse the reaction of enol silanes with the secondary benzylic sul_de "04# ð89TL154Łand with both primary and secondary benzylic chloroformates ð81TL840Ł[ p!Acetoxybenzylation ofdiketones can be achieved with p!acetoxybenzyl acetate in the presence of caesium carbonate in areaction which probably involves a quinone methide intermediate "Equation "24## ð81TL4176Ł[

S NN

NN

Ph

(15)

O O+

O O

OAc

AcO

OAc

(35)65%

"iii# Conju`ate reduction of aryl!containin` a\b!unsaturated ketones

b!Phenyl a\b!unsaturated ketones can be reduced with many of the reagents available for theconjugate reduction of a\b!unsaturated ketones[ In addition\ their very mild reduction to thesaturated carbonyl compound with the related\ and unlikely\ mixtures of t!butyl chloride and waterð76BCJ2310Ł and of chlorotrimethylsilane\ sodium iodide and water ð76BCJ0952Ł have been reported[

"iv# Conju`ate addition of aryl nucleophiles to a\b!unsaturated ketones

The conjugate addition of aryl groups to a\b!unsaturated ketones is generally achieved by thesame sorts of methods used for the introduction of alkyl substituents "Section 2[93[0[7[1"ii##\although some variations not applicable to the alkyl case are known[ For example\ diarylzincreagents\ which are conveniently prepared by the sonication of a mixture of the aryl bromide\lithium wire and zinc bromide in an ether solvent\ have been found to add to a\b!unsaturatedketones in the presence of catalytic nickel acetylacetonate ð72JOC2726Ł[ Alternatively\ the coupling

035 Dialkyl Ketones

can be achieved by a palladium"II#!catalysed Heck!type reaction of an aryl iodide and ana\b!unsaturated ketone in formic acid containing triethylamine ð72JOC3125Ł[

The conjugate addition of benzyl groups to a\b!unsaturated ketones is complicated by thetendency of benzyl halides to undergo Wurtz coupling during the formation of an organometallicderivative\ and by the poor thermal stability of benzylic cuprates[ However\ with careful control ofthe reaction conditions and choice of counterion and Lewis acid additive\ very good results can beobtained ð81TL1272Ł[

2[93[1[2[1 From carboxylic acids and carboxylic acid derivatives

The tendency for preparations of benzylmetal reagents to give Wurtz!coupled products com!plicates the use of such species for coupling with carboxylic acid derivatives\ as it does their conjugateaddition chemistry[ Fortunately\ a number of methods have been developed for generating anucleophilic benzyl species in the presence of an acid chloride or anhydride which can react beforedimerization occurs[ Thus electroreduction of benzylic halides in the presence of acid chloridesð66CL0910Ł\ or anhydrides ð75TL3064Ł gives moderate to good yields of alkyl benzyl ketones[ Thecoupling can also be achieved chemically with metallic nickel ð72TL1340Ł\ or with zinc and 4 mol)Pd"PPh2#1Cl1 in DME ð70CL0024Ł[


Several methods have been developed for the homologation of aryl ketones to benzyl ketones[For example\ addition of phenylselenylmethyllithium to an aromatic ketone gives a tertiary alcoholwhich\ after oxidation to the selenoxide\ undergoes rearrangement to the homologated ketone inreasonable yield "Equation "25## ð89JCS"P0#0586Ł[ The analogous homologation of cyclic arylalkylketones can be achieved by Wittig alkenation to the exo!methylene derivative and oxidativerearrangement with thallium"III# nitrate ð66TL0716Ł[ Tolyl methylthiomethyl sulfone has also beenused to prepare benzylic ketones from aromatic aldehydes "Scheme 18# ð75CL0486Ł[

PhPh

O

Ph

O

Ph (36)

i, PhSeCH2Liii, mcpba

83%

K2CO3

85%

NaBH4

97%

i, MeI, NaHii, HCl

96%SO2Tol

SMe

SO2Tol

SMe

Ph SO2Tol

SMe

Ph

O

Scheme 29

Ph

PhCHO +

Although pinacol rearrangements are generally of rather limited synthetic utility\ the highmigratory aptitude of aryl substituents allows the regio! and stereospeci_c rearrangement of chiralvic!diol monosulfonates to a!aryl ketones of high optical purity "Equation "16## ð72TL3886Ł[

2[93[1[3 Alkynyl!substituted Dialkyl Ketones


"i# Ethynylation of saturated ketones

Ethynylation of ketone enolates has received far less attention than ethenylation or arylation\although tertiary enolates are known to react with dichloroethyne ð71TL1262Ł[


"ii# Propargylation of saturated ketones

Although propargyl halides are good alkylating agents which can be used for enolate alkylations\they tend to give mixtures of allenic and propargylic products[ This di.culty can be avoided by theuse of cobalt!stabilized propargyl cations which react with ketones\ enol silanes and enol acetatesto give pure acetylenic products after decomplexation ð79JA1497Ł[

"iii# Conju`ate addition of unsaturated nucleophiles to a\b!unsaturated ketones

The conjugate addition of alkynyl groups to enones is limited by the reluctance of either alkyn!ylcuprates or alkynylzinc reagents to undergo such reactions\ although alkynylzinc reagents willreact with b!monosubstituted enones in the presence of trialkylsilyl tri~ates ð89TL6516Ł[ Fortunately\the transformation can be achieved with a variety of other reagents including alkynylboranes whichreact with "E#!acyclic enones and a!methylene ketones ð66JA844\ 81CL584Ł\ and mixed tetra!organothallium ate complexes which deliver alkynyl preferentially over methyl to cyclic ketonesð81TL0652Ł[ Alkynylalanes in the presence of a nickel catalyst will add in a conjugate fashion toenones with either an s!cis or s!trans conformation ð79JOC2942Ł[

2[93[1[3[1 Fragmentation reactions

The fragmentation of an a\b!epoxy ketone on treatment with tosyl hydrazone to give an alkynylketone was _rst described by Eschenmoser|s group\ and is now generally referred to as an Eschen!moser fragmentation "Equation "26## ð56HCA697Ł[ N!Aminoaziridine derivatives of epoxy ketonesfragment in a similar manner on heating "Scheme 29# ð61HCA0165Ł\ as do the tosyl hydrazones ofa\b!unsaturated ketones on treatment with N!bromosuccinimide ð68HCA1544Ł[ Cyclic 2!hydroxy!vinylselenones fragment under basic conditions to give alkynyl ketones\ although in this case thescission is between the a and b rather than the b and g carbons of the precursor enone "Equation"27## ð70JOC4135Ł[

(37)O

OTsNHNH2

80%

O

H2NN

Ph

Ph

Scheme 30

O

OO110 °C

68%

N

O

N

Ph

Ph

BunHO

SeO2Ph

Bun

O

(38)NaH

84%

037 Dialkyl Ketones

2[93[2 HALO!SUBSTITUTED DIALKYL KETONES "a!\ b! AND MORE REMOTEHALOGENS#


Although there is a considerable body of information on haloketones scattered throughout theliterature\ few attempts have been made to gather and collate the data[ One notable exception tothis is a _ne chapter by DeKimpe and Verhe on the synthesis and chemistry of a!haloketones in oneof the Updates from the Chemistry of the Functional Groups monographs edited by Patai andRappoport ðB!77MI 293!90Ł[

2[93[2[1 Fluoroaliphatic Ketones

2[93[2[1[0 a!Fluoroaliphatic ketones

The synthesis of a!~uoro ketones has been reviewed by Rozen and Filler ð74T0000Ł\ and that oftri~uoromethyl ketones and related ~uoromethyl ketones by Begue and Bonnet!Delpon ð80T2196Ł[

"i# From alcohols

The oxidation of b!~uoro alcohols appears to be a fairly di.cult transformation which fails withthe majority of conventional alcohol oxidants[ Good results\ however\ are reported for the Dess!Martin periodinane reagent "3# ð78JOC550Ł\ for which an improved preparation has recently beenreported ð82JOC1788Ł[

"ii# From epoxides

Treatment of a!chloro epoxides with silver tetra~uoroborate gives a!~uoro ketones containingonly small quantities of a!chloro ketone by!product ð70CB0747Ł[ The analogous reaction of 0!~uoro!1!chloro epoxides can be used to prepare a\a!di~uoro ketones "Equation "28## ð72CB1530Ł[ a!Fluoroketones have also been prepared from functionalized a!trimethylsilyl epoxides "Equation "39##ð78JFC"31#324Ł[ The reaction involves initial ~uoride!induced Peterson elimination to give an alleneoxide which reacts further with ~uoride to give the _nal product[

OCl

F

O

F F

(39)AgBF4

90%

OF3C

O

TMS

O

O

F(40)

Bu4NF

70%

"iii# From stable enol derivatives and enamines

Although in the early literature elemental ~uorine was reported to be unsatisfactory for the a!~uorination of ketone derivatives\ the treatment of enol silanes at low temperatures with 4) ~uorinein nitrogen and with Freon 00 as solvent does give good yields of a!~uoro ketones[ In some cases\however\ over!~uorination is a problem\ particularly with enol silanes derived from methyl ketonesð75TL1604Ł[ A range of N!~uoropyridinium salts of varying reactivity have been developed forelectrophilic ~uorination of enol silanes[ Fluorinations can be achieved with these reagents in the

038Halo!substituted

presence of enol acetates\ ethers and double bonds\ and some remarkably selective transformationshave been reported "Equation "30## ð89JA7452Ł[ Steroidal enol silanes have also been ~uorinatedwith p!iodotoluene di~uoride ð71TL0054Ł\ and both steroidal enol silanes and enol acetates with thestable electrophilic ~uorine source 0!"chloromethyl#!3!~uoro!0\3!diazabicycloð1[1[1Łoctanebis"tetra~uoroborate# "05# ð82JOC1680Ł[ The ~uorination of enol acetates in the presence of ketonesby N!~uoropyridinium pyridine hepta~uorodiborate ð80JOC4851Ł\ of enol silanes with tri~uoro!methyl hypo~uorite ð79JA3734Ł and of cyclic enamines with di~uorodiimide ð66TL1686Ł has alsobeen reported[

HTMS-O

TMS-OO-TMS

HO

OO

F

NF

(41)

+

–OTf

51%

N

N

F

Cl

(16)

+

+(BF4

–)2

"iv# From ketones

One important traditional approach to a!~uoro ketones which still _nds applications today is bythe halide exchange of a!chloro\ or preferably\ a!bromo ketones[ The transformation is mostcommonly achieved with a heavy!metal ~uoride such as mercury"II# ~uoride ð66JOC2416Ł or silvertetra~uoroborate ð68TL2246Ł\ which drives the reaction to completion by the formation of a less!soluble halide salt[

Although a number of reagents have become available over the last few years for the electrophilic~uorination of enol acetates and silanes\ no comparably general methods for the ~uorination ofketones are available[ However 0\2!diketones can be mono! or di~uorinated with N!~uoro!bis"tri~uoromethylsulfonyl#imide "06# ð80CC068Ł^ benzylic ketones can be ~uorinated by anodicoxidation in acetonitrile and triethylamine trihydro~uoride ð76TL1248Ł^ and alkyl aryl ketone enol!ates can be ~uorinated with N!~uorosultam "07# ð80TL0668Ł[ The sultam chemistry has been extendedby the use of the chiral camphor!derived N!~uorosultam "08# to allow the enantioselective ~uo!rination of the lithium enolates of b!keto esters and alkyl aryl ketones\ although both the chemicalyields and enantiomeric excesses reported are quite modest "Equation "31## ð82TL2860Ł[

N F

F3CSO2

F3CSO2

SN F

OO

Cl

Cl

NS FO

O

(17) (18) (19)

(42)

O– Na+ O

F

(–)-(19)

40%, 75% ee

049 Dialkyl Ketones

"v# From acids or esters

The preparation of more highly ~uorinated ketones is often approached by the assembly ofappropriately ~uorinated building blocks using carbon!to!carbon bond forming reactions[ Forexample\ the reaction of ethyl tri~uoroacetate with Grignard reagents ð76JOC4915Ł\ of ethylper~uoroalkanoates with phosphorus ylides ð81JOC2796Ł\ and of esters with per~uoroalkyllithiumreagents ð76CL0042Ł have all been used to prepare alkyl per~uoroalkyl ketones[ Ketenes derivedfrom primary\ but not secondary\ acid chlorides can be trapped with tri~uoroacetic anhydride togive tri~uoromethyl ketones after hydrolysis and decarboxylation "Equation "32## ð81TL0174Ł[

Cl

O

AcOH

OAc

AcOCF3

O

AcOH

OAc

AcO

(43)

i, pyridineii, TFAA

67%


"vi# Miscellaneous other preparations

Homochiral a!~uoro ketones\ for which relatively few syntheses are available\ have been preparedfrom a!~uoro esters using sulfoxide chemistry "Scheme 20# ð77CC107Ł[ The synthesis of a\a!di~uoroketones has given rise to some interesting chemistry] for example\ Percy et al[ have developed anumber of equivalents of the di~uoroacetaldehyde anion such as the vinyllithium "19# ð81CC0366\81SL372Ł^ and the Claisen rearrangement of allyl di~uorovinyl ethers to a\a!di~uoroketones has beenfound to proceed under unusually mild conditions ð74TL1750Ł[

S F

OO :S

OO :

F i, LDA

ii, Me2CH(CH2)2Br

i, NaIii, Raney Ni

69%

O

F

Scheme 31

O

Li

NEt2

F

F

O

(20)

2[93[2[1[1 b!Fluoroaliphatic ketones

Relatively little work has been reported on the preparation of speci_cally b!~uorinated ketones[However\ both silyl enol ethers and enamines can be tri~uoromethylated electrophilically with

040Halo!substituted

"tri~uoromethyl#dibenzothiophenium tri~ate "10# ð89TL2468Ł\ and homologous per~uoroalkylketones have been prepared by the ðCpFe"CO#1Ł1!catalysed addition of per~uoroalkyl iodides to theb position of enol ethers ð80CC75Ł[

S

CF3

(21)

–OTf

+

2[93[2[2 Chloroaliphatic Ketones

2[93[2[2[0 a!Chloroaliphatic ketones

"i# From alkenes or alkynes

The preparation of a!chloro ketones by the oxidation of disubstituted alkenes with a variety ofchromium!based oxidants\ in particular Etard|s reagent "CrO1Cl1#\ has been known for many years\and a recent study of the reaction recommends cyanopyridinium chlorochromate as the preferredreagent for the conversion ð77TL5696Ł[ Photooxidation of disubstituted alkenes in the presence ofiron"III# chloride also gives modest yields of a!chloro ketones\ although carbon!to!carbon bondcleavage reactions occur with tri! or tetrasubstituted alkenes ð70JOC498Ł[ Neither method allows theregioselective oxychlorination of unsymmetrical alkenes[

The preparation of a\a!dichlorocyclobutanones by the ð1¦1Ł cycloaddition of dichloroketeneand an alkene has been widely exploited because of the synthetic versatility of the products[ Thereaction\ which is promoted by ultrasound ð74SC880Ł\ has been reviewed in a recent article onhaloketene chemistry ð70T1838Ł[ Dichloromethyl ketones can be prepared by the treatment ofterminal alkynes with Oxone "1KHSO4 =KHSO3 =K1SO3# in the presence of hydrogen chloride"Equation "33## ð81CL592Ł[

n-C6H13 n-C6H13Cl

O

Cl

(44)Oxone, HCl

71%

"ii# From epoxides

Epoxides can be smoothly converted into a!chloro ketones by treatment with a chlorosulfoniumchloride "e[g[\ Me1S =Cl1# ð68TL2542Ł[ Trisubstituted epoxides react regiospeci_cally placing thechlorine on the more!substituted carbon atom ð66CL884Ł[ Alternatively\ dimethylchlorosulfoniumchloride can be generated in situ from DMSO and oxalyl chloride and allows the conversion to beachieved under very mild and low!temperature "−59>C# conditions ð81TL5910Ł[ The method iscompatible with ester and alkene functionality\ and proceeds with high\ although not readilyrationalized\ regioselectivity "Equation "34##[

OAc

OCl OAc

O

(45)DMSO, (COCl)2

90%

"iii# From alcohols or their derivatives

The oxidation of chlorohydrins is less problematical than that of ~uorohydrins\ and mono!\ di!and trichloromethyl ketones can be prepared by the chromium trioxide oxidation of the appropriatechlorohydrin or b!chloroalkyl methyl ether precursors ð71TL0598Ł[ The oxidation has been suc!

041 Dialkyl Ketones

cessfully applied to the preparation of quite highly functionalized\ and unracemized\ peptide ana!logues "Equation "35## ð78S355Ł[

chromic acid

83%NH

HN

CCl3

O

O

OHPh

NH

HN

CCl3

O

O

OPh

(46)

"iv# From stable enol derivatives and enamines

Oxidation of a wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or withlead"IV# salts ð71S0910Ł\ in the presence of chloride leads smoothly and regiospeci_cally to thea!chloro ketone[ Enol silanes can also be chlorinated by treatment with copper"II# or iron"III#chlorides in DMF ð79JOC1911Ł or by sulfuryl chloride ~uoride or sulfuryl chloride ð73JOC1921Ł[

Hexachloroacetone has been recommended as a convenient and mild source of electrophilicchlorine for the chlorination of enamines ð66JA5561Ł\ although high yields can also be obtained withelemental chlorine itself ð68CB0569Ł[

"v# From ketones

The direct chlorination of ketones not only su}ers from problems of regioselectivity but is alsocomplicated by the formation of over!chlorinated by!products[ The considerable body of knowledgeof the e}ect on the reaction of variations in the substrate and conditions "particularly the solvent#has been well summarized by DeKimpe and Verhe ðB!77MI 293!90Ł[ Alternatively\ a methoxycarbonylgroup can be used to direct the chlorination to the required position\ and is easily removed afterwardsby acid hydrolysis ð76S077\ 89S484Ł[ Ketones can also be chlorinated via their lithium enolates usingNCS ð73JOC687Ł[

"vi# From acids or esters

a!Chloro acid chlorides react with organomanganese reagents to provide a convenient preparationof a!chloro ketones ð73S26Ł[ The reaction may also be performed with Grignard reagents\ althoughin this case the temperature must be kept below −67>C ð73S623Ł[ A related\ and conceptually veryattractive\ approach to chloromethyl ketones is by the addition of chloromethyllithium to an ester[Although the reagent is fairly unstable\ it can be prepared by the metalÐhalogen exchange ofbromochloromethane at low temperature "−009>C#\ and it reacts smoothly with esters "Equation"36## ð73TL724Ł[ Barluenga|s research group has reported extensively on the analogous preparationof dichloromethyl and bromochloromethyl ketones by the reaction of esters with a dihalomethyl!lithium\ which is generated in situ by the addition of lithium dicyclohexylamide to a mixture of thedihalomethane and carboxylic ester at −67>C ð80TL0668Ł[ The preparation of a\a?!dihalo ketonesand a\a\a?!trihalo ketones from a!halo esters using this chemistry has also been described ð89S0992Ł\as has its extension\ by the use of a!chloroalkyllithium reagents\ to the preparation of highera!chloroalkyl ketones ð70S57Ł[ These products can also be prepared by treatment of the initialbromochloromethyllithium adduct with an alkyl cuprate "Equation "37## ð80JCS"P0#1789Ł[

ClCH2Li

62%C6H13 OEt

O

C6H13

O

Cl (47)

Prn OEt

O

Prn

O

Bun

Cl

(48)

i, BrClCHLi ii, (Bun)2CuLiiii, H3O+

87%

Trichloromethyl ketones have been prepared both by the reaction of trichloroacetyl chloride

042Halo!substituted

with organozinc reagents\ and by the addition of trichloromethyl anions\ generated by the faciledecarboxylation of sodium trichloroacetate\ to aldehydes\ followed by oxidation of the resultingalcohols with chromic acid ð81TL2324Ł[

"vii# Miscellaneous preparations

An interesting approach to a!chloro ketones involves the reaction of lithio chloromethyl phenylsulfoxide with an aldehyde[ The resulting a!chloro!b!hydroxy sulfoxide can be converted into the_nal product either by thermolysis ð66TL0114Ł or in two steps by Swern oxidation followed bydesul_nation with ethylmagnesium bromide "Scheme 21# ð81BCJ1799Ł[

PhS Prn

X

O

PhS

O

n-C9H19

O

X Prn

n-C9H19Prn

X

O

Scheme 32

i, LDA, n-C9H19CHO

ii, Swern oxidation

EtMgBr

X = Cl, Br

2[93[2[2[1 b!Chloroaliphatic ketones

b!Chloro ketones can be prepared by the treatment of cyclopropyl ketones with pyridine hydro!chloride in pyridine "Equation "38## ð67S116Ł[

(49)O O

Cl

pyridine•HCl

70%

2[93[2[3 Bromoaliphatic Ketones

2[93[2[3[0 a!Bromoaliphatic ketones

"i# From alkenes

The oxidative hydrolysis of vinyl bromides with NBS in aqueous acetonitrile provides an e.cientand regiospeci_c synthesis of a!bromo ketones which is compatible with ester\ amide\ ketone andtosylate functionality "Equation "49## ð82TL3370Ł[

Br

O

O

O

Br (50)NBS (aq.)

85%

"ii# From epoxides

Epoxides can be converted smoothly\ but not regioselectively\ into a!bromo ketones by treatmentwith the complex of dimethyl sul_de with bromine ð68TL2542Ł or by reaction with bromo!trimethylsilane and Jones oxidation ð70TL0318Ł[ Bromomethyl ketones can be prepared by thephotocatalytic bromination of epoxides derived from terminal alkenes ð67S028Ł[

043 Dialkyl Ketones


Oxidation of a wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or withlead"IV# salts ð71S0910Ł\ in the presence of bromide leads smoothly and regiospeci_cally to thea!bromo ketone[ Elemental bromine has been used to prepare a!bromo ketones from both enolsilanes ð65S083Ł\ and in near!quantitative yield from enamines ð68CB0569Ł[

"iv# From ketones

The a!bromination of ketones has been a particularly active area of research\ with a large numberof electrophilic brominating reagents being developed for this purpose[ For example\ 4\4!dibromoMeldrum|s acid "11# ð67S039Ł\ and 3!"dimethylamino#pyridine bromide perbromide ð73SC828Ł willmonobrominate ketones in high yield[ Perhaps more interesting is the combination of t!butylbromide and DMSO ð73T1924Ł which\ like the photobromination of ketones in the presence ofcyclohexene oxide ð66JCS"P0#490Ł\ has been shown to brominate the more highly substituteda!carbon of an unsymmetrical ketone with very high selectivity[

O

O

O

O

Br

Br

(22)

"v# From acids or esters

Barluenga|s research group has reported on the preparation of dibromomethyl ketones by thereaction of esters with dibromomethyllithium\ which is generated in situ by the addition of lithiumdiisopropylamide to a mixture of the dibromomethane and a carboxylic ester at −67>C ð80TL0668Ł[The preparation of a\a?!dihalo ketones and a\a\a?!trihalo ketones from a!halo esters using thischemistry has also been described "Equation "40## ð89S0992Ł\ as has its generalization by the use ofa!bromoalkyllithium reagents to prepare higher a!bromoalkyl ketones ð70S57Ł[ Although themethod does not appear to be extendable to the preparation of bromomethyl ketones from estersand bromomethyllithium\ bromomethyl ketones can be prepared from dibromomethyl ketones bymetalÐhalogen exchange with n!butyllithium to give an a!bromo ketone enolate which is protonatedduring the workup ð74JOC4039Ł[

OEt

O

Cl

O

Cl

Br

Br

LiBr

Br

(51)67%

"vi# Miscellaneous preparations

An interesting approach to a!bromo ketones involves the reaction of lithio bromomethyl phenylsulfoxide with an aldehyde[ The resulting a!bromo!b!hydroxy sulfoxide can be converted into the_nal product either by thermolysis ð68CL198Ł or in two steps by Swern oxidation followed bydesul_nation with ethylmagnesium bromide "Scheme 21# ð81BCJ1799Ł[

044Halo!substituted

2[93[2[4 Iodoaliphatic Ketones

2[93[2[4[0 a!Iodoaliphatic ketones

"i# From alkenes

a!Iodo ketones can be very conveniently prepared by the treatment of alkenes with silver chromateand iodine^ with terminal alkenes\ iodomethyl ketones are formed with high selectivity ð66JOC3157Ł[Cyclic a!iodo ketones can be synthesized by the related oxidation of alkeneÐiodine complexes withpyridinium dichromate ð79TL3410Ł\ and bis"sym!collidine#iodine"I# tetra~uoroborate in dimethylsulfoxide will oxidize alkenes to a!iodo ketones\ although in neither case is much regioselectivityobserved in the reaction of unsymmetrical substrates ð75S616Ł[

"ii# From epoxides

Epoxides are considerably less important precursors of a!iodo ketones than of a!chloro ora!bromo ketones\ although a simple regiospeci_c preparation of a!iodo ketones by the nucleophilicaddition of iodide to an a!nitro epoxide\ followed by elimination of nitrite\ has been reported"Equation "41## ð78CL0130Ł[ The conversion can also be achieved nonregioselectively by reactionwith iodotrimethylsilane and Jones oxidation ð70TL0318Ł[

(52)O

NO2

O

I

DMSO, BF3•Et2O, NaI

75%


As well as having the advantage of regiospeci_city\ preparations of a!iodo ketones from enolacetates or enol silanes are frequently both very e.cient and very general[ These methods thus oftenprovide the method of choice for the preparation of a!iodo ketones[ For example\ the oxidation ofa wide range of enol derivatives\ either electrochemically ð79JOC1620Ł or with lead"IV# salts ð71S0910Ł\in the presence of iodide leads smoothly and regiospeci_cally to the a!iodo ketone[ The iodinationof enol silanes can be accomplished in high yields by treatment with iodine and silver acetateð68JOC0620Ł\ with N!iodosuccinimide\ conveniently prepared in situ from sodium iodide andN!chlorosuccinimide ð73TL122Ł\ and by reaction with sodium iodide and mcpba in the presence ofhexamethyldisilazane ð76JOC2808Ł[ Enol acetates can be iodinated with iodine and thallium"III#acetate ð67JCS"P0#015Ł\ and both types of substrate can be iodinated with iodine in the presence ofcopper"II# nitrate ð80JOC5697Ł[

"iv# From ketones

Traditionally a!iodo ketones have been prepared from ketones by treatment with iodine in thepresence of strong base or by the halogen exchange of a!chloro or a!bromo ketones\ althoughneither method was particularly satisfactory ðB!77MI 293!90Ł[ More recently developed iodinationsof ketones with iodine in the presence of copper"I# iodide ð70S201Ł\ ceric ammonium nitrate ð77CL20Łor\ for acyclic ketones\ mercury"II# chloride ð75S567Ł are much more satisfactory and give goodyields of a!iodo ketones[ The conditions for all three methods are mildly acidic\ and with the lattertwo reagents the iodination of unsymmetrical ketones occurs preferentially at the more!substituteda!carbon "Equation "42##[

(53)O

O O

I I

+can, I2, MeOH

83%

96 : 4can = ceric ammonium nitrate

045 Dialkyl Ketones

2[93[2[4[1 b!Iodoaliphatic ketones

Relatively little literature is available on the preparation of b!iodo ketones\ although they can beprepared by the conjugate addition of iodotrimethylsilane to enones\ followed by hydrolysis of theintermediate enol silane ð68JOC0327Ł[

2[93[3 KETONES BEARING AN OXYGEN FUNCTION

2[93[3[0 OH!functionalized Ketones

2[93[3[0[0 a!OH!functionalized ketones

One of the earliest procedures for the direct oxidation of ketones to a!hydroxy ketones usedmolecular oxygen ð57JOC2183Ł\ and the method was ideally suited to oxidation at a hindered\ tertiarya position[ In fact\ under these conditions\ less highly substituted a!hydroxy ketones undergo an insitu decomposition[ Applications of this method can be found in the recent literature ð78JOC3465Ł[The problems associated with the use of oxygen have lead to the development of other methods forenolate hydroxylation ð80COS040Ł[ One of the most frequently used\ MoO4 =Py =HMPA "MoOPH#was originally developed by Vedejs and co!workers ð67JOC077Ł\ and recently a derivative of thiswhich avoids the use of HMPA was prepared and demonstrated to be equally e}ective ð89SL096\81CEN1Ł[ Ketones with only one alpha C0H group or hindered ketones can be oxidized directly toa!hydroxy ketones with "PhSeO#1O[ Furans\ acetates and dioxolanes survive the reaction conditionsð70T362Ł[

Independent work by several groups "e[g[\ ð64JOC2316Ł# has demonstrated that the oxidation ofenol silanes with mcpba gives a!oxygenated ketones\ and this procedure has been used extensively[In the majority of cases regiospeci_c enol silane formation allows regiospeci_c ketone hydroxylation[This reaction was hypothesized to proceed via a silyloxy epoxide "12#\ although the detection of thisintermediate has proved elusive in all but a few cases[ More recently\ however\ dimethyl dioxiraneand methyl tri~uoromethyl dioxirane\ oxidants which produce no acidic by!products\ have beenapplied to the oxidation of silyl enol ethers\ and\ in many cases\ the intermediate epoxides are stableenough to be isolated or observed by 0H NMR ð78JOC3138\ 78TL5386Ł[ A subsequent paper showedthat direct oxidation of enolates with dioxiranes was also successful ð80TL604Ł[ A series of reagentswhich have been used very successfully for the introduction of an a!hydroxy group are the sulfonyloxaziridines "e[g[\ "13##\ which react with ketone enolates\ silyl enol ethers\ or with enamines[ Anasymmetric version of this oxidation\ using oxaziridines derived from the homochiral imine "14#"R�H\ Cl#\ has also been developed ð81CRV808Ł[ Other methods reported for the oxidation ofenol silanes include those using oxygen and a nickel"II# catalyst ð80CL170\ 82CL0468Ł\ OsO3:N!methylmorpholine oxide ð70TL596Ł and the Sharpless asymmetric dihydroxylation conditions[ Inthe last case\ either enantiomer of the product can be obtained in high chemical and stereochemicalyield ð81JOC4956Ł[ Many methods are available for the direct oxidation of ketones to a!sulphonyloxyketones "see Section 2[93[3[2#\ and subsequent hydrolysis gives a!hydroxy ketones ð75JOC029Ł[ Avery useful double hydroxylation of enol silanes derived from methyl s!alkyl ketones gives a\a?!dihydroxy ketones "Equation "43## ð78TL2212Ł[ SAMP and RAMP hydrazones\ which have provedextremely useful in the enantioselective a!functionalization of ketones\ have been used in an asym!metric synthesis of a!hydroxy ketones ð77TL1326\ 78HCA879Ł[

OR3

3SiO

R4 R2

R1N

O

PhSO2

Ph

S NO

O

R

R

(25)(23) (24)

046Bearin` An Oxy`en

(54)

OSiR3

OSiR3HO

O

mcpba

72%

Hydroxymethyl anion equivalents "e[g[\ "15## will attack acids or their derivatives to givea!hydroxy ketones ð68JOC3506\ 76TL0736Ł[ A complementary approach involves attack byorganometallic reagents at O!TMS cyanohydrins ð72TL3964\ 75TL0822Ł\ and many examples of thistransformation have appeared in the literature[

Li

O

O

OLiTMS

(26)

The development and use of acyl anion equivalents ðB!76MI 293!90\ 80COS"0#494Ł\ including0\2!dithiane ð78T6532Ł\ has been one of the more important advances in organic chemistry in the lasttwo decades[ Ogura|s research group has reported extensively on the use of acyl anions in whichthe anion is stabilized by sulfur in a higher oxidation state "e[g[\ "16##[ These acyl anions have beenused for the preparation of a!hydroxy carbonyls ð75TL2554\ 80COS"0#494Ł[ The anion "17# has beenshown to react with aldehydes or ketones to give a!hydroxy methyl or a!hydroxy methyl!a?!hydroxyketones depending on the reaction conditions ð78H"17#410Ł[ Heteroatom substituted alkenyl anions like"17# are\ in fact\ well recognized acyl anion equivalents and readily attack aldehydes and ketones[

Li

SMe

SO2Ar O

O

Li

(27)

OCONEt2

Li

(28) (29)

Other variations "e[g[\ "18## also give oxygenated ketones ð63JA6014\ 89JOC4579\ 80T2642Ł[ Knocheland co!workers have recently disclosed the use of alkenyl boronate esters as acyl anion equivalents"Scheme 22#[ The organozinc reagents add to a number of electrophiles\ including aldehydes\ togive multifunctional ketones ð81TL2606Ł[ Cyanohydrins are also well!known acyl anion equivalents\and their use has been reviewed ð80COS"0#430Ł[ The use of thiazoles and also thiazolium salts for thepreparation of hydroxy aldehydes "Chapter 2[90[3[0# has also been applied toa!hydroxy ketones[ The anion of 2!methylbenzothiazolium bromide reacts chemoselectively\ _rst withaldehydes and then paraformaldehyde to give the expected product "Scheme 23# ð74JOC592Ł[ Theadduct between an aldehyde or ketone and 1!lithiobenzothiazole can be further elaborated viaalkylation\ attack by organometallics and hydrolysis "cf[\ Scheme 18 in Chapter 2[90[3[0[0#ð77BCJ2526Ł[

PrnB

I

O

O

PrnB

Cu(CN)ZnI

O

OR

OH

O

Scheme 33

i, Zn, THF

ii, CuCN•2LiCl

i, RCHO, BF3•Et2Oii, H2O2

75–87%

Prn

N

S

Me

+R

OH

O

Scheme 34

N

S

Me

+

R

O–

OH

base, RCHO, CH2O

A series of papers from Katritzky|s group has demonstrated the use of benzotriazoles for thepreparation of a variety of functional groups[ In one of these publications\ the authors disclose theuse of the anion derived from "29# as an acyl anion\ and describe its capture by aldehydes[ Subsequent

047 Dialkyl Ketones

hydrolysis gives hydroxy ketones ð80JOC5806Ł[ This paper also gives an extensive list of referencesto other acyl anions[ A method for the hydroxyalkylation of acyl anions under mild\ nonbasicconditions has been reported[ Alkyl halides add to aryl isocyanides in the presence of samarium"II#to give a metalloimine which can add to ketones "Scheme 24#[ A number of acid! and base!sensitivegroups are compatible with the reaction conditions^ thus\ the method can be used to prepare highlyfunctionalized a!hydroxy ketones ð82JOC0347Ł[ The direct metallation of aldehydes to acyllithiumreagents can be achieved in only a few speci_c cases\ in particular where there are no a protons[ Whengenerated in situ\ however\ by the attack of BunLi on carbon monoxide at very low temperatures\acyllithium reagents containing a protons can be formed and will attack ketones and a\b!unsaturatedketones "0\1!addition# to give the expected products in high yield ð81JOC4519Ł[

NC

Br

SmI2

NAr

+SmI2, –15 °C

i, cyclohexanoneii, H3O+

60%

OH

O

Scheme 35

N

N

NN

Ph

(30)

Many procedures have been published for the selective oxidation of secondary over primaryalcohols\ but not all of these have examples where the two functional groups are within the samemolecule "for a recent review see ðB!78MI 293!90Ł[ Methods that selectively oxidize the secondaryalcohol of 0\1!diols include chromium on a solid support ð89TL4674Ł and catalytic cerium"IV# in thepresence of NaBrO2 ð75BCJ094Ł[

The oxidation of alkenes or the hydrolysis of alkynes where the multiple bond is similarlysubstituted or unactivated may give mixtures of products owing to regiochemical problems or over!oxidation[ However\ terminal alkenes can be selectively oxidized to a!hydroxymethyl ketones ingood yield ð80CL0388\ 82CL0656Ł[ Regiochemical problems can be overcome when a neighbouringgroup is used to control the addition to the alkene "Scheme 25# ð73JOC690Ł\ by the presence ofsilicon "Equation "44## ð75TL54Ł or phosphorus ð73S0914Ł on the alkene\ or using allylic ethers oracetates to give a!hydroxy a?!oxygenated ketones ð80CL0388\ 82CL0656\ 82JOC1818Ł[ Tertiary pro!pargylic alcohols with a terminal alkyne undergo smooth hydration to a\a?!dihydroxy ketones usingiodine"III#\ whereas terminal alkynes give hydroxymethyl ketones ð74TL2726Ł[ A ~exible approachto dioxygenated ketones has recently been disclosed which can be used to make a variety of systems"Scheme 26# ð80BCJ0471\ 80JOC3018Ł[

n-C5H11

OH

n-C5H11

OH

O

O O

n-C5H11 I

O

Scheme 36

i, BunLi, CO2

ii, I2

Amberlyst A26 F– form


n-C6H13Prn

SiMe2(OR)

OH

n-C6H13Prn

O

(55)

i, mcpbaii, KHF2, KHCO3

80%

ArS

O

Cl

HO

Cl

i, LDA, –78 °C, 2-indanoneii, xylene, reflux OsO4, N-methylmorpholine-N-oxide

HO

OHO

Scheme 37

90% 80%

2[93[3[0[1 b!OH!functionalized ketones

The most popular method for the preparation of compounds in this class\ and one of the mostwidely studied of all chemical transformations is the aldol reaction[ Many reviews of this area havealready been published ð80COS"1#0\ B!81MI 293!90Ł\ and only a few recent developments will bediscussed here[ It appears highly likely that the enzyme!catalysed aldol reaction will become widelyadopted by synthetic chemists during the next decade ð80S388Ł[ The coupling of dihydroxyacetonephosphate ð82JOC0776Ł and other enolate donors ð81JA630\ 81JOC315Ł with an increasingly wide rangeof aldehydes has been demonstrated\ and some of these reactions can be done on a preparativelyuseful scale[ The products are often highly oxygenated and the method has already been applied tocarbohydrate synthesis[ Similar products might also be prepared from the boron enolates "20#"R0�H\ OR2#\ which demonstrate a high preference for the anti con_guration at the new car!bon0carbon bond in their reactions with aldehydes ð82JOC3071Ł[ New catalysts that have beenreported recently for the aldol reaction include BiCl2 ð82JOC0724Ł and Me1Si"OTf#1 "OTf�tri~ate#\which can be used for silyl enol ether formation and subsequent in situ aldol reaction ð82JOC1536Ł[

OBn

R1

OBR22

(31)

Developments have been made in the chemoselective coupling of silyl enol ethers with aldehydesin the presence of acetals\ for example an InCl2!catalysed aldol reaction ð80CL838Ł and an organo!aluminum!promoted ene reaction ð82TL5170Ł[ A remarkably chemoselective aldol:Mukaiyama aldolreaction has been demonstrated by Otera and co!workers[ Thus\ in the presence of dibutyltinditri~ate\ aldehydes but not ketones react with silyl enol ethers to give b!hydroxy ketones[ Followingacetalization\ however\ acetals derived from ketones give b!alkoxy ketones whereas\ under the samereaction conditions\ aldehyde acetals are recovered in high yield[ This communication would indicatethe prospect of unique selective functionalization ð89JA890Ł[ For all of these reactions\ carefulexclusion of water is important\ but Kobayashi and co!workers have developed a procedure whichallows aldol coupling reactions between silyl enol ethers and aldehydes in a mixture of water andTHF ð81TL0514Ł[ The key to the reaction appears to be the use of lanthanide tri~ates and an increasein the scale of the reaction could make this particularly useful\ as the catalyst can be reused[

Treatment of 0\2\4!trioxane with methylaluminum bis"3!bromo!1\5!di!t!butyl phenoxide#"MAPH# results in the cleavage of the trioxane and complexation of the resulting formaldehydewith the metal[ The complex is stable at 9>C for several hours and is a valuable source of thishighly reactive electrophile[ It has been shown to undergo enolate hydroxymethylation and anintermolecular ene reaction with silyl enol ethers "Scheme 27#\ both in good yields ð89JA6311Ł[

The importance of b!hydroxy ketones has meant that many non!aldol!based routes to thesesystems have been developed[ The chiral ortho esters "21# react with silyl enol ethers in the presenceof a Lewis acid to give monoprotected 0\2!diketones[ Diastereoselective reduction of the ketonegives mixtures of stereoisomers whose ratio depends on the substrate ð81T0188Ł[ In a similar method\a combination of conjugate addition\ enolate trapping\ ketone reduction and hydrolysis of acyl

059 Dialkyl Ketones

O-TMS

O-TMS

OHH2CO MAPH

Scheme 38

MAPH

O O

O

MAPH = methylaluminum bis(4-bromo-2,6-di-t-butylphenoxide)

71%

ketene acetals "e[g[\ "22## gives stereochemically enriched products ð80T864Ł[ A reduction step is alsoinvolved in a preparation of terminal b!hydroxy ketones which relies on readily available startingmaterials and a mild deprotection step "Scheme 28# ð89S0948Ł[ The presence of a silyl group canoften be considered as equivalent to a hydroxy group as the carbonÐsilicon bond can be cleaved byoxidizing agents[ When combined with the conjugate addition of a silyl group to an enone\ this can beused to prepare b!hydroxy ketones ð73CC18Ł[ Recently\ this has been combined with an asymmetrichydrosilylation of enones to give optically active b!hydroxy ketones ð83T224Ł[ An elegant and widelyexploited method for the synthesis of b!hydroxy ketones is the nitrile oxideÐalkene cycloadditionð80COS"3#0958\ 80COS"3#0000Ł[ This produces an intermediate isoxazoline\ in which the stereochemistryof the substituents is controlled using an appropriately substituted alkene and\ if required\ chiralitytransfer can occur to other positions[ Ultimately\ the isoxazoline is converted into the desiredproduct "Scheme 39#[ Cyclization of allylsilanes with nitrosium tetra~uoroborate can also be usedto give isoxazolines and\ hence\ hydroxy ketones ð82JA6787Ł[

O O

CO2MeMeO2C

R OMe

O

O

O

Ph

Ph

(32) (33)

EtO

Ph

O O

EtO

Ph

OOO

HO

Ph

O

Scheme 39

(CH2OH)2, C6H6, reflux

93%

i, LiAlH4, 0 °Cii, SiO2, H2O, (CO2H)2

82%

R3 N O–+

+R1

R2

NO

R3 R1

R2R3 R2

O

R1

OH

Scheme 40

A series of papers has dealt with a study of the rearrangement of epoxy silyl ethers to b!oxygenatedaldehydes "see Chapter 2[90[3[2# or ketones[ The epoxides are available in enantiomerically pureform by use of the Sharpless asymmetric epoxidation and\ as the rearrangement is concerted\ thisleads to stereochemically pure b!silyloxy ketones[ The silyl group can be removed in situ if required[As little as 4 mol) catalyst is su.cient to promote the rearrangement ð76TL2404Ł\ which can alsobe used to construct quaternary centres "Equation 45# ð76TL4780Ł[ a\b!Epoxy ketones undergoreductive ring opening at the a position with a number of reagents\ including NaI ð65CB2896Ł\ SmI1

ð75JOC1485Ł and PhSeNa ð76TL3182Ł to give b!hydroxy ketones[ Ring opening reactions of epoxideswith acyl anions also gives b!hydroxy ketones ðB!76MI 293!90\ 78T6532Ł[


OH

ArOHO

O

Ar

(56)BF3•Et2O

97%, 87% ee

The selective oxidation of 0\2!diols in which one of the hydroxyls is attached to a primary carboncan be achieved using many reagents\ including trichloroisocyanuric acid ð81SC0478Ł\ H1O1 and atungsten complex ð80JOC4813Ł\ chromium on a solid support ð89TL4674Ł and cerium"IV# ð75BCJ094Ł[Asymmetric reduction with baker|s yeast has been applied to cyclic and acyclic 0\2!diketones withmixed results[ 1!Methyl!1!alkylcyclopentane!0\2!diones give preferentially the syn adducts "23#\whereas similarly substituted cyclohexanediones favour the anti isomer\ although with more variedstereochemical yields[ Larger ring 0\2!diones appear to be poor substrates[ For 1!monosubstitutedacyclic 0\2!diones\ stereoselectivities can also be very high\ although this is sometimes at the expenseof chemical yield ð89S0\ 80CRV38Ł[

O

R

OH

(34)

2[93[3[0[2 g!Functionalized and more remotely OH!functionalized ketones

Selective oxidations of a secondary alcohol separated from a primary one by at least two methylenegroups can be achieved using molybdenumÐButO1H ð73TL3306Ł or cerium"IV# ð73TL2206Ł "see alsoSection 2[93[3[0[1#[ The preferential reduction of aldehydes over ketones is relatively facile\ withmany methods available ðB!78MI 293!91Ł[ Among the more recently reported reagents which wille}ect this transformation are Zn"BH3#1 ð89TL6552Ł and NaBH3 at low temperature ð77SC0816Ł[

Carbonyl! or protected carbonyl!containing anions which react with aldehydes and:or ketonesinclude "24# ð77JOC0232Ł^ the acetal "25# and homologues\ which also react with a!silyloxy ketonesð81JOC649\ 82T3812Ł^ "26#\ prepared from reductive lithiation of the corresponding phenyl sul_desð81JOC5Ł^ "27#\ which acts as a source of the g!hydroxymethylacyl anion ð80T2642Ł^ and "28#ð83T2326Ł[ Anions containing a protected hydroxyl group which undergo acylation include theoxathiane "39# ð81S741Ł and nitro compounds "e[g[\ "30## which are deprotonated under much lessbasic conditions ð89T6360Ł[ Other hydroxyalkyl anion equivalents have been demonstrated to addto enones to give remote hydroxy ketones "Scheme 30\ Equation 46# ð71CJC83\ 89TL6438Ł[ Alkyl!idenations of lactones give enol ethers which can be considered as protected hydroxy ketonesð76JOC3309Ł[ An earlier review has dealt with the subject of nucleophilic three!carbon homologatingagents\ including those containing protected alcohols and carbonyl groups ð73CRV398Ł[

IZnPh

O

LiOO

Li

R2

R1

OO

OLi

(39) (40) (41)

OR

Li

NO2

O-TBDMSS O

Li

O

O

(36) (38)(37)(35)

O O

OH

Scheme 41

dabco, CH2(COSEt)2

93%

Raney Ni

80%

O

COSEt

COSEt

dabco = 1,4-diazabicyclo[2.2.2]octane

051 Dialkyl Ketones

O

O

O

O

O

O

HO

(57)hν, Ph2CO, MeOH

71%

2[93[3[1 OR!functionalized Ketones

Alkoxymethyl anion equivalents add to acid derivatives to give a!alkoxy ketones\ and there aremany approaches to this problem\ including the use of the lithium salt derived from MeOBut

ð72TL2054Ł and the stannane "31# ð74JOC3544Ł[ Cuprates related to "31# will add to enones "0\3!addition# to give g!alkoxy ketones ð77TL2800Ł[ Knochel and co!workers have capitalized on thechemoselectivity of organozinc reagents to prepare compounds having oxygenation adjacent to\ orremote from\ the metal[ These reagents undergo a number of useful reactions\ including additionto acid chlorides or 0\3!addition to enones to give a!oxygenated or more remotely oxygenatedketones ð82CRV1006\ 82JOC477Ł[

R SnBu3

OBnO

(42)

Several methods are available for the direct oxidation of ketones\ including the use of iodine"III# toprepare a!methoxy ketones ð76JOC049Ł and a mild method involving treatment with a manganese"III#carboxylate to give a!acyloxy ketones[ A range of carboxylate groups can be introduced at the aposition using this approach ð89SC1168Ł[ This reaction has been shown to occur in high yield at thea sp2 carbon of aryl alkyl and alkyl alkenyl ketones and to be highly chemoselective ð81S124Ł[ Areview has recently appeared on the oxidation of a\b!unsaturated ketones at the a? position ð81S124Ł[

The addition of oxygen anions to nitroalkenes is a facile process which occurs under mildconditions[ Silylation of the resulting nitronate permits an especially mild Nef reaction\ giving a!alkoxy ketones in high yield ð76TL4250Ł[ Nucleophilic attack at sul_nyl epoxides occurs regio!speci_cally b to the sul_nyl group to give an intermediate alkoxide anion which collapses withelimination of PhSOH "Scheme 31#[ Intermolecular nucleophilic attack by alkoxides is not ane.cient process\ but intramolecular cyclization gives the corresponding cyclic ethers[ Intermolecularacetoxylation can be achieved using Pb"OAc#3:CsOAc to give a!acetoxy ketones[ These authorshave written a recent review which covers this area ð81SL344Ł[ The treatment of a!halo ketones withoxygen nucleophiles is one possible method for the formation of a!oxygenated ketones\ but theoutcome is very dependent on the structure of the substrate and the conditions used "for a recentreview see ðB!77MI 293!91Ł#[ Oxidative cleavage of allylic acetates with alkenes is an obvious methodfor the synthesis of a!acetoxy ketones\ and many examples are known[ Terminal alkynes can beconverted into a!acyloxymethyl ketones using NaBO2:Hg"OAc#1 ð78SC1484Ł\ whilst addition toalkynylphenyl iodonium salts under acidic or basic conditions gives similar products ð78JOC3927Ł[As an alternative\ the addition of water to propargylic alcohols or acetates using catalytic rutheniumð76JOC1129Ł or NaAuCl3 ð80JOC2618Ł also gives acetoxy ketones[

O

R1

SOPhR2 R3O

O

R2

R1

Scheme 42

R3OO–

R2

R1SOPh

Among the recent developments in the Mukaiyama aldol reaction enol acetates have beenshown to act as enolate donors to give b!alkoxy ketones ð81CL1928Ł[ Lanthanide tri~uoromethanesulfonates\ reusable catalysts\ can be used for a similar transformation ð82S260Ł and TMS bis"~uoro!sulfonyl#imide has been reported to be a more active catalyst than TMS!OTf ð82TL6224Ł[ Oxidative


cleavage of 2!substituted 3\4!dihydropyrans gives g!formyloxy ketones in high yields and\ using oneequivalent of ozone\ remote\ isolated alkenes survive ð82JOC2058Ł[

A novel intramolecular reduction is part of a recent synthesis of d!acyloxy ketones[ Thus\treatment of an iodo ester with SmI1 and an acylating agent results in rearrangement to anequilibrium mixture of d!hydroxy ketones in which steric crowding is believed to control the directionof the reduction "Equation 47# ð82JA4710Ł[

PhO

I

O

Ph

OAc O(58)

i, SmI2 ii, AcCl

79%, 90% ee

2[93[3[2 OX!functionalized Ketones

The high reactivity of the a carbon in a!sulfonyloxy ketones has meant an increased interest intheir synthesis ð89SL254\ 80T0098Ł[ Enol acetates\ silyl enol ethers and enamines have been shown toreact regiospeci_cally with arylsulfonyl peroxides to give the desired products in high yieldsð75TL4700Ł[ a!Sulfonyloxy ketones can also be prepared directly from aromatic and symmetricalketones using iodine"III# reagents ð77JOC109\ 81TL6536Ł and the even more reactive a!tri~uoro!methanesulfonyloxy ketones can be prepared by the oxidation of enol silanes under similar con!ditions ð78TL556Ł[ A number of methods are available for the synthesis of a!phosphoryloxy ketones[These include the direct phosphoryloxylation of ketones ð77JA1876Ł\ the oxidation of enol phosphateswith dioxiranes ð80CB1250Ł and the hydration of alkynes using iodine"III# ð82TL668Ł[ Of these\ thelast two are perhaps the most attractive\ as they avoid the formation of isomeric mixtures or theuse of sensitive reagents[

Silyloxy ketones are isolable intermediates in several of the procedures for the direct oxidation ofketones\ see Section 2[93[3[0\ and could also be prepared from many other intermediates in thatsection[ A direct preparation of silyloxy ketones uses morpholine enamines derived from aldehydeswhich react with CO and a silane "Scheme 32# ð81JOC1Ł[ Depending on the speci_c protecting groupand the structure of the substrate\ many oxidants are capable of demonstrating selectivity for onesilyl ether in the presence of another[ This has been the subject of a very useful review ð82S00Ł[

N

O N

O

MeEt2SiOMeEt2SiH, [RhCl(CO)2]2

50 atm CO, 140 °C

72%

p-TsOH, H2O, 70 °C

100%

OSiEt2Me

O

Scheme 43

The aldol reaction of an enol derivative with a C!0 electrophile often requires the use of formal!dehyde\ which can be di.cult to generate from its commercially available form\ and so a number offormaldehyde equivalents have been developed including chloromethyl benzyl ether ð78CC0523Łand b!trimethylsilylethoxymethyl chloride ð89SL006Ł used to introduce an alkoxymethyl and asiloxymethyl group respectively "Equation 48#[ In a surprising reaction\ THF act as an electrophilein the TMS!OTf!catalysed reaction with SAMP or RAMP hydrazones[ A 3!silyloxy butyl group isintroduced at the a position of the hydrazone and the ketone can be unmasked without removal ofthe silyl group[ Chemical and stereochemical yields are very good ð82S0981Ł[

(59)

O O

ORbase, ROCH2Cl

R = CH2CH2–TMS, Bn

053 Dialkyl Ketones

2[93[4 KETONES BEARING A SULFUR FUNCTION

2[93[4[0 SH! and SR!functionalized Ketones

2[93[4[0[0 a!SH! and SR!functionalized ketones

The synthesis of a!thiol ketones is complicated by their chemical instability[ Their usual prep!aration\ involving the treatment of a!bromo ketones with sodium hydrogen sul_de\ requires a largeexcess of the sul_de to prevent formation of "32# ð74TL0870Ł and results in the isolation of the cyclicdimer "33# ð64JOC0183Ł[ The formation of "32# can be eliminated by the use of monoprotected sulfurnucleophiles such as thioacetate or thiocarbamates[ The thiol ketone is then released by hydrolysisð74JA3064Ł[ The synthesis of thiol ketones has been part of a previous review ð66HOU"6:1C#1206Ł[

R2S

R2

O O

R1R1 S

S

R1

R1

R2

OH

R2

HO

(43) (44)

The two best!established methods for the synthesis of a!sulfenyl ketones are the direct sul!fenylation of ketones or their derivatives or via substitution at a!halo ketones by a thiolate anion[For the former\ the success of the method depends on the ability to control a number of sidereactions[ Many sulfenylating agents are known\ including thiocyanates\ sulfenyl acetates\ thios!ulfonates\ sulfenyl chlorides\ disul_des\ thioamines and N!thioamides\ with the choice of the mostappropriate reagent being dependent on the reactivity of the enolate donor[ For example\ silyl enolethers frequently require the use of the highly reactive sulfenyl chlorides\ whose use may beincompatible with other functional groups[ Conversely\ enolate anions will react readily withdisul_des[ Other problems associated with the sulfenylation of ketones include the formation ofregioisomeric mixtures\ the possibility for a\a or a\a? bissulfenylation\ a facile elimination of PhSHfrom the product to give a\b!unsaturated carbonyl compounds and the greater acidity of the productwith respect to the starting material\ which means that an extra equivalent of base may be requiredto compensate for proton transfer[ Additionally\ regiospeci_c sulfenylation is\ as expected\ cruciallydependent on regiospeci_c enolate generation[ The acidity of a!sulfenyl ketones means that theintroduction of further substituents at the a position is relatively easy to achieve "for a review ofmuch of the early work in this area see ð67CRV252Ł^ see also ð80COS"6#008Ł[ Recent developmentshave lead to a number of improvements in the procedures or reagents used for the sulfenylation ofketones[ Usually a!phenyl sulfenyl or a!methyl sulfenyl ketones are prepared as intermediates forfurther elaboration^ however\ alkylation of the potassium salt of thiosulfonic acids with appropriatealkyl halides allows access to a greater range of sulfenylating agents[ Using these thiosulfonateesters\ one equivalent of base may be enough for e}ective reaction with ketones ð73LA148Ł[ Thio!sulfonate esters have also been used for the sulfenylation of silyl enol ethers[ Under the reactionconditions\ the silyl enol ether is cleaved by tetra!n!butylammonium ~uoride\ and the resultingammonium enolate reacts within a few minutes even at low temperatures ð78S353Ł[ For chiralketones\ where diastereofacially selective addition is observed\ the use of lithium amide bases orthioamines as sulfenylating agents may be problematic because the presence of a basic amine as theby!product can cause epimerization at the a position[ Under these circumstances\ the use of silylenol ethers and N!phenylthio lactams may be bene_cial ð81JOC0837Ł[ Sulfenylation of enol borinatesoccurs in very high yields with phenyl sulfenyl chloride or the ester "34#[ Reaction occurs at the lesshighly substituted side of the ketone and bissulfenylation occurs as a minor pathway in only onecase ð80SL034Ł[ Diastereofacial addition to an enantiomerically pure enol borinate ð80SL034Ł or tinenolate ð75CL0798Ł gives only low selectivities\ but this may be improved using bulkier sulfenylatingagents ð75CL0798\ 81JOC0837Ł[ A recently reported reagent for the sulfenylation of silyl enol ethers"35# appears to have a number of advantages over other reagents[ No activating agent or Lewis acidis required to facilitate the reaction\ which proceeds without the use of very low temperatures togive monosulfenyl ketones ð81TL5000Ł[

In many of the examples discussed above\ modern methods for regiospeci_c ketone enolizationensure regioisomerically pure products^ however\ this is not always the case and in addition attemptsto prepare a\a bissulfenyl ketones using this approach often gives mixtures of isomers[ An alternativeprocedure for a\a bissulfenylation has been developed for cyclic ketones which involves a one!

054Bearin` a Sulfur

ClSCO2Me Ph S

NTs

N

Ts

SPh

(45) (46)

carbon ring expansion[ In cases where the two a positions are substituted to di}erent degrees\ bondmigration is selective with only a small amount of the alternative isomer being formed "Scheme 33#ð79TL3290Ł[ For acyclic ketones\ bissulfenylation can follow a two!carbon homologation\ althoughthe _nal hydrolysis requires the use of a strong acid "Scheme 34# ð76S492Ł[

O O

SMe

SMe

Scheme 44

(MeS)3CLi

73%

(MeCN)4CuClO4

60%

C(SMe)3HO

O

O

O

OR2

OHR1

S

S R1

R2

O

Scheme 45

i, ButLi, –78 °C

ii, R1R2CO

i, BF3•Et2O, HS(CH2)3SHii, 40% H2SO4, THF

60–90%

An experimentally simple procedure has been reported for the synthesis of a!methoxy!carbonylsulfenyl ketones which involves neither base nor low temperatures[ Under the standardconditions\ the thermodynamically favoured isomer predominates "Equation "59##^ however\ kin!etically generated silyl enol ethers react regiospeci_cally to give the kinetic product ð81JOC0942Ł[a!Thiocyanato acetophenones\ which are useful reagents for the preparation of heterocycles\ can beprepared from acetophenones and potassium thiocyanate using iodine"III# in a one!pot procedureð82SC0344Ł[

(60)

O O

SCO2Me

MeOCOSCl, 0 °C, CH2Cl2

68%

Treatment of a!halo ketones with sulfur nucleophiles is a standard method for the preparationof a!sulfenyl ketones and many examples exist in the literature ð79JA2437\ 71TL4920Ł[ Bromides\chlorides or iodides act as substrates and organic or inorganic bases can be used to form the thiolateanion[ A previous review has covered in detail much of the work in this area ðB!77MI 293!91Ł[ Thiolsthemselves are pungent\ readily oxidizable materials which may not store for prolonged periods\and therefore methods have been developed for their generation and use in situ from thioimidatesð76IJC"B#0000Ł or disul_des ð78BCJ0247Ł[ Despite the presence of an easily oxidizable sul_de\b!hydroxy sul_des\ prepared from the ring opening of epoxides by sul_des or the reduction ofa!sulfenyl esters with LiBH3\ can be oxidized to a!sulfenyl ketones using the DessÐMartin reagentor SO2 =pyridine ð77JMC1088Ł or chloral on Al1O2 ð66TL2116Ł[

Alkenes or epoxides act as intermediates in a number of syntheses of a!sulphenyl ketones[ Thus\regiospeci_c sulfenylation is achieved using alkenyl sul_des or alkenyl silanes as substrates\ wherethe carbonyl group arises from the heterofunctionalized carbon atom "Equation "50##[ The majorityof the published examples lead to terminal phenyl sulfenyl methyl ketones\ and hydroxy and ketogroups survive the reaction conditions ð77CC0357\ 82T1900Ł[ Thiolate anions add to a!substitutedb!aryl nitroalkenes in the presence of a reducing agent to give isolable a!sulfenyl oximes which canbe hydrolysed to the corresponding ketones ð74SC332Ł[ The bisfunctionalization of alkenes tosulfenyl ketones is not a trivial process but one that has been achieved via initial electrophilic attackwith dimethyl"methylsulfenyl#sulfonium tetra~uoroborate[ The resulting sulfonium ion can be trap!ped with DMSO\ and\ after elimination of dimethyl sul_de\ a!methyl sulfenyl ketones are obtainedin good yield[ Terminal alkenes give a!methyl sulfenyl methyl ketones and 0!phenyl propene gives

055 Dialkyl Ketones

0!phenyl!1!methyl sulfenyl propanone "Scheme 35# ð71JA2117Ł[ It might be anticipated that additionto nonsymmetric\ dialkyl alkenes or alkynes would give mixtures of regioisomers[ This has beenobserved with a related method "Equation "51##\ although again in this case terminal alkynes givegood yields of a!sulfenyl methyl ketones ð77TL1270Ł[

R2

R1 X

R3

R4SR3

R2R1

O

(61)

X = SR5, SiR63

Ph

Ph

O

SMe

S +Me

MePh

O

SMe

Scheme 46

Me2S+SMe•BF4–

then DMSO

Pri2NEt

80%

(62)Prn

SPh

O

O

SPh

+ i, ArNH(SPh)BF3

–

ii, H3O+

+

30% 40%Ar = C6H4NO2-p

Several procedures for the regioselective synthesis of a!sulfenyl ketones have been reported whichrely on a homologation reaction[ Phenylthiotrimethylsilylmethyl lithium adds e.ciently to esters\but not to acid chlorides or to anhydrides[ On exposure to silica gel\ the adducts lose the TMSgroup via a protiodesilylation to give a!phenyl sulfenyl methyl ketones ð70TL1792Ł[ A methyl sulfenylmethyl group can also be introduced using the reaction between the ketene silyl acetal of ethyla!methyl thioacetate and an acid chloride followed by a decarboxylation "Scheme 36# ð68JOC3506Ł[Decarboxylation forms part of another one!pot synthesis of sulfenyl ketones "Equation "52##[ Inthis case\ the method works best for a!substituted ketones ð67BCJ2997Ł[ A bissulfur!stabilized anionadds to aldehydes in high yield\ and the adducts undergo an acid!catalysed rearrangement "Scheme37# ð68JCS"P0#0963Ł[ Conjugate addition of an alkyl thiol to the vinyl phosphonate "36# generates anylide which reacts with aryl aldehydes as shown in Scheme 38 ð72S221Ł[

MeS OEt

O-TMS C7H15SMe

O

C7H15

TMS-O

SMe

OEt

O

Scheme 47

C7H15COCl H3O+

57%

(63)

O

CO2Me

O

SPh

Ph2S2, HMPA, NaI, 160 °C

49%

Another method which does not require regiospeci_c enolate generation is the Rh1"OAc#3!cat!alysed addition of thiophenol to a!diazo ketones[ As the diazo ketones are readily available fromthe corresponding acid chloride and diazo alkanes\ and the sulfenylation occurs in high yield\ thetransformation could be widely applicable\ limited only\ perhaps\ by the need to generate potentiallyhazardous diazo alkanes on a large scale[ The reaction can be used to make nonterminal sulfenylketones by use of the appropriate diazo ketone "e[g[\ "37## ð71TL1498Ł or heterocyclic ketonesfollowing an intramolecular reaction "Scheme 49# ð89T5490Ł[ In the presence of phenyl sulfenylchloride\ diazo ketones are converted into the adducts "38#[ These undergo inter! "Scheme 40# or

056Bearin` a Sulfur

Li

PhS

R1

PhS

SPh

R1

O

R2

Scheme 48

R2CHO p-TsOH, C6H6

PhS

R1

PhS

OH

R2

R1 = H, alkyl

SMe

(EtO)2PO Ph SMe

O

Scheme 49

Ph SMe

SMeMeSNa, PhCHO

70%

TiCl4, H2O, MeCN

73%

(47)

intramolecular FriedelÐCrafts reactions to replace the chloride with an aryl group at the a positionð72TL006Ł[ Aryl sulfenyl alkyl boronate esters "e[g[\ "49## can be deprotonated adjacent to the sulfur\and the resulting anion reacts with esters[ Under the reaction conditions\ the boron group migratesfrom carbon to oxygen and the enol borinate is hydrolysed to the ketone using acid ð71OM179Ł[ Areview has some examples of sulfur!stabilized anions ðB!76MI 293!90Ł[

Ph N2

O

PhB

SPh

O

O

(50)(48)

S

O

S

OCO2Me

SH

CO2Me

O

N2

N2

Li CO2Me

Scheme 50

58%

Rh2(OAc)4

34%

PhN2

O

PhPh

O

SPh

Scheme 51

PhCl

O

SPh

PhSCl

96%

C6H6, SnCl4

70%

(49)

Anions stabilized by an adjacent sul_nyl group have been used in a number of syntheses ofa!heterofunctionalized ketones[ For example\ the treatment of "40# with lithium diisopropylamide"LDA#\ followed by an aldehyde or ketone\ gives a b!chloro alcohol which could be elaborated ina number of di}erent ways[ In one example\ thermal elimination of phenyl sulfenic acid followedby epoxidation gives an epoxide\ which can be readily attacked by thiolate anions to give a!sulfenyl!a?!oxygenated ketones "Scheme 41#[ An alternative procedure\ but one which can give structurallycomplementary products\ involves a Darzens condensation of chlorosulfoxides with aldehydes orketones to give a\b!epoxy sulfoxides[ Nucleophilic attack at such systems is directed towards the bposition to give an alkoxide anion which can react further by spontaneous elimination of the geminalsul_nyl group[ Dioxolanes remain una}ected by the reaction conditions\ and thiols containingesters\ heterocycles or alcohols can be used in addition to simple alkyl or aryl thiols "Scheme 42#[Further examples of the use of haloalkyl aryl sulfoxides for the synthesis of a!heterofunctionalizedaldehydes and ketones can be found in the review ð81SL344Ł[

057 Dialkyl Ketones

TolS Cl

O

R1

TolS

O

R1

Cl

R3

OHR2

i, LDA, –60 °C

ii, R2R3CO

PhMe, 110 °C

VO(acac)2, ButO2H, C6H6 R4SNa, EtOHCl

R1

R3

OHR2

ClR3

OHR2

O

R1

R1 R3

OHR2

O

SR4

Scheme 52

(51)

PhSOPh

Cl OPhSO

Ph

Ph

O

S CO2Me

Scheme 53

i, LDA, –60 °C ii, MeCHO

iii, KOH, MeOH

NaSCH2CO2Me, EtOH

2[93[4[0[1 b!Functionalized and more remotely substituted SH! and SR!functionalized ketones

There appear to be fewer published methods for the synthesis of b and more remote sulfenylketones\ although the thio analogue of the Mukaiyama reaction using chloroalkyl sul_des and silylenol ethers "Scheme 43# has been used with some success in this regard ð68TL1068Ł[ A number ofLewis acids have been shown to promote the reaction\ which is characterized by high regioselectivityat the silyl enol ether and a tolerance for a number of functional groups\ including alkyl halides\esters\ ketones\ alkenes and silyl ethers ð77T3196Ł[ The chloro sul_des are easily prepared from thecorresponding sul_des[ Since these initial reports\ other sources including dithioacetals ð74CL0760\89JOC4855Ł\ vinyl sul_des ð75TL2918Ł and a!nitro sul_des ð76CC836Ł of the presumed thioniumintermediate have been disclosed[ Thionium ions a to a carbonyl "e[g[\ "41## also act as substratesfor silyl enol ethers to give products in which the sulfenyl group is both a and b to carbonyl groupswithin the same molecule ð73CL0420Ł[ b\b!Disulfenyl ketones can be prepared by an analogousMukaiyama reaction between cyclic or acyclic silyl enol ethers and trimethylthio orthoformateð74TL5402Ł and from the conjugate addition of propane!0\2!dithiol to a\b!ynones ð81JOC6238Ł[

R3

OSiR43

Scheme 54

R1 Cl

SR2

R1

SR2

R3

O

R1

SR2+

SAr

O+

(52)

The number of synthetically useful homoenolate anion equivalents has been increasing steadilysince the 0879s\ and some of these have been shown to react with sulfenylating agents to give b ormore remote sulfenyl ketones[ Much of the work in this area has been the subject of the reviewðB!76MI 293!91Ł[ Among the preparations of stable sulfur ylides "i[e[\ "42## one of the more recent isperhaps the most direct\ involving coupling of a 0\2!dicarbonyl compound with the CoreyÐKimreagent ð89CPB2203Ł[

The sul_nyl epoxide "43#\ prepared analogously to that shown in Scheme 42\ can be used toprepare b!sulfenyl or a\b?!disulfenyl ketones\ depending on the reaction conditions "Scheme 44#ð81SL344Ł[ b\g!Epoxy nitro compounds\ which are readily available from allylic nitro compounds\

058Bearin` a Sulfur

undergo a base!catalysed ring opening and double!bond rearrangement accompanied by dis!placement of the nitro group\ to give b!sulfenyl ketones "Scheme 45# ð89JOC484Ł[

R1 R2

O O

SMe

(53)

+

O O

OPhS

PhOS

(54)

PhSe–PhS–

97% 96%

O O

OPhS

O O

OPhS

SPh

Scheme 55

O OO O

O PhS

O

Scheme 56

O O

OO2N

PhSH, Et3N, DMF, 70 °C

65%

i, MeNO2, H2NC2H4NMe2, C6H6, reflux

ii, mcpba, CH2Cl2

The lithium enolates of cyclic ketones have recently been shown to undergo a 0\3 addition toa\b!unsaturated sulfoxides in good yield[ Reduction of the sul_nyl group then givesg!sulfenyl ketonesð82JOC5365Ł[ Earlier\ this same conjugate addition had been achieved for acyclic ketones using thelithium enolate of acetone or via the dianion of ethyl acetoacetate and a subsequent decarboxylationð72TL394Ł[ As an alternative to this\ episulfonium ions\ generated from alkenes ð72TL850Ł or1!phenyl sulfenyl alcohols ð81CL128Ł react with silyl enol ethers to give similar products[ In the lattercase\ reaction takes place at the most!substituted terminus of the episulfonium ion^ homochiralalcohols have been used to give optically active products "Equation "53##\ and the reaction could beused to generate compounds with adjacent quaternary centres[ The conjugate additions of 1!lithio!0\2!dithiane ð76S0015\ 78T6532Ł and a!lithiosul_des "Equation "54## ð66TL0850Ł to a\b!unsaturatedketones has also been reported[ The synthesis of sulfenyl ketones has been part of a previous reviewð66HOU"6:1C#1206Ł[

OH

SPhH

Ph

Pri

O

SPhH

Ph

Pri

O-TMS

(64)TiCl4

100% ee 92%, 100% ee

(65)SPh

+

OO

SPh

ButLi, HMPA

57%

069 Dialkyl Ketones

2[93[4[1 Higher!coordinated Sulfur!functionalized Ketones

Oxidations of a!sulfenyl ketones "see Section 2[93[4[0[0# can be an excellent method for thesynthesis of a!sul_nyl ketones\ and one for which a number of reagents are known[ This is perhapsthe most frequently used method\ particularly where the products are to be thermolysed to thecorresponding a\b!unsaturated carbonyls[ However\ direct sul_nylation of ketones or their deriva!tives is a viable alternative\ and a number of sul_nylating reagents have been developed\ including O!alkyl aryl sul_nates ð64TL810\ 82JOC0468Ł\ aryl sul_nyl aryl sulfones ð82SC0404Ł and sul_nyl chloridesð71S172Ł[ Interest in the synthesis of a!sul_nyl ketones "b!keto sulfoxides# has greatly increased asthe importance of a homochiral sul_nyl group in chirality transfer reactions has become widelyrecognized ðB!72MI 293!91\ 80COS"5#022Ł\ and optically active sul_nates capable of reacting with ketoneenolates are becoming available ð75CL54\ 81JOC6124\ 82JOC3444Ł[ The other widely recognized methodinvolves the reaction of a sulfoxide stabilized anion with an acid derivative\ and many similarprocedures have been developed to achieve this ðB!77MI 293!92\ B!77MI 293!93\ 80COS"5#022\ 80JOC217Ł[

Anions stabilized by an adjacent sul_nyl group have been used in a number of other syntheses ofa!heterofunctionalized ketones[ For example\ treatment of chloromethyl phenyl sulfoxide with LDAand an aldehyde gives a highly functionalized adduct which can\ on further exposure to LDA\undergo elimination of HCl to give an a!sul_nyl ketone "Scheme 46# ð89BCJ0155Ł[ On treatmentwith a ketone\ however\ a di}erent mechanistic pathway results[ Under these conditions "Scheme47#\ a 0\1 elimination of HCl is not possible and so\ on the basis of the products formed\ a 0\0elimination is postulated to give a sul_nyl carbene which rearranges to give the observed productsð81TL6070Ł[ The di}erence in the relative migratory aptitude of the two groups adjacent to thecarbene will determine the selectivity and\ hence\ the usefulness of the procedure[

PhS Cl

O

PhS

O

Cl

n-C9H19

OH

PhS

O

n-C9H19

O

Scheme 57

LDA, –65 °Cn-C9H19CHO

98%

LDA (3 equiv.)

95%

O

OH

S

Cl

PhO

OLi

SPh

O

:Ph

S ClO

Li

Scheme 58

LDA H2O

70%

SO

PhO

100%

a!Sulfonyl ketones are generally prepared by the addition of sulfonyl!stabilized carbanions toacid derivatives\ and many examples of this reaction can be found in the literature "for reviews onall aspects of sulfone chemistry see ðB!77MI 293!92\ 80COS"5#022\ B!82MI 293!90Ł[ Acid chlorides andesters have been used as the acylating agent\ and the reaction requires either an extra equivalent ofbase or the use of an a\a!sulfonyl dianion ð77JOC895Ł for complete conversion\ owing to the enhancedacidity of the keto sulfone with respect to the lithio sulfone[ A one!pot preparation of a!sul_nyl ora!sulphonyl ketones was reported recently\ involving in situ generation of an acyl imidazole "Scheme48# ð78JOC4519Ł[ The sulfonylation of enamines with sulfonyl halides has been reported to givea!sulfonyl ketones ðB!82MI 293!91Ł\ but the reaction of sulfonyl halides with ketone enolates has beenshown to be strongly dependent on the counterion[ Lithium enolates react predominantly from thea position\ whereas larger cations promote increasing amounts of O!sulfonylation ð71CB2576Ł[a!Sulfonyl ketones can undergo further reaction at the a or a? positions via alkylation of their mono

060Bearin` a Sulfur

or dianions ð89SL171\ B!82MI 293!92Ł[ Sulfonate esters can also stabilize adjacent anions which undergosubsequent acylations ð80JOU0120Ł[

N

CO2H

N

O N

N

N

OSO2Me

Scheme 59

Im2CO LiCH2SO2Me

67%

One method for the preparation of b!keto sulfones which may be particularly attractive for large!scale work involves the oxidation of a!sulfenyl ketones "see Section 2[93[4[0[0# with Oxone ð76SC712Ł[Other methods for the synthesis of a!sulfonyl ketones include one of unsaturated sulfonyl ketonesusing a carbanion!accelerated Claisen rearrangement "Scheme 59# ð71JA3861Ł and a recently reportedprocedure which occurs in the absence of base "Equation "55##[ In the latter case\ branching at thea position of the aldehyde leads to a reduction in yield ð81TL0020Ł[ Two procedures involvingconjugate addition reactions have been used as routes to a!sul_nyl or a!sulfonyl ketones[ TheMichael addition of diethyl amine to allenic sulfoxides generates an unstable enamine "Scheme 50#ð71LA0985Ł\ and alkenyl selenoxides undergo hydrolysis via conjugate addition of water or alcohols"Scheme 51# ð72JOC2966Ł[

ONa

65%

KH, HMPA, 50 °C

80%•

PhSO2

PhSO2

O

Scheme 60

OPhSO2

ArS

N2

OO

+Ph

O

Ph

O

SAr

OO(66)

SnCl2

80%

•

SOAr

SOAr

O

Scheme 61

Et2NH H3O+

82%

NEt2

SOAr

C8H19SO2Ph

OO

C8H19SO2Ph

SeOPh

C8H19SO2Ph

O

Scheme 62

KOH, HOCH2CH2OH

76%

HClO4, H2O

60%

A number of more unusual\ higher!coordinated a!S!functionalized ketones\ which may attractincreasing attention owing to their potential for further elaboration or structural similarity tobiologically active structures\ have been reported sporadically in the literature[ Keto sulfoxoniumylides "e[g[\ "44##\ prepared from the reaction between an acid derivative and dimethyl sulfoxoniummethylide\ have been shown under photolytic conditions or following treatment with transitionmetal salts to give products characteristic of a!keto carbenes "Equation "56## ð82CC0323Ł[ Thesulfonamide group can also stabilize adjacent anions and this has been used to prepare sulfonamide!containing renin inhibitors "Equation "57## ð81TL6180Ł[ a!Sulfonamido ketones "e[g[\ "45##\ have alsobeen prepared by the reaction of enamines ð74S55Ł or silyl enol ethers ð81TL2566Ł with sulfamoylchlorides\ and when the keto sulphonic acid is available they can be made from the correspondingketosulfonic acid chloride "Equation "58## ð89OS"58#047Ł[ a!Oxo sul_nes\ "e[g[\ "46##\ can be preparedfrom silyl enol ethers and SOCl1 ð70S550\ 73TL4836Ł\ although under apparently similar conditions a

061 Dialkyl Ketones

di}erent product\ "e[g[\ "47## may predominate ð83T716Ł[ These chloro sulfenyl chlorides can beconverted into the sulfenamide\ "i[e[\ "48##\ in good yield[

MeS

O

Me

O–

NH-BOC

CO2Bn

N

O

BOC

CO2Bn(67)

(55)

Rh2(OAc)4

62%

NMeOMeBOC-NO

O

BOC-NO

O

SO2NHR (68)LiCH2SO2NHR

98%

(56)

O

SO2NHMe

(57) (58) (59)

O

S

O S

O

Cl

SCl

S

O

Cl

SNEt2

(69)

OSO3H

OSO2NH2

i, PCl5 or SOCl2

ii, NH4OH

A multistep but high!yielding synthesis of b!sul_nyl ketones has been reported which appears~exible enough to be used for a number of di}erent systems "Scheme 52# ð68TL2056Ł[ Potentiallyalso this could be used to prepare b!sulfonyl ketones[ Propargylic sulfones can be used to preparea! or b!sulfonyl ketones depending on the reaction conditions[ On simple treatment with NaOMe\followed by dilute HCl\ a!sulfonyl ketones were isolated in excellent overall yield[ In the presenceof a mercury"II#\ salt however\ the regioselectivity of the hydration is reversed to give b!sulfonylketones ð78TL6278Ł[

O

R1S S

S i, R1SH, Et3Nii, HS(CH2)3SH, BF3•Et2O

86–92%

i, BunLi, –40 °C ii, R2Iiii, Tl(ONO2)3

70–90%

R1S R2

O

S R2

O

R1

O

Scheme 63

NaIO4

76–93%

The conjugate addition of enolate anions to alkenyl sulfoxides has been used sparingly despite itsbeing potentially the most direct route to g!sul_nyl ketones[ Ten years ago it was shown that theacetone enolate or the dianion derived from ethyl acetoacetate could be used in this mannerð72TL394Ł\ and since then enolates derived from acyclic ð72JOC803Ł or cyclic ð82JOC5365Ł ketoneshave been shown to behave in the same way[ a\b!Unsaturated sulfones also serve as Michaelacceptors in their reaction with SAMP and RAMP hydrazones to give g!sulfonyl ketones[ Gooddiastereoselectivity is observed in the addition of a homochiral hydrazone to b!substituted sulphonesð82T0710Ł[


2[93[5 KETONES BEARING A Se OR Te FUNCTION

2[93[5[0 SeH!\ TeH!\ SeR! or TeR!functionalized Ketones

The conversion of ketones to a\b!enones is often a di.cult process\ but one that is facilitated bythe facile syn elimination of selenic acids from a!selinyl ketones[ This has lead to considerableinterest in the synthesis of the immediate precursor\ a!selenyl ketones "Scheme 53# "for excellentreviews on selenium chemistry see ð67T0938\ 74T3616\ B!75MI 293!90\ B!76MI 293!92Ł#[

R1 R2

O

R1 R2

O

SeR3

R1 R2

O

SeO R3

R1 R2

O

Scheme 64

The a!selenylation of carbonyl groups was _rst studied independently by three research groupsð62CC584\ 62JA4702\ 62JA5026Ł\ although the substrates varied from enol acetates\ to enolates\ and toketones\ respectively[ In situ enolization and selenylation of ketones is obviously the most directð62JA5026\ 64JA4323Ł and can be surprisingly chemoselective with esters\ silyl ethers\ isolated alkenes\epoxides and ketals being some of the groups that remain una}ected ð67JOC3441\ B!76MI 293!93Ł[ Thereaction proceeds via the enol form of the ketone\ and\ in di.cult cases\ enolization may beenhanced by the presence of hydrogen chloride or an acidic ion exchange resin ð67JOC3441Ł[N!"Phenylselenyl#phthalimide also requires the presence of acid "one equivalent of p!TsOH# in orderto react directly with ketones[ Selenylation occurs preferentially at the more!substituted side of acycloalkanone\ and 1!cyclohexenone gives 5!phenyl selenyl 1!cyclohexenone in 49) yieldð82TL6644Ł[

The requirement in most of these methods for acidic conditions to promote enol formation isincompatible with the presence of some functional groups\ and it may be more practical to use apreformed enol derivative[ This can lead to a complementary or more regioisomerically predictableoutcome because of the myriad of methods that are available for regioisomeric ketone enolization[Enol acetates ð62CC584Ł\ enol borinates ð80SL034Ł and silyl enol ethers ð66S763Ł\ the last even in thepresence of ketones ð70JACS2359Ł\ undergo direct reaction with PhSeCl or PhSeBr\ to give thecorresponding a!phenyl selenyl ketones[ With silyl enol ethers two new selenium species\ "59# and"50#\ have been shown to give high yields ð81TL5000\ 82CC0520Ł[ The latter introduces an acyl selenogroup at the a position[

(60) (61)

Ph Se

NTs

N

Ts

SePh R SeCl

O

Metal enolates have also been used for the formation of a!phenyl selenyl ketones\ and the greaterreactivity of such systems may allow for the use of the less reactive\ but more stable\ diselenides asthe selenylating agents[ In some examples\ however\ this procedure is complicated by the estab!lishment of an equilibrium reaction owing to the selenophilic nature of the selenate anion "Equation"69##[ Lithium enolates generated by direct deprotonation ð62JA4702\ 64JA4323Ł or conjugate additionð64JA4323Ł and aluminum or zirconium enolates generated by conjugate addition ð79TL0386Ł areamong those that have proved e}ective in their reaction with selenylating reagents[

(70)R1

R2

OM+ PhSeSePh R1

R2

O

SePh

+ PhSeM

M = metal

The most common selenylating agents\ Ph1Se1\ PhSeCl and PhSeBr have already been mentioned\although the last occasionally acts as a brominating agent[ There are\ however\ a number of otherreagents or methods that can be used[ Perhaps the most cost e}ective\ involves the reaction of an

063 Dialkyl Ketones

enolate with selenium metal to give a selenate anion[ This can then be alkylated on selenium with avariety of alkyl halides to give less common a!selenyl ketones ð79TL2532Ł[

Several published procedures do not require the use of a strong base[ Thus\ PhSeBr\ generated insitu from the electrolysis of Ph1Se1 reacts directly with ketones ð79TL0752Ł\ and the oxidation ofdiselenides with SeO1 gives a more electrophilic selenylating species which can also react directlywith simple ketones ð71TL3702Ł[ A selenylation which is promoted by acid!catalysed enol formationemploys 1!pyridyl selenyl bromide[ Prior work had indicated that the pyridyl group would enhanceselenoxide elimination when compared to phenyl and\ as expected\ yields of a\b!unsaturated car!bonyl compounds were increased by approximately 19) for otherwise identical reactionsð71TL1094Ł[ A later paper from the same group demonstrated that ketone enolates and silyl enolethers react with the same reagent ð73JOC2685Ł[ 0\2!Diketones or 0\2!keto aldehydes are selenylatedat the central position with PhSeCl in pyridine ð70JOC1819Ł or selenium metal ð70TL2932Ł[ Remark!ably\ ketones protected as cyclic acetals react directly to introduce a phenyl selenyl group at the aposition without loss of the protecting group ð68S871Ł[

Diazo groups have been involved in two conceptually di}erent syntheses of a!selenyl ketones[Seleno esters\ which are readily available from the corresponding carboxylic acids\ undergo insertioninto diazomethane to give terminal a!methyl selenyl or a!phenyl selenyl ketones "Equation "60##ð74T3648Ł[ Alternatively\ cyclic and acyclic a!diazo ketones undergo spontaneous a\a addition ofPhSeCl\ PhSeBr or PhSeOAc to give bis heterofunctionalized adducts "e[g[\ "51#\ X�Cl\ Br\ OAc#[Elimination of either of the a substituents is possible under di}erent conditions "Scheme 54#ð74JCS"P0#1082Ł[ a!Phenyl selenyl a\b!unsaturated ketones are available using a more convenientprocedure via the addition of PhSeCl to enones in the presence of base ð74T3770Ł[

(71)SePh

O O

SePhCH2N2, CuI

55%

O

Cl

O

SePh

O

X

SePh

Scheme 65

(62)

H2O2

82%

Li2CO3

77%

Nucleophilic displacement of halides by selenate anions is a well!established method for thesynthesis of selenides\ but for a!selenyl ketones this reaction is complicated by nucleophilic attackat the initial product to give the reduced ketone "see Equation "69##[ However\ some successfulexamples have appeared in the literature ð79JOC79\ 70JOC1485Ł[ For mechanistic reasons\ reductionmay be less of a problem in the nucleophilic addition of selenate anions to a!chloro tosyl hydrazones[The conversion of hydrazone into ketone can be achieved without elimination of the selenideð71JCS"P0#1608Ł[

Phenyl selenyl acetaldehyde has been shown to be a useful reagent for the preparation of a!selenylketones "Scheme 55#[ Nucleophilic attack by Grignard reagents gives a secondary alcohol whichcan be oxidized to the ketone\ without oxidation at selenium\ using 1\2!dichloro!4\5!dicyano!0\3!benzoquinone or the CoreyÐKim procedure ð68HCA0395Ł[ 1!Hydroxy alkyl or 2!hydroxy alkylselenides can be prepared from the hydroxyselenylation of alkenes\ the ring opening of epoxides byselenium anions and the attack of selenium!stabilized carbanions at aldehydes\ ketones or epoxidesðB!75MI 293!91\ B!76MI 293!92Ł[ Thus\ these methods also constitute indirect approaches to a! orb!selenyl ketones[

SePh

O

SePh

O

SePh

OHMgBr

Scheme 66

74%

ddq

63%

ddq = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

Terminal alkenes undergo Markovnikov addition of PhSeBr to give bromo selenides "Scheme56#[ Subsequent treatment with silver"I# in DMSO results in displacement of the bromide by the


solvent to give a sulfonium salt which\ on exposure to Et2N\ gives a terminal a!selenyl ketone[ Thereaction may go through the episelenonium ion "52# as the isomeric bromo selenide "53# gives thesame a!phenyl selenyl ketone rather than a selenyl aldehyde ð67TL1150Ł[ An identical transformationhas been achieved using PhSeOSnBu2 or "PhSe#1O generated in situ ð70BCJ2099Ł[ With these last tworeagents\ the proportion of a!selenyl aldehyde formed can be higher\ indicating poor regiochemicalcontrol during the addition[ In the oxyselenylation of allylic alcohols\ ethers or acetates\ additionto the alkene was predictable and consistent\ with the selenyl group becoming bonded to theterminus of the double bond adjacent to the pre!existing oxygenation "Equations "61# and "62##[The regioselectivity of the addition is lower in homoallylic ethers ð67TL0166\ 70BCJ2409Ł[ Addition ofPhSeBr to alkenes in a protic solvent has been shown to result in isolable alkoxy alkyl selenides"e[g[\ "54##[ Oxidation at selenium to the selenoxide was followed by a thermally catalysed rearrange!ment to the a!phenyl selenyl ketone ð67TL688Ł[ Vinyl selenides can also be oxidized to a!selenylketones ð79CC840Ł[ a!Chloro sul_des are valuable sources of the thionium ion and the correspondingselenides can be prepared as shown in Equation "63# ð78TL1554Ł[

SePh

Br

SePh

O

SePh

OS

Me

Me

Scheme 67

+

PhSeBr

DMSO

AgI

DMSO

Et3N

70%

(63) (64)

Se+

Ph

PriPri

Br

SePh

n-C5H11 SePh

OEt

(65)

AcO Ph AcO Ph

O

SePh

(72)PhSeOSnBu3

73%

PhSeOSePh

89%

O

SePh

TBDMS-O

PhPh

TBDMS-O

(73)

ArSe

R

ClCl

O

ArSe

R

O

Cl

(74)pyridine

Selenium\ like sulfur\ has the ability to stabilize adjacent carbanions[ In fact\ the di}erence in theacidity between the a protons of otherwise identical sul_des and selenides may be as little as 0Ð1pKa units[ The two most common methods for the synthesis of a!selenyl carbanions are the directdeprotonation of selenides ð68JACS5527Ł and metalÐselenium exchange in diseleno acetalsð58AG"E#349Ł\ and using di}erent electrophiles a number of remote selenyl ketone substitutionpatterns can be constructed[ Reactions with acid derivatives ð65TL342Ł or aldehydes lead directly\or following oxidation\ to a!selenyl ketones[ A number of recent reviews have dealt with the synthesisand reactivity of selenium!stabilized anions ð79T1420\ B!75MI 293!93\ B!76MI 293!94\ B!76MI 293!95Ł[

The conjugate addition of selenol anions to a\b!unsaturated ketones can be facilitated by anumber of di}erent reaction conditions[ Using base catalysis\ benzeneselenol adds as its potassiumð67TL4976Ł or sodium salt ð62TL0868Ł[ The former is generated from PhSe!TMS and KF\ but this silylselenide can react directly with enones using PPh2 ð67TL4980Ł or TMS!I ð68TL3078Ł[ Neutralization ofPhSeNa with a slight excess of acetic acid allows conjugate addition to occur under mildly acidicconditions ð79S553Ł[ Aluminum and titanium complexes have also been shown to promote theaddition of selenate ions to enones ð74TL5320Ł[ In a related transformation\ ketals derived from

065 Dialkyl Ketones

b!amino ketones undergo direct substitution of the amino group to give a selenide "Equation "64##ð79JA1345Ł[ In the presence of a Lewis acid\ seleno acetals ð73TL3330Ł or selenyl orthoformatesð74TL5402Ł lose a selenate group to generate monoselenyl! or bisselenyl!stabilized carbocations\respectively[ These react in situ with silyl enol ethers to give b!monoselenyl or bisselenyl ketones\respectively "Equation "65##[

OO

NMe2

OO

SePh (75)PhSeNa, RuCl3

98%

(76)

O-TMS O

SePh

SePh

(PhSe)3CH, SnCl4

97%

Two procedures for the synthesis of g!selenyl ketones have been published which use readilyavailable starting materials[ The _rst involves ring opening of cyclopropyl ketones orbicycloðn[0[9Łalkanones by phenyl selenide ð67TL0538Ł[ For the second\ the well!known ability ofselenate anions to cleave esters or lactones is exploited to transform 1!acetyl!3!butyrolactone into4!phenylselenyl!1!pentanone by nucleophilic attack at the 3 position of the lactone "Equation "66##ð66TL3250Ł[ Both of these methods would seem suitable for application to more complex systems[

(77)O

O O

SePh

OPhSeNa, DMF, 110 °C

92%

Until recently\ there appeared to be little interest in the use of organotellurium compounds inorganic synthesis[ This situation is slowly changing\ but there are still very few reports describingthe synthesis of isolable tellurium!substituted ketones[ a!Phenyl telluro ketones have been preparedby the reaction of ketone enolates with PhTeI[ The products decompose rapidly in light and air\but can be handled in an inert atmosphere[ The application of other procedures for the synthesis ofa!selenyl ketones\ for example the reaction between silyl enol ethers and selenyl halides and thedisplacement of halo ketones by selenate anions\ did not work for telluro ketones ð76S0985Ł[ Ketalsderived from a!bromo ketones\ however\ will undergo displacement of the halide with PhTeNað75JCS"P0#0872Ł[ Diphenacyl tellurides or phenacyl tellurides have been prepared from reduction ofthe dichloro derivatives "55# "R0�Ar\ ArCOCH1# "see Section 2[93[5[1# ð75OM316Ł and the diphen!acyl tellurides can also be prepared from the reaction of bis"triphenylstannyl#telluride with phenacylbromide ð89TL5180Ł[ Tellurium salts can be prepared from dialkyl tellurides and phenacyl halides[Their ylides give alkenes on reaction with carbonyl compounds ð77JOC3751Ł[

Conjugate addition of a phenyl telluro group to cyclic and acyclic a\b!unsaturated ketones canbe achieved using PhTeAlBui

1[ The products are slightly air sensitive but can be isolated[ Theintermediate aluminum enolate can be used in aldol reactions to generate more heavily functionalizedb!telluro ketones "Scheme 57# ð78CL596Ł[ A recent review has dealt with the use of tellurium reagentsin organic synthesis ð80S682\ 80S786Ł[

RTe

Ar

OClCl

(66)

O OBui

2Al

TePh

O

TePh

OH

Scheme 68

PhTeAlBui2 n-C3H7CHO

76%


2[93[5[1 Higher!coordinated Se! or Te!functionalized Ketones

Although higher!coordinated selenium species are not uncommon\ very few of these have aproximal aldehyde or ketone group[ The main exception to this are the b!keto selenoxides "a!selinylketones#\ formed as intermediates during the oxidative elimination of selenyl aldehydes or ketones"see Chapter 2[90[5[0 and Section 2[93[5[0# to a\b!unsaturated carbonyl compounds[ This trans!formation has proved particularly successful because the syn elimination of benzene selenic acidoccurs at room temperature\ a process which has been studied by NMR ð74T3660Ł[ Therefore\b!keto selenoxides can be isolated in only a few speci_c cases] where there is steric crowding at thecarbon b to the selenoxide\ where there are no b!hydrogen atoms\ or where the selenoxide and itsb!hydrogen cannot adopt the correct syn conformation[ The more highly oxidized selenones areeven less well known ðB!75MI 293!92Ł[ Direct introduction of a selenoxide is possible with phenylselinyl chloride\ although again elimination occurs without isolation of the a!phenyl selinyl ketoneð64JA4323Ł[ Selenium oxychloride reacts with phenacyl chlorides to give the adducts "56# ð77TL0288Ł[

PhSe

Ph

O OClCl

(67)

On simple treatment with ketones\ PhSeCl2 acts in a manner analogous to PhSeCl except that theproduct contains a tetravalent selenium group "e[g[\ "57##[ Further transformation of the productcan result in the enone\ via the selenoxide\ or the selenide "Scheme 58# ð74TL5274Ł[ Stabilizedselenonium and tellurium ylides\ "e[g[ "58## can be prepared by the reaction between seleniumdichlorides ð61JOM"31#288Ł or selenoxides or telluroxides ð79BCJ706Ł and 0\2!diketones[

PhCl2Se

O

O

Ar2Se

O

(69)(68)

R1

O

R1

O

PhSeNaHCO3

50–97%

thiourea

71–99%

R1

O

PhCl2Se

Scheme 69

R2 R2 R2

a!"Aryldichlorotelluro#ketones "i[e[\ "69## have been prepared by the reaction between an aryltellurium trichloride and either a ketone or silyl enol ether[ The yields are typically quite high"79Ð099)# ð75OM316\ 76SC332\ 82CL450Ł[ Alkyltellurium trichlorides react only poorly with aromaticketones but give much higher yields with their silyl enol ethers ð80OM0067Ł[ Cycloalkanones giveeither the dichlorides "60# or the trichlorides "61# with TeCl3 depending on the ketone usedð75OM316Ł[ Silyloxy cyclopropanes undergo a regioselective ring opening with TeCl3 to give eitherb!trichlorotelluro ketones or the corresponding dimers depending on the amount of metal chlorideused "Scheme 69# ð80TL118Ł[

O

TeCl2Ar

Te

O OClCl

(70)

O

TeCl3

(72)(71)

067 Dialkyl Ketones

But

O TeCl3 TMS-O

ButBut Te But

O

Cl Cl

O

Scheme 70

TeCl4 (0.5 equiv.)

95%

TeCl4 (1 equiv.)

96%

2[93[6 KETONES BEARING A NITROGEN FUNCTION

2[93[6[0 NH1\ NHR and NR1!functionalized Ketones

The combination of adjacent nucleophilic and electrophilic centres within the same moleculemakes the isolation of free primary or secondary amino ketones less than straightforward becauseof a competing dimerization reaction[ For this reason\ the majority of methods for the preparationof compounds within these two classes involve the isolation of a species in which either the aminogroup "as the amide\ carbamate or salt# or the carbonyl group "as the acetal or hydrazone# is in aprotected form[ Sometimes interconversion of these stabilizing groups is necessary prior to furtherderivatization[ Under appropriate conditions\ amine salts can be converted into the correspondingamides without base "Equation "67## ð81SL380Ł\ or into the t!butoxycarbonyl "BOC# carbamatesusing an ultrasonically accelerated reaction "Equation "68## ð80SL26Ł[ An excellent review hasrecently been published dealing with the synthesis of amino ketones ð89OPP288Ł[

NH3Cl

O

ON

NHCOR

O

ON (78)

(RCO)2O, DMF (cat.), 55 °C

50–99%

R = Me, Et, Ph

(79)XH3N

O

BOC-HN

O(BOC)2O, NaHCO3, ultrasound

98%

2[93[6[0[0 a!NH1\ NHR and NR1!functionalized ketones

The displacement of a halide from an a!halo ketone with a nitrogen nucleophile is a well!established reaction which has been widely employed in organic synthesis[ The reaction is mostuseful when using secondary amines and primary halo ketones since primary amines often give bisadducts "Equation "79## and secondary or tertiary a!haloketones can undergo elimination under thereaction conditions "for a review see ðB!77MI 293!94Ł#[ In cases where this is a problem\ the use of aless!basic aminating agent may be bene_cial^ imidates are ideal in this respect\ retaining a signi_cantdegree of nucleophilicity and able to provide a range of alkyl!substituted amine nucleophiles"Equation "70##[ The reaction works even with secondary halo ketones\ and the formyl group canbe removed using acid hydrolysis ð70JOC0113Ł[ The direct oxidation of ketones to their a!aminoderivatives using a nucleophilic aminating agent\ in this case a secondary amine\ can be achievedusing iodine"III#[ Regiospeci_c amination is observed only when enolization is directed to one aposition by thermodynamic factors ð89SL254Ł[

R1Br

O

R1

O

R1N

O(80)

R2R2NH2

BzO

BzO

O

Br BzO

BzO

O

N

CHO

Ph+ PhN OMe (81)

MeCN, reflux

91%

The transformations outlined above demonstrate that useful direct aminations of a!halo ketonesexist\ but\ particularly for the introduction of an NH1 group\ a number of alternatives exist[ For


example\ reduction of a!azido ketones "see Section 2[93[6[2# gives primary a!amino ketones ð74LA674\75JOC2263Ł[ The same products can be obtained from the reaction between a!bromo ketones andhexamethylene tetramine "Equation "71##\ although the strongly acidic conditions required to hydro!lyse the intermediate adduct might limit the opportunities for its use ð53RTC0936\ 71JHC58Ł[ Theallylic chlorides "62# "R0�H\ Cl# react in an SN1 manner with LiN!TMS1 to give protected aminoketones ð82JOC6339Ł[

Br

O O

Br Br

O O

NH3Cl(82)

i, hexamethylene tetramine

ii, HCl, EtOH

R Cl

O-TMS

(73)

Potassium phthalimide ð57AG"E#808\ 57JPR01\ 80COS"5#54Ł and sodium diformylamide ð89S504Ł arepowerful nitrogen nucleophiles which readily displace halides[ The latter has the advantage that oneor both of the formyl groups can be removed selectively "Scheme 60#[ Although no experimentaldetails were given\ the monoformyl derivatives "63# were alkylated at the a position to give productsthat could not be made by direct substitution[ The a!alkylation of a!amino ketones has\ however\been studied by other groups and full details are available[ As might be expected\ the presence ofan electron!de_cient nitrogen "amide or carbamate# favours deprotonation between carbonyl andamino groups "Equation "72## and the resulting enolate can be trapped and isolated as the silyl enolether ð79JOC1296Ł[ Later papers by Muchowski and co!workers explored the reactivity of theseenolates with a number of alkylating agents ð75JOC2263\ 80CJC1948Ł[ These researchers demonstratedthat the monoanions of N!formyl and N!BOC amino ketones react with primary and secondaryalkyl\ benzyl and allyl halides to give the a!substituted adducts in\ usually\ good yield "Equation"73##[ The activating groups are easily removed\ and\ therefore\ the method can be used to preparea series of a!alkyl a!amino ketones[ As already discussed\ however "see Chapter 2[90[6[0[0#\ anN!8!phenyl ~uorenyl "PhFl# protecting group prevents racemization at the a position during treatmentwith a variety of reagents[ In fact\ it does so to such an extent that deprotonation occurs regio!speci_cally at the a? position "Equation "74## to give the isomeric a?!alkyl a!amino ketonesð77JA6336Ł[

ArN

O

CHO

H

ArNH3Cl

O

+

Scheme 71

ArBr

O

CHO

NaN

CHO MeCN, RT, 2 h

87–98% ArN

O

CHO

CHO (74)

NaOH, EtOH

91–98%

HCl, EtOH

91–99%

PhN

MeO2C O

PhN

MeO2C OSiR3

(83)LiHMDS, –78 °C to 0 °C

LiHMDS = lithium hexamethyldisilazide

PhN

R

HO

PhN

R

HO

Bun

(84) i, NaH

ii, BunI

R = CHO, 45%R = BOC, 60%

079 Dialkyl Ketones

O

NPhFl H

O

NPhFl H

(85)

i, KN(TMS)2ii, allyl bromide

85%

In a rather speci_c example of amino ketone monoalkylation\ and one which goes via a fun!damentally di}erent mechanism\ allyl!substituted imines are subjected to a thermally catalysedrearrangement[ Two competing pathways\ a ð2\2Ł sigmatropic rearrangement to give the N!allylketone "64# or a 0\1!allylic transposition to give "65# are theoretically possible "Scheme 61#[ In theend\ only the latter was observed\ to give a!amino!a!allyl ketones in reasonable yield[ A number ofN!functionalized imines\ such as "66# and "67#\ rearrange in the same way to give compoundssuitable for further synthetic elaboration[ Propargylic imines rearrange as shown in Equation "75#ð89TL1166Ł[

OR1

R2

BnHNN

OR1

R2

Bn

Scheme 72

NBnR2

HO

R1

(76) (75)

∆

TMS

OH

NBn

TMS

NHBn

O

(86)58%

N

OH

OMe

OMeN

OH

CO2Me

(77) (78)

Just as the reduction of amino acid derivatives is an excellent method for the preparation ofamino aldehydes "see Chapter 2[90[6[0[0#\ their reaction with organometallic reagents to give aminoketones has been equally widely exploited[ Most conveniently\ Rapoport and co!workers have shownthat amino acids in which the amino group is protected as an amide\ carbamate or sulfonamide canbe used directly in such transformations[ The acidity of the carboxyl and amino groups must becompensated for by the use of an excess of the organometallic reagent\ but this\ at least in part\ canbe done with relatively cheap organolithium reagents "Scheme 62#[ Very little tertiary alcohol wasformed\ and\ despite the use of at least three equivalents of a strong base\ no racemization at the aposition was observed ð72JOC1159\ 73JA0984Ł[ The same group had earlier shown that N!acyl a!aminoacid chlorides were also susceptible to attack by Grignard reagents to give the correspondingketones[ Using this approach\ the addition of a second equivalent of Grignard reagent to give atertiary alcohol may be a competing process[ In those cases where this is a problem\ stabilization ofthe tetrahedral intermediate by intramolecular chelation can result in an improved yield of theketone[ This has been achieved using 1!pyridyl thioesters ð71TL1422Ł\ although in one direct com!parison these were shown to be less e}ective than N\O!dimethyl hydroxamates or acyl oxazolidinesð74JOC2861\ 75JCS"P0#0784Ł[

The reaction of an acylating agent with an amino acid to introduce an alkyl group and form analkyl ketone\ the DakinÐWest reaction\ was _rst reported in 0817 and has been the subject ofconsiderable synthetic and mechanistic interest[ Early indications were that the reaction was limitedto amino acids with at least one a proton and the use of acetic anhydride to form methyl ketones"Equation "76## but\ although yields may be highest under these circumstances\ this has now been


BnO

CO2H

NH CO2Et BnO

CO2Li

NH CO2Et

Scheme 73

MgBr (2 equiv.)BunLi (1 equiv.)

BnON

Li CO2Et

OLiLiO

BnON

H CO2Et

O

H3O+

71%

shown not to be the case[ Thus\ a broader range of alkyl ketones can be made using this method\particularly as the most common acylating agents\ acid anhydrides\ are readily available[ Theconditions developed originally\ acetic anhydride at 099>C\ or 019>C for less reactive substrates\were quite harsh\ but it has been demonstrated that the use of the acyl transfer catalyst 3!dimethyl!aminopyridine dramatically reduces the reaction temperature ð77CSR80Ł[

CO2H

NH2

NH

O (87)(MeCO)2O, heat

70%

O

The amination of ketone enolates is limited by the relative paucity of electrophilic aminatingagents\ although such species are known ð78CRV0836\ 80TL1248Ł[ Silyl enol ethers have been used inconjunction with ethyl azidoformate "Equation "77## ð72TL482Ł or p!NO1PhSO1ONHCO1Etð83T2718Ł to introduce an N!ethoxycarbonyl amino group in reasonable yield and with azo!dicarboxylates to give a!hydrazino ketones ð74SC538\ 83TL1316Ł[ The recent\ elegant work by Magnusand co!workers on electrophilic addition to silyl enol ethers with double!bond transposition hasbeen extended to the synthesis of a!amino ketones "Equation "78##[ The p!toluenesulfonyl residuecan be removed without loss of the silyl group\ and the stereochemistry at the a position can beinverted using an oxidationÐreduction sequence "Scheme 63#[ Perhaps the most unusual aspect ofthe overall sequence is that the sulfonamide group is introduced initially into an axial positionð89JA351Ł[

(88)

O-TMS O

NHCO2EtEtOCON3, 110 °C, 15 h

40%

Pri3SiO Pri

3SiO

NHTs(89)

(p-TsN)2Se

51%

Scheme 74

Pri3SiO

NHTs

Pri3SiO

NH2 Na, NH2

70%

i, SeO2

ii, NaBH4

Pri3SiO

NHTs

The addition of 1!lithio!0\2!dithiane to aromatic nitriles results in the formation of an enaminewhose anion reacts further from the a position "Scheme 64#[ The imine "68# is surprisingly stableand undergoes further alkylation at nitrogen[ A _nal reduction gives a product resulting from

071 Dialkyl Ketones

addition of an acetyl anion to an imine ð76CC664Ł\ a transformation which can also be achievedusing the vinyl anion "79# ð89JOC4579Ł[ Acyl anion equivalents are also components of the benzoinreaction\ of which there are many variants[ The thiazolium salt "70# has recently proved quitee}ective in its addition to aldehydes and in the stabilization of the resulting anion[ In the presenceof an iminium salt\ an a!amino ketone results "Equation "89## ð77S203Ł[ The chemistry of acyl anionshas been covered in a recent review ðB!76MI 293!96Ł[

S

S

Li

S

S NH2

PhS

SPh

HN

(79)

PhCN

i, BunLi, MeIii, NH4Cl

100%

i, BunLi, MeIii, B2H6

63%

S

SPh

MeHN

Scheme 75

NONO

Ar

O

(90)+ ArCHO, (81)

25–50%

Li

OCONEt2

N

S

Bn

(80)

+

(81)

Cl–

This same connectivity can be achieved in the opposite sense by the addition of an a!nitrogenanion to an acylating agent[ One obvious example involves the acylation of a nitronate anion "seeSection 2[93[6[1#\ although this requires an additional step involving reduction of the nitro groupto an amine[ There are\ however\ many ways in which nitrogen in a lower oxidation state canstabilize adjacent anions\ although not all of these have been shown to react with acylating agentsðB!76MI 293!97Ł[ Perhaps the most common approach involves the use of an amine substituted witha cleavable\ electron!withdrawing group capable of coordination to\ and hence stabilization of\ anadjacent anion "Scheme 65#[ This frequently means employing amides "e[g[\ "71##\ thioamides\ "e[g[\"72## or formamidines "e[g[\ "73## ð65AG"E#202\ 79JA6014\ 70JOC3205\ 78JOC4540\ 78TL0086Ł[ The useof formamidine!stabilized carbanions has been extensively exploited by Meyers and co!workers\particularly for the synthesis of anions derived from cyclic amines ð74JOC0908\ 80JOC1640Ł[ Aminomethyl stannanes can act as amino alkyl anion equivalents without the need for strong base\providing the electrophile is a highly reactive one such as an acid chloride[ Simple mixing of bothreagents\ in the absence of solvent for liquid acid halides\ gives tertiary a!amino ketones "Equation"80##[ Aliphatic or aromatic acid chlorides behave as expected\ and formyl and nitrile groups remainintact ð75TL1250Ł[ Additional anion stabilization can be provided by an adjacent conjugatedp!system[ Thus\ the dianion derived from ethyl N!benzoyl glycinate reacts from the a position withacid anhydrides to give a!amido b!keto esters\ and decarboxylation proceeds smoothly to givea!amino or amido ketones ð67CC642Ł[ Two complementary modes of reactivity are demonstrated bythe adduct "74#\ which is readily prepared by condensation of an aldehyde with an amino!substitutedphosphine oxide[ In the presence of base\ a conventional Wittig reaction gives the correspondingenamine\ but\ in the presence of a proton source\ a thermal elimination of Ph1POH gives the aminoketone ð70TL1688Ł[ A similar reaction occurs using a nitrile!stabilized carbanion[ Following additionto an aldehyde\ elimination of HCN occurs regioselectively to give the desired product "Scheme 66#[This route has excellent synthetic ~exibility\ relying\ as it does\ on readily available aldehyde and


amine starting materials ð71TL528Ł[ The synthesis and reactions of nitrogen!stabilized carbanionshas been covered in a previous reviews ð73CRV360\ B!76MI 293!92Ł[

N

O

Et

EtEt

MeN But

S

Me

MeN

NR

Me

PhP

R3

NR1 R2

OHO

Ph

(82) (83) (84) (85)

R1 N R3

X

R2R2HN R3

EBunLi i, E+

ii, H3O+R1 N R3

X

R2

Li

X = O, N, S

Scheme 76

OO

Cl

O

OO

O

NEt2

+ Et2N SnBu3 (91)THF, 60 °C

84%

MeCHO + Et2NHCN

NEt2

NEt2

O

Ph

Scheme 77

KCN, H2O i, LDA, –78 °C, cinnamaldehydeii, distil

79%

Epoxides bearing a geminal leaving group have been used extensively for the preparation ofa!heterosubstituted ketones\ as the electron!de_cient substituent serves to activate nucleophilic attackat the b position of the epoxide as well as providing the means for carbonyl group formation via a0\0!elimination[ A number of substituents have acted in this way "Equation "81## ð89OPP288Ł\ ofwhich the most successful are the sul_nyl epoxides[ The substrates "e[g[\ "75## are easily preparedusing a Darzens type condensation of sul_nyl!stabilized carbanions with an aldehyde or ketone\and the addition of a secondary amine gives good yields of the expected products "Equation "82##ð75BCJ346\ 81SL344Ł[ 0\1!Disubstituted enamines react with sulfonyl oxaziridines to give a!aminoketones via the possible intermediacy of a!amino epoxides[ For example\ the morpholine enamineof cyclohexanone is converted into 1!morpholinocyclohexanone in 55) yield under mild reactionconditions ð77TL3254Ł[

OR2

ZR1 R2

R1

XR4

O

(92)R4XH

Z = Hal, OR3, NO2, PhSO

OPhSO

PhN

OPh

(93)pyrrolidine

100%

(86)

Despite their high reactivity as acylating agents\ acyl cyanides\ readily available from a carboxylicacid derivative\ can be reduced to a!amino ketone hydrochlorides using SnCl1 ð61JOC207Ł or toacetamido ketones "Equation "83## ð73TL1866Ł[ In the latter case\ isolated alkene\ ester or ketone

073 Dialkyl Ketones

groups survive\ although a\b!unsaturated acyl cyanides give mixtures of products[ Chemoselectivereduction of an a!nitro ketone to an a!amino ketone hydrochloride is possible using a poisonedplatinum catalyst ð75TL4648Ł[ Azides can also be reduced in the presence of ketones using catalytichydrogenation ð58CJC2378\ 74LA674Ł[ The Neber\ and mechanistically related\ rearrangements arevaluable routes to a!amino ketones which still _nd wide applicability owing to the ready availabilityof the principal substrate\ O!tosyl oximes ð89OPP288\ 80COS"5#652Ł[ In fact\ any imine with an attachedleaving group will participate in the reaction\ and hence N!chloroimines and quaternary salts ofhydrazones behave in an analogous manner[ A common intermediate is an azirine "Scheme 67#whose hydrolysis gives the desired products in which the carbonyl group is attached at the originalimine carbon[ For unsymmetrical imines\ the product arises from thermodynamic deprotonationduring the azirine!forming step[ Using anhydrous alcohols as solvents\ the amino ketals can beformed instead of the ketones ð79S218Ł[ a!Halo imines can be used in an analogous manner "Scheme67# ð71S654Ł[

MeO2C CN

O

MeO2C

O

NHAc (94)Ac2O, AcOH, Zn

83%

R1 R2

O

NH2(HR3)•HCl

H(R3)N

OR4

R2R1

R1 R2

NOTs

R1 R2

NR3

Hal

N

R2

R1

Scheme 78

base

R4O–

H2O, HCl

R4O–

The oxidation of 0\1!amino alcohols is an obvious method for the preparation of a!amino ketones\although it can only be used for the formation of N!protected compounds^ otherwise\ side reactionsmay cause a reduction in yield[ The other problem is the con_gurational instability of the products\although this can be reduced by using N!phenyl~uorenyl ð76JA125Ł or N!TBDMS protecting groupsð75TL3280Ł[ The alcohol oxidation can be done under Swern conditions ð75TL3280Ł\ with the CoreyÐKim reagent ð77JA6336Ł or using chromium"VI# species ð89OPP288Ł[

2[93[6[0[1 b!Functionalized and more remotely NH1\ NHR and NR1!functionalized ketones

The importance of the Mannich reaction as a method for the formation of b!amino ketones isenhanced by the biological activity of the products and also because of their value as intermediatesto a\b!unsaturated ketones and\ hence\ other multifunctional systems[ The immense amount ofliterature in this area ð68T502\ 89T0680\ 80COS"1#782\ 80COS"1#842\ 80COS"1#0996Ł cannot be covered com!prehensively in the space available here^ as a consequence\ only a brief summary of this reactionand recent developments will be discussed[

The archetypal Mannich reaction consists of a three!component coupling between ammonia\ oran amine\ a nonenolizable aldehyde and a carbon acid "pKa³19#[ The optimum yields are obtainedusing formaldehyde\ a ketone and a secondary amine "Equation "84## because primary aminespossess the ability to undergo dialkylation "Equation "85## and aldehydes as enolate donors tend toundergo competing aldol reactions[ The former drawback can be overcome using additional\temporary protection on the amine\ but the latter has been less successfully addressed[ Typicalconditions involve the use of an acid or\ occasionally\ base catalyst in a protic solvent where thecommonly accepted mechanism is as shown in Scheme 68[ Control of the regiochemistry of theamino alkylation may be di.cult\ although the thermodynamic conditions mean that enolizationtends to occur towards the more!substituted a position "Equation 86#[ The main focus of recentresearch has been directed towards the discovery of new methods that permit the use of the Mannich


or related reactions in aprotic solvents\ without the use of acid or base catalysis or with increasedregioselectivity[

R1 R1

O R1 R1

O

NR2R3

(95)CH2O, R2R3NH

R1 R1

OR1

N

O

R1 R2 R1

OCH2O, R2NH2 R1

(96)

Scheme 79

R1 R1

OH

R2R3NH + CH2OR2

N X

R3

R2

N

R3

+

R1 R1

NR2R3

O

X = OH, R2R3N

(97)

O O O

NMe2Me2N

+Me2NH, CH2O

1 : 3.5

One important component of this search has been the development of new procedures for theformation of the intermediate aminal\ imine or iminium salt\ particularly those which allow forthe preformation or isolation of these reactive intermediates[ The simplest and most frequentlyencountered Mannich reaction\ the introduction of a dimethylaminomethyl group as a means togenerate an a\b!unsaturated carbonyl compound\ is often done using the preformed iminium salts"76# "X�I\ Cl\ CF2CO1 or tri~ate "OTf## of which the _rst is the most familiar\ being Eschenmoser|ssalt[ The solubilities of these salts are very dependent on the counterion\ with the TFA and OTfsalts being most soluble\ particularly in less polar solvents where the use of these two reagents isbene_cial ð68T502Ł[ The iminium salts can be prepared in a number of ways\ perhaps the mostcommon being one of the variations of the Bohme procedure in which N\N\N?\N?!tetra!methylmethylenediamine undergoes elimination of dimethylamine promoted by TMS!I\ TMS!Cl orAcCl[ However "77#\ "78# and many other compounds have been used to prepare similar iminiumspecies[

N

Me

Me

BunO NMe2

N

N

NR1 R1

R1

(87) (88) (89)

X–+

As indicated above\ many Mannich reactions use a mixture of ketone\ formaldehyde and sec!ondary amine\ although the frequent need for an acid or base catalyst and the regioselectivityproblems make this procedure far from general[ The use of preformed iminium salts "see above#\which often work in the absence of a catalyst\ and the methodological advances that have beenmade in the preparation of regioisomerically pure ketone enolates have enhanced the use of thistransformation[ The regioselective introduction of a dialkylaminomethyl group can be achieved

075 Dialkyl Ketones

using cyclic TMS enol ethers and Eschenmoser|s salt ð79TL794Ł or dialkylaminomethyl ethersð71TL436Ł[ Since these initial reports\ many other applications of the aminoalkylation of silyl enolethers have appeared\ demonstrating high levels of chemoselectivity ð80COS"1#782Ł[ Silyl dienyl ethersmay react preferentially from the g position "Equation "87## ð79TL794Ł\ while acyclic TBDMS enolethers undergo a synthetically useful amino methylation with double!bond inversion "Equation"88## ð73TL4394Ł[ The low reactivity of these enol ethers and the related enol borinates is such thatuseful yields can only generally be obtained with iminium salts[ Other than iminium salts\ a fewother species have been shown to act as e}ective partners in Mannich type reactions[ Imines or acylimines will react under some conditions\ but the reaction is often restricted to imines derived fromaryl or other nonenolizable aldehydes because of a competing isomerization of the imine to theenamine ð83SC788Ł[ The more reactive N!acyl iminium salts will react with silyl enol ethers undermild conditions to give the expected adducts in moderate diastereomeric excess "Equation "099##ð89SL508Ł[

(98)

TMS-OO

NMe2

Me2NCH2•I

65%

(99)

O-TBDMS O-TBDMS

NMe2

Me2NCH2•I

58%

N OBn

OMe

Me

O

Ph N OBn

O

Me

OPh

O-TMS

(100)TMS-OTf, –40 °C

61%

syn:anti 86:14

Two procedures have extended the Mannich reaction to the preparation of nonterminal b!aminoketones by the use of aldehydes other than formaldehyde[ As indicated above\ this transformationis very di.cult under classical Mannich conditions because of the self!condensation of enolisablealdehydes[ Seebach and co!workers showed that aminoalkyl titanium alkoxides\ "89#\ prepared fromthe corresponding aldehydes\ react directly with ketone enolates at low temperature "Scheme 79#ð73HCA0482Ł[ In the second\ lithium enolates react with aminomethyl benzotriazoles to give aminoketones[ This reaction is particularly useful for the preparation of highly hindered a\a!disubstitutedamino ketones "Equation "090## ð89T876Ł[

NH

N

OLi i, BunLi, –78 °C

ii, PrnCHO

TiCl4, –70 °C

N

Prn O

N

OTiCl3

(90)

OLi

Scheme 80


NN

N

NO +

OLi

N

O

O

(101)66%

The development of the Mannich reaction as a method for the introduction of an NH1 or an RNHgroup has not been particularly successful until comparatively recently[ Using the benzotriazolemethodology developed by Katritzky and co!workers\ however\ this can be achieved directly foraromatic amines "Equation "091## or\ potentially\ from further derivatization of a secondary amide"Equation "092## ð89T876Ł[ The imine "80#\ derived from formaldehyde and ammonia has beengenerated\ in situ\ from TMS azidomethane and reacts with TMS enol ethers to give the expectedamines\ which could only be isolated following benzoylation "Scheme 70#[ Under otherwise identicalconditions\ 0\0\2\2!triisopropylsilyl "tips# enol ethers react with inversion of the double bond to givecompounds containing a primary amine "Equation "093## ð81JOC6998Ł[

+

OLi

(102)NN

N

NHPh

85%PhHN

O

+

OLi

(103)NN

N

NHBz

85%BzHN

O

TMS N3 + R1AlCl2 N

AlCl2R1

TMS

i,

ii, BzCl

R2 R3

O-TMS

R2R3

O

NHBz(91)

Scheme 81

(104)

tips-O

NH2

(91)

94%

tips-O

cis:trans 6:94

Although the transformation is not primarily aimed at the preparation of simple b!amino ketones\brief mention must be made of the intramolecular Mannich reaction for the preparation of saturatednitrogen heterocycles ð80COS"1#0996Ł[ A number of elegant syntheses have involved this reaction asone of the key steps "Scheme 71# ð82JOC3551Ł[

The conjugate addition of nitrogen nucleophiles to electron!de_cient alkenes is a facile processfor which many procedures are available ð80COS"3#0Ł[ Benzophenone imine has been used as anammonia equivalent in the Michael addition to a\b!unsaturated carbonyl compounds[ Not sur!prisingly\ perhaps\ with such a bulky nucleophile\ the addition is prevented by the presence of somesubstituents at the b position of the enone ð78S248Ł[ For the addition of a dialkyl amine to exocyclica!methylene ketones\ a dramatic improvement was observed using aluminum oxide as a catalystð79TL798Ł[ Using titanium"IV# amides in aprotic solvents\ one of the dialkyl amino groups isdelivered from the metal to the b position of an enone to give a titanium enolate which can undergofurther in situ aldol or Mukaiyama aldol reactions resulting in a b!amino b?!oxygenated ketonesð80TL1260Ł[ b!Chloro ketones\ when accessible\ can act as surrogates for enones ð60JA1381Ł[

One problem with the Gabriel synthesis of amines is that the removal of the phthalimide grouprequires relatively harsh conditions which may be incompatible with the presence of some other

077 Dialkyl Ketones

N

O

Ar

H Bn

N

Ar

Bn

O–

H

aza-CopeBF3•Et2O, –20 °C

Mannich

97%N

O–

Bn

Ar+N

H

H

ArO

Bn

+

Scheme 82

functional groups\ and a number of modi_cations have been developed to address this "for a reviewon the Gabriel reaction see ð80COS"5#54Ł#[ Among the ammonia equivalents which have been usedto prepare protected a! or b!amino ketones are the iminocarboxylates ð67JCS"P0#0977Ł\ dibenzylamineð80JOC346Ł and the sodium salts of tri~uoromethyl acetamide ð73S830Ł and the phosphoramidate"81# ð71S811Ł[

EtOP

NNa

OBut

O O

EtO

(92)

The reductive amination of aldehydes or ketones is often done using conditions where acid!sensitive groups do not survive[ Using Ti"OPri#3 as a Lewis acid catalyst and NaBH2CN as thereducing agent\ cyclic and acyclic acetals remain intact\ demonstrating the usefulness of this pro!cedure for the synthesis of a wide range of carbonyl!protected amino ketones "Equation "094##ð89JOC1441Ł[ 0\2!Diimines can be reduced to b!amino ketones ð72JOC1144Ł[

O

OO +

NH

O

ON (105)

i, Ti(OPri)4ii, NaBH3CN

50%

The conjugate addition to enones of carbanions stabilized by an adjacent nitrogen atom hasrecently been shown to be feasible\ although not without some problems[ Higher!order cyano!cuprates derived from lithio formamidines undergo e}ective 0\3!addition "Equation 095#\ butattempts to hydrolyse the formamidine lead to a mixture of products ð81TL4582Ł[ More successfulwas the use of carbamate!stabilized anions\ generated by transmetallation "Equation 096#\ whichgive good yields even with b\b!disubstituted ketones[ In some examples\ direct deprotonation of thecarbamate is e}ective\ and this obviously eliminates the requirement for formation of the stannylamine "Equation "097## ð82SL396Ł[ Unlike the formamidine protecting group\ the BOC group caneasily be removed[ Dianions derived from ethyl acetoacetate react with N!tosyl aziridines ð82SL653Ł[

(106)O Me

N NBut

Me ButN N

Me O+

ButLi, CuCN, TMS-Cl

98%

(107)

O

+Me

N SnBu3

BOC

O

NMe

BOC

CuCN, –78 °C

64%


O

+Me

NMe

BOC

O

NBOC

Me (108)BusLi, TMEDA, CuCN, –78 °C

63%

The reductive cleavage of the isoxazole ring was demonstrated many years ago to be a viablemethod for the synthesis of b!amino ketones "Scheme 72# ð61JA8017Ł\ the isoxazole being preparedfrom oxidation of the corresponding a\b!unsaturated oxime using iodine[ Now such ring systemscan be prepared from the 0\2!dipolar cycloaddition of nitrile oxides to acetylenes[ The regioselectivityof the cycloaddition and the isolated yields of the adducts are often very high\ making the inter!mediacy of isoxazoles one possible route to the preparation of b!amino ketones "for reviews on0\2!dipolar cycloadditions see ðB!78MI 293!92\ 80COS"3#0958\ 80COS"3#0000Ł#[

R1 R2

NOH NO

R2R1R1 R2

NH2O

Scheme 83

I2, KI Na, NH3, ButOH

2[93[6[1 NHX and NX1!functionalized Ketones

In a procedure developed by Oppolzer and co!workers\ nitroso compounds have been used forthe introduction of a hydroxylamine group[ Enantiomerically pure "82# reacts with zinc enolates togive the nitrone adduct in at least 89) enantiomeric excess and good chemical yield "Scheme 73#[This nitrone can be hydrolysed to the keto hydroxylamine and the chiral auxiliary recovered andrecycled if required ð81JA4899Ł[ A nitro group can be reduced to the corresponding hydroxylamineusing SmI1[ Under the obviously mild conditions\ cyclic and acyclic acetals remain intact\ thusallowing this method to be used for the synthesis of protected keto hydroxylamines "e[g[\ "83##ð80TL0588Ł[ On the basis that the oxidation of amino alcohols is an attractive preparation of aminoketones "see Section 2[93[6[0#\ a similar transformation of hydroxylamino alcohols "Equation "098##should give hydroxylamino ketones ð80TL2444Ł[ The reaction between an a!bromo ketone and theoxime of benzaldehyde gives a keto nitrone arising from nucleophilic displacement of the bromideby the oxime nitrogen[ Hydrolysis then releases the hydroxylamino ketone\ which is isolated at thehydrochloride salt ð60ZOR0576Ł[

O OZnClO

N–O Xc

LiHMDS, THF

ZnCl2

(93)

90%, 90% ee

1 mol l–1 HCl

65%

O

Scheme 84

NHOH•HCl

+

(109)

CHO HONHOBn

CH2NOBn, SmI2, ROH, HMPA

59%

089 Dialkyl Ketones

N

Cl

OR2NO2S

OONHOH

(93) (94)

2[93[6[2 NY!functionalized Ketones

a!Nitro ketones are valuable intermediates in a number of synthetic transformations\ despite thefact that the direct nitration of ketones is not a facile or high!yielding process ð68LA501\ 79S150Ł[Prior conversion of the ketone into a more reactive enol derivative results in increased yields[ Ofthe enolate anions\ the potassium enolates appear most useful\ and they undergo nitration withalkyl nitrates ð70JOC4040\ 71S286Ł\ although with poor regioselectivity for dialkyl ketones ð55JOC2041Ł[Enol acetates\ both regioisomers of which can be prepared from unsymmetrical\ 1!substitutedketones\ generally give much higher yields of the desired nitro ketone using a variety of nitratingagents\ the nitration being regiospeci_c in each case[ The more substituted enol acetate may undergoa competing carbonÐcarbon bond cleavage reaction\ although the use of a mixture of tri~uoroaceticanhydride and ammonium nitrate as the nitrating agent may minimize this ð71JOC0065\ 72S434\80TL4242Ł[ Potentially the most useful procedure would involve nitration of silyl enol ethers and thishas been achieved under particularly mild conditions using tetranitromethane as the nitrating agent[Unfortunately\ dialkyl ketones give the lowest yields and the reaction is not regiospeci_c "Equation"009## indicating that the mechanism probably involves charge transfer activation rather thanstraightforward electrophilic addition ð82TL0748Ł[ Most simple a!nitro ketones can be preparedusing one of these approaches\ and additional substituents can then be introduced at the a or a?positions by alkylation[ Thus\ allyl carbonates and vinyl epoxides react at the a position of a!nitroketones using palladium"9# "Scheme 74# ð75HCA0503\ 75JOC1721Ł\ and 1!nitro cyclohexanone gives1!methyl!1!nitro cyclohexanone under basic conditions ð71JOC0065Ł[ In the presence of excess base\1!nitro ketones give the a\a? dianions\ which undergo alkylation at the less stablized a? positionð71JOC0065\ 81SL53Ł[ The alkylation of the a\a?!dianions derived from a!nitro hydrazones has alsobeen shown to occur at the a? position ð77JOC0140Ł[

(110)

TMS-O TMS-O

or

O

NO2

C(NO2)4

R2

O

O2N R1

R2 R1

O

NO2

R2

O

O2N R1

OH

Scheme 85

OCO2Et

Pd(PPh3)4

70–80%

O

Pd(PPh3)4

73–94%

The conjugate addition of ButO1Li to b!nitro styrenes results in one of two products\ dependingon the substituents on the aromatic ring[ In the presence of electron!withdrawing groups the nitroketone is formed in good yield^ on the other hand\ for adjacent electron!donating groups the reactiongives the nitro epoxide "Scheme 75#[ The latter pathway can be avoided by the addition of excessbase to accelerate deprotonation at the benzylic position ð77S118Ł[

The very strong anion!stabilizing properties of an NO1 group have a signi_cant impact on theacidity of the adjacent protons "pKa½09# and\ as a result\ there is an enormous body of literatureon the synthesis and reactions of anions adjacent to a nitro group[ Although alkylation of suchsystems is di.cult\ they react with a\b!unsaturated ketones "0\3 addition#\ acid derivatives andaldehydes[ C!Acylation adjacent to the nitro group is complicated by competing O!acylation\ but afew acid derivatives have been used successfully\ including phenyl esters ð68S184Ł or\ morecommonly\ acyl imidazoles[ The latter can be used either with isolated lithium nitronate saltsð71JOC3939Ł or with potassium or sodium salts generated in situ ð67S367\ 76S421Ł[ In a series of papers


ArNO2

R

ArNO2

O

R

O

RNO2

Ar

Scheme 86

ButO2

R

NO2Ar 30–80%

BuLi, ButO2H

Seebach and co!workers have demonstrated that the a\a!dianions of primary nitro compoundsdemonstrate enhanced nucleophilic character with respect to the monoanions to the extent thateven simple esters act as e}ective C!acylating agents "Scheme 76# ð68HCA1147Ł[ The e.ciency of thenitro group in charge delocalization is demonstrated by the fact that b!alkoxy groups\ as in "84#\ donot undergo elimination during the deprotonation or subsequent acylation ð74JA2590Ł[

NO2NO2

O

Scheme 87

BuLi (2 equiv.) Me2CHCH2CO2Me

70%

NO2Li

Li

NO2

OO

O-THP

(95)

The coupling of nitronate anions to aldehydes to give 0\1!nitro alcohols\ the Henry nitroaldolreaction\ is a facile process for which many experimental variations are known[ The products canbe oxidized to a!nitro ketones\ although elimination and retro aldol reactions may act as competingpathways[ The optimum conditions appear to involve the use of chromium!based oxidants\ eitherin the presence of a phase transfer catalyst ð73S596Ł or adsorbed onto a solid support ð75TL382Ł[The synthesis and reactions of a!nitro ketones has been part of a recent review ð89OPP696Ł[

The formation of dianions from primary nitro compounds is complicated by the possibility ofgenerating two structural isomers[ Under Seebach|s conditions "Scheme 76# the a\a!dianion isfavoured and reacts with carbonyl!containing electrophiles to give 0\1!nitro alcohols[ However\ bychanging the concentration of HMPA and reversing the order of addition of the nitro alkane to thebase\ the a\b!dianion is preferred\ giving rise to 0\2!nitro alcohols "Equation "000## ð78CC009Ł[ Suchcompounds could represent useful intermediates to b!nitro ketones\ but these can be prepareddirectly from the addition of nitrite anions to a\b!unsaturated ketones or b!halo ketones ð70CL0566\71CL72Ł[

NO2Ph

NO2

OH

Ph

OH

NO2

(111)+ i, BunLi, THF, HMPA

ii, PhCHO

Addition of BunLi to EtNO2Addition of EtNO2 to BunLi

85 : 15 5 : 95

The other class of electrophile most frequently employed with nitronate anions are a\b!unsaturatedcarbonyl compounds to give g!nitro ketones[ A wide variety of bases\ organic\ inorganic\ homo!geneous and heterogeneous ð77S722Ł\ has been demonstrated to promote the addition\ althoughcompeting side reactions\ such as polymerization of the intermediate enolate and the addition oftwo molecules of enone to one of nitro alkane\ can reduce the yield in some cases[ One experimentallysimple procedure has been developed which requires no solvent and gives good yields of 0 ] 0 adducts

081 Dialkyl Ketones

"Equation "001##\ although it is susceptible to steric hindrance at the b position of the enone ð75S126Ł[In a related reaction\ simple mixing of methyl vinyl ketone with nitromethane\ in water\ withoutadditional catalyst gives\ in quantitative yield\ a 3 ] 0 mixture of the adducts "85# and "86#[ There isa strong rate enhancement of this reaction in the presence of sugars which has been attributed tothe hydrophobic e}ect ð81TL7962Ł[ The allylic anion derived from nitro alkenes adds from thea!carbon to the b position of enones to give adducts like "87# ð76S147Ł[

NO2

O OO O

NO2

OO

(112)+Al2O3, 5–8 h

88%

O2N

OO O

NO2

(97)

O

NO2

(98)(96)

g!Nitro ketones can also be obtained from the addition of enolate equivalents to nitro alkenesð75CRV640\ 76T702\ 81TL4530Ł[ The products are frequently required only as intermediates to0\3!dicarbonyl compounds ð78CC730Ł\ obtained following a Nef reaction\ but can be isolated ingood yield[ For the reaction between substituted enolates and substituted nitro alkenes\ the diastereo!selectivity of the addition has been extensively investigated ð74HCA051\ 89JOC0238Ł[ Variants of thisMichael addition which retain a nitro alkene in the product have been reported[ One proceeds viaexclusive SN1? addition to an allylic ester "Equation "002## ð74T3750Ł and the other via an additionÐelimination to a b!nitro enamine "Equation "003## ð76S618Ł[ This retention of the double bond allowsgreater ~exibility in synthetic planning\ and in these two examples the position of the alkene iscomplementary[ Chemoselective reduction of the nitro alkene in the presence of the ketone ispossible "Equation "004## ð77BCJ3918Ł[

OLi

ButCO2

NO2

Bun

Bun

NO2

O

(113)+–78 °C

75%

(114)

OLi

+ NNO2

O

NO2

O–78 °C to 0 °C

55%

(115)NO2

O

NO2

OHantzsch ester

90%

The preparation of a!keto oximes "a!hydroxyimino ketones# from ketones or from 0\1!diketonesis limited by the paucity of good electrophilic oxaminating agents or by regiochemical problems\respectively[ Twenty years ago\ Hassner and co!workers demonstrated that silyl enol ethers reactwith NOCl to give a!hydroxyimino ketones or a!nitroso ketones\ depending on the substitutionpattern at the a position "Scheme 77# ð63JOC1447Ł[ That a!nitroso ketones could not be isolated butrapidly dimerized at room temperature was con_rmed later following the reaction between an enolether and methyl nitrite[ The dimers\ however\ are stable and could be isolated\ in some cases incrystalline form[ Isomerization of the nitroso ketone dimers to the a!oximino ketones can beachieved using acid\ base or heat ð68JOC164Ł[ Regiochemical control of the oxamination can alsobe achieved using an in situ 0\3!reduction and enolate trapping procedure "Scheme 78# ð80BCJ1837Ł[

The reaction between a diazoalkane and an acid chloride to produce an a!diazo ketone is\ perhaps\the best method for the preparation of such systems and one which has been widely used for many


R1R2

O

NOR3

R1R2

O

NOH

R1R2

O-TMS

R3

Scheme 88

NOCl

R3 = H

NOCl

R2, R3 = alkyl, aryl

OO

NOH

Scheme 89

CoII, PhSiH3, BunONO

67%

OCoL2

years[ The reaction is most useful when using diazomethane to give terminal diazo ketones althoughhigher diazoalkanes have been used in some circumstances[ The diazotization of amino ketones israrely useful for the synthesis of a!diazo ketones\ except for a few speci_c examples\ but a moregeneral approach employs the Forster reaction "Equation "005##[ Some of the diazo ketones preparedusing these approaches can be found in the reviews ðB!75MI 293!94\ B!76MI 293!98\ 80COS"2#776Ł[ SeeChapter 2[01 for further discussion of diazo ketones[

R1

R2

O

NOH

R1

R2

O

N2

(116)chloramine

The diazotization of 0\2!dicarbonyl compounds with azides is a reaction which has been knownfor many years and for which there are many experimental variations incorporating changes in theazide used\ the solvent and the presence or absence of catalysts[ The relative safety of some of themore common organic azides has been evaluated ð70SC836Ł\ but it is important to recognize thatany use of these reagents is potentially hazardous[ More recently\ 1!diazo!0\2!dicarbonyl compoundshave been prepared in the absence of solvent ð80SC080Ł\ using KF or K1CO2 as the base ð78SC1456\89CC541\ 80S084Ł or with p!acetamidobenzenesulphonyl azide as the diazo source ð76SC0698Ł[ Twodiazotizing reagents which may be useful in speci_c cases are the phosphonium azide "88# ð89TL3876Ł\which requires only a catalytic amount of base\ and the pyridinium salt "099#\ which works underneutral conditions ð76SC872Ł[

N

PEt2N NEt2

NEt2

N2+

N N3

Et

(99) (100)

BF4–

+

The diazotization of simple ketones is a less facile process owing to the reduced acidity of thesubstrates\ but it can be achieved using mesyl azide ð75JOC3966Ł or arylsulphonyl azides in thepresence of phase transfer catalysts ð79S257Ł[ The former is attractive because of the lower cost\although regioisomeric mixtures may result[ A more indirect route to the same products requirestemporary activation of the ketone with an electron!withdrawing group to direct diazotization"Scheme 89# followed by in situ removal of the activating group ð57JOC2509\ 80SC080Ł[ A recentlyreported version of this reaction involves regiospeci_c ketone tri~uoromethyl acylation prior todiazo transfer "Scheme 80# ð89JOC0848Ł[ Possibly\ one of the many methods for regiospeci_c ketoneenolisation could be used to introduce the diazo group at either of the a!positions[

R1 R2

OR1 N2

O

R2

Scheme 90

R1

O

R3

O

R2

R3 = H, Ph

083 Dialkyl Ketones

i, LiTMP, –78 °C

ii, CF3CO2EtC5H11

O

C5H11

O

CF3

O MeSO2N3

C5H11

O

N2

C5H11

O

Scheme 91

N2

+

9 : 1

LiTMP = lithium tetramethylpiperidide

In the presence of an oxidizing agent\ azides react with dicarbonyl compounds to give di}erentproducts[ For example\ using iodosobenzene\ 0\2!diketones undergo incorporation of azide at thecentral position ð77T0592Ł[ In a more recent procedure\ Magnus and co!workers have disclosed auseful a!azidonation of triisopropyl silyl enol ethers using NaN2 and cerium ammonium nitrate[The isolated yields are good\ the reaction is regiospeci_c\ even for the thermodynamic enol silanederived from 1!methylcyclohexanone\ and acetals and ethers survive the reaction conditionsð81TL1666Ł[ In a highly unusual reaction from the same group\ triisopropyl silyl enol ethers reactwith TMS azide and iodosobenzene to introduce azide regiospeci_cally at the b!position in highyield "Equation "006##[ In this case\ the silyl group is retained during the oxidation ð81JA656Ł[a!Azido ketones can be prepared from a!diazo ketones via the intermediate bromo ketones "Equation"007## ð82CC83Ł\ and halo ketones in general react with NaN2 to give products arising from halidedisplacement ð79TL820\ 75JOC2263\ B!77MI 293!94Ł[

O O

O-tips

O O

O-tips

N3

(117)TMS-N3, PhIO

76%

(118)N2

O

NHZ

N3

O

NHZ

i, HBr (1 equiv.)ii, NaN3

70%

2[93[6[3 NZ!functionalized Ketones

The synthesis of 1!keto isocyanates and isothiocyanates is complicated by their spontaneouscyclization to oxazolidines "Scheme 81#[ Compounds without hydrogens at the a position can beisolated easily using the method shown "Scheme 81# ð65CB043Ł but for enolizable ketones\ analternative method involving condensation of amino ketones with thiophosgene may be more usefulð72CCC2310Ł[ The treatment of a!halo ketones with cyanate or thiocyanate salts gives identicalproducts[ The anion derived from methyl isocyanide has been shown to react with electrophilesð60AG"E#380Ł and b!keto isocyanides are isolable intermediates during the reaction of acid chlorideswith tosylmethyl isocyanide ð66TL3122Ł[

The decomposition of a!azido ketones using triphenylphosphine has been used in a number ofimportant synthetic transformations and the intermediate imino phosphoranes "090# react with arylisocyanates or isothiocyanates to give the corresponding b!keto carbodiimides "091# ð80PS"59#70Ł[The ability of a nitrosamine to stabilize an adjacent anion has been demonstrated in the synthesisof b!keto nitrosamines "Equation "008## ð67CB1529Ł[

S NH

S

HOR1 R3

R2

R1

HN SH

O

R2 R3S

R1NCS

O

R2R3

NHO

S

R1 R3

Scheme 92

carbodiimide R2 = H

084Bearin` a P\ As\ Sb or Bi

Ph3PN

R

O

ArNCNR

O

(101) (102)

R1N

Me

NO

R1N

NO

R2

O(119)

i, BuLi, KOBut

ii, R2COCN

2[93[7 KETONES BEARING A P\ As\ Sb OR Bi FUNCTION

Much of the interest in the synthesis of ketones substituted by a phosphorus atom in one of itsoxidation states stems from the use of such species in the Wittig\ Horner and WadsworthÐEmmonsreactions to construct alkenes "for reviews see ð66OR"14#62\ 77CSR0\ 78CRV752Ł#[ More recently\ theylides derived from organoarsenic\ antimony and bismuth compounds have also attracted increasedattention[

2[93[7[0 XR1 and X¦R2!functionalized Ketones

The reaction of ketone enolates with phosphorus"III# halides usually results in O!phosphinylationto give a compound which can be readily isomerized "Scheme 82#\ ð72JGU545Ł and the phos!phoramide "092# can be made via phosphinylation of the corresponding ketone with "Et1N#1PClð67MI 293!90Ł[ An identical transformation involves the reaction between the same halides and ab!keto stannane to give "093# "Equation "019## ð61CA"67#025269Ł or the coupling of a dialkylphosphineto an a!bromo ketone ð79JCS"D#188Ł[ These keto phosphines can be converted into the correspondingphosphonium salts "094# by treatment with the appropriate alkyl halide ð72JGU509Ł[

Ph

Na+ –O

Ph

O

PEt2

Scheme 93

Ph

Et2POEt2PCl heat

O

P(NEt2)2Ph

PMePri2

O+

(105)(103)

Bu3Sn

O

R2P

O(120)

R2PCl

(104)

The use of phosphonium salts for the Wittig reaction explains the vast amount of literaturedealing with the synthesis of these species and their derived ylides[ Such a body of literature cannotbe covered comprehensively here\ but other recent reviews are available ð80COS"5#060\ B!83MI 293!90Ł[The usual method for the preparation of b!keto phosphonium salts involves treatment of an a!haloketone with a phosphine "see the above reviews and ð76S0944\ 80T2236Ł#\ although the acylation ofylides has also been reported ð77JOC4447Ł[ More remote keto phosphonium salts "e[g[\ "095# and"096## can be prepared by the 0\3!addition of phosphines to enones ð80COS"5#060Ł or the addition of

085 Dialkyl Ketones

phosphines to cyclopropyl ketones ð76S537Ł[ Phosphonium salts "097# can be prepared from theelectrochemical oxidation of 0\2!diketones with PPh2 ð77CPB502Ł[

Ph3P

O

Ph

O

Ph3P R1 R2

O O

PPh3

(108)

+

(107)(106)

+

+

The chemistry of arsonium ylides has attracted recent attention owing to their ease of preparationand the fact that their reaction with aldehydes or ketones can give alkenes with stabilized ylides orepoxides with nonstabilized ylides[ For semistabilized ylides the outcome of the reaction dependson other factors such as solvent\ base and the substituents on the arsine "for recent reviews seeð76CSR34\ B!89MI 293!91Ł#[ Normally\ arsonium ylides are prepared by treatment of an alkyl halidewith an arsine ð69JOC1567\ 76TL1044\ 77S864Ł\ although for less reactive substrates a combination ofan alkyl tri~ate and a lithio diarylarsine may be more useful ð70JA0172Ł[ The arsonium salts andtheir ylides are relatively easy to handle but the more volatile arsines should be treated with extremecaution[ Arsenium ylides stabilized by two electron!withdrawing groups can be prepared from1!diazo!0\2!dicarbonyl compounds and arsines ð71T2244Ł or 0\2!dicarbonyl compounds and arsineoxides ð62T0586Ł\ and similar routes can be used for the preparation of stibonium ylides ð75T2776\89TL4786Ł[

Ylides derived from bismuth and antimony are less well known than those derived from phos!phorus and arsenic and are largely restricted to those derived from 0\2!dicarbonyl compounds[ The_rst examples of bismuth and stibonium ylides were reported by Lloyd et al[ in the 0869|s and weremade by a thermal decomposition of a 0\2!diazo carbonyl compound in the presence of triarylbismuth or triaryl antimony species[ These two\ and arsenium ylides\ can be made using the sameprocedure\ but at lower temperature\ by employing a copper catalyst ð77S208Ł[ An alternativeprocedure for bismuth ylides has been developed using a b!diketone and a bismuth dichloride or abismuth oxide ð89BCJ849Ł[ This procedure has since been used to prepare one of the _rst examplesof a monocarbonylbismuth salt in very high yield "Equation "010## ð82TL7346Ł[ The chemistry ofarsenic\ antimony and bismuth compounds has been reviewed ðB!83MI 293!91Ł

R

TMS-O

RBiAr3 BF4

–

O(121)+

Ar3BiF2, BF3•Et2O

87–100%

2[93[7[1 Higher!coordinated P\ As\ Sb or Bi!functionalized Ketones

2[93[7[1[0 a!Higher!coordinated P\ As\ Sb or Bi!functionalized ketones

Perhaps the two best!known methods for the synthesis of b!keto phosphonates are the reactionof phosphonate!stabilized carbanions with acid derivatives and the Arbuzov reaction of a!haloketones with trialkyl or triaryl phosphites[ The latter\ discovered in the late 0799|s\ has been widelyused for the synthesis of b!keto phosphonates\ although there is a competing rearrangement "Perkowrearrangement# which may predominate for a!chloro or a!bromo ketones[ a!Iodo ketones do appearto give useful yields of the desired Arbuzov products "Scheme 83#[ Under appropriate conditions\that is with a readily available\ nucleophilic phosphorus"III# ester and a primary halo ketone\ theArbuzov method can be useful for the synthesis of simple b!keto phosphonates or more complexderivatives "Equation "011## ð81CC174Ł^ for a review see ð70CRV304Ł[

RPO(OEt)2

O

R

OPO(OEt)2

Scheme 94

Arbuzov

X = I

Perkow

X = Cl, BrRX

O

PhBr

O

PhP

O

N(Bn)Pri

O

OEt

(122)(EtO)2PN(Bn)Pri

50%


A number of methods which rely on a nucleophilic phosphorus species have been developed otherthan the Arbuzov reaction[ Sodium diethyl phosphite reacts with a!halo ketones or 3!halo 0\2!dicarbonyl compounds ð79TL1176\ 76TL234Ł to introduce a phosphonate group\ as in "098#\ andtrialkyl phosphite esters or dialkyl phosphite anions react with chloro or sulfonyl epoxides "Equation"012## ð71CB590\ 82TL1036Ł[

O SO2Ar

EtOP

O

EtO

O

(123)NaPO(OEt)2

82%

EtOP

OEt

O O O

EtO

(109)

Many applications of organophosphorus chemistry are dependent on the ability of phosphorusto stabilize an adjacent carbanion[ Anions derived from phosphine oxides react with esters\ lactonesor acid chlorides to give b!keto phosphine oxides ð76JCS"P0#1458\ 77JCS"P0#0688Ł[ In the acylation ofphosphonate!stabilized carbanions\ many acid derivatives have been used\ including acid chloridesð67S25\ 75SC0634Ł\ esters ð72JOC4990\ 73S580\ 76TL500Ł\ nitriles ð80SC168Ł and lactones ð89TL1480Ł[ Thepresence of halogens adjacent to the phosphonate group is well tolerated "Equation "013## ð77JOC0412\81JOC1652Ł[ The doubly activated methylene group in b!keto phosphonates means that introductionof additional alkyl groups at the central position is a facile process "Scheme 84# ð81CC089Ł[ Aheteroatom substituent can be introduced at the a position using enamine anions\ which undergoexclusive C!functionalization "Scheme 85# ð80SC168Ł or via direct dichlorination of b!keto phos!phonates to give "009# ð76JGU194Ł[

EtOP

R

O

EtO

O

FF

EtOP

O

EtOF

F(124)Br

i, Zn, CuBrii, RCOCl

40–60%

POEt

O O

OEt

POEt

O O

OEt

Scheme 95

POEt

O O

OEt

Bun4NBr, NaOH

MeI

piperidine, (CH2O)n

EtOP

Me

O

EtOEtO

P

O

EtOE

R

O

Scheme 96

EtOP

O

EtOE

R

NH2 i, BunLi, RCNii, EX

66–90%

H3O+

50–83%

E = PhS, PhSe, Cl

EtOP

O O

EtO

(110)

ClCl

An alternative procedure has been developed by Oh and co!workers for the synthesis of b!ketophosphonates having substitution at the a position[ Conjugate addition of organolithium reagentsto the silyl!substituted vinyl phosphonate "000# generates an intermediate anion which can beacylated and desilylated in a one!pot procedure "Scheme 86# ð78TL2296Ł[ Another procedure starts

087 Dialkyl Ketones

with formyl phosphonates\ which can be converted into the corresponding enamines "Scheme 87#[These enamines undergo kinetic deprotonation adjacent to the heterocycle to give an anion whichreacts with a range of electrophiles including alkyl\ allyl and benzyl halides and chloroformatesð78TL3676Ł[ More conventionally\ perhaps\ the acid chlorides "001# react with a range of organo!metallics to give the corresponding ketones ð75S550Ł[ Hydrolysis of b!keto phosphonates to b!ketophosphonic acids can be done with TMS!Br ð78JMC0775Ł[

TMS

PO(OEt)2

But

Ph(EtO)2OP

O

Scheme 97

TMS

PO(OEt)2

But

Li(111)

ButLi, –78 °C i, PhCOClii, H3O+

73%

EtOP R

O

EtOEtO

P

O

EtON

R

i, BunLi, –78 °C, THF then DMFii, pyrrolidine, C6H6, reflux

60–70%

i, BunLi, –78 °C, THF then MeIii, H3O+

70–80%

EtOP

O

EtOR

O

Scheme 98

EtOP

Cl

O O

EtOR

(112)

Wiemer and co!workers have developed several procedures for the synthesis of b!keto phos!phonates using electrophilic phosphorus species[ In one of their early publications\ a!bromo ketoneswere converted into dilithium reagents which react with chloro phosphates as shown in Scheme 88[The phosphonates "002# and "003#\ which cannot be made by conventional Arbuzov chemistryowing to competing elimination in the bromo ketone or the low nucleophilicity of an electron!de_cient ~uorinated phosphine\ respectively\ can be made in 51) and 39) yields using thisapproach ð75JOC3231Ł[ A modi_cation of this procedure was reported subsequently in whichO!phosphorylation of anenolate anion was followed by a base!promoted 0\2!shift of the phosphonategroup[ This migration occurs without the need for potentially hazardous ButLi and in higher yield"Scheme 099^ cf[ Scheme 88#[ Unfortunately\ this procedure does not work for acyclic ketones orfor cyclic ones larger than cyclohexanone[ For ketones with more than one set of a protons\ amixture of products may be obtained "Equation "014##\ suggesting\ in these cases\ the intermediacyof an allylic anion[ However\ in cases where the steric environment at the two a positions issigni_cantly di}erent\ the reaction may still be synthetically useful "Equation "015## ð75TL3154\76JOC3074Ł[ Cyclohexadienyl phosphates\ prepared as shown in Scheme 090\ also undergo a regio!speci_c migration arising from removal of the proton at the terminal position of the diene ð89JOC1731\81JOC206Ł[ Tertiary b!keto phosphonates\ which may not be generally available using the methodsoutlined above\ can be prepared from a!hydroxy ketones and diethyl chlorophosphite "Equation"016##[ The reaction may proceed via the intermediate mixed phosphite ester ð78JOC516Ł[ Perhapsthe most intriguing method developed by this group involves the C!phosphitidation of ketoneenolates followed by air oxidation to the phosphonate "Scheme 091#[ Unlike some of the methodsdescribed earlier\ this route is applicable to the synthesis of medium! and large!ring ketophosphonates and acyclic ones\ and it has been used on a scale up to 9[0 mol ð80JOC4445Ł[ Thismethod was independently investigated by another group who used H1O1 as the oxidantð80TL1470Ł[


O

Br

OLi

Li

O

PO(OEt)2

Scheme 99

i, LiHMDS, –78 °C

ii, ButLi, –100 °C

ClPO(OEt)2

20%

O OPO(OEt)2 O

PO(OEt)2

Scheme 100

LDA, ClPO(OEt)2 LDA

70%

OPO(OEt)2

D

O

D

(EtO)2OP

O

D

PO(OEt)2(125)+

LDA

1 : 1

(126)

OPO(OEt)2 O

(EtO)2OPLDA

80%

OPO(OEt)2 O

(EtO)2OP

O

Scheme 101

i, LDA

ii, ClPO(OEt)2

LDA

58%

OR

O

PO(OEt)2

O

(127)(EtO)2PCl, FeCl3

R = H, 96%R = Et3Si, 67%

R1

R2

O

R1

R2

OLi

R1

R2

O

PO(OEt)2

Scheme 102

LDA, Et2O, HMPA i, ClP(OEt)2ii, air or O2

44–80%

PhP

OEt

O O

OEtPh

POCH2CF3

O O

OCH2CF3

(113) (114)

199 Dialkyl Ketones

Two complementary procedures have been developed for the synthesis of b!keto phosphonatesor phosphine oxides using diazo compounds[ In the _rst\ 1!diazo ketones or 1!diazo 0\2!diketonesreact directly with dialkyl hydrogenphosphite in the presence of a copper catalyst ð89S404Ł^ in thesecond\ aldehydes insert into diazo phosphonates or phosphine oxides to give identical productsusing SnCl1 as the catalyst "Equation "017## ð81TL0020Ł[ Nucleophilic addition of ethoxide to theallenic phosphonate "004# occurs at the central carbon atom of the allene to give an enol ether whichcan be hydrolysed to a b!keto phosphonate ð71AG"E#260Ł[ Allene oxides "005#\ which can be preparedin enantiomerically pure form\ react with water as shown in Equation "018# ð82TL7432Ł\ andhydroxy!substituted keto phosphonates can also be prepared using a 0\2!dipolar cycloaddition"Equation "029## ð76BCJ1352Ł[ The hydration of alkynes is a well!known method for the synthesisof ketones\ and the presence of a phosphonate group on the alkyne does not appear to prevent thereaction from occurring as expected "Equation "020## ð76JOC3709Ł[

PhP N2

O

Ph

+ PhCHO

PhPOPh2

O(128)

SnCl2

53%

•

C5H11

PO(OEt)2O

O

(115)

O

PO(OR)2

Bun Bun PO(OR)2

O

OH

(129)H2O

74%

(116)

(EtO)2OPCO2Me

O OH(EtO)2OP

N O–+

i, ii, Raney Ni

52%

CO2Me

(130)

O

PO(OEt)2

O

PO(OEt)2

O

(131)HgSO4, H2SO4

98%

2[93[7[1[1 g!Coordinated and more remotely higher coordinated P\ As\ Sb or Bi!functionalizedketones

A number of procedures have been developed to promote the conjugate addition of phosphorusnucleophiles to enones[ Simple mixing of diethyl methyl phosphonite with a\b!unsaturated ketones\even methyl vinyl ketone "MVK#\ in EtOH gives the corresponding acetals\ from which the ketonescan be regenerated by hydrolysis "Scheme 092# ð77JOC3958Ł[ In the presence of a silylating agent\ thephosphinate "006# and ammonium phosphinate are converted into the nucleophilic phosphorus"III#species "007# and bis"trimethylsilyl#phosphonite "BTSP#\ respectively[ Both of these will add to theb!position of enones to give the expected adducts "i[e[\ "008# and "019## ð73TL3630\ 81TL702Ł[ The useof BTSP "010# may be particularly attractive in some applications because it can participate insuccessive Michael addition reactions "Scheme 093# ð81TL702Ł[ One procedure which involves mildconditions uses Me2Al as the catalyst and appears relatively resistant to steric hindrance\ as evidencedby the formation of "011# in 73) yield ð78TL3796Ł[ Treatment of MVK with triethyl phosphite hasbeen demonstrated to give the heterocycle "012#[ This undergoes a synthetically useful reaction with


bromine\ nitrogen and oxygen electrophiles to introduce a heteroatom adjacent to the ketone "e[g[\"013## ð80TL4202Ł[

O

PO(Me)OEt

O

PO(Me)OEt

OEtEtO

Scheme 103

MeP(OEt)2, EtOH HCl

(120)

PhPO(OEt)H

PhP

O-TMS

OEtPh

P

OEt

O

O

(117)

H(HO)OP

O

(118) (119)

HP

O-TMS

O-TMS

Prn PO-TMS

O

O-TMS

i, 1-hexen-3-one

ii, HMDS

i, 2-hexen-4-oneii, H3O+

83%

(121)

Prn P

O

OH

O

Et

O

Scheme 104

HMDS = hexamethyldisilazide

PO(OMe)2

O

PO

OEt

OEt

OEt PO(OEt)2

O

OH

(122) (123) (124)

Although the preparation of a!phosphonate carbanions can be accomplished by simple depro!tonation\ the b anions are not so accessible[ Knochel and co!workers have demonstrated that thezinc and copper salts "014# can be made by metalÐhalogen exchange\ and that they will add toenones and nitro alkenes to give 0\3! or 0\4!keto phosphonates "Scheme 094# ð89TL0722Ł[

(EtO)2OP

R

Ph O

(EtO)2OP

R

Prn

O

(EtO)2OP

M

R

Scheme 105

PhCHCHCOMe

R = H, 88%

i, PrnCHC(Et)NO2ii, O3

R = H, 70%

(125)

191 Dialkyl Ketones

2[93[8 KETONES BEARING A METALLOID FUNCTION

2[93[8[0 Silicon!functionalized Ketones

2[93[8[0[0 a!Silyl ketones

"i# From alcohols

b!Hydroxy silanes have been oxidized to a!silyl ketones with chromium trioxide in pyridineð80JCS"P0#0782Ł\ and with tetrakis"triphenylphosphine#rhodium hydride in the presence of an enoneas hydrogen acceptor ð74TL3118Ł[ The rhodium catalyst can also be used to prepare a!silyl ketonesby the double!bond migration of a b!silyl alcohol "Equation "021## ð77JOM"233#60Ł[ The TFA!mediated silapinacol rearrangement of a\b!dihydroxy silanes has been found to provide a generalroute to a!t!butyldimethylsilyl ketones which\ because of the stabilization of cations b to silicon andthe good migrating propensity of silyl groups\ is both regiospeci_c and high yielding "Equation"022## ð75TL3158Ł[

TMS

HO

Ph

TMS

O

Ph(132)

RhH(PPh3)4

56%

OH

PrnPrn

HO

TBDMS

TBDMS

PrnPrn

O

(133)TFA

90%

"ii# From aldehydes or ketones

Reaction of a ketone enolate with a silyl electrophile occurs speci_cally on oxygen to give enolsilane products[ a!Silylation can\ however\ be achieved via ketone dianions which are prepared bymetalÐhalogen exchange of lithium enolates of a!bromo ketones with t!butyllithium "Scheme 095#ð79JA4300Ł[ Homochiral trialkylsilyl ketones can be prepared by the reaction of metallated SAMPor RAMP derived ketone hydrazones with t!butyldimethylsilyl tri~ate\ followed by hydrolysis[Although the overall yields of the sequence are quite modest\ the enantiomeric excesses of theproducts are excellent ð76AG"E#240Ł[ In the presence of magnesium bromide\ trimethyl!silyldiazomethane reacts with aldehydes to give reasonable yields of trimethylsilylmethyl ketones"Equation "023## ð77S117Ł[

OAc

Br

O

TMS

Scheme 106

OLi

Li

i, MeLi

ii, ButLi

i, TMS-Clii, TFA

64%

(134)n-C9H19CHO + TMS-CHN2 TMSn-C9H19

OMgBr2

57%

"iii# From acids and their derivatives

The reaction of a!silyl esters with Grignard reagents\ which has been developed for the synthesisof unsubstituted ketones\ may also be used with a modi_ed workup that avoids protodesilylationto prepare a!silyl ketones "Equation "024## ð74JOC4159Ł[ An alternative approach to a!dimethyl!phenylsilyl ketones from acid chlorides introduces the silyl group in the form of an

192Bearin` A Metalloid

a!silylalkylmagnesium halide "Equation "025## ð81JOC275Ł[ In both methods the bulky a!silyl substi!tuent is responsible for preventing over!reaction to form a tertiary carbinol[

n-C8H17OEt

SiPh2Me

O

n-C8H17Prn

SiPh2Me

O

(135)

i, PrnMgBrii, H3O+

78%

n-C5H11 SiMe2Ph

Cl

n-C5H11n-C7H15

SiMe2Ph

O

(136)

i, activated Mg ii, CuBr•Me2S

iii, n-C7H15COCl

"iv# Miscellaneous preparationsThe hydroboration of silylacetylenes with 8!borabicycloð2[2[0Łnonane followed by oxidation with

alkaline hydrogen peroxide provides a convenient preparation of a!triisopropylsilylmethyl ketonesð78JA3762Ł[ Rather more generally\ a!diazoketones\ which are well established as precursors of awide variety of a!hetero!substituted ketones\ can also be used to prepare a!triethylsilyl ketones bya rhodium"II#!catalysed reaction with triethylsilane "Equation "026## ð77JOC5047Ł[

O

N2

But

O

SiEt3

But

(137)Rh2(OAc)4, Et3SiH

88%

2[93[8[0[1 b!Silyl ketones

b!Trialkylsilyl ketones are most conveniently prepared by the conjugate addition of tri!alkylsilylithium ð67TL1548Ł or of trialkylsilylcopper reagents ð73JCS"P0#0794\ 78SC164Ł to enones[Conjugate additionÐenolate trapping is possible with the silyl cuprate reagents and has been shownto proceed with high diastereoselectivity "Equation "027## ð73CC17Ł[

n-C6H13

O

n-C6H13

OPhMe2Si

n-C6H13

OPhMe2Si

(138)+

i, (PhMe2Si)2CuLiii, MeI

78%

>95 : <5

2[93[8[1 Germanium!functionalized Ketones

b!Triphenylgermyl ketones can be prepared by the photoinduced radical cyclization of unsat!urated acyl germanes[ The reaction may be used for the preparation of both cyclopentanone andcyclohexanone derivatives\ and has the advantage over tin hydride!based radical cyclization chem!istry of giving a highly functionalized product suitable for further elaboration "Equation "028##ð89JOC4451Ł[

GePh3

OO

GePh3

(139)hν

92%

2[93[8[2 Boron!functionalized Ketones

Despite their importance as synthetic intermediates\ most compounds containing a boron0carbon bond are too reactive to be readily isolated[ An important exception to this generalization

193 Dialkyl Ketones

are boronates\ and methods for the preparation of b! and g!boronate ketones are known[ Bothpreparations depend on the ready availability of a!halo boronic esters\ which react with enolates togive the b!boronate derivatives "Equation "039## ð82T066Ł or can be used as precursors of organo!copper reagents which add 0\3 to enones to give g!boronate compounds ð89JA6320Ł[

OO

B

O

O

OB

OCl

(140)

, LDA

83%

2[93[09 KETONES BEARING A METAL FUNCTION

2[93[09[0 Tin!functionalized Ketones

b!Trialkylstannyl ketones can be prepared by the addition of a trialkylstannyllithium ð67TL1548Łor a trialkylstannyl cuprate ð78TL3506Ł to an enone[ In the former case the addition occurs initially0\1 but the adduct rapidly isomerises to give the 0\3 system[ Homochiral b!stannyl ketones havebeen prepared by the addition of trialkylstannyllithiums to the hydrazone derivatives of enoneswith SAMP or RAMP "Scheme 096# ð82AG"E#487Ł[

NOMe

NH2

Scheme 107

90%

O

NN

OMe

NN

OMe

SnMe3

i, Me3SnLiii, MeI

77%

O3

77%

O

SnMe3

de > 98%, ee, > 96%


3.05Ketones: a,b-Unsaturated KetonesWARREN J. EBENEZER and PAUL WIGHTZENECA Specialties, Manchester, UK

2[94[0 KETONES BEARING AN a\b!ALKENIC BOND 1952[94[0[0 a\b!Unsaturated Ketones without Further Unsaturation 195

2[94[0[0[0 From diazo ketones 1952[94[0[0[1 By elimination reactions 1952[94[0[0[2 From vinyl compounds and carboxylic acid halides or their equivalents 1092[94[0[0[3 From a\b!unsaturated acid chlorides or their equivalents and carbon nucleophiles 1012[94[0[0[4 From alkylations of a!b!unsaturated aldehydes and their equivalents 1022[94[0[0[5 By oxidation reactions 1042[94[0[0[6 Rearranèment reactions 1052[94[0[0[7 By displacements of a b!leavin` `roup on an a\b!unsaturated ketone 1062[94[0[0[8 OxyÐCope and Claisen rearranèments 1062[94[0[0[09 Carbonylation and related reactions 1072[94[0[0[00 By isomerisations 1072[94[0[0[01 By aldol condensation reactions 1082[94[0[0[02 By Witti` reactions 1192[94[0[0[03 By DielsÐAlder reactions 1102[94[0[0[04 By oxidations of furans 1102[94[0[0[05 From alkynes 1112[94[0[0[06 From cyclopropanes 1132[94[0[0[07 By ð2¦1Ł cycloaddition reactions 1142[94[0[0[08 Miscellaneous reactions 114

2[94[0[1 a\b!Unsaturated Ketones with Further Unsaturation 1142[94[0[1[0 By elimination reactions 1142[94[0[1[1 By displacement reactions of a b!leavin` `roup with a vinyl nucleophile 1172[94[0[1[2 By isomerisations of double and triple bonds 1182[94[0[1[3 From oxidations of further unsaturated allylic alcohols 1182[94[0[1[4 From reactions of further unsaturated a\b!unsaturated acids and their equivalents with

carbon nucleophiles 1182[94[0[1[5 By FriedelÐCrafts acylations of dienes 1292[94[0[1[6 a!Allenic ketones 1292[94[0[1[7 By aldol condensation reactions 1292[94[0[1[8 By Witti` reactions 1202[94[0[1[09 From pyrilium salts 1212[94[0[1[00 From cyclopropanes 1212[94[0[1[01 By Claisen rearranèments 1222[94[0[1[02 Carbonylation reactions 1222[94[0[1[03 Miscellaneous methods 122

2[94[0[2 Haloènated a\b!Unsaturated Ketones 1232[94[0[2[0 1!Haloènated a\b!unsaturated ketones 1232[94[0[2[1 2!Haloènated a\b!unsaturated ketones 127

2[94[0[3 Oxyèn!substituted a\b!Unsaturated Ketones 1392[94[0[3[0 1!Oxyèn!substituted a\b!unsaturated ketones 1392[94[0[3[1 2!Oxyèn!substituted a\b!unsaturated ketones 132

2[94[0[4 a\b!Alkenic Ketones with Sulfur!based Substituents 1362[94[0[4[0 1!Thio a\b!unsaturated ketones 1362[94[0[4[1 2!Thio a\b!unsaturated ketones 140

2[94[0[5 Selenium! and Tellurium!substituted a\b!Unsaturated Ketones 1452[94[0[6 a\b!Alkenic Ketones with Nitroèn!based Substituents 146

2[94[0[6[0 1!Nitroèn!substituted a\b!unsaturated ketones 1462[94[0[6[1 2!Nitroèn!substituted a\b!unsaturated ketones 150

194

195 a\b!Unsaturated Ketones

2[94[0[7 Phosphorus! and Arsenic!substituted a\b!Unsaturated Ketones 1582[94[0[8 a\b!Alkenic Ketones with Silicon!based Substituents 169

2[94[0[8[0 1!Silyl a\b!unsaturated ketones 1692[94[0[8[1 2!Silyl a\b!unsaturated ketones 160

2[94[0[09 a\b!Alkenic Ketones with Metal Substituents 161

2[94[1 KETONES BEARING AN a\b!TRIPLE BOND 162

2[94[1[0 By Acylations of Alkynes 1622[94[1[1 Elimination Reactions 1632[94[1[2 By Oxidation of Alkynic Alcohols and Propar`ylic Methylene Groups 1642[94[1[3 By Reaction of a Carbon Nucleophile with Alkynic Acid Halides and Derivatives 1642[94[1[4 Miscellaneous Methods 165

2[94[0 KETONES BEARING AN a\b!ALKENIC BOND

2[94[0[0 a\b!Unsaturated Ketones without Further Unsaturation

2[94[0[0[0 From diazo ketones

Diazo ketones have been reacted intermolecularly leading to a\b!unsaturated ketones on heatingwith Cu"acac#1[ The reactions work best for larger rings "×6#\ and produce mainly the "E# isomersfor ×ten!membered rings "Equation "0## ð69CC610\ 67CC0958Ł[ Smith and co!workers have developeda cycloalkenone synthesis using the diazoalkene cyclisation shown in Equation "1# ð64CC163\ 64TL3114\70JA0885\ 73S418Ł[ Rhodium acetate ð80JCS"P0#843Ł\ cupric tri~ate ð73JOC0085Ł and HClO3 ð71JOC4242Łhave also been used to catalyse the latter reaction[

O

ON2

O

O

N2(1)

Cu(acac)2, 60 °C

70%

(E):(Z) 10:1

O

N2

O(2)

BF3•OEt2, 0 °C

65%


"i# By oxidative elimination of H1 from a ketone

Oxidative reaction of an enol derivative with a Pd catalyst\ usually Pd"OAc#1\ is a very well!known method for preparing a\b!unsaturated ketones[ The reaction has been studied extensively byTsuji and co!workers ð71JA4733\ 73CL0022\ 75TL1680Ł\ who have used enol acetates ð72TL4528Ł\ enolcarbonates ð72TL0686Ł and silyl enol ethers "Equation "2## ð72JA464\ 72TL4524Ł in conjunction withdiphosphine ligands[ If the enol can be made regiospeci_cally\ then only one regioisomer for thedouble bond is seen\ and the reaction generally gives the "E# stereoisomer where possible "Equation"3## ð67JOC0900Ł[ The thermodynamically favoured silyl enol ether\ as formed in Equation "4#\ givesa single regioisomer ð70T1974Ł[ p!Quinone has been used as the oxidant\ and PdCl1 can also catalysethe reaction ð66S662Ł[ The oxidation of silyl enol ethers by hydride abstraction with Ph2C¦BF3

−

has been investigated\ and proceeds regioselectively if the enol ether is formed selectively "Equation"5## ð66JOC2850\ 70JOC4237Ł[ 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq# and CrO2 =pyridine1

have been used to oxidise enol ethers to enones ð76TL20\ 89SC020Ł[

196a\b!Alkenic Bond

O-TMS O

(3)Pd(OAc)2

87%

Pd(OAc)2, 25 °C

94%

O-TMS O

(4)

(E)

O CO2MeH

H

O CO2MeH

H

(5)

i, TMS-Cl, Et3N, DMF, 130 °Cii, Pd(OAc)2, 20 °C

55%

O-TMS O

(6)Ph3C+ BF4

–, 25 °C

70%

"ii# By elimination of selenoxides

Treatment of enolates or enol ethers with a selenyl halide "typically PhSeCl# gives the cor!responding a!seleno compound\ which can be oxidised and then undergoes a subsequent thermalelimination to give the corresponding enone ð64JA4323\ 67T0938Ł\ for example Equation "6# ð62JA4702Łand Equation "7# ð79TL2668Ł[ Oxidants commonly used include mcpba ð78JOC3543Ł\ H1O1 ð79JA1986\70CPB1622\ 70JOC1819Ł and NaIO3 ð62CC584\ 79JA2853Ł[ The elimination of PhSeOH proceeds in a synfashion and usually produces "E# stereochemistry where possible[ Boron enolates have also beenused ð79SC556Ł\ and phenylselenyl chloride has been reported to react with ketones directly\ even inthe absence of base "Equation "8## ð62JA5026Ł[ Selenium can be used as the selenating reagent\followed by an alkylation and oxidative elimination "Equation "09## ð70TL2932\ 71JOC0487Ł[b!Selenoketones can also be oxidised and eliminated using CrO2 ð67TL076Ł[

O O

(7)

i, LDA, PhSeBrii, H2O2

72%


O-TMS

CO2Me

O

CO2Me(8)

i, PhSeClii, mcpba

51%

O O(9)

i, PhSeCl, EtOAcii, H2O2

64%


O O O O

(10)i–iv

62%

i, NaH, HMPA, THF; ii, Se; iii, MeI; iv, mcpba


"iii# By elimination of HBr or HCl from an a!halo ketone

This method usually starts with monobromination of a ketone\ followed by base!induced elim!ination to the alkenone "e[g[ Equation "00## ð61JOC157\ 61TL0742Ł[ Bromination is sometimes con!trolled by _rst forming a ketal\ as in Equation "01#\ ð60JOC3013\ 75S769Ł[ The regiochemistry of thebromination has been controlled by various means\ for example\ by making one site more enolisable"Equation "02## ð89TL2746Ł[ Thionyl chloride selectively chlorinates a!alkylated ketones\ which canthen eliminate to give the enones "Equation "03## ð52OSC"3#051\ 70SC6Ł[ However\ it has been reportedthat use of NBS:CCl3 in this reaction gives the same product as that produced when using thionylchloride\ but the reaction proceeds through the C!4!brominated material via a rearrangementð89S566Ł[ Similarly PhNMe2

¦Br2− can be used in a regioselective enone formation "Equation "04##

ð51BSF89Ł[ In some cases\ a conjugative dehydrobromination occurs\ via an enol "e[g[ Equation"05## ð54JOC1831\ 69JOC642Ł[ Phosphorus oxychloride has been used with a!hydroxy enol ethers toa}ord enones "Equation "06## ð54JCS029\ 68JOC2955Ł^ see also ð50JCS1421\ 71TL0640Ł[

O O

(11)

i, Br2, CH2Cl2ii, MgO, DMF, 140 °C

96%

O O

, p-TSA; ii, Br2; iii, KOH, DMSO; iv, p-TSA, H2Oi, HOOH

(12)i–iv

67%

HMeO2C

OO

(13)

i, NaH, THF ii, Br2iii, LiCl, DMF

70%

O O

(14)

i, SO2Cl2, CCl4ii, LiBr, Li2CO3, DMF, 153 °C

76%

O O

(15)

i, PhNMe3+ Br3

–

ii, pyridine

77%

H

O

Br

PhH OPh

(16)HBr, 118 °C

55%

198a\b!Alkenic Bond

OMeHO

O

(17)

i, POCl3, pyridineii, H+

64%

"iv# By elimination of sulfoxides and sulfones

The reaction of an enolate with a sulfur electrophile such as "MeS#1 gives the correspondinga!thio derivative\ which is easily oxidised and then undergoes elimination to give the enone\ forexample Equation "07# ð62JA5739Ł[ The method has been reviewed ð67CB252Ł[ The sul_de can beoxidised to the sulfoxide using mcpba ð72JOC2141Ł[ Sulfones have also been used in the elimination\and can be made from sulfonic acid esters "RSO2Me#\ for example Equation "08# ð71TL1512\ 72JA1929Ł[Both Taber and Yamakawa have developed the transformation of ketones to homologated enonesusing epoxy sulfoxides^ the reaction proceeds as shown in Scheme 0 ð68JOC349\ 75TL1360\ 76BCJ0728Ł[

O O

(18)

i, LDA ii, MeSSMeiii, NaIO4, 120 °C

79%

MeOO

MeOO

(19)NaH, PhSO3Me, DME, ∆

O SO

Ph

O

–O SO

Ph

SPh

O

O

O

PhS

O

Cl

+

i, LDAii, CaCO3, 150 °C

62%

Scheme 1

+

"v# By elimination of a hydroxy or alkoxy `roup

Enones can be prepared from a!hydroxy ketones by dehydration under acid conditions "Equation"19## ð68JOC2955Ł[ The a!hydroxy compounds themselves can sometimes be prepared by oxidationof the ketone with persulfuric acid ð72JOU148Ł[ Silyloxy enol ethers can be dehydrated with phos!phoric acid "Equation "10## ð79BCJ058Ł^ see also ð71SC684\ 72CB2691\ 77JOC0009Ł[


OMeHO

O

(20)p-TsOH

74%

O-TMS

O-TMSO

(21)H3PO4

73%

"vi# By elimination of a leavin` `roup b to a ketone

A hydroxy group b to a ketone can be eliminated under mildly acidic conditions\ as in Equation"11# ð76JOC0592Ł\ which is the synthetic equivalent of an Aldol reaction\ for a sterically hinderedketone[ The b!hydroxy amide in Equation "12# could be alkylated intramolecularly and theneliminated ð73TL3030Ł^ see also ð62JOC2526Ł[ b!Hydroxy and b!alkoxy groups have been used asleaving groups from vinyl thioethers in the preparation of a\b!unsaturated ketones ð71CL704\ 72TL3714\77T3352Ł[ Oxidative elimination of formic acid from b!keto acids can be achieved either chemically"with\ e[g[ Pb"OAc#3## "Equation "13## ð44JA0488\ 63JOC1106Ł\ or electrochemically ð70CJC834Ł[ Otherexamples of the elimination of b!leaving groups include with CN ð76HCA0282Ł\ PhSO1 ð68JOC2337Ł\NO1 ð78TL2574Ł\ SO1 extrusion ð74JOC1009Ł[ The elimination of a b!amino group can be performedby a Ho}mann reaction[ The ammonium compound is made by a Mannich reaction followed byquaternisation of the nitrogen "Equation "14## ð62TL4926Ł[

O

But But+

MgCl

O

ButBut

(22)

i, Grignard reagent ii, O3, Me2Siii, (CO2H)2

30%

PhS N

Ph

O

OH O

Me OS

Ph

O

(23)LDA, THF

77%

O

CO2H

H

H

OH

H

(24)Pb(OAc)4, Cu(OAc)2, pyridine

89%

+ HCHOn-C6H13CO2Me

O

n-C6H13

O

(25)

i, Me2NH•HCl ii, MeIiii, DMF, 75 °C

52%

2[94[0[0[2 From vinyl compounds and carboxylic acid halides or their equivalents

"i# By reaction of a carboxylic acid derivative and a vinyl metallic rea`ent

a\b!Unsaturated ketones have been prepared from vinyllithium species and carboxylic acids ingood yields "Equation "15## ð63TL1766\ 76TL1976Ł[ Allylic lithium compounds have also been used\and the double bond in the initial product isomerises into conjugation with the carbonyl group onworkup ð72JOC1159Ł[ Esters can also be used as the acylating agent "Equation "16## ð79TL0058\77S453Ł[ For the more reactive acid chlorides\ various vinyl metallics can be used\ including

100a\b!Alkenic Bond

palladium!catalysed vinyl Grignard reagents "Equation "17##\ vinylstannanes ð72JOC3523Ł\ vinyl!manganese compounds ð74S49Ł and vinylmercury compounds ð67JOC609Ł[ The reactions occur withretention of con_guration of the metalloalkene\ but isomerisation of the product to the mostthermodynamically stable product is sometimes seen[ Vinylzirconium compounds have been usedin this reaction and can be prepared in situ from the corresponding alkyne "Equation "18## ð70JA0166Ł[Amides ð74JA7955\ 74S655Ł and even selenoesters ð72TL3248Ł have been used as the acylating agents[In an interesting variant\ Meyers et al[ have used an oxazine and a vinyllithium to preparea!branched\ a\b!unsaturated ketones "Equation "29## ð62JOC1018Ł[

OH

O+

Li O(26)

DME

92%

MgBr+ EtO

OEt

O

O

OEt

O

O

(27)THF, Et2O

87%

+But Cl

OMgBr

But

O(28)

Pd(PPh3)4, Et2O

82%

Cl, AlCl3

O

61%

AlMe2+CpZr

Cl

MeO

(29)

O

N O

45%

2 Li

(30)

"ii# From vinyl silanes and acid chlorides

Vinyl silanes react cleanly with acid chlorides under Lewis acid catalysed conditions\ for exampleEquation "20# ð68TL0884\ 79JCS"P0#1374\ 70TL1874\ 74JOC0510Ł[ Intramolecular cyclisations of this typeare also well known\ using either AlCl2 or TiCl3 "Equation "21## ð70JOC1399\ 72CC388\ 72TL684Ł[ Thereaction has been used to prepare cyclopentenyl vinyl ketones "which subsequently undergo Naz!arov!type cyclisations# ð79JOC2906\ 71OM0139\ 73S880Ł[

TMS O

+Cl

O(31)

AlCl3, CH2Cl2, 0 °C

77%

OCOCl

(32)

TMS

AlCl3, CH2Cl2

95%

"iii# From alkenes and an acid chloride\ anhydride or acid derivative

Alkenes are well known to react with acid chlorides in FriedelÐCrafts type reactions to a}ordvinyl ketones "Equation "22## ð60OS"40#004\ 66CB0996Ł[ Use of an activated zinc species as the catalyst


has also been described "Equation "23## ð72JOC1492Ł[ Corey has published an intramolecular variant\which proceeds via formation of a mono acid chloride "Equation "24## ð89TL2746Ł\ and spirocyclisations are also known "Equation "25## ð61JA7526Ł[ Acid bromides have been used to acylatealkenes leading to a\b!unsaturated ketones ð68TL3442Ł[ Similar cyclisations have been reported usingcarboxylic acids with alkenes\ using P1O4 or phosphoric acid as the catalyst[ Frequently the pro!cedure starts from a lactone\ and the alkene "or carbocation# is produced in situ "Equation "26##ð62JOC3960\ 79TL0194\ 71CL576\ 78JOC2877Ł[ Alternatively\ a free acid is used\ and the reaction involvesa double bond shift "Equation "27## ð62JOC2718\ 63S667\ 64AJC1558\ 67TL1350Ł[ Acid anhydrides havebeen reported to work under special conditions ð42JCS2517\ 70TL2240\ 71JMC149Ł[

n-C7H15 Cl

O

n-C7H15

O(33)+

AlCl3, CCl4, 100 °C

62%

(34)+Cl

OO i, Zn, CuCl, CH2Cl2

ii, LiOH

76%

MeO2C

MeO2C MeO2C

OH

H

(35)

i, LiOH ii, (COCl)2, DMFiii, EtAlCl2

72%

COClClOCO

O

(36)AlCl3, MeNO2

51%

(37)O

O

O

i, P2O5ii, K2CO3

94%

(38)CO2H

OH3PO4, 110 °C

87%

2[94[0[0[3 From a\b!unsaturated acid chlorides or their equivalents and carbon nucleophiles

"i# From acid derivatives and or`anometallic rea`ents

Acrylic acid chlorides\ esters and amides are all known to react with organolithium compoundsto give vinyl ketones "Equation "28# ð75S833Ł and Equation "39# ð62S426\ 80CC457Ł#[ Grignard reagentsreact well\ and the reaction can be palladium!catalysed "Equation "30## ð65TL2986\ 67S031\ 70CL0024\72TL4970\ 75T0258\ 89JHC0698Ł[

N

O

Me

OMe

+

MeO

CO2Et

OMeMeO

CO2Et

OMe

O

(39)LDA

58%

102a\b!Alkenic Bond

OMe+

NMe

N

O

(40)O BF3•OEt2, BusLi

69%

NMe

N

O

OMe

MeNMe

O

(41)MeMgCl

79%

"ii# From a\b!unsaturated acid chlorides and an activated alkene

As a complement to the basic condition of the organometallics\ acid:neutral conditions have beeninvestigated[ If the alkene is su.ciently activated\ as in silyl ketene acetals "Equation "31##\ the acidchlorides react directly ð62TL0186\ 74TL3084Ł[ Allyl silanes can also be acylated with a\b!unsaturatedacid chlorides "Equation "32## ð65TL0760\ 68TL318Ł[ Unactivated double bonds can be acylated byFriedelÐCrafts catalysis "e[g[ SnCl3#\ similar to those reactions described in Section 2[94[0[0[2ð64TL2188Ł[

O O-TMS+

Cl

O

O O

O

(42)20 °C

80%

+Cl

O

TMS

O

(43)AlCl3

90%

2[94[0[0[4 From alkylations of a!b!unsaturated aldehydes and their equivalents

The alkylation of {umpoled| a\b!unsaturated aldehydes and their equivalents is well established[Hunig and co!workers have used the adducts of trimethylsilyl cyanide and a\b!unsaturated alde!hydes\ which can subsequently be deprotonated and alkylated electrophilically "Equation "33##ð79CB2672\ 78CB1020\ 89CB096Ł^ see also ð79TL0194Ł[ Sulfonyl allylcarbamates such as "0# can bealkylated and undergo carbamyl transfer and elimination of sul_nate "a single diastereomer isformed in this case# "Equation "34## ð78TL1808Ł^ see also ð73CL0148Ł for elimination of sul_de[Takahashi has developed an intramolecular macrocyclisation leading to large ring enones using ana\b!unsaturated aldehyde umpolung reaction "Equation "35## ð72TL2378\ 72TL3584\ 78JOC3162Ł[

(44)CN

O-TMS O

i, LDA ii, BunBriii, Et3N, HF, NaOH

54%

SO2Tol

O

O

NPri2

O

O

O

NPri2

O-TMSO

O-TMS

(45)+

i, BuLi ii, Ti(OPri)4iii, aldehyde

62%

(1)


O CN

ClO

(46)NaN(TMS)2

50%

Corey has used the dithiane "1# which can be alkylated predominantly at the sulfur!substitutedcarbon "Equation "36## ð64TL814Ł[ Similarly the anion of "2# is alkylated adjacent to the cyano group"Equation "37## ð75CB611Ł^ see also ð62AG"E#58\ 73TL1474Ł[ Seebach has shown that the dithiane "3#can act as a formyl dianion equivalent\ and can be alkylated with two di}erent electrophiles"Equation "38## ð63TL2060Ł[ a\b!Unsaturated aldehydes can also be umpoled with a metal catalystsuch as CoCl1\ which is believed to proceed via a radical mechanism "Equation "49## ð77CC581Ł^ seealso ð77JOM"237#012\ 89JOC1443Ł for use of Ni"cod#1 in the addition a\b!unsaturated aldehydes toalkynes[ A further aldehyde umpolung strategy is to use an allenyl ether\ which can be a!metallatedand alkylated[ Hydrolysis then gives the a\b!unsaturated ketone "Equation "40## ð62TL1474Ł[Hegedus and co!workers have developed a palladium!catalysed version of this transformation\which can be used to give divinyl ketones[ The reaction proceeds with retention of con_guration"Equation "41## ð72JA832Ł[ Parsons has described a similar reaction using an allenyl thioetherð67CC711Ł[

(47)

SSO

(2)

i, LDA ii, MeIiii, HgCl2

74%

(48)

i, LDA ii, MeIiii, Et3N•HF

59%

CN

O-TMS

(3)

O

S S

TMSLi

+ +

IO

(4)

i, BuLi, HMPA

ii, NH2OH

O

(49)

O+

O

O OO

O

(50)CoCl2, MeCN

89%

n-C5H11

•

OMe

n-C5H11

O

(51)

i, BunLi, MeIii, H+

100%

•

OMe

+I

(52)O i, BuLi, ZnCl2

ii, Pd(dba)2PPh3, vinyl halideiii, H+

104a\b!Alkenic Bond

2[94[0[0[5 By oxidation reactions

"i# By oxidations of allylic alcohols

The oxidation of secondary allylic alcohols to a\b!unsaturated ketones is a very well!establishedreaction[ A huge number of reagents have been described\ with varying selectivities[ One of themildest and most used is manganese dioxide\ for example Equation "42#[ The use of this reagent hasbeen reviewed ð48QR50\ 65S022Ł[ Other reagents include potassium dichromate ð60JOC276Ł\ ddqð74JOC4786Ł\ ddq:HIO3 ð67S737Ł\ CrO2 ð71JOC0676Ł and NiO1 ð71JA1531Ł[ Several authors havereported the use of transition metal catalysed oxidations of secondary allylic alcohols\ for exampleH1Ru"PPh2#3\ as in Equation "43# ð75TL0794Ł\ Cp1ZrH1:PhCHO ð75JOC139Ł\ and K1FeO3 "Equation"44## ð74TL1764Ł^ see ðB!78MI 294!90Ł for a comprehensive list of reagents and references[

O

O

O

OH

n-C5H11 O

O

On-C5H11

(53)O

MnO2, CH2Cl2

(54)OH OH2Ru(PPh3)4

95%

Ph

OH OH(55)

Ph

O OHK2FeO4

95%

"ii# By oxidations of allylic methylene `roups

Both hydrogens of an allylic methylene group can be oxidised to give a\b!unsaturated ketones"Equation "45##[ This transformation has been reviewed ð75BSF54Ł[ Reagents include CrO2 "Equation"46## ð76JOC2235Ł\ tBuO1H "Equation "47## ð74JCS"P0#156Ł and SeO1 ð65OR"13#150Ł[ Mercuric acetatehas also been used ð62CC45Ł^ for other reagents see ðB!78MI 294!90Ł[

(56)RR

O

[O]

O

O

OMe

O

O

OMe

O

(57)CrO3•pyridine

58%

(58)CO2Me CO2MeO

ButO2H, Cr(CO)6 (cat.)

83%

"iii# Miscellaneous oxidation reactions

Ozonolyses of dienes can lead to a\b!unsaturated ketones\ for example Equation "48# ð77CB0684Ł^see also ð52JCS1319\ 52JCS2564\ 58JA2565\ 67JA5183Ł for related oxidations[

ButBut

ButBut

O

(59)O3

37%


2[94[0[0[6 Rearrangement reactions

"i# By Rupe rearran`ements

The rearrangement of an a!alkynic alcohol to an a\b!unsaturated ketone is known as the Ruperearrangement\ and the reaction has been reviewed previously ð60CRV318Ł[ The mechanism is notcompletely clear\ but it is a useful way of preparing a\b!unsaturated ketones\ although side productshave been reported in some cases[ The reaction is performed under acid conditions\ for examplewith formic acid "Equation "59## ð70CL44Ł\ ion exchange resins ð70S362Ł or P1O4 ð44OSC"2#11Ł[

(60)

HOO

HCO2H

63%

"ii# By rearran`ement of propar`ylic alcohols

Related to the Rupe rearrangement\ is the rearrangement of 1!butyn!3!diols\ for example\ Scheme1\ which proceeds through a Nazarov reaction[ The reaction has been reviewed\ along with othercyclopentenone syntheses ð73S418Ł[ The reagents are usually sulfuric acid ð68JA0488Ł\ phosphoruspentoxide ð65HCA0115Ł or methanesulfonic acid ð77CB0350Ł[

Scheme 2

O

R1

R3

R2

R1

R3

R2

HO

OH

R1

R2

O

R3

"iii# By ð1¦1Ł cycloaddition reactions

Ketenes react smoothly with allenes to give cyclobutenones "Equation "50## ð64T738Ł\ in whichthe central carbon of the allene becomes attached to the carbonyl carbon of the ketene[ Underharsher conditions\ alkenes add to ketenes "4#\ which can subsequently be oxidised and eliminatedto give the cyclobutenone "Equation "51## ð67CC01Ł[ Alkynes are not normally ketenophilic enoughto undergo reaction\ unless the ketene is activated\ for example dichloroketene "Equation "52##ð76TL2188Ł[ The chlorines in the product can be removed by reduction[ Similarly\ keteniminiumsalts\ formed in situ by dehydration of an amide\ cycloadd to alkynes[ The imine can then behydrolysed to release the cyclobutenone "Equation "53## ð73TL4932Ł[

+

•O

O

• (61)50 °C

90%

+

O

•

PhS

O

(62)mcpba, 150 °C

45%

(5)

106a\b!Alkenic Bond

Cl3C Cl

O+ OAc

Cl

Cl

O

AcO

(63)80%

+ But

O

But

(64)NMe2

O

i, TFAA, collidineii, NaOH, 41 °C

69%


2[94[0[0[7 By displacements of a b!leaving group on an a\b!unsaturated ketone

The reaction of an organometallic with an a!haloenone is well known[ Good yields can beobtained\ even with sterically hindered groups present\ and the reaction usually proceeds withretention of con_guration "Equation "54## ð67TL0252\ 71CJC0145Ł[ 0\2!Diones can be transformedinto disubstituted enones by displacement of a phosphonate leaving group "Equation "55##ð68CJC0320Ł[ Alkyl and aryl thio moieties can also be used as leaving groups[ Deiter et al[ reportgood stereoselectivity\ with con_guration "retention or inversion# depending on the solvent\ thecuprate and other factors "Equation "56## ð75JOC3576Ł[ Thioketene acetals have been used and thethio groups can be displaced sequentially with di}erent nucleophiles ð74JA3568Ł[

O

Br

O

But

(65)ButCuLiSPh

70%

(66)O O O

i, ClPO(OEt)2ii, Me2CuLi 83%

O SPh BunO(67)

Bun2CuLi

99%

2[94[0[0[8 OxyÐCope and Claisen rearrangements

The oxyÐCope rearrangement is an important synthetic procedure for the preparation of func!tionally complex a\b!unsaturated ketones[ The use of a propargylic alcohol leads directly to bothcyclic "Equation "57## ð73JA2758\ 75TL108\ 77TL5786Ł and acyclic\ unsaturated ketones ð79TL0236\75T0222Ł\ and similarly the use of a doubly allylic alcohol leads directly to unsaturated ketones"Equation "58## ð66JA3075\ 72JA2237\ 77BCJ0196\ 77JA789Ł[ The Claisen rearrangement can be used inan analogous fashion to furnish acyclic ð58TL2132Ł and cyclic!a\b!unsaturated ketones "Equation"69## ð80JA1509Ł[

OMeO

HOO

O OMe(68)

170 °C

62%


OH

O

(69)KH, 18-crown-6, 25 °C

75%

OO

(70)toluene, 180 °C

60%

2[94[0[0[09 Carbonylation and related reactions

The PausonÐKhand reaction is a versatile\ stereoselective synthetic route to cyclopentenones\commonly as fused bicyclic systems ð74T4744Ł[ The reaction usually involves the treatment of anenyne with Co1"CO#7 under an atmosphere of carbon monoxide\ and enables functionally complexmolecules to be assembled in a single step "Equation "60## ð77T1546\ 78JOC4037\ 78TL4754\ 89JA330Ł[ Aclosely related transformation has been observed using Ni"CO#3 as the catalyst ð76TL3634Ł^ seealso ð57LA"601#68\ 74TL5286Ł[ The sequential insertion of carbon monoxide and alkynes into alkylmanganese pentacarbonyl complexes\ followed by acidolysis\ leads to enone systems ð76TL1122Ł\and if the alkyl manganese pentacarbonyl complex is derived from the ring opening of an epoxide\cyclopentenones are isolated\ presumably via a Nazarov cyclisation ð77JOC3781Ł[ Palladium catalysisfacilitates the cross!coupling accompanied by carbon monoxide insertion of alkyl halides andvinyltin reagents to produce unsymmetrical unsaturated ketones in good yield[ The reaction is mild\tolerant of a wide spectrum of functionality\ and retention of double bond geometry in the vinyltinreagent is observed "Equation "61## ð73JA3722Ł[ Palladium!catalysed carbonylation and cyclisationof an iododiene system derived by zirconium!promoted allylmetallation of an alkyne has been usedto form doubly unsaturated cyclic ketone systems ð72JA5650Ł[ A bulky isonitrile behaves as a carbonmonoxide equivalent in a reaction involving sequential attack by a nucleophile followed by electrophilicquench[ Unsymmetrical unsaturated ketones have been prepared by this routeð71JOC41Ł[

MOM-O

O-TBDMS

HMOM-O

O

O-TBDMS

(71)

i, Co2(CO)8ii, sealed tube, CO, 85 °C

64%

Br CO2Et

OMe+

O-THP

Bun3Sn

O-THP

O OMe

CO2Et

(72)CO, 50 °C, Pd(dba)2

74%

2[94[0[0[00 By isomerisations

A common method of forming a\b!unsaturated ketones is to isomerise a b\g! or g\d!unsaturatedketone to the more thermodynamically stable conjugated isomer[ These isomerisations occur mostreadily with base catalysis often in very high yield ð59JOC0855\ 75JA1989\ 78TL6186Ł[ Acid catalysis hasalso been reported ð42JA2157Ł as has thermal isomerisation ð75HCA117Ł and the use of rhodiumcompounds which can be tuned to give either the more or less substituted enone where a choice isavailable ð68TL0388Ł[ Oxidations of homoallylic alcohols can result in concomitant isomerisation tothe unsaturated ketone ð45JA765\ 76TL2004Ł[ Birch reductions of phenol derivatives are commonlyfollowed by isomerisation to the more stable cyclohexenone in situ or on acidic workup ð67CC741\68BSF270Ł[

108a\b!Alkenic Bond


Probably the most important and versatile route to a\b!unsaturated ketones is the aldol conden!sation[ This involves the reaction of an enolate or enol with an activated carbonyl\ followed bydehydration or similar elimination of the resulting adduct[ Thus\ reaction of the 0\2!diketone "5#with dichloroaldehyde "6# followed by elimination of acetic acid gives the ketone "7# in 66) yield"Equation "62## ð70JOC2115Ł[ Aldol reactions are often carried out in situ after the removal of acarbonyl protecting group and occur with both acid and base catalysis "Equations "63# and "64##ð70JA2359\ 73JOC299Ł^ see also ð64JA5800\ 67TL1844\ 79JOC3491\ 70JOC1317\ 74CL0034\ 76JHC386Ł[ Similarly\functionality can be manipulated to give a dicarbonyl compound which undergoes an intramolecularaldol condensation leading to a cyclic unsaturated ketone[ Thus\ opening the lactone "8# with aGrignard reagent gives a 0\4!diketone which cyclises under basic conditions to give the cyclo!hexenone "09# in the FujimotoÐBelleau reaction "Equation "65## ð78JOC3691Ł^ see also ð54JCS0245\71CJC1417Ł[ Another method of unmasking dicarbonyl functionality is to ozonise an alkene\especially a cyclic alkene "Equation "66## ð60JA3221\ 71SC884\ 80TL4586Ł[ Other oxidations leading toprecursor dicarbonyl systems are known ð72JA4577\ 75NJC456Ł[ Reductions leading to dicarbonylsystems have been reviewed ð78JOC3562Ł as have reductions of heteroaromatic ring systems "e[gEquation "67## ð64JA279\ 71TL4998\ 89JOC1126Ł[

O OOHC

Cl

Cl Cl

O

Cl

(73)+K2CO3, THF, 67 °C

77%

(6) (7) (8)

MeO2C

OMeO

MeO O

O

O

(74)p-TsOH, toluene, 130 °C

51%

N

O

O

OO

N

O

(75)

i, 1N HClii, 1N NaOH, 100 °C

50%

(76)BnN

O O

BnN

O

(9) (10)

i, MeMgI, Et2O, –25 °C

ii, KOH, MeOH (aq.), 20 °C

i, O3 ii, Me2S or Zniii, PhCH2NMe3Cl, 50% NaOH, CH2Cl2

38%

O

(77)

(78)

N

O O

O

O

i, Na, NH3 ii, NaOH, EtOH (aq.)iii, H3O+

52%


The aldol reaction can be made regioselective by preparing an enol derivative of the ketone\ inorder to ensure that coupling occurs on the desired side of an unsymmetrical ketone[ A number ofpreformed enolates have been used\ the most common being the silyl enol ether which is reactedwith the aldehyde or ketone in the presence of a Lewis acid catalyst\ for example TiCl3 ð66AG"E#706Ł[Silyl enol ethers also react with acetals in the presence of a stoichiometric amount of TiCl3 toprovide Aldol products in high yield ð76S0932Ł[ This reaction\ known as the MukaiyamaÐaldolcondensation\ has become an important synthetic tool facilitating aldol condensations which donot proceed under conventional conditions "Equation "68## ð67TL3194\ 78JA7166Ł^ see also ð71TL0936\73JOC2593Ł[ Enamines are also commonly used as preformed enolates ð51CB0384\ 70S088Ł[ Anotherimportant aldol reaction leading to unsaturated cyclic ketones is the Robinson annulation reactionin which a cyclic ketone is treated with methyl vinyl ketone "or a derivative# under basic conditionsð65S666Ł[ Another annulation procedure for cyclic ketones has been reviewed ð76JOC0339Ł "Equation"79## and other variants are known ð64JOC2510\ 66S597\ 67JA5183\ 67JOC3549\ 89S882\ 89TL5034Ł[

(79)

TMS-O

O

O

O

TiCl4, 0 °C

60%

(80)

O

+ ClOP(O)(OEt)2

O

i, LDA, THF ii, (Ph3P)4Pdiii, NaOH, EtOH (aq.)

79%


The Wittig reaction is an important and well!used preparative tool in the synthesis ofa\b!unsaturated ketones[ The major route to these systems involves the reaction of an a!ketophos!phorane with an aldehyde and leads to the "E# isomer stereoselectively "Equation "70## ð73TL3848Ł^see also ð71TL1244\ 74JOC1087\ 76S0944\ 89JOC3386Ł[ The corresponding stabilised arsonium ylides havealso been investigated ð78CC501Ł[ The use of a!ketophosphonates "00#\ the WadsworthÐEmmonsreaction\ has several advantages over the use of phosphoranes\ for example the ylides are morereactive than the corresponding phosphoranes enabling reactions with ketones\ and the phosphoruscontaining side product is water!soluble\ unlike triphenylphosphine oxide\ simplifying the workupð76S0901\ 76TL0782Ł[ Intramolecular Wittig condensations enable the synthesis of cyclic unsaturatedketones even when the product is highly strained ð67JOC3562\ 68AG0994\ 71TL2432Ł[ Condensation ofan a!ketophosphorane with an a\b!unsaturated aldehyde can result in an intramolecular Michaeladdition to give cyclohexenone derivatives "Equation "71## ð77JOC1726Ł[ Intramolecular WadsworthÐEmmons cyclisations are also well known[ The reacting ylide is often derived by the treatment ofan ester with an a!lithioalkylphosphonate "Equation "72## ð67TL3486\ 74JA6856\ 74JOC0654\ 76JOC0264Ł[Other routes to a\b!unsaturated ketones using Wittig methodology include] reaction of an unstabil!ised ylide with a monoprotected 0\1!diketone ð66TL2494Ł\ use of a diphosphonium salt in a fourcarbon annulation procedure with a b!ketoester ð74JOC3141Ł\ addition of a lithiated dithiane to avinylphosphonium salt generating an ylide which undergoes an intramolecular Wittig condensation"Equation "73## ð63TL3112Ł and reaction of Grignard reagents with the ketenylidenetriphenyl!phosphorane "01# and subsequent hydrolysis yielding a!ketophosphoranes which can then be con!densed with aldehydes ð75TL0888\ 77S38Ł^ see also ð75S30Ł[

(81)MeCHO + Ph3P

O

OAcPhH, 60 °C

90%

OAc

O

R1P(OR2)2

O O

(11)

110a\b!Alkenic Bond

(82)Ph3P CO2Et

O+ OHC

O

CO2EtNaH, THF

38%

(83)

O

O O

+ (MeO)2P Li

O THF, –78 °C

37%

S

SO

O

+SS

OPh3P (84)+LDA, –5 °C

55%

•

Ph3P

O+

–

(12)

2[94[0[0[03 By DielsÐAlder reactions

The DielsÐAlder reaction enables the synthesis of several cyclohexenones especially via the use ofDanishefsky|s diene "Equation "74## ð64JOC427\ 72JOC030\ 78TL3298\ 80TA067Ł or via the use of analkynic ketone as dienophile ð80TL4610Ł^ see also ð76TL1570Ł[ DielsÐAlder reactions are sometimesused to protect enone systems and thus a retro!DielsÐAlder unmasks the a\b!unsaturated ketone"Equation "75## ð73CC068\ 76S196\ 78CC160\ 78JOC5997Ł[

O

SO2Ph

O

O

MeO

O-TMS(85)

H SO2Ph+

i, xylene, 140 °Cii, H+

69%

MeAlCl2

, DCE, 70 °C

89%

O

O

O

OH

H

H

H

HO2C

( )7

O

HO2C

(86)

( )7

DCE = 1,2-dichloroethane

2[94[0[0[04 By oxidations of furans

The oxidative ring opening of 1\4!disubstituted furans provides a useful route to enedicarbonylcompounds in high yield "Equation "76## ð80CC669Ł[ A wide variety of oxidising agents have beenemployed in this transformation including peracids\ bromine and singlet oxygen ð72S014\ 78IJC"B#2\89TL6558Ł[ In some cases the oxidised furan has been isolated\ and it is then hydrolysed or reductivelycleaved to the dicarbonyl compound ð73JA4474\ 74TL1758\ 89TL6190Ł[ There are a number of reportsof the oxidative conversion of furanmethanols to 5!hydroxypyran!1!ones "e[g[ Equation "77##


ð89JCS"P0#528Ł^ see also ð72SC196\ 76JOC4417\ 78JA6523\ 80JHC586\ 82TL6978Ł[ The application of Sharplessepoxidation conditions to racemic secondary 1!furanmethanols results in a kinetic resolution fur!nishing unchanged 1!furanmethanol and 5!hydroxy!1!pyranone both of high enantiomeric purityð89JCS"P0#0622\ 80TL0356Ł[

(87)O SMe O O

SMepcc, DCM, 20 °C

70%

pcc = pyridinium chlorochromateDCM = dichloromethane

(88)O

OH

C10H21

O

O

C10H21

OH

NBS, THF, H2O

93%

2[94[0[0[05 From alkynes

a!Alkynic carbonyl compounds are useful precursors to a\b!unsaturated ketones[ Organocopperreagents "RCu and R1CuLi# add exclusively in a 0\3 sense to a!alkynic ketones furnishing a\b!unsaturated ketones usually as a mixture of "E# and "Z# isomers "Equation "78## ð76TL4970\ 89JOC116Ł[Some intramolecular cyclisations of enolates onto alkynic ketones have also been observed\ leadingto both _ve! and six!ring unsaturated ketones ð75TL4344\ 76TL2346Ł[ Similarly 0\3!additions ofnucleophiles to a!alkynic esters\ followed by Dieckmann cyclisations lead to cyclic unsaturatedketones ð73JOC2922\ 76TL4130Ł[ Additions of carbon nucleophiles 0\3 to an a!alkynic ketone can alsobe achieved by an ene reaction "Equation "89## ð78HCA0404Ł[ The addition of lithium divinyl cuprateacross certain functionalised alkynes "02# has also been reported\ and leads to an intermediatecuprate "03# which on hydrolysis furnishes an a\b!unsaturated ketone "Scheme 2# ð79T0850Ł[

(89)

O O-MOM O O-MOM

i, Me2CuLi

ii, PriSLi

(90)+O

O O+

3 : 1

ZnI2CH2Cl2, 20 °C

64%

Bun CuLi X2

+ Bun

X

CuLi

220% HCl

75% overall

(13) X = SR, OR (14)

Bun

O

Et2O, THF, –40 °C2

Scheme 3

112a\b!Alkenic Bond

The reduction of a!alkynic ketones similarly leads to a\b!unsaturated ketones "Equation "80##ð68CL0910\ 75S073Ł[ In general catalytic partial hydrogenation leads exclusively or predominantly to"Z#!alkenes\ whereas reduction with metals and metal salts gives predominantly "E#!alkenes ðB!73MI294!90Ł^ for a comprehensive list of reagents and references see ðB!78MI 294!90Ł[

(91)

OOCrSO4, DMF, H2O, 25 °C

80%

The synthetically useful reaction of trialkylboranes with a!alkynic ketones occurs only in thepresence of catalytic amounts of oxygen and yields the a\b!unsaturated ketone\ as a mixture ofstereoisomers\ after hydrolysis of the intermediate allene "Equation "81## ð69JA2492Ł[ A multistagesynthetic procedure to 2\2!dimethyl unsaturated ketones has been reported which involves theanionotropic rearrangement of 0!halodienylboranes with sodium methoxide followed by oxidationand isomerisation "Scheme 3# ð77S029Ł^ see also ð62CC595Ł[

(92)B3

+

OTHF, H2O, 20 °C

65%

Oair

B

I

R

B

R

OMeR

O

Scheme 4

NaOMe, MeOH i, H2O2, NaOH (aq.), THF

ii, ButOK, ButOH

Dreiding has reported that the pyrolysis of a!alkynic ketones leads to fused and spiro!cyclo!pentenone systems\ via an alkylidene carbene intermediate\ in high yield enabling a total synthesisof the triquinane modhephene "Equation "82## ð70HCA0012\ 74HCA227Ł[ Radical chemistry alsoenables the synthesis of a\b!unsaturated ketones from a!alkynic ketones[ Thus a radical cyclisationfollowed by protiodestannylation provides a neat synthesis of a!methylenecyclohexenones "Equation"83## ð89TL4928Ł^ also see ð89JA891Ł[ Electrophilic alkylation of an allenic anion\ derived by metal!lation of the silyl alcohol "04# also leads to a\b!unsaturated ketones in high yield "Equation "84##ð79TL512Ł[

(93)

H

O O

620 °C

95%

(94)

CO2Me

O O

CO2Me

i, Bun3SnH, AIBN, PhH

ii, HCl (conc.), Et2O

58%


(95)Ph

TMSHO O

Ph

i, BunLi

ii, MeI

(15)



Cyclopropanes have proved useful intermediates in the synthesis of a\b!unsaturated ketones viaring cleavage reactions[ Thus\ Conia et al[ have reported that the cycloadditions of chloro!methylcarbene to the trimethylsilyl enol ethers of cyclic and acyclic ketones\ followed by eliminationof TMS!Cl with ring opening of the cyclopropane\ leads to a!methylalkenones "ring expanded byone carbon atom in the case of cyclic ketones# "Equation "85## ð70S178\ 70S180Ł^ see also ð63TL898\63TL2186Ł[ A similar overall result is achieved by the reaction of a!haloketones with dilithio!alkylsulfones via a cyclopropane intermediate "Equation "86## ð74JOC2563Ł[ The acidic hydrolysis ofdichlorocyclopropylcarbinols such as "05# leads to cyclic enone systems in good yield[ This reactionhas been postulated to occur via conjugate dehydration\ Nazarov!type cyclisation and hydrolysisof the resulting chlorodiene "Equation "87## ð63JA2602Ł\ and it is also applicable to forming bicyclicsystems ð67TL660\ 79BCJ0909Ł[

(96)

Cl

TMS-O

Otoluene, 111 °C, 6 d

91%

(97)

O

Cl

O

PhSO2

Li

Li+

THF, 0 °C

45%

(98)OH

ClCl O

HBr (aq.), 100 °C

83%

(16)

Ring opening reactions of oxycyclopropane systems derived from the reaction of a!diazocarbonylintermediates with enol ethers or enol acetates lead to 0\3!dicarbonyl functionality which can thenundergo Aldol cyclisations leading to cyclic enones "Equation "88## ð60TL1464\ 67JA0156\ 89CB252Ł[The ring opening of other oxycyclopropane systems has been widely used in synthesis[ Base!catalysed cleavage of 0!siloxy!1!vinylcyclopropane leads to an a!methylenone function ð62TL1656Ł^see also ð62JOC293Ł[ Treatment of bicyclic cyclopropanes such as "06# with FeCl2 followed by sodiumacetate results in cleavage of the bridging bond to give the cyclic enone "07#\ possibly via a radicalmechanism "Equation "099## ð65JOC1962\ 79OS"48#002\ 77CL810\ 82TL6180Ł[ By contrast treatment withTeCl3 followed by dimethylsulfoxide provides the corresponding a!methylene in good yields via anintermediate b!trichlorotelluro ketone ð80TL118Ł[

(99)

OOAc

O

NaOH, MeOH, 100 °C, 1 h

85%

(100)

O

O-TMS

(17) (18)

i, FeCl3, py, DMFii, NaOAc, MeOH

98%

The ring opening of cyclopropylphenyl sul_des has also been used synthetically to makea\b!unsaturated ketones[ Thus the alcohol "08#\ prepared from the addition of 0!lithiocyclo!propylphenyl sul_de to 3!methyl!0\1!epoxypentane\ has been cleaved\ hydrolysed and dehydratedin a single pot using mercuric chloride\ to a}ord the enone "19# "Equation "090## ð71TL1268Ł[

114a\b!Alkenic Bond

(101)

SPh

HO

O

SPh

HgCl2, MeCN, H2O, reflux

42%

(19) (20)

2[94[0[0[07 By ð2¦1Ł cycloaddition reactions

The ð2¦1Ł cycloaddition reaction has proved useful in the synthesis of cyclopentenone systems[Thus the addition of a\a?!dibromoketones to enamines has been reported with a variety of reagentsincluding Fe1"CO#8 and a mixture of CeCl2 and SnCl1 "Equation "091## ð61JA0661\ 78BCJ1237Ł[ Thisreaction does not occur intramolecularly onto an unactivated double bond\ but undergoes a ð2\3Łsigmatropic shift instead ð70BCJ1122Ł^ however such a cycloaddition\ with an alternative 0\2!dipole\has been utilised to furnish an enone system ð89JCS"P0#242Ł[ A formal ð2¦1Ł cyclisation has alsobeen observed by the Michael addition of a zinc homoenolate to an alkynic ester\ followed byintramolecular acylation of the intermediate allenolate\ leading to cyclopentenone systems "Equation"092## ð89JOC3124Ł[

(102)

O

BrBr

+ N

O

OFe2(CO)9, PhH, 25 °C

77%

C5H11

MOM-O

CO2Et

O

CO2Et

MOM-O

C5H11

Et2OZn

(103)

2

CuI, HMPA, 25 °C

71%

2[94[0[0[08 Miscellaneous reactions

The palladium"II#!catalysed intramolecular cyclisation of a silyl enol ether onto an unactivatedalkene is another useful route to cyclopentenones "Equation "093## ð68JA383\ 75JA1989Ł^ see also therelated reactions ð70TL0004\ 73JOC849\ 75TL1112Ł[

(104)

O-TMS O

Pd(OAc)2, 25 °C

99%

2[94[0[1 a\b!Unsaturated Ketones with Further Unsaturation


"i# By oxidative elimination of H1

The elimination of hydrogen can be performed on a\b! and g\d!unsaturated ketones to givea\b!unsaturated ketones with further unsaturation "Scheme 4#[ The commonest reagents used are


chloranil\ ddq and chromium oxidising species[ Chloranil was used to oxidise the g\d!unsaturatedketone in Equation "094# to the a\b\g\d!unsaturated ketone\ with the enamine functionality beinguna}ected ð65JA2534Ł[ g\d!Dehydrogenation has been performed more frequently\ often on steroids\using ddq "Equation "095## ð56JCS0619\ 60JCS748Ł\ chloranil ð59JA3182\ 78JOC2873Ł and CrCl1ð56HCA158Ł[ A palladium!catalysed reaction has also been reported ð80TL0322Ł[

O O

O O

Scheme 5

[O]

–H2

[O]

–H2

NN

H H H

O

NN

H H H

O

(105)chloranil, C6H6, 20 °C

47%

H

H H

O

O

H

H H

O

O

(106)ddq, p-TsA, 25 °C

90%

"ii# By elimination of halide

Elimination of hydrogen halide is known for both a\b and g\d!unsaturated ketones\ for examplefrom a!haloketones "Equation "096## ð59JA1391\ 62CC050Ł[ Similar conditions have been used forg!halo!a\b!unsaturated ketones "Equation "097## ð42JA4378\ 89JCS"P0#0634Ł^ see also ð46BSF0178\46JA0029Ł for related examples[

(107)

BrO O

LiF, Li2CO3, 120 °C

85%

(108)O

Br

OAc

O

OAc

Li2CO3, DMF, 120 °C

90%

"iii# By elimination of hydroxy and alkoxy `roups

The elimination of b!hydroxy groups from g\d!unsaturated ketones to form dienones has beenreported\ as shown in Equation "098# ð71SC410Ł[ Formation of the mesylate prior to eliminationcan also be used "Equation "009## ð65TL00\ 73TL2510Ł[ g!Hydroxy and alkoxy groups can be eliminated

116a\b!Alkenic Bond

from a\b!unsaturated ketones "Equation "000## ð71S23\ 75JCS"P0#850Ł\ as can d!hydroxy and alkoxygroups ð43JA4561\ 46JA5297\ 72JA4568Ł[ Hydrolysis of 1!alkoxy!2\3!bisalkoxymethylfurans gives riseto further unsaturated a\b!unsaturated ketones ð73JA4474Ł[

(109)EtO

OH

EtO

O

OEt

silica, 20 °C

94%

(110)OHO OMeSO2Cl, Et3N

85%

(111)p-TsA, toluene, 110 °C

60%

PhO

Ph

OH

PhO

Ph

"iv# By elimination of sulfur and selenium `roups

The elimination of sulfoxides can be performed to produce dienones "Equation "001##\ similar tothe case where there is no further unsaturation ð75S736Ł[ The bis elimination of sulfoxides\ as inEquation "002##\ gives the corresponding "E# dienones in good yields ð77CPB0058Ł^ see also ð67CC710Łfor an example of a 0\2!pyrolytic elimination of a sulfoxide[ Julia and co!workers have used theisoprenoid sulfoxide in Equation "003# ð67TL0044Ł as an isoprene cation equivalent[ After Michaeladdition and liberation of the protected carbonyl\ the double bond is isomerised and the sulfoxideeliminates to give the dienone[ Fleming et al[ have shown that the trimethylsilyl enol ethers ofb\g!unsaturated ketones are sulfenylated almost exclusively in the g!position\ and can then beoxidised:pyrolysed to the corresponding dienone ð68TL2194Ł[ A versatile synthesis of enones utilisingthe elimination of b!sulfoxides has been described by Albrecht et al[ "Scheme 5#[ A range ofelectrophiles instead of the enone was used in the anion capture step ð77S109Ł^ see also ð77HCA0608Łfor an example of a 0\5!elimination of a sulfoxide to form an a\b\g\d!dienone[ Chou has used theextrusion of SO1 to produce novel dienes "Equation "004## ð70CL0230\ 77JOC4\ 78SC0482Ł[

(112)

O

SMe

O

NaIO4, NaHCO3, 110 °C

93%

(113)n-C6H13

O

n-C6H13 SPh

O

SPh

mcpba

75%

(114)Ph

S

O–

+O

NC O OEt–

+

i, HClii, NaOH

50%

(115)

S

O

Ph

O O

O

Ph∆

80%


CN

N(Me)Ph

i, ButLi, THF

ii,

SPh

SPh

CN

N(Me)Ph

–

O

Scheme 6

SPh

CN

N(Me)Ph

O

i, HCl

ii, mcpba

O

O

b!Selenoaldehydes undergo a stereoselective Wittig reaction followed by an oxidative eliminationto give the "E\E#!diene "Equation "005## ð75TL1838Ł^ see also ð79TL2198Ł[ Eliminations fromd!ammonium compounds "Equation "006## also give dienones ð65JCS"P0#1178\ 79TL794Ł[

(116)But

O

PhSe O+ But

O

PO(OMe)2

i, NaH, THFii, H2O2, HCO3

–

87%

(117)O

NMe2

O

i, MeIii, dbu

73%


2[94[0[1[1 By displacement reactions of a b!leaving group with a vinyl nucleophile

Reactions of a substituted a\b!unsaturated ketone with a vinyl nucleophile can lead to dienones[The nucleophile is often a Grignard reagent "Equation "007## ð75T0258Ł\ and the leaving group\ aswell as halo\ can be dialkylamino ð47CB0756\ 59BSF404Ł[ Normant has prepared "E#!alkynenonesfrom alkynic Grignard reagents and dialkylaminoenones ð59BSCF404Ł[ Brown has made use of vinylboranes as the nucleophilic component\ with an alkoxy enone "Equation "008## ð73JOC4913Ł\ andalkynenones are also available from this route ð47CB0756\ 66JOC2095Ł[ Vinyl boranes have been usedwith haloenones in a palladium!catalysed coupling ð76BCJ2360Ł[ Lithium acetylides also react withalkoxyenones to give alkynenones ð42HCA371Ł[ a!Alkenylation of an a\b!unsaturated ketone hasbeen achieved by a lithiumÐhalogen exchange reaction "Equation "019## ð76CL0996Ł[

(118)MgCl

+n-C5H11 Cl

O

n-C5H11

O i, 3% Pd(PPh3)4ii, NH4Cl

89%

O

OMe

+n-C7H15

B

O

n-C7H15

i, Et2Oii,

95%

HOOH

(119)

118a\b!Alkenic Bond

(120)OOBr + I

n-C6H13

O

n-C6H13

i, BunLi ii, ZnCl2iii, alkenyl iodide, Pd(PPh3)4iv, HCl

92%

2[94[0[1[2 By isomerisations of double and triple bonds

Alkynic ketones can be isomerised to conjugated dienones using Ru ð77TL0934Ł\ Ir ð78JOC0094Ł"Equation "010##\ or Pd ð77JA1290Ł catalysts[ The reaction appears to give "E\E#!dienes exclusively[The isomerisation of two double bonds into conjugation with a ketone is also known ð43JCS0291\62JA2178Ł\ as is the isomerisation of b!allenes to a\b\g\d!unsaturated ketones ð56HCA0047Ł[

(121)

n-C8H17

O

O

n-C6H13

IrH5(PPri3)2, 60 °C

92%

2[94[0[1[3 From oxidations of further unsaturated allylic alcohols

The oxidation of further unsaturated allylic alcohols to further unsaturated a\b!unsaturatedketones proceeds in much the same way as it does for a\b!unsaturated ketones without furtherunsaturation "see Section 2[94[0[0[5 for reagents and references#[ Examples include the use ofBaMnO3 ð77HCA057Ł\ MnO1 ð41JCS0983Ł and Al"OiPr#2:acetone ð69HCA863Ł[ Oxidations of tertiarydienols\ prepared by 0\1!reactions of a vinyl metallic with an enone\ can proceed via a 0\2!rearrange!ment "Equation "011## to give dienones ð78TL0922Ł[ This reaction can also be performed on thecorresponding alkynols to give alkynenones ð64CC781\ 76TL0958Ł[

(122)OHMeO2C

MeO2C

O

pdc, 25 °C

62%

pdc = pyridinium dichromate

2[94[0[1[4 From reactions of further unsaturated a\b!unsaturated acids and their equivalents withcarbon nucleophiles

These reactions are very similar to those used for simple a\b!unsaturated ketones "see Section2[94[0[0[4#[ For example\ the lithio methylphosphonate in Equation "012# reacts with the dienoateat the ester group to give the corresponding ketone ð73JA2764Ł[ The acid chloride can also beused as the electrophile "Equation "013## ð35HCA693\ 41JCS2834Ł[ Nitriles "with Grignard reagents#ð36HCA894Ł and amides "with organolithiums# ð79JCS"P0#1740Ł have also been reported[

(123)CO2MeP(OMe)2

O O

Li P(OMe)2

O+

–78 °C

52%

n-C6H13

OO

+ THP-O

O

O-THP

n-C6H13Cl

O(124)

i, Na, C6H6 ii, acid chlorideiii, HOAc

90%


2[94[0[1[5 By FriedelÐCrafts acylations of dienes

Acid chlorides and their equivalents have been reported to react with dienes to give furtherunsaturated a\b!unsaturated ketones[ For example\ Naso et al[ have used the disilyl diene inEquation "014#\ and were able to mono! and diacylate e}ectively ð80CC126Ł[ In other cases\ activationof the double bond has been achieved by substitution with sulfur or nitrogen "Equation "015##ð75TL242Ł[

TMSTMS

Cl OMe

O O

CO2Me

O

O

(125)

i, AlCl3, 0 °Cii, MeCOCl, AlCl3, 20 °C

39%+

S

S

F3C

O(126)

S

S+

F3C O CF3

O O pyridine, CHCl3, 25 °C

100%

2[94[0[1[6 a!Allenic ketones

a!Allenic ketones have been prepared by a variety of methods\ for example additions of Grignardreagents to protected b!alkynones "Equation "016## ð74TL3812\ 76T1610Ł[ The reaction of propargylicsilanes with acid chlorides has been used to prepare allenic ketones "Equation "017## ð70TL2390Ł[Reactions of ketones with the sodium acetylide in Equation "018# lead to a tertiary alcohol whicheliminates to the cumulene on treatment with acid ð79T0220Ł^ see also ð68JA1197Ł for the preparationof allenic ketones from the ring opening of furans\ and ð67CC0995Ł for a reaction of dibromoketoneswith alkynic compounds[

(127)

OH

OEt

OEt

THP-O

•

O

Et

THP-O

EtMgBr, CuBr, –60 °C

77%

(128)TMS

O

•

MeCOCl, AlCl3, –60 °C

60%

(129)Ph

O

OMe

+EtO

Na Ph

•

OMe

O i, NH3(l) ii, NH4Cl (aq.)iii, HCl, H2O

50%


The aldol condensation provides a simple route to a\b!unsaturated ketones possessing furtherunsaturation[ This is most often seen with an unsaturated aldehyde condensing with a ketone such

120a\b!Alkenic Bond

as acetone\ under basic conditions to give the "E# product "Equation "029## ð32CB565\ 32OS"12#67\ 38JCS626\40JA608Ł[ Anhydrous lithium iodide in diethyl ether has been reported as an exceedingly mildreagent for such condensations ð79CC375Ł[ The reaction is also known using unsymmetrical ketonesð49RTC296\ 67CPB2766\ 73JA2273\ 74TL1762Ł\ and the addition of one equivalent of trimethylsilyl chlorideresults in improved yields when using lithium diisopropylamide as the base "Equation "020##ð80TL0680Ł[ The intramolecular aldol condensation of a ketone with a second unsaturated ketone isa useful annelation procedure\ and occurs under both acid ð69CC41\ 69TL3958\ 60TL2792\ 78CB0542Ł andbase catalysis ð43BSF679\ 68JA4969Ł "Equation "021## ð89JOC2Ł[ Vinylogous aldolisation reactionslead to similar products "Equation "022## ð58JA1795\ 64JA279\ 64LA763Ł[

(130)O CHO O

O+O 0.5% NaOH, 20 °C

71%

(131)But

O+ CHO

But

O

i, LDA, THF, hexane, –78 °Cii, aldehyde, TMS-Cl (1 equiv.), 20 °C

98%

(132)O

H

OH

HH

O

HOH

OH

ButOK, ButOH, 20 °C

90%

(133)

O

O

O

p-TsOH

84%


The Wittig and similar reactions are exceptionally useful in the synthesis of dienones[ TheWadsworthÐEmmons reaction is most commonly employed\ yielding the "E# product selectivelyð56BSF1366\ 57JGU290\ 79TL1176\ 74JA4108\ 74JCS"P0#1396\ 76TL448\ 80S102Ł\ and has been used intra!molecularly to e}ect macrocyclisation "Equation "023## ð73JA0037Ł[ The use of the phosphoniumsalt "10# "Equation "024## ð70T1280Ł and its arsenic equivalent ð76TL1044Ł have also been reported[

O

O

CHO

O

(EtO)2P

O

S

S

Et O

O

O

S

S

Et

(134)K2CO3, 18-crown-6, 75 °C

76%

(135)PPh3Br–

O+ + Ph CHO

Ph

O

(21)

ButOK, ButOH, 20 °C

19%


2[94[0[1[09 From pyrilium salts

The reduction of 1\3\5!trisubstituted pyrilium salts with sodium borohydride leads to 1\3!dienonesin moderate yield "Equation "025## ð51T146\ 61BSF1409Ł[ These pyrilium salts can also be cleaved bya range of other nucleophiles including Grignard reagents\ amines and cyanide\ to give 3!substituted1\3!dienones ð47BSF0347\ 50JCS2455\ 51LA"543#020Ł[ A related reaction involves the preparation of anintermediate pyran which undergoes an electrocyclic ring opening to a substituted 1\3!dienone"Equation "026## ð89CL002Ł[

(136)

O+

O

NaBH4, Et2O, H2O, 0 °C

40%

(137)

O

OEt

F3C OEt

+ EtSHF3C SEt

O i, p-TsOH, 50 °Cii, TFA, CHCl3, 40 °C

74%


The opening of cyclopropane ring systems has been used to synthesise doubly unsaturated ketones[Treatment\ usually with base\ furnishes cyclic ring expanded ketones in moderate yields "Equation"027## ð70TL534Ł^ see also ð45JA3394\ 54CI"L#073\ 72JA4568Ł[ Thermolysis of the cyclopropane "11# leadsto the ketone "12# via a homo ð0\4Ł sigmatropic H!migration\ in 53) yield "Equation "028##ð70JCS"P0#2036Ł[ The reaction of a!ketocarbenes with furans\ followed by in situ electrocyclic ringopening of the intermediate cyclopropane\ yields doubly unsaturated ketone systems mainly as the"Z\E# isomer "Equation "039## ð66AG"E#535\ 72TL4074\ 73TL24\ 78JOC4015Ł[ This reaction has also beenreported to occur intramolecularly yielding cyclopentenones "Equation "030## ð63TL1144\ 76HCA0318Ł[Similar reactions involving intramolecular cyclisations onto aromatic rings are also known ð62CC771\89JCS"P0#0936Ł^ see also ð67JA6816Ł[

(138)

TMS-O

O

i, Cl2CHMe, BuLi, Et2O, –30 °C ii, MeOH, 25 °Ciii, Et3N, reflux

42%

(139)

O O

(22) (23)

300 °C, PhH

64%

(140)O

+

MeO2C

N

O

N–

MeO2C

O

CHO+

[Rh(OAc)2]2, 20 °C

80%

(141)

O

O

N+

N– O

CHO

[Rh(OAc)2]2, CH2Cl2, 20 °C

95%

122a\b!Alkenic Bond

2[94[0[1[01 By Claisen rearrangements

The Claisen reaction can also be used to synthesise doubly unsaturated ketones in high yield frompropargylic alcohols via an intermediate isolable allene which is isomerised under basic conditions"Equation "031## ð56HCA0047Ł[ Pyrolysis of propargyl acetoacetates results in a similar Claisenrearrangement followed by decarboxylation to give doubly unsaturated ketones ð46JOC0500Ł[ Thesulfoxide "13# undergoes a zinc carbonate induced Claisen rearrangement and subsequent elim!ination of benzene sul_nic acid to yield the ketone "14# in 74) yield "Equation "032## ð67CC597Ł[ Anexceptionally facile Claisen rearrangement has also been reported which yields a cyclohexadienoneð65JOC567Ł[

(142)OH +MeO

O i, TsOH, ligroin, 10 atm, 92%ii, NaOH, MeOH, 0–10 °C

95%

(143)O

SOPh

O

(24) (25)

ZnCO3

85%

2[94[0[1[02 Carbonylation reactions

Doubly unsaturated ketones can be prepared via acylation reactions of dienes using carbonmonoxide and methyl iodide with cobalt catalysis "Equation "033## ð67CC200\ 68TL1554Ł[ Relatedreactions involving iron! and nickel!catalysed carbonylations include ð74AG"E#385\ 76CB12Ł[

(144)PhPh

OCO, MeI, Co2(CO)8, 20 °C

86%

2[94[0[1[03 Miscellaneous methods

Metal catalysis enables the coupling of an enone with a vinyl halide to give a dienone "Equation"034## ð70T3924Ł^ related reactions reviewed include ð74JOC426\ 76S69\ 77S593\ 78CL0848Ł[ The thermalring opening of cyclobutene has been used to furnish dienone systems in high yield "Equation "035##ð59JA3222\ 58TL3876Ł\ as has the retro DielsÐAlder reaction ð74S010Ł[ The novel selenium!substitutedhalobutadiene "15# leads to seleno!substituted dienone systems via the DielsÐAlder reaction withmethyl vinyl ketone followed by subsequent elimination of HCl "Equation "036## ð72TL336Ł[ Theaddition of enamines to propargylic ketones gives a!alkenyl a\b!unsaturated ketones "Equation"037## ð46CB1154Ł[ This is in contrast to the reaction of the enamine in Equation "038# ð52JOC2021Łwith dimethyl alkynedicarboxylate\ which Huebner et al[ report to occur via a cyclobutene to givea dienone which is isomeric with the product that would have been obtained if the reaction hadgone according to Equation "037#[

(145)

O

O

O

I

O

O

O

PdCl2, MeCN, Et3N, 25 °C

55%


(146)

O O

320–330 °C

91%

(147)

Cl

Cl

PhSe

+

OO

Cl

PhSe

BF3, 25 °C

86%

(26)

(148)

O

+

O

NH2

O O

NH2

MeOH, 20 °C

90%

(149)MeO2C CO2Me +

O

NH2

NH2

CO2MeO

MeO2C

THF, 20 °C

63%

2[94[0[2 Halogenated a\b!Unsaturated Ketones

2[94[0[2[0 1!Halogenated a\b!unsaturated ketones

"i# By elimination reactions

Elimination of an acid function from a substituted ketone such as "16# or "17# "Scheme 6# leadsto halo!substituted conjugated ketones[ For cyclic and:or symmetric ketones\ the "E#:"Z# geometryis unambiguous\ and thus the elimination reaction is most often applied to these substrates[ Theelimination of HBr from "18# thus leads to "29# in excellent yield "Equations "049# and "040##ð36OS"16#8\ 47CCC1044Ł[ Alternatively\ the hydrogen b to the carbonyl group can also be eliminatedunder more forcing conditions "Equation "041## ð50JCS0472Ł\ "Equation "042## ð79JOC1925\ 72JA6247\74JCS"P0#1082Ł[ AdditionÐelimination sequences on unsaturated ketones leading to halo!substitutedunsaturated ketones are also well known "Equation "043## ð50CB0114\ 50JCS1421\ 69JOC3030\ 79JOC0098\77SC0212Ł[ Some noncyclic\ asymmetric cases where "E#:"Z# isomers are possible have been reported\and single isomers have resulted in some examples ð70TL2920\ 71CJC1157Ł[ Other less commonreagents used in additionÐelimination type reactions have been IN2 ð60CJC2934Ł\ IF ð74JOC2231Ł\ICl ð56AJC528Ł\ FClO2 ð50BSF448\ 72JOC0996Ł\ FSO1Cl ð65S22Ł\ and SO1Cl1 ð51CPB318Ł[ In a relatedreaction\ epoxyketones "Equation "044## ð45JOC0321\ 63TL3266\ 65CL384\ 77JCR"S#199Ł\ can be treatedwith halide ion to give a!halo substituted a\b!unsaturated ketones[

LGR

O

X

XR

O

XR

O

XR

O

LG

(27)

(28)

base

base

Scheme 7

X = halogen

124a\b!Alkenic Bond

(150)Ph Ph

Br

Br

O

Ph Ph

Br

ONaOAc, EtOH

94%

(29) (30)

(151)

H

Br

Br

O

H

Br

O

pyridine, RT

80%

(152)

H

Br

Br

O

H

O

Brcollidine, 210 °C

90%

(153)

O

SePh

ClO

ClH2O2, pyridine, CH2Cl2

82%

(154)

O O

Brpy•HBr•Br2, pyridine

57%

(155)

O

O

OMe

OH

H

O

O

OMe

Cl

LiCl, THF, 65 °C

80%

"ii# From cyclopropanes

Silyl enol ethers react with dihalocarbenes to a}ord 0\0!dihalo!1!siloxycyclopropanes in goodyields[ The cyclopropane can undergo rapid and e.cient ring opening to give the a!halo!a\b!unsaturated ketone "Scheme 7# ð65S085Ł[ This is a simpler and more general procedure than thatpreviously established for enol acetates ð62JA5544Ł[ A related reaction has been applied to severalcyclic enol ethers[ In Equation "045# the ketone "20# is postulated to be derived via a dichloro!cyclopropene intermediate ð58JOC23Ł[ However\ treatment of the cyclopropane "21# with silvernitrate leads to the ketone "22# "Equation "046## ð61JCS"P0#778Ł[ The chloroketone "23# was isolatedin good yield by the reaction of the enamine "24# with sodium trichloroacetate in DME "Equation"047##^ there is supporting evidence for the involvement of a dichlorocyclopropane intermediate inthis reaction ð69CC270Ł[

Scheme 8

O O-TMS O-TMS

Br Br

O

BrTMS-Cl, TEA

DMF

CHBr3, KOBut

85–95%

PhH, reflux

86%


(156)

S

EtO ClCl

S

Cl

ONaOMe, DMSO

2-9%

(31)

(157)

N

EtO

Ts

BrBr

N

O Br

Ts

AgNO3, EtOH

48%

(32) (33)

(158)

O

N

O

O

Cl

NaO2CCCl3, DME, reflux

(35) (34)

"iii# Miscellaneous methods

A one carbon ring expansion has been used in the preparation of the enantiomerically purea!chloroenone "25# "Scheme 8# ð76JA3641Ł[ The key ð1¦1Ł cycloaddition proceeded with very high"84 ] 4# diastereofacial selection[ A one pot HornerÐWittig procedure has been developed for thesynthesis of "E#!a!chloro!a\b!unsaturated ketones in which the keto enolate reagent "26# is preparedin situ and reacted with the requisite aldehyde "Scheme 09# ð67S18Ł[ This bears a strong resemblanceto the Wittig reaction between the halophosphorane "27# and benzaldehyde leading to the a!chloro!a\b!unsaturated ketone "28# "Scheme 00# ð51JOC887Ł[ An alternative approach to the formation ofa!halo!unsaturated ketones involves the attack of a carbon nucleophile onto an a!halo!a\b!unsatu!rated ester "Equation "048## ð76BSF750Ł[ Simple Grignard reagents can also be used as the nucleophileð69BSF880Ł[

Ph

O

Cl

ClO

RO Ar RO

Cl

Cl

O

Ar

O

Ar

Scheme 9

ClCl3CCOCl

Zn-Cu

CH2N2 Cr(ClO4)2

0 °C

(36)

Cl3C P(OEt)3

OP(OEt)3

O

But

O

Cl LiPh But

O

Cl

Scheme 10

(37)

i, BunLi, –90 °C

ii, ButCOCl, –125 °C

PhCHO, 40 °C

76% overall

126a\b!Alkenic Bond

PPh3Br

OPPh3

O

Cl

O

Cl

Ph

Scheme 11

(38) (39)

i, Cl2

ii, NaOH

PhCHO, 90–95 °C

98%

MeS

Me

O–

+

F CO2Et

+CH2Cl2, Et2O

93%

F

O

S

O–

MeMe (159)

+

A general route to tri~uorovinyl ketones involves a copper"I#!mediated acylation of tri~uorovinylzinc at room temperature "Equation "059## ð75BSF765Ł[ The same reaction has also been observedusing palladium as the catalyst ð74TL2888Ł[ A similar reaction involving benzoylsilanes as theelectrophile has been reported ð80TL72Ł[ A general procedure for the preparation of both a!~uoroð67S017Ł and a!chloro a\b!unsaturated ketones ð67S347Ł has been reported by Normant et al[ Itinvolves a three stage procedure via an intermediate carbinol "39# and subsequent isomerisation insulfuric acid at low temperature "Scheme 01#[ The same rearrangement has also been used in asynthesis of the a!~uoroketone "30# "Scheme 02# ð78JOC4539Ł[

FZnX

F

F

+ But COCl F

F

F

But

O

(160)CuBr, TRIGLYME

81%

R1 R2

O

R2 F

F

X

OLiR1

R2 R3

F

X

OHR1

R1 O

X

R2 R3

F

F X

Li

Scheme 12

X = F, Cl

i, R3Li

ii, H3O+

96% H2SO4

–30 °C

(40)

F OHFF

F

OH

F

F

O

F

Scheme 13

(41)

MeLi, RT

56%

H2SO4, 100 °C, TCE

A mild transformation for the conversion of a!hydroxy!a\b!unsaturated ketones into a!halo!a\b!unsaturated ketones has been developed as a result of the failure of traditional reagents "e[g[ SOCl1#[Thus the ketone "31# is halogenated as shown in Scheme 03 to give the ketone "32# in 79) overallyield[ The reaction is general for both _ve! and six!membered rings\ and will tolerate signi_cantsubstitution\ for example synthesis of the ketone "33#[ The mechanism is postulated as involving thebicyclic intermediate "34# ð75JOC3640Ł[ Reaction of dichloroketene with alkynes gives an equilibriummixture of dichlorocyclobutenones following rearrangement of the primary products in situ withzinc chloride "Equation "050## ð59JA2091\ 76HCA210Ł[

HO

O

X

O

Scheme 14

O

O

Me2N

S

(42) (43)

Me2NC(S)Cl, LiOH

MeCl, H2O

LiX, MeCN, AcOH

80 °C


Cl

O

S

OMe2N

O

(44) (45)

+

R1

R2

+

O

•

Cl Cl

O

R1

R2

Cl

Cl

O

Cl

R2

Cl

R1

(161)+35 °C

2[94[0[2[1 2!Halogenated a\b!unsaturated ketones

The syntheses of b!halo substituted a\b!unsaturated ketones have been reviewed previouslyð55CRV050Ł[

"i# From alkynes

Reactions of acid halides with alkynes under FriedelÐCrafts conditions is a well!establishedmethod for preparing b!halo substituted a\b!unsaturated ketones ð25JOC052\ 53JOC274\ B!53MI 294!90Ł[Where the alkyne is acetylene\ solely trans b!addition is observed\ for example Equation "051#ð52OSC"3#074Ł[ Apparently mixtures of "E# and "Z# isomers can be produced if other alkynes areused ð69TL0710\ 62T3130\ 64T066Ł\ although the "E# and "Z# isomers of these compounds can beinterconverted under some reaction conditions[ A number of intramolecular cyclisations using thisreaction have also been reported "e[g[ Equation "052## ð67TL1290\ 79JHC178Ł[ In addition\ {alkyneequivalents| have been used ð38JCS0329\ 74TL3800Ł\ for example vinylidene chloride "Equation "053##[

(162)Cl

O O

Cl

AlCl3, acetylene

60%

(163)

S

Cl O

S

OClAlCl3, (CHCl2)2

64%

(164)Cl

O

Cl Cl+ Cl

O

Cl

AlCl3

80%

A highly ~exible general route to b!halo!substituted a\b!unsaturated ketones that can give goodyields of either "E# or "Z# isomers is the addition of HX to an alkyne ketone "Scheme 04#ð58JCS"C#0193Ł[ Kishi et al[ have shown that TFA solutions of sodium iodide give good yields of the"E#!iodo vinyl ketones "35# "Scheme 05#\ but in acetic acid the major product is the "Z# compound"36# ð75TL652Ł[ The reaction will work even on disubstituted alkynes with TMS!I etc[ to give the"E#!b!iodo vinyl ketones "37# "Equation "054## ð75TL3648Ł[ Alternatively\ the intermediate iodo!metallated species can be trapped by other electrophiles "Scheme 06# ð75TL3656Ł[ The hydro!chlorination of allenic ketones has been investigated and is useful for the preparation of the b!"E#isomers "Equation "055## ð72BSF"1#78Ł[

128a\b!Alkenic Bond

R

O

X

R

O X

Scheme 15

R

O

HX (or DX)20 °C

HX (or DX)–40 °C

n-C5H11

O

I

n-C5H11

O I

n-C5H11

O

NaI, TFA95%

NaI, AcOH70%

Scheme 16

(46)

(47)

(165)OO

O

OO

O

ITMS-I

(48)

n-C5H11

O

n-C5H11 •

OM

In-C5H11

O

R

OH

I

Scheme 17

RCHOMI, M = TMS, Et2Al or Bun4N

(166)

•

OO

Cl

SnCl4

82%

"ii# By halo`enations of 0\2!dicarbonyl compounds

The halogenation of 0\2!dicarbonyl compounds or their equivalents is one of the most widelyreported reactions for the preparation of b!halo!a\b!unsaturated ketones[ The reaction proceeds ina similar fashion to the VilsmeierÐHaackÐArnold reaction discussed in Section 2[91[0[2[1[ Unlesscyclic and symmetric diketones are used\ a mixture of stereo! and regioisomers can result[ Reagentsused for the reaction include "COCl#1 ð63S36Ł\ POCl2:DMF ð74S673Ł\ Br1:PPh2\ SOCl1\ PCl2 etc[ð36G438\ 47JGU2913\ 63CJC509\ 67CL354\ 77JCR"S#197Ł[ Good yields can be obtained for cyclic symmetricalketones ð64S697\ 64SC082\ 71CJC109\ 78TL2642Ł\ for example Equation "056#[ For asymmetric cyclicsystems\ mixtures often result "Equation "057## ð75CJC419Ł\ but single regioisomers have beenisolated in certain cases\ "Equation "058## ð46JA3376Ł[ The regiochemistry has also been controlledin cases where one carbonyl group is more readily enolisable "Equation "069## ð65JOC525Ł[ Thestereochemistry seems more complex\ with the "E#!isomer predominating in most cases "Equation"060## ð70S761Ł\ although pure "Z#!isomers have also been reported ð65JOC525\ 71CJC109Ł[ Enolsulfonates also react with halogen nucleophiles to produce b!halo!a\b!unsaturated ketones "Equa!tion "061## ð58LA"612#000\ 70JOC086Ł[


(167)

O O O ClEt3N, Ph3PCl2, 25 °C

91%

O

O

H

HEtO2C

O

Cl

H

HEtO2C

Cl

O

H

HEtO2C

(168)+LiH

PhOPOCl2

2 : 3

(169)

O

O

O

Cl

PCl3, CHCl3

(170)

O

CHO

O Cl

(COCl)2

(171)

O

O O

Br

(E):(Z) 93:7

Ph3PBr2

(172)

O

Ms

O

X

BF3•Et2O, PhCH2NEt3X

72–93%

X = Cl, Br, I

2[94[0[3 Oxygen!substituted a\b!Unsaturated Ketones

2[94[0[3[0 1!Oxygen!substituted a\b!unsaturated ketones

"i# From a!metallated enol ethers and acylatin` a`ents

The easiest method to achieve a!acylation of an enol ether is via a Pd!catalysed reaction of thevinyltin derivative with an acid chloride "Equation "062## ð72TL1250\ 78JOC3610\ 89TL2322Ł\ as usedextensively by Kocienski et al[ The reaction has also been applied to stannyl dioxin compounds "38#"Equation "063## ð89S644Ł[ The vinyllithium compounds have also been used\ but yields seemgenerally lower "Equation "064## ð77H"16#540\ 78JOC2802Ł[ 1!Acyl benzodioxins have been preparedby a FreidelÐCrafts acylation reaction of the 1!silyl substituted derivative "Equation "065## ð75S226Ł[

(173)Me3Sn OMe

+ n-C7H15COCl OMen-C7H15

OPd

85%

(174)

O

O

SnBu3

+ OCl

OO

O

O

O

(49)

PdCl(PPh3)2CH2Ph, C6H6

95%

130a\b!Alkenic Bond

(175)

O O+

OO OH

O

ButLi, THF

59%

(176)

O

O

TMS

+O

O

n-C5H11

O

n-C5H11COClAlCl3

66%

"ii# From a!alkoxyketones and a carbonyl compound

Condensation reactions of a!alkoxyketones with aldehydes or ketones\ as in Equation "066#\ leadto the formation of an a!alkoxy a\b!unsaturated ketone[ This procedure has been used several timeswith a!alkoxy vinylketones in a Robinson annelation type reaction "Equation "067## ð71JA2656\74TL692Ł[ Synthetic equivalents to vinyl ketones have also been used in this procedure "Equation"068## ð72JA1929Ł\ and enamines can be used instead of carbonyl compounds under acidic conditions"Equation "079## ð68JOC2955Ł[ The condensation reactions of aldehydes with 2!furanones leading toaurones "Equation "070## gives only the "Z# isomers ð61JCS"P0#1017\ 68JHC710Ł^ see also ð31JA271\63BSF0932\ 66CB380Ł[ In a similar manner\ bromoketones have been used to prepare the aurones whena b!hydroxy group is present in the ketone "Equation "071## ð44JCS751\ 53JOC1914\ 80JHC700Ł[

R2OR1

O

R4 R3

O+

R2OR1

O

R4 R3

(177)

(178)

MeO

O

O

OO

MeO

O

O

O

H

i, Zr(OPrn)4ii, NaOMe

63%

trans : cis 25 : 1

(179)

O

+MeO

O

OMe

O

MeO

KOEt

57%

(180)+

OMe

O

OMe

ONAcOH

69%

(181)O

O

OMe

O

O

O

OMe

+

i, EtOHii, HCl

83%


(182)

OOH

Br

O

O

O

O

Ph

+ PhCHOMeOH

89%

"iii# From oxidative cyclisations of hydroxy!substituted vinyl ketones

A related scheme to that shown under "ii# above for the preparation of aurones is fromb!hydroxy chalcones "Equation "072## ð64CC661Ł[ Use of Hg"OAc#1 gives only the "Z#!aurones by astereoselective oxymercuration and deoxymercuration process[ Hydrogen peroxide has also beenused ð59CI"L#237\ 63IJC0941Ł\ and silver nitrate is reported to give only the "Z#!aurones on reactionwith "1!hydroxyaryl#alkynones ð89JCS"P0#312Ł[

(183)

MeO OH

O

Ph

MeO O

O

Ph

i, Hg(OAc)2ii, CaO

54%

"iv# By elimination reactions from a!alkoxy!substituted ketones

Additions of alcohols to a!epoxyketones under basic conditions lead to a!alkoxyenones "Equa!tion "073## ð43JA3007\ 60JCS0181\ 73JOC0940Ł[ Alternatively\ Trost et al[ have shown that a!thioketonescan be a!acetoxylated\ then oxidised and pyrolysed to give a!acetoxyenones "Equation "074##ð65JA4906Ł[

(184)

O

O

O

OMeNaOH, MeOH, H2O

95%

(185)

O

SPh

OCOPh

O

OAc

OCOPh

i, Pb(OAc)4ii, mcpba

86%

"v# From a\b!unsaturated ketones

The hydrazones of a\b!unsaturated ketones can be brominated and alkoxylated to give thecompounds "49# "Equation "075##[ These can subsequently be transformed into the correspondinga!alkoxy!a\b!unsaturated ketones by a hydrazone exchange and elimination procedure ð89CB288Ł[

O

OMe

NN

NS Me

OMe

Br

(186)

i, HCHO, HClii, dbu

78%

(50)

132a\b!Alkenic Bond

"vi# Miscellaneous methods

Additions of Grignard reagents to a!alkoxyacrylonitrile give good yields of the a!alkoxy!vinylketones "Equation "076## ð60CR"161#0934\ 72JCS"P0#50Ł[ Transition metal catalysed carbonyl inser!tion reactions have been investigated\ including the Pd!catalysed coupling reactions of a!alkoxyvinylstannanes and vinyl tri~ates "Equation "077## ð89JOC2003Ł\ and intramolecular PausonÐKhand reactions ð89TL6494Ł[ A Wittig!type reaction has also been described ð64TL3242Ł[

(187)NC OEt

OEt

O i,

ii, H+

MgBr

(188)

O2SCF3

+EtO SnMe3

O

OEtCO, Pd(PPh3)4, LiCl, THF

82%

2[94[0[3[1 2!Oxygen!substituted a\b!unsaturated ketones

Note] 2!hydroxy!a\b!unsaturated ketones are not covered here as these are tautomeric isomers of0\2!diketones[

"i# By DielsÐAlder reactions

An important and well!used synthetic procedure furnishing cyclic 2!oxygen!substituteda\b!unsaturated ketones "dihydro!g!pyrones# involves a hetero DielsÐAlder reaction between thedioxygenated diene "40#\ commonly known as Danishefsky|s diene\ and an aldehyde carbonyl group\as the dienophile\ in the presence of a Lewis acid catalyst "Equation "078## ð71JA247\ 71JOC2072Ł[High Cram rule selectivity was observed in similar reactions with chiral aldehydes enabling thesynthesis of homochiral dihydropyrones "Equation "089## ð71JA259\ 71JOC0870\ 77JA6323Ł[ Numerousmodi_cations have been made to Danishefsky|s diene enabling greater functionality to be introducedinto the adduct[ The use of alkyl substituents on the diene leads to the possibility of cis:transisomerisation[ Thus the cyclocondensation of the diene "41# with aldehyde "42# gave the cis!1\2!dihydropyran almost exclusively in the presence of zinc chloride\ whereas if BF2 =Et1O was used asthe Lewis acid catalyst\ the reaction is assumed to proceed via a di}erent pathway and the majorproduct is the trans!1\2!dihydropyran "Equation "080## ð74JA0135Ł[ Other noteworthy exampleswhich have been reviewed include ð74JOC3459\ 77JA3257Ł[

(189)

OMe

TMS-O

+

O

OBn

O

OOBn

PhH, ZnCl2, 20 °C

87%

(51)

OMe

TMS-O

+

O

O

O

O

H

H

OO

O

H

(190)PhH, ZnCl2, 20 °C

72%

(191)+ OPh ZnCl2, THF, 25 °C

83%

O

OPh

OMe

TMS-O

(52) (53)


The introduction of further oxygen functionality into the diene has also proved successful[ Thusthe diene "43# gave the oxygen!substituted pyrone "44# "Equation "081## ð73JOC281Ł "reaction of thisdiene with an ordinary dienophile also leads to an oxygen!substituted enone system ð67JOC268Ł#\whereas the diene "45# gave the cis!pyrone "46# which has been used in the total synthesis oflincosamine "Equation "082## ð74JA0163Ł[ The diene "45# has also been substituted with furtherunsaturation in the form of an aromatic system ð77JA2818Ł[ Asymmetric induction has been observedvia the use of chiral Lewis acid catalysts ð77JA209\ 78TL0078Ł\ and some ketones have been reportedto act as dienophiles for this cyclocondensation ð76CC645Ł[

OMe

TMS-O

OMe (192)+O

Ph

Eu(fod)3, CDCl3

85%

OMeO

O

Ph

(54) (55)

fod = 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedionate

(193)

OMe

TMS-O

OBz

+ OO

O

BzO

(56) (57)

i, BF3•Et2Oii, TFA

67%

"ii# From alkynes

Barrett et al[ have reported a reaction in which the dianion of a 0\2!diketone condenses with anester carbonyl to furnish a dihydropyrone in high yield ð70CC445Ł[ A very similar transformationinvolves the addition of a lithium acetylide "47# to a lactone or other carbonyl group followed byacid!catalysed cyclisation to give a 1\2!dihydro!3!pyrone "Equation "083## ð72TL4292\ 89JOC4783Ł[

(194)

OO

O

OO

MeO

+

i, BunLi ii, K2CO3, MeOH

iii, HClO4

(58)

A commonly used route to 2!oxy!a\b!unsaturated ketones involves the addition of an alcohol toan alkynyl ketone\ which can be carried out both intermolecularly ð36JA62\ 80JCS"P0#0228Ł andintramolecularly ð66JOC2735\ 76TL2352Ł^ see also ð77TL4830\ 89SC2952Ł[ The hydration of substitutedacetylenic alcohols has been reported to lead to cyclic furanones in good yield[ Thus\ treatment ofthe alkynic alcohol "48# with BF2 in ethanol\ catalytic mercuric oxide and trichloroacetic acid\followed by aqueous work up gave the furanone "59# "Equation "084## ð70TL2454Ł[ Other examplesinclude ð52JOC576\ 72BCJ2977Ł\ and hydroxybutadiynes behave similarly ð64JOC0319Ł[

(195)

(59) (60)

OH

OEtEtO

BF3•Et2O, CCl3CO2HHgO, EtOH

68%O

O

"iii# By Witti` reactions

The Wittig reaction has provided a useful route to 2!oxyenone systems[ 2"1H#!Furanones havebeen synthesised by the intramolecular WadsworthÐEmmons condensation of g!"acyloxy#!b!

134a\b!Alkenic Bond

ketophosphonates in high yield "Equation "085## ð73TL3356\ 75JOC1414\ 77JOC1900Ł[ This reaction wasused in a formal total synthesis of the triquinane modhephene ð80JOC3036Ł[ Other Wittig reactionsof interest include the reactions of a!ketophosphonates with formate esters ð89JCS"P0#0228Ł\ and theaddition of ketones to 1\1!diethoxyvinylidenetriphenylphosphorane "50# to give a new phosphoranewhich then undergoes Wittig reactions with aldehydes "Scheme 07# ð65CB392\ 66AG"E#238Ł[

(EtO)2P O But

O

OO

O

O

But(196)

K2CO3, DMF, 115 °C

70%

• PPh3

EtO

EtO

OEtO

Ph

(61)

acetone

55%

Ph CHO

Scheme 18

53%PPh3

OEtO

"iv# Preparation of 2"1H#!furanones

There have been many methods reported for the preparation of 2"1H#!furanones\ and theseinclude] oxidations of furans ð76TL1186Ł\ hydrolysis of substituted furans ð46HCA1351\ 52HCA0148Ł\intramolecular alkylations and subsequent acid eliminations "Equation "086## ð75JHC0088Ł\ hydro!lytic cyclisations of allene systems such as "51# "Equation "087## ð64TL0630Ł\ and cyclisation of1\1?!dibromoketones with DMF under Fe1"CO#8 catalysis "Equation "088## ð62JA3092Ł[ An inter!esting transannular aldol condensation has also been reported\ yielding the bicyclic 2"1H#!furanone"52# "Equation "199## ð77TL5786Ł as the only product[

(197)

O

O

PhPh

OH

O i, Br2, CCl4ii, NaOH, EtOH

90%

p-TsOH, H2O, MeCN, 100 °C

93% O

O

Ph

Ph

•

MeS

OMe

Ph

Ph

OH

(198)

(62)

(199)

Br Br

O

O

O

Me2NCHO, Fe2(CO)9

64%

(200)

O

O

O

O

O

(63)

i, NaH, DMSO, 95 °Cii, H2SO4

62%

"v# By acylations of vinyl ethers

The Pd!catalysed Heck aroylation of vinyl ethers gives "E#!b!alkoxyenones "53# in good yields"Equation "190## ð76TL3104\ 77JOC3146Ł[ b!Alkoxyvinylstannanes also couple with acid chloridesunder palladium catalysis ð89S644Ł[ More reactive acid halides and anhydrides "e[g[ trichloro ortri~uoroacetyl# do not appear to need palladium catalysis\ and they react directly with vinyl ethers


via an additionÐelimination mechanism\ to give the "E#!b!alkoxyenones "54# "Equation "191##ð65CL388\ 71CB1655\ 77S163\ 78CB0068\ 80S372Ł[ Acetals can also be acetylated under similar conditions"Equation "192## ð75S0902Ł and a similar procedure using silylenol ethers and oxalyl chloridegives furandiones "Equation "193## ð64AG"E#525Ł[ Enol lactones have also been acylated by aceticanhydride in perchloric acid ð58JOC1656Ł[ In a related reaction\ ketene acetals have been shown toreact with ketenes to give b\b!dialkoxyenones ð70JOC3936Ł[

(201)

O Cl

OMe

+OBut

O

OMe

OBut

Pd(OAc)2, Et3N

77%

(64)

(202)Cl3C Cl

O+

OEt

Cl3C OEt

Opyridine

79%

(65)

(203)

MeO

O

CF3

OMe

OMe+ (CF3CO)2O

pyridine, CHCl3

94%

Ph O-TMS

O

ClCl

O

+

OPh O

O

(204)Et2O

85%

"vi# From 0\2!dicarbonyl compounds\ and a 0\1! or 0\2!dielectrophile

Furan!2!ones\ e[g[ "55# can readily be prepared by the reaction of a 0\2!dione with an a!halo acidchloride or other 0\1!dielectrophile "Equation "194## ð61CR"164#786\ 62CL314\ 62RTC620\ 64JOC0816\67S180Ł[ There are also many examples of 0\2!diones reacting with 0\2!dielectrophiles to give dihydro!pyranones "Equations "195# and "196## ð70T698\ 72TL1948\ 73JHC02\ 74TL3616\ 76BSF762\ 89CB0064Ł[

O

Cl

Cl

+O

OEtO2C

MeO

OCO2Et

OMe

(205)Mg(OEt)2

70%

(66)

PhCO2Et

O

Cl Cl

O O

OO

O

CO2Et

Ph

(206)+MeLi

52%

(207)CO2Et

O

Cl

O

O

O

CO2Et+

Mg(OEt)2

50%

136a\b!Alkenic Bond

"vii# From ð1¦1Ł cycloaddition reactions between alkoxyalkynes and ketenes

Alkoxy and siloxy alkynes add smoothly to ketenes leading to 2!alkoxy!1!cyclobutenones "Equa!tion "197## ð47RTC650\ 62JOC0340\ 74S0007\ 77JA2582Ł[

(208)ButO + H2C • O

O

ButO

CH2Cl2

70%

"viii# Miscellaneous methods

The displacement of a leaving group from a 2!substituted enone by an oxygen nucleophile hasbeen utilised to provide 2!oxy enone systems[ The leaving groups used have included chloride\quaternary nitrogen and alkylthio ð60CB109\ 79S0902\ 89TL1102Ł[ Other miscellaneous reactionsinclude] alkoxy methylenations of 0\2!dicarbonyl compounds by treatment with an orthoester inacetic anhydride ð40JA4057\ 50JCS2143Ł\ hydrogenations of 4!hydroxymethylisoxazoles under acidicconditions furnishing dihydrofuranone systems in very good yield ð64JGU1461\ 80H"21#838Ł andoxidations of 2!oxy!allylic alcohols using manganese dioxide and silver carbonate on celiteð69HCA0378\ 72TL3640Ł[ The oxygenated furan "56# is an e}ective diene in DielsÐAlder reactions andthe resulting adducts rapidly ring open to give highly substituted cyclic 2!oxy enones in very goodyields "Equation "198## ð71TL242Ł[

O

MeO

O-TMS

+ O

O

O

O

O

OMeO

OH

O

(209)

(67)

80%

2[94[0[4 a\b!Alkenic Ketones with Sulfur!based Substituents

2[94[0[4[0 1!Thio a\b!unsaturated ketones

"i# By aldol condensation reactions

Probably the most common procedure for the preparation of a 1!thio!a\b!unsaturated ketone isvia an aldol condensation from a 1!thioketone[ Thus condensation of the ketone "57# with thealdehyde "58# gave a low yield of the natural product conjugated thietanone "69# "Equation "109##ð63CB1004Ł[ Woodward et al[ found that 2!ketotetrahydrothiophene "60# condensed smoothly twicewith furfuraldehyde or benzaldehyde to give the doubly unsaturated ketone "61# in good yield"Equation "100## ð35JA1118Ł[ A similar aldol condensation involving the thienothiophene "62# underacidic catalysis gave the dinitro condensate "63# in high yield "Equation "101## ð51LA"548#89Ł[ Thistype of methodology has been most commonly applied to make aromatic ketones from thioindoxyltype systems "Scheme 08# ð36JIC362\ 42JIC268\ 47CB219\ 51JOC2777Ł\ and isothiachromanone systemsð68ACS"B#558\ 79CB0697Ł[ A similar condensation involving the dialdehyde "64# led to the bicycle "65#"Equation "102## ð65AG"E#271Ł[ Activation of the methylene a to the carbonyl group by a sulfonemoiety accelerates the reaction "Equation "103## ð41JGU167\ 58JOC1228Ł[ A related condensation gavethe ketone "66# by acylation of the precursor "67# "Equation "104## ð65CB1817Ł[

(210)S CHO S

S

O

S

O

(69) (68) (70)

+KOH, MeOH


NaOH (aq.), EtOH

(71)

S

O

(72)

R OS

O R

R

+

R = Ph,O

(211)

(212)

SS

O OH

+

CHO

NO2

SS

O O

NO2

O2N

Ac2O, AcOH, 120 °C

82%

(73)

(74)

S

OS

O Cl Cl

Cl

S

O S

O

Cl

Cl Cl

CHO

OO

BF3•Et2O86%

HCl, AcOH, 110 °C87%

Scheme 19

S

Cl Cl

O O

NH

CHOOHC

+morpholine

84%

(75)

S

Cl

O

Cl

O

(213)

NH

(76)

(214)

CO2Et

CO2Et

O

SO2Me

SO2Me

NaH, DMSO, THF

70%

138a\b!Alkenic Bond

(215)

S

S

O

S

S

OH

O

(78) (77)

i, ButLiii, AcCl, 70 °C

33%

"ii# By Pummerer reactions

The Pummerer reaction has proved to be an e}ective tool in the synthesis of a number of sulfur!substituted cyclopentenones "Equation "105## ð74S532Ł[ A related Pummerer rearrangement hasgiven rise to a number of 1!phenylthio!a\b!unsaturated ketones\ both cyclic and acyclic\ in highyield under mild conditions\ from the precursor sulfoxides "Equation "106## ð64S326Ł[ A Pummererreaction was used by Trost et al[ to give the ketone "68# in order to characterise the sulfoxide "79#\an intermediate in the synthesis of a gibberellin model compound "Equation "107## ð67JOC0920Ł[ Arelated procedure involves the treatment of cyclopentanone with an excess of phenylsulfenyl chlorideand gives the ketone "70# in 59) yield via 1!phenylthio!1!cyclopentanone "Equation "108##ð66JOC1213Ł[

(216)O

S

O

Me

SMe

OHp-TsOH, PhH, 80 °C

75%

(217)

O

SPh

O O

SPhAc2O, MeSO3H

75%

(218)

OS

O

Ph3CO

OS

Ph3CO

(79)(80)

I2, MeOH

(219)

(81)

O O

SPhPhSCl, MeCN, 20 °C

60%

"iii# Miscellaneous methods

A general method leading to 1!alkylthio!1!cyclohexenones involves the nucleophilic cleavage ofa 1\2!epoxycyclohexanone by a sulfur nucleophile followed by in situ dehydration\ for examplewith an alkylthiol as nucleophile "Equation "119## ð69JOC0698Ł or with thiocyanate as nucleophileð68TL0018Ł[ Treatment of a series of butanones with thionyl chloride produces 2!thiatanones viaexclusive oxidation of the methylene position and subsequent cyclisation "Scheme 19# "Equation"110## ð69JA4147\ 64JOC2068Ł[ 1!Sulfonyl!1\2!enones have been prepared via formation of the sul!fonylvinyl anion from phenylvinyl sulfone and quenching with an aldehyde to give an intermediatecarbinol "71#[ The alcohol is then oxidised by a modi_ed Jones oxidation to give the requisite ketone


"72# in moderate yield "Scheme 10# ð80JOC3987Ł[ Similarly acylation of the lithiated propenoate "73#with the acid chloride "74# gave the ketone "75# in good yield "Equation "111## ð68CL674Ł[

(220)

O

O+ SH

O

SNaOH, EtOH, 20 °C

81%

Ar

O

Ar

O

SClCl

Ar

O

SCl

Cl

H

S

O

Cl

Ar

H

SAr

O

Scheme 20

(221)

NO2

O

O2N

S

OSOCl2, pyridine, 70 °C

43%

PhSO2PhSO2

R

OH

PhSO2R

O

Scheme 21

dabco, RCHO Jones oxidation

(82) (83)

dabco = 1,4-diazabicyclo[2.2.2]octane

(222)

(84) (86)

PhSCO2Me

Li

PhSCO2Me

But OButCOCl (85), THF, –80 °C

72%

Thermal rearrangement of the diazoketone "76# gives a quantitative yield of the ketone "77#\ andthe reaction is postulated to proceed via a Wol} rearrangement involving a selective shift of thesulfur bridge "Equation "112## ð79JOC3793Ł[ A similar rearrangement occurs with the ketone "78# inthe presence of triphenylphosphine dibromide^ this reaction is thought to involve an unstablesulfonium salt formed by transannular reaction "Equation "113## ð58RTC883Ł[ 1!Sulfonyl!a\b!unsatu!rated ketones can be prepared by the oxidative ring cleavage of 3!isoxazolines with mcpba inexcellent yield[ The starting isoxazolines are easily prepared by the cycloaddition of nitrones andalkynes "Equation "114## ð76TL802\ 77JOC1127Ł[ Additions of 0!lithio!0!phenylpropa!0\1!diene toketones\ followed by tri~uoroacetylation\ 2\2!rearrangement and methanolysis of the resultingdienol tri~uoroacetate\ lead to the C!2 homologated a!phenylthioenones in moderate yield "Equation"115## ð72CC374Ł[ An exactly analogous reaction has been achieved by the photolysis of a diketonewith a sulfur substituted alkyne^ this reaction is thought to proceed via ring cleavage of an inter!mediate oxete "Equation "116## ð63TL3068Ł[ An excellent yield of the 1!alkylidene!3\4!dihydro!thiophen!2!one "89# can be obtained by the cyclo!condensation of a!thiolcinnamic acid "80# withthe nitrostyrene "81# under DeanÐStark conditions "Equation "117## ð62IJC017Ł[

140a\b!Alkenic Bond

(223)

(87) (88)

S

O NN–

+

S

O99 °C

100%

(224)

S

O OH

S

O

(89)

Ph3P•Br2, DMF, 153 °C

55%

(225)ON

PhSO2

PhMe

O

Ph

PhSO2mcpba, 25 °C

98%

(226)

O Li

•

PhSO

SPh

+

i, TFAA, 0 °C ii, 65 °Ciii, MeOH, K2CO3

47%

PhPh

O

O

SBut

+Ph SBut

O

Ph

O

(227)hν, PhH

45%

PhSH

CO2H

S

PhPh

O NO2

(228)+ O2NPh PhH, 80 °C

90%

(91) (92) (90)

2[94[0[4[1 2!Thio a\b!unsaturated ketones

"i# By condensation reactions

The condensation of an enolate with carbon disul_de and subsequent alkylation is a facileprocedure to 2\2!dithio a\b!unsaturated ketones[ The usual method is to use a hindered base toform the enolate "Equation "118## ð70JOC4920Ł^ however\ potassium ~uoride on alumina has beenfound to be e}ective ð80S290Ł as has the use of a silyl enol ether ð72CC0267Ł[ This reaction has alsobeen used in the preparation of the dihydrothiapyrone "82# involving intramolecular cyclisation ofthe intermediate dithiocarboxylic acid "Equation "129## ð66S361Ł[ A very similar preparation of athiapyrone has also been reported ð76TL3156Ł[ A related reaction involves treatment of a ketonewith two equivalents of 0\2!benzodithiolylium "83# to a}ord the unsaturated ketone "84# as product[It is postulated that the second equivalent of "83# is involved in oxidising the intermediate adductformed by alkylation of the ketone enolate "Equation "120## ð76CL828Ł[ The 2!hydroxythiophene"85# can be dimerized oxidatively using ferric chloride to give the purple pigment "86# "Equation"121## ð43CB730Ł[ This methodology has been widely used in the synthesis of thioindigo and relatedspecies ð95CB0959\ 61JHC060\ 79CB0697Ł[

(229)

O O

SMe

SMe i, LDA, CS2, 0 °Cii, LDA, MeI

84%


(230)

Ph

O

CN

Ph

O

CN

S SMe

i, NaH ii, CS2iii, MeI

75%

(93)

(231)

O

+S

S+ BF4

–S

S

O

DCM, 20 °C

74%

(94) (95)

(232)

S

OH

HO2C S S

O O

CO2HHO2C

(96) (97)

FeCl3, 20 °C

"ii# By b!leavin` `roup displacement reactions

The displacement of a halogen leaving group from an activated 2!halo!1!alkenone by a sulfurnucleophile has been used to prepare b!thioalkenones in very high yields[ Thus\ reaction of theb!chloroenone "87# with thiophenol "88# gave the ketone "099# in quantitative yield "Equation "122##ð65JCS"P0#0035Ł[ Similarly\ the hindered thiol "090# reacts with b!chloroenone "091# under basicconditions to yield the ketone "092# "Equation "123## ð68TL1798Ł[ Sodium thiocyanate has also beenused as the nucleophile ð52JOC1422Ł as has sodium sul_de ð65IZV1939Ł[ An analogous procedureutilising a nitrogen leaving group has also been reported[ Thus the thiophene precursor "093# wasisolated from the condensation reaction between the ketone "094# and the thiol ester "095# "Equation"124## ð89SC1426Ł[

(233)

SH

NH2

+

Cl

O O

S

NH2

(99) (98) (100)

NaOEt, EtOH, 20 °C

100%

(234)

(101) (102) (103)

ButSH +Cl

O SBut

ONaOH (aq.), 25 °C

85%

(235)

(105) (106) (104)

NEt3

O

+ + HS CO2EtS

O

CO2Et

EtOH, reflux

82%

"iii# From alkynes

Additions of H0S across the triple bond of an acetylenic ketone provide a general route to2!thio a\b!unsaturated ketones[ Exposure of the alkynic ketone "096# to hydrogen sul_de gavepredominantly the trans!dihydrothiapyrone "097# in very good yield "Equation "125## ð70JA3486Ł[Similarly the thiophenol "88# added twice to the ketone "098# to give the adduct "009# in 49) yield"Equation "126## ð63JOC732Ł[ Other similar additions reviewed include ð35JCS834\ 40JA1433Ł[ Tandem

142a\b!Alkenic Bond

additions to two alkynes have also been observed\ "Equation "127## ð56CB096Ł\ and similarly otherreviews include ð57T3174\ 66JOU368Ł[

O

OMe

OMe

CO2MeO

OMe

OMe

CO2Me

S

H

H

(236)

(107) (108)

H2S, NaOAc, EtOH, 80 °C

78%

(237)

SH

NH2

+

O

S S

O

NH2 NH2

(99) (109) (110)

NaOMe, MeOH, 20 °C

50%

(238)

O

SSONa2S2, MeOH, 20 °C

94%

"iv# From 0\2!dicarbonyl compounds

2!Thio a\b!unsaturated ketones can be prepared from the corresponding 2!hydroxy compoundby condensation reactions with a thiol under acidic DeanÐStark conditions[ Then!butylthiomethylenegroup has been used as a blocking group for the directed alkylation of ketones "Equation "128##ð51JOC0504Ł[ Other examples reviewed include ð62JA149\ 71TL3720\ 76RTC438Ł[ The conversion of 2!hydroxy to 2!thiol can also be achieved under nonacidic conditions via the tosyl ester ð51JOC0504Ł[

(239)Ph

OH

O

PhSBun

O

BunSH, TsOH, 80 °C

80%

"v# By acylation reactions

C!Acylations of ketene thiols provide a useful route to 2\2!dithio!a\b!unsaturated ketones[ Thustreatment of the ketene dithioacetal "000# with tri~uoroacetic anhydride under basic conditions hasbeen shown to give the tri~uoromethyl ketone "001# in high yield "Equation "139## ð64TL0998Ł^oxalyl chloride and its half ester can also be used as the acylating agent ð75S026Ł[ Related reactionsinclude an intramolecular acylation of a thioenol ether "Equation "130## ð72JOC012Ł\ and a usefulannulation involving the reaction of thiovinylsilane with a cyclic a\b!unsaturated acid chloride togive a sulfur!substituted cyclopentenone "Equation "131##[ The annulation is postulated to proceedvia initial C!acylation and subsequent Nazarov cyclisation ð74JOC0510Ł[

(240)

S S

S S

CF3

O

(111) (112)

TFAA, pyridine, CHCl3, 20 °C

93%


(241)EtO2C

R CO2Et

SEt

O

R

CO2EtEtS

NaH, DMSO, 0 °C

82%

Cl

O

+TMS S

NO2

NO2

O

SAr

H

H

(242)AgBF4, CH2Cl2, –25 °C

58%

"vi# By Witti` reactions

The Wittig reaction is an e}ective procedure for the synthesis of sulfur!substituted unsaturatedketones[ Thus\ the phosphonium salt "002# reacts smoothly with the dicarbonyl compound "003#giving a quantitative yield of the ketone "004# "Equation "132## ð68JOC829Ł[ Condensation of thephosphonium salt "005# with the dithio lactone "006# gave the ketone "007# in 79) yield "Equation"133## ð67SC204Ł[ Reaction of the dithiane anion derived from the dithioacetal "008# with the vinylphosphonium salt "019# leads to an intermediate ylide which then condenses with the neighbouringdiketone functionality to form a cyclopentenone "010# used in the synthesis of prostaglandin D0"Equation "134## ð71TL450Ł[

S S

MeO2C CO2Me

PBu3+

O O

+

O

S S

MeO2C CO2Me

(243)Et3N, 5 °C

100%

(113) (114) (115)

(116) (117) (118)

OMe

O

PPh3

+ SSPh

OOMe

O

S S

Ph(244)+

NaNH2, PhH, 20 °C

80%

S

SO

OR

SSO

R SMe

Ph3P

MeS

(245)+

+

(119) (120) (121)

NaH

79%

"vii# From 0\1 and 0\2!dithioles

A large number of 2!thio!a\b!unsaturated ketones have been synthesised via the reactions of 0\1!and 0\2!dithiole ring systems[ Treatment of 2!methylthio "or 2!chloro#!4!phenyl!0\1!dithiolyliumsalts with ketone enolates gives dithiolidene ketones in very good to moderate yields[ Thus reactionof the 0\1!dithiolylium salt "011# with sodium benzoyl acetate "012# in ethanol occurred rapidly togive the 2!phenacylidene!0\1!dithiole "013# in 35) yield "Equation "135## ð69JCS"C#0191Ł^ closelyrelated reactions include ð55JOC2378\ 69BSF1907\ 69TL0148\ 66CC740Ł[ Hydrolysis of dithiolylium salts

144a\b!Alkenic Bond

leads to 2!thiol!1\2!enone anions which can subsequently be alkylated "Equation "136## ð54JCS21Ł[Similarly\ hydrolysis of trithiapentalenes "a cyclised form of dithiolylidene thioketones# yieldsdithiolidene ketones "Equation "137## ð47G0115\ 59AG304\ 62BSF2228Ł[ The reaction of a!diazoketoneswith 0\1!dithiole!2!thione also forms dithiolidene ketones "Equation "138## ð53CI"L#350\ 62ACS2770Ł[0\2!Dithiolylium salts react very similarly to the corresponding 0\1!dithiolylium salts\ condensingwith an enolate to give dithiolidene ketones[ Thus 4!methyl!1!morpholino!0\2!dithiolylium!3!thio!late "014# condenses with pentane!1\3!dione "015# under basic conditions to provide the productdiketone "016# in excellent yield "Equation "149## ð74TL0516Ł[ A methylthio group can be used inplace of the morpholine leaving group and an enamine can be utilised instead of an enolate ð64JPR026\66CL176\ 70CL794Ł[ A very similar reaction has also been reported using a 0\2!oxathiolylium salt"Equation "140## ð60CPB1083\ 60TL0026Ł[

SS

SMe

Ph +HO2C

Ph

O+

SSPh

Ph

O (246)NaOEt, EtOH

46%

(122) (123) (124)

(247)

SS

Ph

Ph +

Ph O

SPh Ph

i, 2N KOH

ii, PhCH2Cl, 20 °C

(248)H2SO4, H2OS SS OSS

Ph

OS

S

Ph

+ N2O

Ph

SS

Ph

S(249)

(125) (126) (127)

S

SN O

HS

+

+O O O

OS

S

HS

(250)dbn, pyridine, 110 °C

94%

dbn = 1,5-diazabicyclo[4.3.0]non-5-ene

OS

N+

Ph

+

O O

Et3N, CH2Cl2

56%OS

Ph

O O(251)

Thiapyrylium iodide reacts in a similar fashion to 0\1!dithiolylium salts with activated methylenecompounds "Equation "141## ð63BSF0085Ł[ Treatment of pyran!3!thiones with sodium hydrogensul_de and subsequent oxidation yields dithiolidene ketones in good yield "Equation "142##ð53BSF2143\ 69JCS"C#1301Ł[

SPh

Ph

S–+

+ Ph

CN

O

SPh

Ph

CN

Ph

O(252)

pyridine

97%


(253)

OPh

S

SS

Ph

O

i, NaSHii, K3Fe(CN)6

67%

"viii# Miscellaneous methods

The annulation of the lithiated propenoate "017# with an a\b!unsaturated ester yields a highlysubstituted cyclopentenone in good yield "Equation "143## ð68CL674\ 70CC603\ 71CL704Ł[ Vinyl sulfonescan be alkylated similarly ð77JOC3697Ł[ Treatment of the cyclic sulfoxide "018# with TMS!Cl producesthe enone "029# via a Pummerer rearrangement "Equation "144## ð73TL0928Ł[ Elimination of HIfrom the sulfone "020# gave a high yield of the vinyl sulfone "021# "Equation "145## ð77JCS"P0#0918Ł[Oxidation of dithiocarboxylic acids produces 0\1\3!trithiolanes "Equation "146## ð60CJC0366\61JOC2115\ 65JCS"P0#0695Ł[

(254)

PhS Li

CO2Me

+ MeO2C O-TBDMS

TBDMS-O SPh

MeO2C

O(128)

–50 °C

70%

(255)

(129) (130)

S

O

O

CO2Me

S

O

CO2MeTMS-Cl, DCM, 42 °C

74%

(256)O SO2Ar

IO SO2Ar

(131) (132)

TEA, CH2Cl2

95%

TEA = triethylamine

(257)But

O+ CS2

SS

S

O

ButBut

O

i, NaNH2ii, (NH4)2S2O8

34%

2[94[0[5 Selenium! and Tellurium!substituted a\b!Unsaturated Ketones

a!Selenium! and a!tellurium!substituted a\b!unsaturated ketones can be made by chemoselectiveelimination of HCl from a!phenylselenoketones "Equation "147## and a!phenyltelluroketones respec!tively ð74JCS"P0#1082Ł[ Phenylselenyl chloride undergoes addition to enones and eliminates in situwith pyridine to give the a!selenoenones ð68SC586Ł\ and propargyl selenoxides can undergo a1\2!sigmatropic rearrangement as shown in Equation "148# ð68TL3322\ 70JA2001Ł[ a!Seleno and telluroketones are converted into a!seleno!a\b!unsaturated ketones by condensation reactions "Equation"159## ð01CB0724\ 51CB0126\ 65BSF183Ł\ or by oxidative dimerisation ð01CB0724\ 61CB808\ 70JOM"197#24Ł[b!Selenoenones have been made from isoselenoazoles and a Grignard reagent as illustrated inEquation "150# ð78H"18#238Ł[ They have also been prepared from phenacyl benzselenazolesð68JPR219Ł[

(258)

O O

SePhSePh

ClLi2CO3, DMF

77%

146a\b!Alkenic Bond

OH

SePhO

O

OOO

O

SePh O

OH(259)

i, mcpbaii, pyridine

78%

(260)

Se

O

+

NH

O

OSe

O

NH

O

piperidine

71%

(261)N

Se

O SePh i,. PhMgBr

ii, H+

(E):(Z) 12:41

2[94[0[6 a\b!Alkenic Ketones with Nitrogen!based Substituents

2[94[0[6[0 1!Nitrogen!substituted a\b!unsaturated ketones

"i# From nitro`en substituted ketones and carbonyl compounds

The reaction of an a!nitrogen!substituted ketone with a carbonyl compound\ as illustrated inEquation "151#\ leads to an unsaturated a!nitrogen!substituted ketone[ So\ for example\ N!acetylindole!2!one "022# reacts with benzaldehydes "Equation "152## ð77JHC0176Ł to give the dyes "023#""Z# isomers# in good yields[ Thiophene aldehydes also react with the indole!2!one to give thethienylideneindoxyls "024# "Equation "153## ð64CCC0649Ł[ Similarly the a!sulfonamidoketone "025#reacts moderately well with benzaldehydes to give the a!nitrogen!substituted ketone "026# "Equation"154## ð57JCS"C#1370Ł\ although the "E#:"Z# geometry was not determined in this case[

Nsubst.R1

O Nsubst.R1

O

R3 R2

O

R3 R2

(262)

(263)N

O

O

+

O

NMe2

N

O

NMe2

(133) (134)

Et3N, DMF

88% H

(264)N

O

O

+NH

O

(135)

S

S CHO

C6H6

74%


(265)

N

O

TsN

O

Ts

Ph

+ PhCHO60%

(136) (137)

Bender et al[ showed that the "Z# geometry was exclusively obtained on condensation of thequinoline aldehyde "027# with the quinuclidone "028# "Equation "155## ð57JOC1493Ł[ A mixture of"E#:"Z# isomers can be prepared by treating "039# with acid\ but the "E# isomer is unstable andslowly rearranges to the "Z# compound[ a!Pyridinium salts "e[g[ "030## also react well with aldehydes\giving the highly coloured betainecyanine "031# in excellent yield "Equation "156## ð59CB0957Ł[

(266)

(138) (139) (140)

N

MeO

CHO

N

ON

O

N

MeO+

NaOEt

91%

(141) (142)

Br

ON+

O

N

Ph

Me

N Ph

Me

N

O

Br(267)

+

+Ac2O

96%

a!Nitro substituted a\b!unsaturated ketones have been reported[ For example\ nitroacetone "032#reacts with the imine "033# to give a mixture of "E# and "Z# isomers of the nitro!substituted ketone"034# "Equation "157## ð46LA"591#03Ł[ Apparently\ if the aldehyde derivative of "033# is used\ reactionoccurs at the methyl group of the nitroacetone[ Nitromethyl 0\3!diketones\ for example "035# havebeen cyclised to give the novel nitro!1!cycloalkene!0!ones "036# in good yield "Equation "158##ð80S518Ł[

(268)Ac2O

69%

N

Bu

Cl Cl

O

NO2

NO2

O+

(144) (143) (145)

(269)

(146) (147)

O

O

NO2

O

NO2

K2CO3, MeOH

87%

Azidoacetophenones "037# have been reported to react with substituted benzaldehydes to givea!azidovinylketones "038# "Equation "169## ð69M046Ł[

148a\b!Alkenic Bond

(270)

(148) (149)

PhN3

O+

CHO

X X

O

PhN3

"ii# From a!halo ketones and an azide

a!Azidovinylketones have been prepared by several methods[ Reactions of the dibromides ofa\b!unsaturated ketones "049# with two equivalents of sodium azide in DMF a}ord the "Z#!a!azidovinyl ketone "040# "Equation "160## ð60JA870\ 60JOC147\ 68LA063Ł[ Alternatively\ IN2 can beadded and eliminated from a\b!unsaturated ketones[ Addition of IN2 to "041# gave a 59 ] 39 mixtureof the a! and b!iodo compounds "042# and "043#\ which were subsequently reacted with sodiumazide in DMF to give the azido vinyl ketone "044# "via a rearrangement# "Scheme 11# ð60JOC147Ł[A third method involves treatment of a!bromovinylketones "e[g[ "045## with equimolar amounts ofNaN2 and HN2 in DMF "Equation "161## ð60JA870Ł[

(271)

(150) (151)

TsO

O Ph

Br

Br

TsO

O Ph

N3

NaN3, DMF

81%

Ph

O

Ph

O

N3

Ph

O

I

N3

Ph

O

N3

I

IN3

83%

(152) (153) (154) (155)

+

40 : 60

Scheme 22

(272)

(156)

Ph

O

Br

Ph

O

N3

NaN3, HN3, DMF

72%

"iii# From enamines and an acylatin` a`ent

a!Haloenamines "e[g[ "046## can be metallated and substituted with electrophiles\ including acy!lating agents "e[g[ "047##\ to give a!amino!substituted a\b!unsaturated ketones "048# "Equation "162##ð65AG"E#260Ł[ The a!metalloenamines can also be formed under harsher conditions by use of ButLion the enamine "e[g[ "059##\ as in Equation "163# ð65AG"E#060Ł[ This gives excellent yields of theaminovinylketone "050#[

(273)N

Me

Cl

NMe

O

(157) (159)

i, Mg, THFii, Ac2O (158)

56%


(161)

Et2N N

O

Et2N N

OO Ph

(160)

(274)

i, ButLi, –110 °Cii, PhCO2Me

87%

"iv# Miscellaneous methods

a!Diketones react with amines to give aminovinylketones[ For example\ cyclohexane!0\1!dione"051# reacts with the chiral amine "052# under DeanÐStark conditions to a}ord the product "053#"Equation "164## ð73CL1944Ł[ 0\2!Diketones can be attacked by nitrogen electrophiles such as thenitrosyl cation\ and the resulting nitroso compound reduced to the aminovinylketone\ for example"054# "Equation "165## ð51LA"548#53Ł[ a!Diazovinyl ketones have been synthesised by the use of adiazonium ion coupling onto an activated vinylketone[ Thus the ketene aminal "055# is electron!rich enough to undergo coupling with the aryl diazonium ion "056# "Equation "166## ð80SC0296Ł\ togive "057#[ Oxidation of the 0\1!aminoalcohol "058# a}ords the a!amino!a\b!unsaturated ketone"069# directly "Equation "167## ð60JOC598Ł[

(275)

(162) (163) (164)

O

O +

HN

OMe

MeO

O

N

OMe

OMeC6H6

85%

(276)

O

O

OH

O

NH2

i, NaNO2ii, H2, PtO2

90%

(165)

(166) (167) (168)

Ph

O

NH

HN

Ph

O

NH

HN

NN

Br

N2+

Br

(277)+DMF, EtOH

67%

(278)NH

OH

NH

O

(169) (170)

Ag2CO3

57%

150a\b!Alkenic Bond

2[94[0[6[1 2!Nitrogen!substituted a\b!unsaturated ketones

The chemistry and reactions of enaminones have been reviewed ð35CRV72\ 66CSR166Ł[

"i# From enamines and an acid chloride

A commonly used method for preparing enaminones is reaction of an enamine with an acidchloride\ as illustrated in Equation "168#[ "E#:"Z# Isomers are possible for open chain enamines\ andmixtures of isomers often result\ but there is evidence that enaminones with a free NH exist mainlyin the cis form\ held by intramolecular hydrogen bonding[ The trans isomer is normally producedpredominantly when no N0H [ [ [O1C hydrogen bonding is possible ð46CB1722Ł[ The reaction ismost useful for cyclic enamines\ for example the enecarbamate "060# reacts with acetyl chloride:SnCl3to give the enaminone "061# "Equation "179## ð71JA5586\ 71TL0190Ł[ More reactive enamines can beacylated without the need for a catalyst[ For example\ "062#\ "063# and "064# all react directly withacid chlorides "Equations "170#Ð"172## ð69S476\ 63JHC108\ 65TL410\ 71TL0190Ł[ More reactive acylatingagents\ such as tri~uoroacetic anhydride have also been examined and give tri~uoromethyl enam!inones "e[g[ "065## in excellent yields "Equation "173## ð65CL388Ł[

(279)R22N

R22N

R1

O

R1COCl

(280)N

CO2Me

+Cl

O

N

CO2Me

O

(171) (172)

SnCl4, CH2Cl2

58%

(281)PhNEt2 +

COCl

NO2

Ph

NEt2

O

NO2

(173)

Et3N, CHCl3

32%

(282)+

COCl

(174)

MeHN

CO2Me

Et3N, toluene

62%CO2Me

O

MeHN

(283)

(175)

NO2

NMe2 +

COCl

F NO2

NMe2

O

F

Et3N, C6H6

(284)Ph

NHSO2Ph

F3C NHSO2Ph

PhO

(176)

(CF3CO)2O, pyridine

92%


Intramolecular cyclisations of an enamine and acylating agent are well known\ generally with anester as the acylating group[ In Equation "174# the N!b!carbomethoxyethyl enaminone "066# iscyclised to the dihydro!3!pyridone "067# in good yield ð50JPR183Ł[ Similarly\ the N!b!carbo!ethoxyethyl pyrrolidone "068# a}ords the hexahydro indolizine "079#\ via a mixed anhydride"Equation "175## ð79TL0262Ł[ In addition\ the enamine can be prepared in situ and cyclised directly[For example\ substituted cyclohexanones react with pyrrolidones and cyclise under the action ofcatalytic p!TsOH "Equation "176## ð65JCS"P0#893Ł[ The b!aminoester "070# in Equation "177# con!denses and cyclises\ in the same manner\ with cyclopentanone "or cyclohexanone# ð68JHC416Ł[

(285)NH

CO2Me

Ph

MeO2C

NH

Ph

MeO2C

O

(177) (178)

NaOMe, MeOH

84%

(286)N

EtO2C

CO2Et

N

O

EtO2C

(179) (180)

i, NaOHii, Ac2O, MeCN

71%

(287)

O

NH

CO2MeN O

+p-TsOH

60%

(288)

N

NH

CO2Me

+

O

N

N

O

TFA, toluene

81%

(181)

Alternative tactics for performing the acylation of an enamine or derivative have been investigated[Formation of an organometallic reagent such as a lithium derivative directly from the imine followedby the addition of an ester gives excellent yields of the enaminone "Equation "178## ð89S784Ł[ The"Z#!enaminone can be formed stereospeci_cally and in good yield under more mild conditions if theintermediate vinyl bromide is formed _rst\ as in Equation "189# ð72JCR"S#111Ł[ This reaction wouldappear to be very useful\ since other methods of preparing N\N!dialkylenaminones would give the"E# isomer[ A related reaction that has been observed to proceed quite well is the oxidation oftertiary amines to give "E#!enaminones "071# "Equation "180## ð70TL712Ł[

(289)N NH

Ph

O

i, LDAii, PhCO2Me

86%

(290)Et2N +But Cl

O Et2N

O But

i, Br2 ii, Et3Niii, BunLi

80%

152a\b!Alkenic Bond

(291)N N CCl3

O

Cl3C CCl3

O

65%

(182)

"ii# From b!dicarbonyl compounds or derivatives\ and an amine

A second common strategy for the formation of enaminones is the condensation of aminocompounds with 0\2!dicarbonyl compounds "Equation "181## ð69AJC730\ 70S779\ 72S891Ł[ The regio!chemistry is usually controlled by using symmetrical 0\2!dicarbonyl compounds\ or having one ofthe carbonyl groups more electrophilic "e[g[ b!ketoaldehydes#[ Although some cases of single "E#:"Z#stereoisomer production have been reported\ in many examples mixtures of isomers are isolated[The simplest cases are for cyclic diketones[ For example\ with primary amines\ cyclohexane!0\2!diones "072# give excellent yields of the corresponding enaminone "073# "Equation "182## ð72S891Ł[Secondary amines react well\ for example Equation "183#\ and ammonia itself can also undergo thereaction "Equation "184## ð54JA763\ 58JCS"B#188Ł[ The reaction is also sensitive to steric factors\ since1!methylcyclopentane!0\2!dione "074# reacts well with primary amines and some secondary amines"e[g[ pyrrolidine#\ but not with Et1NH\ PhNHMe or Pri

1NH "Equation "185## ð80S004Ł[ Intra!molecular cyclisations of amines and 0\2!diones have been reported "Equation "186## ð35CRV72Ł[

(292)R1 R2

O O

R1 R2

O NR32R3

2NH

(293)

O O O NHEt

(183) (184)

EtNH2

96%

O O O NEt2

(294)Et2NH

65%

(295)

O

O

Ph

NH2

O

PhNH4OAc

97%

(296)O O O NHMe

(185)

MeNH2, AcOH

90%

O

O

Ph

NHPh

Ph

O

O

(297)AcOH, NaOAc

35%

NPh

Ph

O

Ph

For open chain 0\2!dicarbonyl compounds the simplest cases of amination are for symmetrical0\2!diones[ Thus aqueous ammonia and acetoacetone a}ord the enaminone "075# very conveniently"Equation "187## ð89S784Ł[ In non!symmetrical cases\ the most electrophilic carbonyl group seemsto be aminated[ For example\ in "076# "Equation "188## ð73S552Ł\ the carbonyl group next to the methylgroup is aminated\ and similarly in Equation "299# ð56JOC2706Ł[ The stereochemistry can depend onthe solvent\ with internal hydrogen bonding providing cis isomers in many cases ð63JPR358Ł[


(298)O O O NH2

(186)

NH3 (aq.)

90%

Ph

O O

Ph CO2Et

NH2

+Ph N

H

O

CO2Et

Ph

(299)xylene

81%

(187)

(300)Ph

O O O

Ph

O O NHPhPhNH2, EtOH

75%

Other nitrogen nucleophiles that have been used include hydrazones and hydroxylamines[ Thuscyclohexane!0\2!dione reacts with N!methylhydrazones "077#\ but only in moderate yields "Equation"290## ð62CB349Ł[ Similarly\ phenylhydroxylamine "078# gives the N!hydroxyenaminone "089# inexcellent yield "Equation "291## ð62TL3422Ł[ The purpose of the ascorbic acid in this reaction is toprevent decomposition of the phenylhydroxylamine[

(188)

O O

+ Ph NNHMe N

N

Me

Ph (301)OTsOH, C6H6

30%

(302)

O O

+ N

OH

OPhNHOH

(189)

Ph

(190)

ascorbic acid, C6H6

93%

A reaction related to the amination of 0\2!diones is the intramolecular cyclisation of nitriles with0\2!diones\ for example "080# in Equation "292# gives the dihydropyridone "081# ð54TL1150\ 65JOC525Ł[

(303)

(191) (192)

O O

CN

O N

O

H

MeCOCl

39%

In addition to using the 0\2!diones directly\ b!alkoxy!a\b!unsaturated ketones have been used[Stereoselectivity is observed in some cases\ but not in others[ In this respect\ cyclic alkoxyenonesare the simplest and can give excellent yields of enaminones with amines[ For example\ thealkoxycyclopentenone "082# gives the aminocyclopentenone "083# when reacted with ammoniaunder pressure "Equation "293## ð80S065Ł[ Alternatively\ the alkoxyenone can be formed in situ andreacted directly with a nitrogen nucleophile "Equation "294## ð70S114Ł[ The same method may beused for open chain compounds\ for example "084#\ and gives the "E# compound under theseconditions\ as expected for dialkylated enaminones "Equation "295## ð77S027Ł[ DMF acetals havealso been used ð68T0564\ 79JOC3411\ 71SC24Ł[

O

OEt

O

NH2

(193) (194)

NH3

95%(304)

154a\b!Alkenic Bond

O O

+ +(EtO)3CHH2N NH2

O

O O

NH

O NH2

(305)AcOH, DMF

85%

(306)

O O

Et2N(EtO)3CH, Et2NH

44%

(195)

Reaction of the alkoxyenone "085# with a primary amine "086# leads to the formation of the "Z#enaminone "087# in quantitative yield "Equation "296## ð78TL5062Ł[ The "Z#!enaminone is alsoreported by Tietze et al[\ from the reaction of benzylamine with the alkoxyenone "088# "Equation"297## ð78CB72Ł[ Dialkoxyenones "ketene acetals# also undergo the reaction and are reported to givethe "E# isomer "as shown# in most cases "Equation "298## ð89S084Ł\ even though this is an N\N!dialkylenaminone[

EtO CF3

O+ NH2

CF3

ONH

(307)

(196) (197) (198)

MeO2C

EtO

OMeO2C

N

O

H

Ph(199)

(308)PhCH2NH2

87%

EtO CF3

OEtO

EtO CF3

OMe2N(309)

Me2NH, MeCN

100%

Gerus et al[ have reported that the reaction of the "E#!enol ether "199# gives rise to the"Z#!enaminone "190# when a primary amine is used\ due to internal hydrogen bonding\ but secondaryamines "such as pyrrolidine# give the "Z# product "Equation "209## ð80S196Ł[ Silyl enol ethers canalso be used "Equation "200## ð78CB72Ł[ In addition to alkoxy derivatives of 0\2!dicarbonyls\ otherheteroatom based leaving groups have been investigated "e[g[ S or N#[ Equation "201# illustrates thetransformation of a ketene S\S acetal "191# into a ketene S\N acetal "192# ð66JPR434\ 89S051Ł[ Sulfonicacid and sulfones have also been used as the leaving group "Equation "202## ð67TL632\ 89JCS"P0#0780Ł[

F3C OEt

O

F3C

O NH

CO2H

NH2

CO2H

(310)+1N NaOH

89%

(200) (201)

CH2Cl2

88%

O O-TMS

NH2

OMe

OMe

O NH

OMe

OMe

(311)+


MeS

MeS

O

O+ HS

NH2

O

OS

NH

(312)EtOH

92%

(203)(202)

(313)

O

O

SO3–

O

O

N(Me)Ph

PhNHMe, Ni(OAc)2, AcOH

42%

b!Halo substituted a\b!unsaturated ketones have been used to prepare b!nitrogen!substituteda\b!unsaturated ketones[ For cyclic haloenones the reaction works extremely well "Equation "203##ð53JOC683\ 58JCS"B#188Ł[ For open chain cases\ the stereochemistry is usually "Z# if an internalhydrogen bond is possible\ but this can be converted to "E# by acetylation of the free N0H"Equation "204## ð60JA2188Ł[ Use of stereochemically pure b!haloeneones provides products withretention of con_guration when reacted with tertiary amines "Equation "205## ð53JOC274Ł[

O

Br

O

N

+ But NH2But

H

(314)EtOH

79%

N

H

NH2

N

H

HN

O

+Cl

O(315)

Et3N

92%

(316)Cl

O

NMe3

O

+

Me3N

88%

"iii# From ketones and a formamide acetal

Equation "206# outlines the production of a b!dialkylamino enone from a ketone and a dialkyl!formamide acetal[ The "E# isomer is often observed\ but can depend on the other substituents of theketone[ For unsymmetrical ketones with two enolisable sites\ a mixture results unless one site ismore readily enolisable[ For example\ the ketone "193# is aminomethylated at the benzylic carbon"Equation "207## ð79S125\ 72LA189Ł[ Generally\ this problem is overcome by having only one enolis!able site\ and the "E# stereoisomer is usually produced "Equation "208## ð62JA6751\ 68S890Ł[

R2

O

R1 R2

O

R1

R32N

R32N

OMe

OMe(317)

OMe

O

OMe

O

NMe2Me2N

OMe

OMe(318)

(204)

156a\b!Alkenic Bond

(319)

OO

Me2N

OBut

Me2N

Me2N

95%

Thio!substituted ketones also work well "Equation "219## ð76S785Ł[ Variations on this reactioninclude the use of other aminomethylenating agents for which conditions have been reported thatcan select one carbon of an unsymmetrical ketone\ and the use of the novel N!acyl imido!thiocarbamate "194# under basic conditions to give the cis compound "195# "Equation "210##ð72JOC512Ł[

PhS OEt

O

O

PhS OEt

O

OMe2N

Me2NOMe

OMe(320)

100%

(205) (206)

ON SEt

O SEtO

HN

O SEt

O Ph

ButOK, THF

78%

Ph

O

(321)

"iv# From amines and a ketoalkyne

Primary and secondary amines\ including aromatic amines\ react smoothly with alkynyl ketonesto give enaminones "Equation "211## ð35JCS34\ 54JCS2509\ 55JCS"B#0106Ł[ Some investigators reportequilibrium mixtures of cis and trans isomers\ with the ratio depending on the solvent[ Single isomershave been reported however\ that is cis when intramolecular hydrogen bonding is possible "Equation"212## ð68JCS"P0#25Ł and trans products in other examples[ Tertiary amines\ for example "196# inEquation "213# ð77JA2854Ł\ and nitroamines in Equation "214# also undergo the reaction ð43BSF623\62JOC3213\ 73JGU17\ 78JOC5901Ł[

(322)

OMe O OMe O

NEt2Et2NH, MeOH

(323)

O O N

MeOMeO

PhH

PhNH2

75%

(324)

O O

NMe3

+Me3NH+ BF4

– (207), MeOH

58%

(325)Ph

O

Ph

O

NNO2

Me

+ MeNHNO2

Et3N


"v# Reactions of ketones with a cyano compound

Nucleophilic addition of an enolate to a nitrile leads to an enaminone\ "Equation "215##ð66H"5#0874Ł[ Interestingly\ b!diketones such as "197# can add to benzoyl cyanide at the cyanocarbon\ when Ni"acac#1 is used as a catalyst "Equation "216## ð73CC0482\ 73JOC3585Ł[ Tin"IV# chloridealso catalyses the reaction\ and in these cases the nitrile seems to need further activation by anelectron withdrawing group\ for example CO1Et\ etc[ "Equation "217## ð77JCR"S#135Ł[

(326)O CN

+O

O

NH2 O

MeNH2

80%

Ph CN

O

Ph

OO+

Ph

OO

H2NPh

O

(327)

(208)

Ni(acac)2

87%

OO+

CCl3O

O

SnCl4Cl3C CN NH2 (328)

"vi# From carbonyl or thiocarbonyl compounds and Witti`!type rea`ents

Reaction of the reagent "198# in a Wittig!type reaction with an imide "e[g[ succinimide "109##gives only poor yields of the enaminone "100# as the "Z# isomer "Equation "218## ð73LA0767Ł[Intramolecular examples of the reaction are also known and proceed rather better "Equation "229##ð76TL3284\ 77LA276\ 89LA286Ł[ In a variant of this reaction\ thioamides can be S!alkylated anddesulfurised by PPh2 or P"OEt#2 to give enaminones "Equation "220## ð60HCA609\ 74HCA0124\78TL3768Ł[

NH

O O

(210) (211)

NH

O

O Ph

Ph3PPh

O

(329)(209)

17%

N

O

O

PPh3

O

N

O

O

(330)56%

N S

CN

+

OMe O

Br i, RTii, PPh3, Et3N

88%

N

CN

OMeO

(331)

158a\b!Alkenic Bond

"vii# From ketenes and an enamine

Ketenes react with enamines at 9>C to give cyclobutanones which spontaneously ring open togive the b!enaminones in excellent yield "Equation "221## ð50JOC3664\ 51AG21\ 52LA"551#067Ł[ Thisreaction is similar to the acylation of an enamine which has already been discussed in "i# above[

(332)Me2N + H2C • O

O

NMe2

93%

"viii# From oxime sulfonates and a silyl enol ether

Oxime sulfonates react with silyl enol ethers under Lewis acid catalysis conditions to provideb!enaminones[ The reaction is reported to proceed as illustrated in Scheme 12 ð72JA5201Ł[

NOMs

N

Scheme 23

O-TMS

N

HO

N

Et2AlCl

O

+

90%

"ix# Miscellaneous methods

Other methods reported to lead to b!enaminones are the reductions of isoxazoles or isoxazilinesð74JCS"P0#0390\ 77JOC1315Ł\ Fries!type rearrangements of N!acyl enamines ð63JOC2965\ 75CC728Ł\ andreactions of isothiocyanates with haloketones ð66S596\ 68JCR"S#139Ł[ Nitro!substituted a\b!unsatu!rated ketones have been made by the nitration of a\b!unsaturated ketones ð68HCA386\ 68JHC0546Ł[

2[94[0[7 Phosphorus! and Arsenic!substituted a\b!Unsaturated Ketones

a!Phosphorus!substituted ketones can be condensed with aldehydes as illustrated in Equation"222# to give a!phosphorus!substituted enones ð57JGU290Ł[ A variation of this reaction has beenreported\ using a DielsÐAlder reaction to make a pyran\ followed by a ring opening and condensationreaction "Equation "223## ð78BCJ759Ł[ Wittig!type reactions have also been reported ð73S24Ł[ DielsÐAlder reactions of arsabenzenes with propargylic ketones lead to mixtures of both a! and b!arsenic!substituted a\b!unsaturated ketones ð67TL1426Ł[

P(OEt)2

OOP(OEt)2

OO

Ph

Ph

O(333)+

piperidine

72%


(334)P(OEt)2

OO+

BuO P(OEt)2

OO i, Pri2NEt

ii, HCl (aq.), THF

78%

b!Phosphorus substituted enones can be made by the oxidation of an alcohol^ the reactionincorporates an allylic transposition "Equation "224## ð80S246Ł[ Arbuzov reactions starting fromb!halovinyl ketones and Wittig!type alkenation are also known ð68LA381\ 74M66Ł[

(335)OH(MeO)2P

O O

P(OMe)2

O

CrO3

76%

2[94[0[8 a\b!Alkenic Ketones with Silicon!based Substituents

2[94[0[8[0 1!Silyl a\b!unsaturated ketones

The PausonÐKhand reaction is a very useful method for the stereoselective synthesis of1!silylcyclopentenones\ usually as 5\4! or 4\4!fused bicycles[ Magnus et al[ have reported that thesilylenyne "101# can be cyclised most e.ciently if the Co"CO#5!acetylene complex "102# is puri_edprior to thermolysis[ The metal complex is then heated under carbon monoxide in a sealed tube togive the fused tricycle "103# in 40) yield as a single stereoisomer "Scheme 13# ð76JA6384Ł[ Similarsyntheses of 4\4! and 5\4!bicyclic 1!silylcyclopentenones reviewed include ð79AG"E#0912\ 72JA1366\74TL3740\ 77LA780Ł[ A closely related zirconium!mediated intramolecular enyne carbocyclisationproceeds via an intermediate isolable zirconabicycle "104# which is converted easily to the silylenone"105# by treatment with carbon monoxide at 9>C "Scheme 14# ð74JA1457Ł[ Similar examples includeð75JOC3979\ 78JA2225Ł[ This reaction has been used to great e}ect by Wender et al[ in the synthesisof fused 4\6!bicycle systems present in several natural products ð89TL2580Ł[ An intermolecularcyclisation involving a chromium alkylidene complex also yields a 1!silyl!a\b!unsaturated cyclicketone ð74JA492Ł[

O

O

TMS

O

O

Co

Co

TMS

O

O

H HH

TMS O

Scheme 24

(212) (213) (214)

Co2(CO)6, 22 °C

94%

CO(g), Bu3PO, 85 °C

51%

TMS

ZnCp2

TMS TMS

O

Scheme 25

Cl2ZrCp2, Mg, HgCl2

90–95%

CO(g), 0 °C

55–60%

(215) (216)

1!Silyl!2!chloro!a\b!unsaturated ketones can be prepared by the addition of an acid chlorideacross a silyl alkyne\ both intermolecularly ð70JGU0094Ł and intramolecularly "Equation "225##ð67TL1290Ł[ Closely related reactions include ð61JOM"26#34\ 71TL3812Ł[

160a\b!Alkenic Bond

(336)Cl

O TMS

O

TMS

Cl

AlCl3, 40 °C

74%

1!Silyl!a\b!unsaturated ketones are available by a DielsÐAlder reaction of the silylketone "106#with many dienophiles "Equation "226## ð79JOC3709Ł\ and also by ð1¦1Ł cycloadditions of dichloro!ketene with alkynylsilanes ð72TL12Ł[ Metallations and subsequent acylations of halovinylsilanesyield unsaturated silylketones in good yields\ both inter! and intramolecularly ð62CJC1913\ 75TL664Ł[

•O

TMSO

O

O

O

TMS

O

O

O

H

H

(337)+CHCl3, 25 °C

89%

(217)

Metallation of the readily available dibromocyclopropane "107#\ followed by a TMS!Cl quenchand hydrolytic ring opening has given rise to the silylketone "108# cleanly "Equation "227##ð67TL2936Ł[ Protected 1!bromo!a\b!unsaturated ketones can be treated similarly to give the cor!responding silylketones in reasonable yield ð67TL3550Ł[ Oxidations of trimethylsilylcylclopropeneshave been reported to produce 1!silyl!a\b!unsaturated ketones under mild conditions ð75TL4032Ł[

(338)

OMe

HBr

Br

TMS

O

(218) (219)

i, BunLi, –95 °C ii, TMS-Cliii, MeOH, K2CO3

57%

2[94[0[8[1 2!Silyl a\b!unsaturated ketones

Fleming et al[ have worked extensively in the area of b!silylenones and presented a brief summaryof the synthetic methods reported prior to 0870 along with three new methods ð70T3916Ł[ The _rstmethod involves the addition of an alkyl cuprate to a silylynone\ whereas in the second methodphenyldimethylsilyl cuprate is reacted with a b!chloroenone to yield the corresponding b!silylenonein high yield[ The third method uses phenylthiotrimethylsilylmethylation followed by oxidation andbase!catalysed elimination "Scheme 15#[ The oxidation must be taken to the sulfone level in orderto avoid the sila!Pummerer rearrangement which occurs with the corresponding sulfoxide[ The useof a!halo!a!"trimethylsilyl#methyl ether in an analogous trimethylsilylmethylenation has also beenreported ð76ACS"B#425Ł[ A related approach involves the allylic sul_de "119# as a homoenolatedianion equivalent enabling the synthesis of functionally substituted b!trimethylsilyl!a\b!unsatu!rated ketones via two alkylations "Scheme 16# ð74TL1566Ł[

O-TMS

+Cl TMS

SPhO

TMS

SPh O

TMS

Scheme 26

ZnBr2

84%

i, mcpbaii, dbu

67%

Silyltin alkenes are readily available by the addition of silylstannanes to terminal alkynes underpalladium catalysis\ and they undergo e.cient Stille coupling reactions with acid chlorides togive 2!silyldivinyl ketones "Equation "228## ð75TL1790Ł^ see also ð73JA6499\ 75JOC2450\ 89SC0554Ł[ Aconceptually similar approach involves the coupling of a b!silylvinyl cuprate\ derived from theaddition of a silyl anion to a terminal alkyne\ with an acid chloride ð79CC165\ 77HCA057Ł[ Vinylsilanes can also be acylated with acid chlorides in the presence of Lewis acid catalysts ð71TL0834\77TL774Ł[


PhS OMe

TMS

PhS OMe

TMSR1

(220)

BunLi, R1X SiO2, hexane

BunLi, R2X NaIO4R1 SPh

TMS OMeR2

R1 R2

TMS O

Scheme 27

R1 SPh

TMS OMe

(339)

SnMe3

TBDMS

+COCl

TBDMS

O

PdCl2(MeCN)2, 60 °C

87%

Rhodium!catalysed allylic oxidation of 2!"trimethylsilyl# cycloalkenes with molecular oxygena}ords b!silylcycloalkenones regiospeci_cally and in high yields "Equation "239## ð67JOC1327Ł[Oxidations of b!silylallylic alcohols to the corresponding ketones have been reported using a varietyof oxidising agents ð72HCA1266\ 77HCA057\ 89SC0984Ł[ The reaction of a\b!unsaturated acylsilanes"110# with allenylsilanes "111# in the presence of a Lewis acid catalyst provides a novel ð2¦2Ł!annulation procedure to b!silylcyclohexenones which proceeds in moderate yield "Equation "230##ð74TL1402Ł[

(340)

TMSTMS

O

Rh(1), O2, 97 °C

83%

(341)

(221) (222)

TMS

O• TMS

O

TMS

+TiCl4, –50 °C

56%

2[94[0[09 a\b!Alkenic Ketones with Metal Substituents

ortho!Diketodiynes react with transition metals "Rh\ Ir\ Pt and Pd# to form metallocyclo!pentadienes\ some in high yield[ Thus the diketone "112# reacts with rhodium"I# to give the complex"113# in high yield "Equation "231##[ The metal complexes are synthetically useful due to the ease ofreplacement of the metal with alkynes\ chalcogens and nitrogen ð60LA"643#53\ 64CB126Ł[

S

O

Ph

O

PhS

RhCl(PPh3)2

O

O

Ph

Ph

(342)

(223) (224)

RhCl(PPh3)4, 140 °C

89%

b!Trimethylstannyl!a\b!unsaturated ketones can be prepared from the correspondingb!iodo!enones via reaction with the cuprate\ PhS"Me2Sn#CuLi\ at low temperature\ in yields up

162a\b!Triple Bond

to 75) ð67CC0922Ł[ An analogous reaction with the b!chloroenone "114# has also been observedusing a tributylstannyl cuprate to give the stannyl ketone "115# in high yield "Equation "232##ð70TL0326Ł[

(343)

(225) (226)

O

ClTBDMS-O

O

SnBu3TBDMS-O

Me2S(Bun3Sn)2CuLi, –25 °C

84%

2[94[1 KETONES BEARING AN a\b!TRIPLE BOND

2[94[1[0 By Acylations of Alkynes

Probably the most important method for preparing an alkynone is via the acylation of an acetylideanion or equivalent[ The lithio acetylide is easily prepared by deprotonation of an alkyne using alithium base or by metalÐhalogen exchange and elimination from a trichloroethylene systemð70C225Ł[ The lithio acetylide can then be acylated using an anhydride "Equation "233## ð53CB0538\63S246\ 73TL1300\ 74JOC2861\ 89S132Ł\ an ester ð65SC492\ 67TL826\ 78TL874Ł\ an amide "Equation "234##ð70TL2704\ 73TL700\ 76TL0746\ 77JA1290Ł\ an acid chloride ð62JOC2477Ł or an acyl cyanide ð64BSF668Ł[Magnesium acetylides behave similarly and have been acylated using anhydrides and imidesð38JCS0716\ 60CPB280\ 89JCS"P0#0496Ł\ whereas alkynyl cuprates have only been reported to undergoacylations with acid chlorides ð58JA5353\ 69TL1548\ 62BSF1026\ 64JOC020Ł[ The formation of copper"I#acetylides\ via an intermediate metal acetylide\ can sometimes be di.cult and a convenient alter!native is to treat the alkyne with copper"I# iodide:triphenylphosphine palladium chloride in tri!ethylamine and acylate with an acid chloride "Equation "235## ð66S666\ 73JCS"P0#424\ 78SC0634Ł[

(344)HO2C Bun

O

Bun Bun

i, ClCO2Et, Et3N, petrol, –20 °Cii,

80%

Bun Li, THF, ether, –50 °C

(345)N(Me)OMe

Ph O+ Ph Li

Ph O

Ph

THF, 20 °C

97%

(346)ClPh

O+Ph Ph

O

Ph

(Ph3P)2PdCl2, CuI, Et3N, 20 °C

96%

The acylation of tin alkyne compounds requires palladium catalysis if the alkyne is carbon!substituted ð71JOC1438\ 74HCA227Ł[ However this is not necessary if the alkyne is activated with aheteroatom "Equation "236## ð79JOM"073#206\ 70LA0896\ 70TL1526\ 77CB1052Ł[ Other less widely usedacetylides for which acylations have been reported include] manganese ð74S49\ 78TL2434Ł\ zincð77JOM"227#178Ł\ silver ð45JA0564Ł\ boron ð56AG"E#73Ł and vanadium\ which undergoes oxidativeaddition to aldehydes in good yields "Equation "237## ð75TL822Ł[ The acylation of silyl acetylides iscarried out with Lewis acid catalysis and usually involves the use of aluminum trichloride with anacid chloride "Equation "238## ð52CB2179\ 68S327\ 70S18\ 74S851\ 75HCA459Ł\ intramolecular exampleshave been reported ð67TL1290Ł[ Silver tetra~uoroborate as Lewis acid with a thioester acylatingagent is also e}ective with silyl alkynes ð72TL4020Ł\ and the use of titanium tetrachloride withdiketene is also known ð76S0981Ł[


O Cl

ClPh

+ Bu3Sn N

Ph

Me NPh

Me

O

ClPh

(347)Et2O, 0 °C

57%

(348)Bun

O

BrMg

Bun

i, VCl3, CH2Cl2ii, PrnCHO, –78 °C to 40 °C

63%

(349)

O

TMS

TMS

TMS

+Cl

OAlCl3, CH2Cl2, 0 °C

89%

2[94[1[1 Elimination Reactions

Elimination of hydrogen halide from an a! or b!haloenone or dihaloalkanone is a useful way ofpreparing alkynic ketones[ Common reagents include triethylamine "Equation "249## ð40JOC40\70JGU0942Ł\ potassium carbonate ð56JA4611Ł and Triton B ð63CR"167#0042Ł[ The parentenones can beused as the starting material by _rst brominating and then performing a double elimination "Equa!tion "240## ð57AG332Ł[ Elimination of iodide is facile\ and the intermediate iodoenones can be madefrom an iodophosphorane and an aldehyde "Equation "241## ð89S520Ł[ The enol form of 0\2b!diketones can eliminate water to give good yields of ynones "Equation "242## ð79CL0216Ł[ Theper~uorinated acid halide in Equation "243# reacts with the phosphorane to give a per~uoroacylatedylide[ The ylide then eliminates Ph2PO in both possible directions to give a roughly 0 ] 0 mixture ofketone and aldehyde which can be separated by distillationð73S24\ 74S048Ł[ See ð54JOC0904\ 71JCS"P0#0452Łfor other reactions involving elimination\ and ð61SC220Ł for a reaction starting from an a!diazoalcohol[

(350)Ph

Br

BrO

O

O

O Ph i, ButOK, DMFii, Et3N, 20 °C

100%

(351)Me2N

O

Me2N

O

i, Br2 ii, Et3Niii, ButOK

70%

OMe O

OMe

+ Ph3PPh

I

O+

OMe

OMe

Ph

O

(352)K2CO3, MeOH, 60 °C

66%

(353)Ph

O OHO

Ph

KF, MeCN, Et2NCF2CFHCF3, 20 °C

72%

Cln-C3F7

OPh3P CHO

+

–

+ +n-C3F7

OO

n-C3F7

(354)

i, C6H6, 80 °Cii, 200 °C

85%

1 : 1

164a\b!Triple Bond

2[94[1[2 By Oxidation of Alkynic Alcohols and Propargylic Methylene Groups

Oxidations of alkynic alcohols proceed in much the same way as oxidations of allylic alcohols"see Section 2[94[0[0[5#[ Manganese dioxide is a common reagent "Equation "244## ð53JA360\ 62CB28\68CL0910\ 78HCA006Ł^ see also ð76JOC1426Ł for a ring opening reaction of cyclohexadienols usingMnO1 and ð49JGU0151Ł for use of a Mn"OAc#2 reagent[ Chromium trioxide:pyridine has beenused in several cases ð35JCS28\ 70JA3486\ 75S073Ł\ and other reagents used include ortho!chloranilð45JCS2969Ł\ oxalyl chloride:DMSO ð73JA4474Ł\ Na1WO3 ð75TL494Ł and electrochemical oxidationð89JOC2547Ł[

(355)O

Ph+

EtO OEtO

Ph

OEt

OEt

i, BuLi, THF ii, aldehydeiii, MnO2

89%

The methylene group adjacent to a triple bond has been oxidised with chromium trioxide:pyridineto a}ord an alkynone "Equation "245## ð60TL3268Ł^ t!butyl hydroperoxide can be used similarly"also for terminal alkynes# ð77TL1210\ 78SC1950Ł[ In a related oxidative procedure\ Brown et al[ haveused the hydroboration of a haloalkyne to give a bromoalkenylborinate intermediate\ which wasthen reacted with a lithioacetylide[ Oxidation of the resulting alkynenylborinate with H1O1:NaOHgave the ynone "Equation "246## ð72S774Ł[

(356)

O

CrO3•pyr•2, 25 °C

42%

(357)Br

O

Li+

i–iv

i, PriCMe2BHCl•SMe2, BBr3; ii, PriOH; iii, RLi, THF; iv, NaOH, H2O2

2[94[1[3 By Reaction of a Carbon Nucleophile with Alkynic Acid Halides and Derivatives

The reactions of alkynic acid halides "e[g[ Equation "247## with carbon nucleophiles have beenreported ð41JCS2834Ł[ Other similar examples using an alkynic ester and an enolate as the nucleophileare known ð63JHC0090Ł[ Dimethyl alkynedicarboxylate reacts with certain enamines at the estergroup to give alkynic ketones ð71CPB52Ł[ The propargylic dithiane in Equation "248# can bedeprotonated and alkylated in an umpoled carbonyl synthesis ð70JOC0401Ł[

Cl

O

Ph

+ n-C6H13

O

O-THP

O

O-THP

O

Ph

n-C6H13 (358)

i, Na, C6H6 ii, RCOCliii, C6H6, AcOH, 80 °C

85%

(359)

S S

TMS

+ Cl

O

TMS

i–iv

72%

i, BunLi; ii, enyne; iii, Tl(NO3)2; iv, HCl


2[94[1[4 Miscellaneous Methods

The palladium!catalysed carbonylation reactions of phenyl alkynes have been investigated "Equa!tion "259## ð70CC222Ł[ Brown has used dichloromethyl ether as a carbonylating reagent for alkynyl!borinates "Equation "250## ð77JOC0280Ł[ Jacobi has reported an oxy!Cope rearrangement of a vinylalkynyl carbinol leading to an alkynic ketone ð89JOC191Ł\ and vinyl alkynyl carbinols also undergoa Lewis acid catalysed 0\1!rearrangement "Equation "251## ð75TL262Ł\ using the low migratoryaptitude of the alkyne group to confer selectivity[ See ð71JOC41Ł for a reaction of an isocyanate withan alkyllithium to form an a!lithioaldimine\ which can be trapped with a 0!bromoalkyne leading toan alkynic ketone[

(360)Ph +I

Ph

Ph

OPdCl2, CO, Et3N, 80 °C

93%

O

BO OH

Cl

O

O

Cl

(361)+ MeO

Cl

Cl

i, LiOCEt3ii, H2O2, NaOH

70%

(362)TMS

OMs

HO

Ph

Ph

OTMSAlMe3, –45 °C

88%


3.06Ketones Bearing an a,b-Aryl or-Hetaryl SubstituentDARYL S. WALTERUniversity of Nottingham, UK

2[95[0 GENERAL METHODS 167

2[95[0[0 FriedelÐCrafts Acylations 1672[95[0[0[0 Reactions with acyl halides 1672[95[0[0[1 Reactions with carboxylic acids and anhydrides 1792[95[0[0[2 Reactions with miscellaneous acylatin` aènts 1702[95[0[0[3 The Houben!Hoesch synthesis 1712[95[0[0[4 Reactions with other acyl cation equivalents 172

2[95[0[1 Electrophilic Acylations of Orànometallic Species 1732[95[0[1[0 Acylations of orànolithium reaènts 1732[95[0[1[1 Acylations of Gri`nard reaènts 1742[95[0[1[2 Acylations of orànocopper reaènts 1752[95[0[1[3 Acylations of orànotin reaènts 1762[95[0[1[4 Acylations of orànozinc reaènts 1772[95[0[1[5 Acylations of miscellaneous orànometallic reaènts 178

2[95[0[2 Aryl Ketones by Carbonylative Cross!couplin` Reactions 1782[95[0[3 Acyl Anion Equivalents in Aromatic Ketone Synthesis 180

2[95[0[3[0 1!Alkyl!0\2!dithianes 1802[95[0[3[1 Protected cyanohydrins 1812[95[0[3[2 Acyl radicals 1812[95[0[3[3 Miscellaneous acyl anion equivalents 182

2[95[0[4 Oxidation 1822[95[0[4[0 Oxidations of benzylic methylene `roups 1822[95[0[4[1 Oxidations of secondary benzylic alcohols 1832[95[0[4[2 Oxidative cleavaès of double bonds 183

2[95[1 PHENYL KETONES AND SUBSTITUTED ANALOGUES 184

2[95[1[0 Phenyl Ketones 1842[95[1[1 Monoalkyl Phenyl Ketones 1842[95[1[2 Dialkyl! and Polyalkylphenyl Ketones 1852[95[1[3 Halophenyl Ketones 1852[95[1[4 Phenolic Ketones 1852[95[1[5 Alkoxyaryl Ketones 1872[95[1[6 Thiophenyl Ketones 1882[95[1[7 N!Substituted Phenyl Ketones 1882[95[1[8 Other Substituents 299

2[95[2 POLYCYCLIC ARYL KETONES 299

2[95[2[0 Naphthyl Ketones 2992[95[2[1 Anthryl Ketones 2902[95[2[2 Phenanthryl Ketones 2902[95[2[3 Other Polycyclic Aryl Ketones 291

2[95[3 HETARYL KETONES 291

2[95[3[0 Furanyl Ketones 2912[95[3[1 Benzofuranyl Ketones 2932[95[3[2 Ketothiophenes 294

166

167 Ketones With an a\b!Aryl or !Hetaryl

2[95[3[3 Benzothiophenyl Ketones 2952[95[3[4 Pyrrolic Ketones 2952[95[3[5 Ketoindoles 2982[95[3[6 Pyridyl Ketones 2092[95[3[7 Ketones Derived from Imidazoles\ Thiazoles and Oxazoles 200

2[95[0 GENERAL METHODS

Aromatic ketones serve as useful intermediates for the synthesis of a range of other functionalisedsystems[ However\ a comparison of the number of synthetic routes to aliphatic ketones and aromaticketones respectively\ reveals that the latter group of compounds are accessible by relatively fewermethods[ Advances in the application of organometallic species have served to remedy theseshortcomings to a considerable degree but in many cases more classical approaches are stillemployed[ This section summarises the most widely used direct methods currently available for thesynthesis of aromatic ketones[ To avoid duplication the emphasis is placed _rmly on those methodswhich speci_cally apply to aromatic systems although many of the methods described for thesynthesis of saturated ketones "Section 2[92[0# will often be suitable[

2[95[0[0 FriedelÐCrafts Acylations

The FriedelÐCrafts reaction is one of the oldest and best!known approaches to the synthesisof aromatic ketones\ and the method has been extensively reviewed ðB!53MI 295!90\ B!62MI 295!90\80COS"1#622Ł[ The ketone is generally prepared by treatment of an aromatic substrate with anacylating agent and a suitable electrophilic catalyst[ Aluminum chloride and boron tri~uoride aretwo of the most commonly employed catalysts but many other Lewis acids and protic acids havefound similar utility[ Molar quantities of catalyst are generally required\ as metal complexes areformed with both the acyl halide and the carbonyl product[ Exceptions include the reactions ofelectron!rich aromatic systems which can often be acylated in the presence of small amounts ofmilder Lewis acids or in the complete absence of catalysts[ Similarly\ acylations using highly reactivespecies such as certain mixed anhydrides again often require no or little catalyst[ The choice ofacylating species has become increasingly varied\ but acyl halides and carboxylic acids and theiranhydrides comprise the majority of literature examples[ The electron!de_cient nature of the aro!matic moiety in the product ketone usually ensures that the reaction stops cleanly after the initialacylation[

2[95[0[0[0 Reactions with acyl halides

The reactions of aromatic substrates with acyl halides is very general and all four types of halo!substituent "i[e[\ ~uorides\ chlorides\ bromides and iodides# can be used[ However\ the reaction ofacyl chlorides in the presence of aluminum trichloride is the most frequently used combination forthe preparation of alkyl aryl ketones[ Electron!rich arenes and electron!de_cient acyl halides resultin the best yields[ Unfunctionalised acyl and aroyl halides generally give high yields of the desiredketones under such classical FriedelÐCrafts conditions[ In certain cases however\ side reactions anddecomposition can be problematic[ For example\ acylation with pivaloyl chloride can be severelyhampered by decarbonylation and subsequent competing t!butylation of the aromatic substrate[This problem has been studied extensively ð38JCS0835Ł\ and is usually avoided by employing morereactive aromatic systems[ More highly functionalised substrates are also tolerated but the oftenstrongly acidic reaction medium can present problems[ In such cases\ and when substrate reactivitypermits\ resorting to milder acylation conditions can lead to high ketone yields in the presence ofacid!labile groups[ In a synthesis of the iso~avone jamaicin ð76JOC0861Ł\ a key acylation failed understandard Lewis and protic acid catalysis but gave the desired ketone on treatment with titaniumtetrachloride in dichloromethane at −67>C "Equation "0##[ Other methods which have beenemployed to reduce unwanted reactions promoted by acids\ include the removal of hydrogenchloride from the solvent by passing air through the reaction mixture ð41BSB583Ł\ and the use ofacid scavengers such as potassium carbonate and 1\5!lutidine ð61JOC2507Ł[

168General Methods

(1)O OHO

OCl

MeO

O

O

MeO

O OH

O

O

+TiCl4

CH2Cl2, –78 °C

Reactions requiring molar quantities of catalyst require workup procedures to decompose prod!uct complexes and the catalyst is consequently not usually recovered[ Reactive aromatics "e[g[\thiophenes# can be acylated over sulfonated polystyrene resins ð44USP1600303Ł\ and benzoyl chlorideswill yield benzophenones on exposure to arenes and the solid Na_on!H catalyst ð67S561Ł[Ammonium salts of Keggin!type heteropolyacids ð81CL0876Ł have also shown promise as solid!phase FriedelÐCrafts catalysts[ These heterogeneous procedures allow for easy recovery of both theproducts and the catalyst[

Acylations of active aromatic nuclei such as aryl ethers\ polynuclear arenes\ and thiophene withacyl halides do not always require a catalyst but trace amounts of a variety of metallic and non!metallic catalysts greatly increase the reactions rates and the yields ð61S422Ł[ The most frequentlyemployed catalysts of this ilk are ferric chloride "Equation "1## ð74BSB786Ł\ iodine "Equation "2##ð37JA0536\ 42JA634Ł\ zinc chloride "Equation "3## ð43JA4358Ł and iron "Equation "4## ð69MI 295!90Ł[Attractive aspects of these methods are the ease of product puri_cation and low costs[ Relativelyhigh reaction temperatures are required and aromatic acid chlorides generally give better yieldsthan aliphatic ones[

(2)+ Cl

O OFeCl3 (0.08 equiv.)4 h, 200 °C

71%

5 equiv. 1 equiv.

(3)+ Cl

O OMeO

MeO

I2, reflux, 8 h

89%

(4)+ Cl

O OOMe

But

But

OMe

ZnCl2 (0.02 equiv.), reflux

66%

(5)+ Cl

O OOMeFe (0.01 equiv.), 85 °C

90%

MeO

Catalytic quantities "ca[ 0)# of tri~uoromethanesulfonic acid e}ectively increase rates and yieldsin FriedelÐCrafts acylations with acyl halides ð61AG"E#299Ł and presumably proceed via the inter!mediacy of labile tri~uoromethanesulfonic!carboxylic anhydrides[ This method allows for acylationswith pivaloyl chloride without the decarbonylation and t!butylation complications mentioned earlier"Equation "5##[ In contrast to all of the above catalytic methods\ acylations of aryl ethers arepromoted e}ectively by small quantities of diphenylboryl hexachloroantimonate ð75CL054Ł at roomtemperature in dichloromethane solutions "Equation "6##[

(6)But

+Cl

OBut

OOMe

MeO

CF3SO3H (cat.), 154 °C, 12 h

54%


(7)Bun

+Cl

OBun

OOMe

MeO

Ph2BSbCl6 (cat.), CH2Cl2, RT, 24 h

88%

2[95[0[0[1 Reactions with carboxylic acids and anhydrides

FriedelÐCrafts acylations with carboxylic acids are possible and although not as popular asacylating agents as the corresponding acyl halides or acid anhydrides\ they have shown considerableutility particularly when preparation of such acid derivatives is di.cult[ In general the catalystsused are milder than those popular with acyl halide reactions\ and the aromatic substrate usuallyneeds to be substantially activated "e[g[\ aryl ethers#[ Zinc chloride ð30OS"10#092Ł is a reasonablyuseful catalyst but reactions are somewhat prone to the formation of side!products[ More frequentlyused catalysts are boron tri~uoride "the Meerwein reaction ð22CB300Ł# and polyphosphoric acid[Boron tri~uoride is particularly suited to acetylations when used in conjunction with acetic acid"Equation "7## ð50JOC2549Ł and to the formation of aryl alkyl ketones with long side!chains "Equation"8## ð50JOC1390\ 64CB0469Ł[ Other protic acids which have been used successfully include phosphoricacid ð78JHC0436Ł\ sulfuric acid ð80TL5698Ł and hydro~uoric acid ð60CI"L#571Ł[

(8)+OH

O OHOH

OMe

O

OMe

BF3, 0–25 °C, 48 h

90%

(9)HO

+O

OH

OH

HO

( )18

OH

HO

HO

( )18

O

BF3, HF, p-xylene, 70 °C

90%

Toluene and xylene can be acylated with fatty acids in the presence of a Y!faujasite!type zeoliteafter exchange with Ce2¦ cations ð75JOC1017Ł[ The shape!selectivity imposed by the dimensions ofthe zeolite channels results in no acylation with acetic acid and increasing ketone yields with higherhomologs\ and maximum yields using dodecanoic and palmitic acids with toluene and p!xylenerespectively[ Carboxylic acids and phosphorus pentachloride ð60AP"293#432\ 77CB006Ł\ phosphorusoxychloride ð72CI"L#368Ł\ and sulfonyl chloride ð73JOC3115Ł provide alternative acylation conditions\but a Lewis acid is usually required and the reactions probably proceed via the corresponding acylchlorides[

Along with acyl chlorides\ acid anhydrides are the most popular acylating species in the FriedelÐCrafts ketone synthesis\ particularly when using reactive aromatic substrates[ Used in conjunctionwith stoichiometric quantities of catalysts such as aluminum chloride\ ferric chloride\ zinc chloride\boron tri~uoride and tri~uoroacetic acid they provide a convenient route to ketones[ However\practical considerations such as the thermal instability and moisture sensitivity of many anhydrideshas largely limited the reactions to acetylation "for which this method is particularly good#\ pro!panoylation and butanoylation[ The in situ preparation of highly reactive mixed anhydrides avoidsthese problems and provides a useful route to ketones based on the corresponding carboxylicacids[ Carboxylic dihalophosphoric anhydrides ð70CB815Ł and acyl tri~uoroacetates ð68S292\ 79S028\77BCJ344Ł have both found some use "Equations "09# and "00##[

(10)+OH

OOMe MeO

O

TFAA, MeCN, 85% H3PO4

66%


170General Methods

(11)+ OH

OO

2-PyOTf, TFA

99%

As with the reactions of acyl halides\ carboxylic acid anhydrides can serve as useful acylatingagents for active aromatic nuclei in the presence of little or no catalyst ð61S422Ł\ but usually underrather drastic conditions[ However\ later work\ mostly by Mukaiyama and his co!workers\ has seenthe development of substoichiometric catalysts which provide aromatic ketones using anhydridesunder very mild experimental conditions[ Diphenylboryl hexachloroantimonate ð75CL054Ł\ galliumchloride:silver perchlorate "Equation "01## ð80CL0948\ 80S0105Ł\ antimony chloride:lithium per!chlorate ð81CL324Ł and lanthanide tri~uoromethanesulfonates ð82CC0046Ł all provide high yields ofketones with electron!rich aromatic substrates\ and with one exception\ at room temperature indichloromethane[ Carboxylic acids "or their trimethylsilyl esters# and p!tri~uoromethylbenzoicanhydride in the presence of a silicon tetrachloride:silver perchlorate catalyst system constitute ane.cient and mild route to the corresponding ketones "Equation "02## ð81CL0640\ 82BCJ2618Ł[

(12)+

OMe

(C5H11CO)2O

MeO

C5H11

OGaCl3 (10 mol%)/AgClO4

CH2Cl2, RT

91%

(13)+

OMe

MeO

O

O-TMS

O SiCl4 (20 mol%)/AgClO4CH2Cl2, RT

100%

2[95[0[0[2 Reactions with miscellaneous acylating agents

Esters and amides are sometimes used as electrophilic substrates in the FriedelÐCrafts reaction[Esters usually result in alkylation products but intramolecular reactions with protic acid catalysts areknown ð62CI"L#078Ł[ Treating aromatic substrates with acyl enolates and stoichiometric quantities ofaluminum trichloride "Equation "03## ð69JOC1240Ł or catalytic amounts of diphenylboryl hexa!chloroantimonate "Equation "04## ð75CL054Ł result in moderate to good yields of ketones[ Thesereactions have only acetone as a by!product and\ particularly in the latter case\ provide a mild andessentially neutral procedure for electrophilic acylation[ Amides have been used to acylate electron!rich aromatic substrates using either acid catalysts ð48JCS0452Ł or phosphorus oxychlorideð48HCA0548\ 55LA"690#110Ł and N!acyl!2\4!dimethylpyrazoles and N!acylimidazoles with aluminumchloride provide access to weaker acylating agents than the corresponding acid chloridesð51LA"542#070Ł[

(14)+AlCl3, reflux

83%

O

O

( )15

O

( )15

(15)+

OMe

O

OMeO

MeO

OMe

OSbCl5/Ph2BCl, NaHCO3 (aq.)

CH2Cl2, RT

71%


Seleno esters provide a useful alternative to classical FriedelÐCrafts acylating agents and givegood to high yields of ketones using active aromatic substrates "e[g[\ anisole\ furan#\ and thecrystalline complex of copper"I# tri~ate and benzene ð"CuOTf#1PhHŁ as catalyst ð79JA759Ł[ The tri~icacid generated can be scavenged by inclusion of calcium carbonate in the reaction mixture[

Some useful reactive reagents for acetylation and tri~uoroacetylation of aromatic systems includeacetylmethanesulfonate ð78SL43Ł\ tri~uoroacetyl tri~ate ð68JOC202Ł and 1!"tri~uoroacetoxy#pyridineð89CL672Ł[ The _rst two reagents require no catalysts for e.cient reaction\ and the latter compoundproduces\ in the presence of aluminum trichloride\ the tri~uoroacetyl derivative of benzene inmoderate yield at 9>C in dichloromethane "Equation "05##[ In a similar vein\ oxocarbonium hexa!~uoroantimonates are equally reactive and provide benzene derived ketones in good yields with noneed for catalysts "Equation "06## ð52JA0217\ 53JA1192Ł[

(16)+ CF3

O

N O CF3

O AlCl3

53%

(17)+

OO

SbF6–

+

benzene, warm

93%

Finally\ ketones behave as internal anhydrides and will acylate aromatic compounds in thepresence of aluminum trichloride and some other catalysts ðB!53MI 295!90\ B!62MI 295!91Ł[ The variedoutcomes of such reactions have led to little practical application[

2[95[0[0[3 The HoubenÐHoesch synthesis

FriedelÐCrafts acylations with nitriles and HCl "H1SO3 is sometimes used instead#\ and subsequenthydrolysis of the so!formed ketiminium salts to give the desired ketones is generally referred to asthe HoubenÐHoesch reaction ð51RCR504\ B!53MI 295!90Ł[ In most cases a Lewis acid catalyst is alsorequired[ Zinc chloride has been used most frequently\ but boron trichloride has often replaced thisin later work[ The reaction usually requires relatively electron!rich aromatic substrates and is mostuseful with polyhydric phenols "Equation "07## ð77MI 295!90\ 78BCJ2260Ł "monohydric phenols giveimino esters#\ phenolic ethers\ aromatic amines ð67JA3731\ 79TL062Ł and combinations thereof "Equa!tion "08## ð64HCA63Ł[ Some reactive heterocyclic compounds can also be acylated[ Aromatic sub!strates lacking electron!releasing substituents can be acylated in some cases if the nitrile moietycontains electron!withdrawing groups that increase the electrophilicity of the reactive species[Equation "19# shows an example where toluene participates in such a reaction ð73LA0289Ł[N!Methylnitrilium salts which are prepared by treating nitriles with methyl tri~ate ð72JCS"P0#0964Łor trimethyloxonium ~uoroborate ð74TL3538Ł are good acyl cation equivalents and give particularlygood yields with heteroaromatic substrates such as pyrroles and indoles[

+

OH

OHHO

OH

OH

OHHO

OH

CN

O

(18)ZnCl2, HCl, Et2O

63%

MeO

OMe

NH

NC

N Me

N

NO

MeO

MeO

Me

H

(19)H2SO4 (conc.)

CHCl3

172General Methods

(20)NH

N

CNNC

NN

ONH2

AlCl3, toluene

34%

2[95[0[0[4 Reactions with other acyl cation equivalents

The formylation of aromatic systems with chloroform and hydroxide ion is a well documentedprocess known as the ReimerÐTiemann reaction[ The reaction proceeds via an electrophilic dichloro!carbene species to give a dichloromethyl benzene product which is then converted into the desiredaldehyde on hydrolytic workup[ The analogous reactions with alkyl trichloromethyl substrateshave only received limited attention but some examples include the formation of purinyl ketonesð52JOC0268Ł and a very e.cient benzoylation\ under FriedelÐCrafts conditions\ using "trichloro!methyl# benzene "Equation "10## ð80S211Ł[ The latter method allows for benzoylation under relativelymild reaction conditions and makes use of a cheap\ nonhygroscopic\ and nonlachrymatory reagent[

(21)

i, AlCl3ii, H2O

98%

HN

O

+CCl3

NH

O

O

Some sulfur!based functional groups which serve as alternative masked acylating agents include1!substituted 0\2!benzoxathiolium tetra~uoroborates ð76S200Ł\ bisphenylthionium ions ð76T0736Łand acyl sulfones ð73JA1358Ł[ The former reagents add e}ectively to active aromatic substrates toprovide intermediate benzoxathioles which are easily hydrolysed to the corresponding ketones[ Thereactions proceed under mild conditions and o}er the possibility of introducing tertiary acyl groups"Equation "11##[ Bisphenylthionium ions are generated by the action of dimethyl"methylthio#sulfonium ~uoroborate "dmtsf# or silver tri~ate on tris"phenylthio#alkanes and\ through sub!sequent hydrolysis of the thioacetals obtained\ provide a useful method for intramolecular acylation"Scheme 0#[ Intramolecular acylations are also possible with reactive acyl sulfones\ generated in situby the action of Lewis acids "BCl2 and TiCl3# on protected alkoxy!bis"sulfonyl# derivatives\ and leaddirectly to the required ketone "Equation "12##[ These three methods are signi_cant in that thestarting materials are easily prepared and are inert to various other functional group manipulations\thus allowing for selective unmasking of the active acylation species as required[

(22)

OMe

MeOO

SBut+

BF4–

OMe

MeO

But

O

+

i, pyridine, MeCN, 50 °Cii, HgO, THF, HBF4 (aq.), RT

60%

MeO

SPh

SPh

SPh

MeO

SPhPhS

MeO

O

Scheme 1

hydrolysisAgOTf

CH2Cl2, RT

91%

(23)

OO

SO2

O2S

TMSTiCl4, CH2Cl2, –10 °C to 0 °C

68%


2[95[0[1 Electrophilic Acylations of Organometallic Species

For a long time the synthesis of ketones by acylation of nonstabilised organometallic specieswith carboxylic acid derivatives was a problematic process[ The fact that the required ketone wasoften considerably more reactive than the usually weakly electrophilic substrate resulted in over!addition and the formation of alcohols[ Relatively recent developments have largely solved suchproblems\ and various single step methodologies are now available ð80COS"0#286Ł[ The aromaticcomponent of the ketone target can be introduced as a nucleophilic or electrophilic moiety"Scheme 1#\ and consequently allows for considerable ~exibility in synthetic design\ often providingmore practical or complementary alternatives to methods such as the FriedelÐCrafts acylation[ Theease of preparation of aromatic anions is central to the importance of these methods[

ArM + + RMX R

O

Ar X

O

Scheme 2

Ar R

O

2[95[0[1[0 Acylations of organolithium reagents

Carboxylic acids can be converted directly into ketones on exposure to many easily accessibleorganolithium species ð69OR0Ł[ Benzoic acid derivatives and phenyllithium species are both com!patible with this method\ and they can provide the corresponding aromatic ketones in good yields[The main side!reaction is over!addition to give tertiary alcohols as products[ The extent to whichthis occurs is highly dependent on the stability of the relevant dilithium intermediates[ Stabilisationof these intermediates can greatly improve yields\ and this can be achieved by addition of TMS!Cl to the reaction mixture ð72JOC0449\ 75JOC840Ł[ Complications can also arise from competitivedeprotonation of substrates although careful choice of conditions or of protecting groups usuallyallows for the circumvention of such problems[ The reaction is e.cient for the annulation ofbromoaromatic acids "Equation "13## ð71ACR299Ł\ but phenyllithium and o!benzylbenzoic acid\ forexample\ give 8!phenylanthracene as the only product ð46JA282Ł[ The formation of the latter ispostulated to occur via competitive deprotonation to give the benzhydryl carbanion[ a!Amino acidshave been used as substrates with successful preservation of their stereochemical integrity "Equation"14## ð70JA5046\ 73JA0984Ł[ Ketones can be prepared by sequential addition of organolithium reagentsto carbon dioxide and the intermediate carboxylates ð81AG"E#0924Ł[

(24)Br CO2H

O

2BuLi, –100 °C

77%

MeO

MeO

Li

+ HO OH

O

NHSO2Ph

MeO

MeO

OH

NHSO2Ph

O

(25)–78 °C

83%

Acylations of organolithium species by simple carboxylic acid derivatives are generally not widelyapplicable\ due largely to the poor stability of the so!formed tetrahedral intermediates\ but exampleshave been reported for a number of such substrates[ Thus\ acid chlorides "Equation "15##ð71JOC0474Ł\ esters ð75JOC840Ł\ lactones "Equation "16## ð72JA6533\ 73CC429Ł\ and amides "Equation"17## ð73TL700Ł have all been utilised in this manner[

(26)+O

N

MeO

Cl

O

OMe

OON

BuLi

174General Methods

OMe

OMe OMe

MeO2C OHO

O

(27)+hydrolysis

60%

OMe

OMe OMe

Li

O OMe

O

O

O

O

(28)+Li

N

O O

The best acylating agents to date are the N!methoxy!N!methylamides developed by Weinrebð70TL2704Ł[ These species are readily available from the corresponding carboxylic acids\ are tolerantof many reaction conditions\ and selectively yield the desired ketone products even in the presenceof excess organolithium reagent[ The product speci_city of these compounds is due to the exceptionalstability of the tetrahedral intermediate which e}ectively masks the ketone product from furtherreaction[ The aromatic moiety may be incorporated into either the nucleophilic ð76JOC1504Ł orelectrophilic ð70TL2704Ł substrate\ and can also be applied in an intramolecular fashion as dem!onstrated in a recent approach to benzocyclobutenones starting from iodo!substituted aromaticWeinreb amides "Equation "18## ð81TL4320Ł[

(29)MeO

MeO I

N

O

OMe

MeMeO

MeO O

ButLi, THF, –78 °C

67%

2[95[0[1[1 Acylations of Grignard reagents

Organomagnesium or Grignard reagents bear some similarities to the lithium species discussedin the previous section[ Once again\ addition of these organometallics to carboxylic acid derivativescan result in isolation of the requisite ketones ð43OR"7#17Ł[ Additions to carboxylic acids themselvesare hampered by the unstable nature of the intermediates and tertiary alcohols are the usualproducts[ In contrast to alkyllithium species\ Grignard reagents are acylated by acid chloridesalthough the mechanism is not fully understood[ Thus acetophenones are readily formed from thestoichiometric combination of aryl magnesium species and benzoyl chlorides ð68TL3292Ł[ Additivessuch as vanadium trichloride "Equation "29## ð75TL818Ł and iron"III# salts "Equation "20## ð73TL3794\74TL0174\ 76TL1942Ł promote monoacylations of Grignard reagents\ the latter in substoichiometricquantities[ Alkyl aryl ketones have been prepared by nickel"II# and then iron"III# salt catalysedadditions of Grignard reagents to S!phenyl carbonochloridothioate ð74TL2484\ 77TL2476Ł[ Thesemethods tolerate functionality such as esters\ nitriles and alkyl halides[

(30)ClOEt

O

OMgBrOEt

O

O

+VCl3, CH2Cl2

76%

(31)

MgBr

MeO

O

Cl

O

+

OMe

Fe(acac)3 (3 mol%), THF

55%

Some Grignard reagents will react with aryl esters in the presence of triethylamine to give thedesired ketones ð79S766Ł[ This method relies on masking of the intermediate ketone by basicenolisation\ and is consequently highly substrate dependent[ As in the previous section\ Weinrebamides ð70TL2704Ł are good acylating agents for organomagnesium compounds but a number of


other acid derivatives rival their success in such transformations[ Some of the best such substratesare the S!"1!pyridyl# thioates developed by Mukaiyama ð62JA3652\ 63BCJ0666Ł[ Derived from thecorresponding acids or acid chlorides\ these compounds do not stabilise tetrahedral intermediatesbut\ rather\ provide highly reactive species by coordination to the divalent magnesium ion\ whichare selectively attacked in preference to other ketone functionality "Equation "21## or ketoneintermediates[ In a similar vein\ esters derived from 7!hydroxyquinoline ð51JA3788Ł\ 1!hydroxy!2!methylpyrazine "Equation "22## ð66CL534Ł\ 1!pyridyl ketone oximes "Equation "23## ð75CL338Ł andN\N!diphenyl!p!methoxyphenylchloromethyleneiminium chloride "Equation "24## ð71TL4948Ł haveall shown some utility in aromatic ketone synthesis\ as have anhydrides ð37JOC481Ł\ mixed an!hydrides of phosphorus ð67SC48Ł and acylimidazoles ð51LA"544#89Ł[

(32)S

NO

O

Ph

O

OPhMgBr, THF, 0 °C

(33)O

N

N

O

O

PhMgBr

79%

(34)PhMgBr

85% C15H31 Ph

OO N

N

C15H31

O

(35)PhMgBr

66%

O NPh

Ph

O

OMe

+

Cl–Ph

O

Finally\ aryl Grignard reagents can add to nitriles to give iminyl intermediates which are easilyhydrolysed to the corresponding ketones on workup ð58JA4775\ 61JOC2258Ł[ Mild Lewis acids suchas LiClO3 ð64JOM"88#30Ł and TMS!Cl "Equation "25## ð80TL5620Ł often improve the e.ciency ofthis transformation[

(36)

MgBr

NC O-TBDMSO O-TBDMS

OO i, TMS-Cl

ii, H3O+

96%+


2[95[0[1[2 Acylations of organocopper reagents

Dialkylcuprates derived from the corresponding organolithium or magnesium reagents and cop!per"I# iodide are relatively unreactive towards ketone functionality at low temperature[ Conse!quently\ additions of these reagents to acid chlorides constitute a useful ketone synthesis ð69TL3536Ł[Some limitations of functional group compatibility in the preparation of these reagents can beavoided by the direct preparation of simple cuprates from functionalised bromides using highlyreactive copper derived from lithium naphthalide reduction of copper"I# iodide triphenylphosphinecomplex ð77JOC3371\ 77TL3402Ł\ copper"I# cyanide lithium bromide complex ð80JA3561Ł\ or lithium"1!thienylcyano#cuprate ð78SC0722\ 82JOC1381Ł[ This method is compatible with ester\ nitrile\ chloride\

176General Methods

and some epoxide and ketone functionalities "Equation "26##[ However\ both methods have draw!backs[ In the former case three equivalents of the dialkylcuprate are required\ and in the latter casea similar quantity of the acid chloride must be used[

(37)Ph

O

+

CNDME, 0 °C

71%Ph Cl

OCu

CN

Alternatives to acid chlorides include thiol esters "Equation "27## ð79TL1902Ł\ and 1!pyridyl esters"Equation "28## ð72JOC1597Ł[ The latter are particularly useful as their high reactivity promotesreaction with the intermediate lithium alkyl "1!pyridyloxy# cuprate complex\ and hence allows fore}ective reaction using a single equivalent of dialkyl cuprate[ The conditions also tolerate functionalgroups such as bromide\ ketone and ester in the pyridyl ester moiety[

N

SPh

PPh3

CO2NB

OO N

Ph

PPh3

CO2NB

OO (38)

Ph2MgCuX, Et2O, THF

(39)

Ph O

NO

Ph But

O+ But

2CuLi (1 equiv.)THF, –78 °C

74%

The uneconomical nature of nonstoichiometric dialkyl cuprates and the thermal instability ofs! and t!alkylcuprates ð58JA3760Ł has led to the development of mixed cuprates with only a singletransferable ligand[ The most successful nontransferable ligands for acylation of cuprates have beenvarious heteroalkyls[ Phenylthio and t!butoxide "Equation "39## ligands give good to excellentresults ð62TL0704\ 62JA6677Ł at −67>C\ and diphenyl "Equation "30## and dicyclohexyl phosphidoligands show similar utility at room temperature ð71JA4713\ 73JOC0008Ł[ More recently\ Knochel andhis co!workers have developed a new class of organocopper reagents "RCu"CN#ZnI# which areeasily prepared from alkyl iodides[ These reagents are stable up to 9>C\ they have one transferablegroup and furthermore they tolerate a wide range of functionality "Equation "31## ð77JOC1289Ł[

(40)Cl

O

+ But(ButO)CuLi But

OTHF, –78 °C

82%

(41)Cl

O

+ ButCu(PPh2)Li But

OEt2O, 0 °C

80%

(42)

O

O

O OO

O

O

I

i, ii, iii

80%

i, Zn, THF; ii, CuCN•2LiCl; iii, , 0 °CCl

O

2[95[0[1[3 Acylations of organotin reagents

Aryl stannanes themselves react readily with acyl halides in the presence of excess Lewis acid togive the corresponding aromatic ketones ð60MI 295!90Ł[ However\ the reactions of the analogous


organosilanes are usually the reagents of choice in such reactions[ Transition!metal catalysedcouplings of acid halides with organotin compounds have also developed into a mild and selectiveapproach to aryl ketones[ Pioneering work by Migita ð66CL0312Ł and by Stille ð67JA2525\ 68JOC0502\75AG"E#497Ł has shown that palladium"9# e.ciently catalyses the reaction and that aromatic andheteroaromatic acid chlorides give high yields of ketones[ The reaction is general with respect to theorganotin compound ð72JOC3523Ł and the acid chloride "Equations "32# and "33##\ it works well insterically demanding cases "Equation "34## and su}ers from virtually no side!reactions while remain!ing experimentally simple[ In the catalytic cycle\ aryl groups are transferred from tin in preferenceto alkyl groups and the use of aromatic trimethyl! or tributyltin derivatives provides an economicalroute to ketones incorporating expensive or synthetically demanding fragments[ The catalyst ofchoice is usually benzoylchloro!bis"triphenylphosphine# palladium"II# "from which the palladium"9#species required is formed in situ#\ and as both this reagent and most organostannanes are air!stable\the reaction can be carried out under an oxygen atmosphere which in turn has been found toaccelerate the transformation[ Finally\ the mild conditions tolerate a variety of functionality\including nitro\ nitrile\ aryl halide "�Br#\ alkenyl\ methoxy\ ester\ and even aldehyde functions"Equation "35##[

(43)Cl

O+ Ph4Sn

Ph

OPhCH2Pd(PPh3)2Cl

76%

(44)+ Me4SnPhCH2Pd(PPh3)2Cl

100%

O

NC

Cl

O

NC


82%But Cl

O

But

O


86%

CHO

O Cl

CHO

O

2[95[0[1[4 Acylations of organozinc reagents

The reactions of arylzinc reagents with alkyl acid chlorides and of alkylzincs with aroyl chlorideshave found considerable use in the synthesis of aryl ketones\ and they are often used in preferenceto the corresponding reactions of Grignard reagents ð43OR"7#17Ł[ The lower reactivity of zinc reagentstowards ketones is often su.cient to prevent over!addition and formation of tertiary alcohols[However\ in many cases only low yields are obtained and the development of other organometallicshas led to a decline in the use of these reagents[ Developments in transition!metal catalysis andparticularly the use of palladium catalysts has led to a reexamination of the role of organozincs insynthesis[ Thus\ as with organostannanes\ organozinc compounds are readily acylated by acidchlorides in the presence of catalysts such as benzylchloro!bis"triphenylphosphine#palladium\"dppf#PdCl1 "Equation "36## ð73JOC1177Ł\ tetrakis"triphenylphosphine#palladium "Equation "37##ð72TL4070Ł\ and Pd"PPh2#1Cl1 ð70CL0024Ł[ Equation "38# ð78CC533Ł illustrates an application of thismethodology to the synthesis of amino acid derivatives[

(47)+ Bun2Zn

(dppf)PdCl2, THF, Et2O

82%

O

Cl

O

178General Methods

Ph

O

Cl

Pd(PPh3)4, THF

95%Ph Cl

O+

ZnCl

Cl

(48)

(Ph3P)2PdCl2

70%Ph Cl

O+ IZn

NHBOC

CO2Bn

NHBOC

CO2Bn

Ph

O(49)

2[95[0[1[5 Acylations of miscellaneous organometallic reagents

A number of organometallic species not mentioned above have been used in the synthesis ofaromatic ketones[ Historically\ organocadmium reagents are of considerable importance and pro!vide ketones on addition to acyl halides ð43OR"7#17Ł[ However\ the instability of many of thesereagents ð59JOC366Ł and high toxicity have led to their relatively low contemporary popularity[Organoaluminum reagents in the presence of a palladium catalyst have been applied to the synthesisof simple alkyl aryl ketones ð74BCJ1314Ł and boronate complexes have been used to prepare ketonesin conjunction with acid chlorides with "Equation "49## ð82JOM"332#142Ł or without ð64JOC0564\64TL3128Ł palladium catalysts[ Nickel"9# catalyses the addition of benzylic halides to aroyl chloridesð72TL1340\ 74JOC0262Ł\ and work by Mukaiyama and co!workers ð70CL420Ł has shown that alkyliodides can be acylated in good yields with aromatic 1!"5!"1!methoxy!ethyl#pyridyl# carboxylates inthe presence of nickel"II# chloride "09 mol)# and zinc dust "Equation "40##[ The latter method istolerant of functional groups such as ketones\ esters\ chlorides and a\b!unsaturated carboxylic acidderivatives[ Lastly\ although the role of rhodium in acylation has been largely overshadowed by theuse of palladium catalysts\ alkyl rhodium complexes provide a mild method for the acylation ofsimple alkyl! and aryllithiums or Grignard reagents ð62JA2939\ 64JA4337Ł[

(50)+Pd(PPh3)4 (1 mol%), THF

76%Na+ –BPh4

O2N

Cl

O

O2N

Ph

O

(51)+NiCl2 (10 mol%), Zn, DMF

81%

O

Cl

N

OMe

O

ClI

2[95[0[2 Aryl Ketones by Carbonylative Cross!coupling Reactions

As described in the previous section\ the transition!metal catalysed coupling of organometallics"e[g[\ organostannanes# with acid chlorides provides a very useful entry to aromatic ketones[ In arelated manner\ metal!catalysed coupling reactions of various organometallic species with certainelectrophiles produce ketones when executed under a carbon monoxide atmosphere "Equation "41##[This carbonylative cross!coupling methodology consequently expands the utility of organometallicreagents in aromatic ketone synthesis\ and in many cases allows for a greater tolerance of func!tionality within the relevant substrates[

(52)transition-metal catalyst

CO atmosphere Ar R

OArX + RM

Palladium catalysts give access to the most general methods for the above!mentioned trans!formations[ Tanaka ð68TL1590\ 70BCJ526Ł _rst showed that aryl halides and organotin compoundsgive ketones in the presence of C5H4PdI"PPh2#1 and carbon monoxide[ However\ this methodrequires high CO pressures and HMPA as cosolvent\ two factors which detract from this reagent


combination[ Aryl diazonium salts react with tetramethyltin and carbon monoxide\ using palladiumdiacetate as catalyst\ to give good yields of acyl arenes ð71CL24Ł[ This method is compatible withvarious aryl substituents "i[e[\ Me\ Cl\ Br\ I\ NO1^ Equation "42## but does not work as well withother tetralkyltin compounds and again requires high CO pressures[

(53)

O2N

N2+ BF4

–

O2N

O

+ Me4SnPd(OAc)2 (2 mol%), CO

85%

Coupling reactions of aryl iodides with alkyl! or benzylzinc compounds and using tetra!kis"triphenylphosphine#palladium gives the desired ketones in moderate to good yield under anatmospheric pressure of carbon monoxide "Equation "43## ð72TL2758Ł[ Aryl tri~ates\ which arereadily available from phenols\ react with organostannanes in the presence of carbon monoxide"0 atm#\ dichloroð0\0!bis"diphenylphosphino#ferroceneŁpalladium"II#\ and lithium chloride to a}orda variety of aryl ketones\ again in variable yields ð77JA0446Ł[ Many functional groups are toleratedby this method "e[g[\ Equation "44##\ but strong electron!withdrawing groups on the organo!stannanes should be avoided[ Unsymmetrical diaryl and aryl!hetaryl ketones are convenientlyaccessed by cross!coupling reactions of organo~uorosilanes with aryl halides in the presence ofcarbon monoxide "0 atm#\ potassium ~uoride and "h2!C2H4PdCl#1 ð78CL1938\ 81T1002Ł[ The reactionconditions tolerate reactive functional groups such as esters\ ketones\ aldehydes "Equation "45## andnitriles[

(54)

O

+ I

I Pd(PPh3)4 (1 mol%), CO (1 atm)Zn–Cu, THF

91%

(55)

O

+

OTf

OAc

PhSnMe3

OAc

PdCl2(dppf) (4 mol%), CO (1 atm)LiCl, DMF

78%

(56)+S Si(Et)F2

I CHO

(η3-C3H5PdCl)2, CO (1 atm)KF, DMI

72% CHO

O

S

Unsymmetrical biaryl ketones and alkyl aryl ketones are available by palladium!catalysed"PdCl1"PPh2#1# carbonylative cross!coupling of 8!alkyl!8!BBN derivatives or arylboronic acids withiodoarenes as described by Suzuki and his co!workers ð80BCJ0888\ 80TL5812\ 82TL6484Ł[ These reactions"e[g[\ Equation "46## generally give good yields of ketones and the conditions used are intrinsicallynon!intrusive to a range of functionality[ Sodium tetraphenylborate ð77JOM"234#286Ł and aryl!aluminum compounds ð74TL3708Ł undergo carbonylative cross!coupling with alkyl! and aryliodidesrespectively[ The former requires a platinum catalyst and high CO pressure\ whereas the latterproceeds at atmospheric pressure with PdCl1"MeCN#1[ The nature of the organometallic speciessomewhat limits the synthetic value of these methods[ Rhodium"I# catalysts have found some usein the carbonylation of arylmercury ð79JOC2739\ 71IZV110Ł and arylbismuth reagents ð81CC342Ł[Isocyanides\ which are isoelectronic with carbon monoxide\ can be utilised in palladium!catalysediminocarbonylative cross!coupling reactions to yield imines which are readily hydrolysed to thecorresponding aryl ketones[ Both organotin ð74TL2352\ 75BCJ566\ 75CL0086Ł and 8!alkyl!8!BBN "8!BBN�8!borabicycloð2[2[0Łnonyl# derivatives ð81TL3354Ł can be utilised in this manner[ The formerreact with imidoyl chlorides and Pd"PPh2#3\ whereas the latter combine with t!butylisocyanide andaryl halides in the presence of Pd"PPh2#3 and K2PO3 to give good yields of functionalised aryl alkylketones after hydrolytic workup "Equation "47##[

180General Methods

(57)+

IO

CO2MeCO2Me

B(OH)2

F

FPdCl2(PPh3)2 (3 mol%)

CO (1 atm), K2CO3, anisole

76%

MOM-O

IB

O

O

MOM-O

O

O

O

+ (58)i, ii

89%

i, Pd(PPh3)4 (5 mol%), ButNC, K3PO4, dioxane, THF; ii, 2M HCl

MOM = methoxymethyl

2[95[0[3 Acyl Anion Equivalents in Aromatic Ketone Synthesis

Acyl anion equivalents ð80COS"0#430Ł are umpoled synthons ð68AG"E#128Ł\ which on alkylation ðAŁor arylation ðBŁ "Scheme 2#\ can provide aryl alkyl ketones either spontaneously or after a simplehydrolytic step[ This section brie~y summarises some of the more commonly used members of thisclass of reagent and examples of their application to the synthesis of aromatic ketones[

R+

[A]

Ar+

[B]

O

Ar –

O

R–Ar R

O

Scheme 3

2[95[0[3[0 1!Alkyl!0\2!dithianes

1!Alkyl!0\2!dithianes\ which are derived from the corresponding aldehydes or by alkylation of1!lithio!0\2!dithiane\ are readily lithiated\ and the resulting anions can then be alkylated with avariety of electrophiles to give masked ketones which are henceforth unveiled on hydrolysis ð66S246Ł[Similarly\ 1!aryl!0\2!dithianes are readily prepared from benzaldehyde and its derivatives or fromother aryl aldehydes ð66OS"45#7Ł[ Examples of metallation and electrophilic alkylation of such com!pounds are found in an approach to lignan lactones "Equation "48## ð67JOC874Ł\ the synthesis of2!acetylindole ð61HCA64Ł\ and in studies of conjugate additions to a!alkylidene!g!butyrolactonesð74TL2916Ł and to a\b!unsaturated esters ð74TL2920Ł[ Alkylations with alkyl halides\ epoxides "Equa!tion "59## and carbonyl compounds are all relatively high yielding ð66S246Ł[ Conversely\ 1!aryl!1!lithio!0\2!dithianes have been successfully arylated using "h5!alkylbenzene# Cr"CO#2 complexes"Equation "50## ð72OM356Ł[

O

O

Li

SS

O

O

O

O

MeO

OMe

OMe

O

H

H (59)

i, 2-butenolide ii, 3,4,5-trimethoxybenzyl chloride

iii, HgO–BF3, THF, H2O

O-MOM

MOM-O

S

S

O-MOM

MOM-OS S

OH

i, BunLi

ii,O

(60)


S S

LiAr

(61)

(OC)3Cr

But

+

But

Ar

S S

Ar

S S

But

80%+

Ar = NMe2

63 : 37

2[95[0[3[1 Protected cyanohydrins

By in situ formation of a cyanohydrin carbanion\ cyanide ions catalyse the conjugate addition ofaromatic and heteroaromatic aldehydes to a\b!unsaturated ketones\ esters and nitriles ð65AG"E#528Ł[More commonly\ the cyanohydrin silyl ethers ðB!70MI 295!90\ 72T2196Ł derived from aryl and hetarylaldehydes ð68CB1934Ł are used[ These are deprotonated with LDA\ and the resulting anions thenreact smoothly with a range of alkylating agents "e[g[\ Equation "51## ð79CB291Ł[ Fluoride!ioninduced hydrolysis subsequently unmasks the ketone functionality "Equation "52## ð73OR36Ł[ Othertypes of protected cyanohydrin\ although perhaps not as popular as the silyl ethers\ can be metallatedand show similar reactivities[ Acetals ð73OR36Ł\ esters ð72CPB2840Ł and carbonates ð73SC632\ 73SC638Łare all useful and the corresponding reagents have all been applied to the synthesis of aryl ketones[As in the case of metallated dithianes\ cyanohydrins derived from alkyl aldehydes can undergoarylation with p!chromium tricarbonyl complexes ð69MI 295!90Ł[ Subsequent workup again providesthe aryl alkyl ketones[

(62)CN

O-TMS

O

CNTMS-O

O

i, LDA

ii,

86%

CN

O-TMS

O

OO i, LDA

ii,

iii, [(C2H5)3NH]F 60%

BrO

O(63)

2[95[0[3[2 Acyl radicals

Free!radical reaction conditions are compatible with most functional groups and have led to theemergence of such methods as important modern synthetic tools ðB!75MI 295!90\ 77S306\ 77S378Ł\particularly in the construction of carbocyclic systems[ Acyl radicals\ and particularly those derivedfrom phenylselenoesters by thermally induced trialkyltin hydride:1\1?!azobisisobutyronitrile "AIBN#homolytic cleavage\ constitute an e}ective method of ketone preparation on addition to doublebonds ð77JOC2266\ 89T1024Ł[ Aryl acyl radicals give the corresponding aryl ketones in useful yieldson intermolecular addition to activated alkenes "Equation "53## ð78JOC0666Ł or on analogousintramolecular cyclisation "Equation "54## ð81JOC0318Ł[ Aryl acyl radicals are less prone to decar!bonylation than some of the alkyl acyl species and are usually immune to intramolecular 0\4!hydrogen abstraction[ Alkyl acyl radicals add to some heteroaromatic systems to give ketonesð77HCA420Ł[

182General Methods

SePh

O

MeO

O

MeO

OMe

O

OMe

O(64)

(5 equiv.)

+

Bun3SnH, AIBN

benzene, ∆

74%

(65)SePh

OO

OMe

O

OMeOBun

3SnH, AIBNbenzene, ∆

84%

2[95[0[3[3 Miscellaneous acyl anion equivalents

Aromatic halides are readily acetylated by enol ethers ð70JOC4303Ł\ or by the zinc ð72JA832Ł andtin ð76BCJ656Ł derivatives of lithiated enol ethers\ in the presence of palladium catalysts[ Similarly\aryl tri~ates undergo a Heck reaction with butyl vinyl ether ð89JOC2543Ł[ These reactions areparticularly useful for acetylations of electron!de_cient aromatics such as nitrobenzene "Equation"55##[ Lithiated diethyl a!trimethylsilyloxy!benzylphosphonate ð67TL252Ł and t!butylhydrazonesð72CC0939Ł have been used as acyl anion equivalents in the preparations of simple phenyl ketones\as have a number of acyl metal complexes[ Acyl tetracarbonylferrates couple with alkyl and acylhalides ð58TL4078Ł\ and with aryl halides and a palladium catalyst "Equation "56## ð77CL0030Ł[Unsymmetrical and symmetrical diaryl ketones have been prepared from arylmercury"II# halides inthe presence of nickel tetracarbonyl ð66S665Ł or dicobalt octacarbonyl ð57JA439Ł[

(66)

i, PdCl2(PPh3)2

ii, H3O+

91%O2N Br O2N

O+

Bun3Sn OEt

(67)Pd(PPh3)4, ZnCl2

69%MeO

I

O

Na[BuiCOFe(CO)3L] +MeO

O

Bui

O

2[95[0[4 Oxidation

Ketones are readily prepared by oxidative methods\ and the extra facility imparted to suchprocedures by the proximity of aromatic groups often makes oxidation a viable route to the desiredaryl and hetaryl ketones[ Benzylic methylene carbon atoms\ secondary alcohols and alkenes can allbe e.ciently transformed into ketones in this manner[

2[95[0[4[0 Oxidations of benzylic methylene groups

Benzylic methylene groups are activated towards oxidation and can be converted into ketones bya variety of reagents[ Diarylmethanes are similarly converted into benzophenones with the extraactivation further facilitating oxidation[ The product ketones are relatively inert to over!oxidation\a feature which often allows for the application of more vigorous conditions when required[ Someof the most commonly employed reagents are chromium based reagents such as sodium andpotassium dichromate ð44JCS1575\ 78CC0244Ł\ pyridinium chlorochromate ð75SC0382Ł\ chromic acid inacetic acid "Equation "57## ð40JA2352Ł and chromate:t!butylhydroperoxide combinations ð75TL2028\76TL1020Ł^ potassium permanganate "Equation "58## ð50JOC3040\ 61CJC0814\ 78S182Ł^ selenium dioxideð30JCS424\ 58BSF804\ 63HCA1190Ł^ 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq# ð66CL476\77JOC3476Ł^ ceric ammonium nitrate ð89SC2148Ł^ manganese dioxide ð72IJC"B#0135Ł^ lead tetraacetate


ð64H"2#338Ł and ruthenium oxide:sodium periodate ð62MI 295!90Ł[ Autooxidations in air "Equation"69## ð60JA3210Ł are sometimes useful\ although a catalyst may be necessary ð56TL2554Ł[ Otherprocedures include photochemical oxidations with iron trichloride in wet acetone ð73HCA755Ł andoxidations of carbanions ð79JOC1674Ł[

(68)

HAcO

Ph

HAcO

Ph

OCrO3, NaOH (0.5N)HOAc (80%)

70%

N

OMeH

OMe

MeO

Me

MeO

N

OMeH

OMe

MeOMeO

OO

KMnO4 (excess), AcOH, acetone

82%(69)

NMeO

O

O

OOMe

OMeOMe

NMeO

O

O

OOMe

OMeMeO

air, EtOH

63% O

(70)

2[95[0[4[1 Oxidations of secondary benzylic alcohols

Secondary benzylic alcohols are readily accessible by nucleophilic additions to aldehydes\ andtheir subsequent oxidations provide an alternative to ketone syntheses by direct acylations ofnucleophiles[ The activated nature of the benzylic C0H bond makes for facile reactions\ and alarge variety of reagents successfully accomplish this transformation[ Chromium! and per!manganate!based reagents are a popular choice "e[g[\ ð64JCS"P0#511Ł and ð53JOC463Ł# "comparethe previous section#\ but many others\ including nickel bromide:benzoyl peroxide ð68JOC1844Ł\ruthenium chloride with acetone ð81CC226Ł or t!butyl hydroperoxide ð82S322Ł\ sodium chlorateð62TL2524Ł\ diethyl azodicarboxylate "dead# ð55JA1217Ł\ bromine ð55JOC1697Ł\ Swern conditionsð77TL4450Ł\ DessÐMartin periodinane ð89JOC5050Ł and mcpba ð89SC526Ł have been used in highyielding ketone preparations[ Manganese dioxide "e[g[\ ð64TL1446\ 77CL0276Ł is particularly useful\since the oxidations of benzylic alcohols occur selectively in the presence of other unprotectedalcohol functionality "excluding allyl alcohols\ which are also oxidised#[ Benzyl ð81JOC4730Ł andsilyl ethers ð79S786\ 72S461\ 89SL234\ 80TL2882\ 81SC0882Ł of secondary benzylic alcohols can be convertedinto ketones directly without a primary group deprotection step[

2[95[0[4[2 Oxidative cleavages of double bonds

Although not a particularly common method for the synthesis of aromatic ketones\ oxidativecleavages of double bonds have found some use[ Permanganate is e.cient under phase!transferconditions and will selectively cleave aryl!substituted double bonds in the presence of alkyl!sub!stituted double bonds ð75JCR"S#347Ł[ The actions of osmium tetroxide:sodium periodate "Equation"60## ð76CC0259Ł and osmium tetroxide:Jones reagent ð82JOC3634Ł on aryl substituted double bonds

184Phenyl Ketones and Analo`ues

give the desired ketones\ as do hexavalent chromium compounds[ Chromium trioxide has foundthe most utility in aromatic ketone synthesis ð37JA2241\ 50JOC569Ł[

(71)OsO4, NaIO4, Et2O, H2O

65%MeO

O OEt

OMeO

O

CO2H

2[95[1 PHENYL KETONES AND SUBSTITUTED ANALOGUES

The FriedelÐCrafts acylation was\ and to a large extent often still is\ the method of choice for thesynthesis of aromatic ketones[ However\ the development of various organometallic methodologiesnow allows for varied and often complementary approaches to this class of organic functionality[This section concentrates on aspects of synthetic methods which are particularly important whenpreparing speci_cally substituted aromatic substrates[

2[95[1[0 Phenyl Ketones

The thermodynamic stability of benzene tends to make FriedelÐCrafts acylations relatively di.!cult[ However\ quite a considerable number of simple phenyl ketones have been prepared frombenzene in good yield by\ in most cases\ the combination of aluminum trichloride and the requisiteacid chloride or anhydride ðB!53MI 295!90Ł[ Benzene has been successfully acylated under somewhatmilder conditions using reactive carboxylic tri~uoromethanesulfonic anhydrides ð61AG"E#299\72CB0084Ł\ and 1!"tri~uoroacetoxy#pyridine is a useful reagent for the analogous tri~uoroacetylationsð89CL672Ł[

The ready availability and:or ease of preparation of phenyl metal species "e[g[\ PhLi# makes thepreparation of phenyl ketones by acylations of such species particularly attractive\ and in manycases the desired products are isolated in excellent yield ð75TL818\ 76JOC1504Ł[ In some cases theinherent basicity of some reagents may be problematic\ and other electrophilic centres may requireprotection[ Palladium catalysed ketone forming reactions of iodobenzene\ phenylboronic acid\ andthe tri~ate of phenol are extremely mild and tolerant to a range of functionality ð72TL2758\ 77JA0446\80TL5812Ł[ Derivatives of benzaldehyde such as dithioacetals and cyanohydrins are easily preparedð66S246\ 68CB1934Ł and provide umpoled synthons for the synthesis of phenyl ketones[ Benzoic acidderivatives such as phenylseleno esters give access to nucleophilic acyl radicals\ and other derivatives"e[g[\ benzoyl chloride# are also often used as the electrophilic component in acylations of organo!metallic species or in FriedelÐCrafts acylation and alkylation reactions[ Alkylations of enolates\although not discussed in this section\ are however particularly relevant to the synthesis of phenylketones due to the ready availability of acetophenone[

2[95[1[1 Monoalkyl Phenyl Ketones

Toluene and other monoalkylbenzenes often give high yields of mostly para!substituted ketoneson FriedelÐCrafts acylation with acid chlorides and aluminum trichloride[ Some alkyl groups "e[g[\propyl\ i!propyl\ t!butyl# are prone to migration under such conditions ð42JOC133\ 45JCS3832Ł\ anddehydrogenation of side chain can sometimes be problematic[ However\ more reactive acylatingagents and lower reaction temperatures can prevent such occurrences[ For example\ tri~uoro!acetylations of various alkylbenzenes using 1!"tri~uoroacetoxy#pyridine and aluminum trichlorideat 9>C gives only the desired para!isomers in good yield ð89CL672Ł[ A number of other reactiveacylating agents have shown promise with monoalkylbenzenes ð61AG"E#299\ 79JA759\ 72CB0084\ 74T3710\80S211Ł\ and toluene itself reacts with aroyl chlorides in the presence of catalytic quantities of ferrictrichloride\ zinc chloride or iron ð61S422Ł and the heterogeneous catalyst\ Na_on!H\ is similarlye}ective ð67S561Ł[ Lithiations at the benzylic positions of alkyl side chains usually prevent directmetallations of the aromatic rings with alkyllithium reagents\ but halogenÐmetal exchange reactionsallow for the ready preparation of many monoalkyl phenyl organometallic species and for thesubsequent ketone forming acylations of such reagents[ Similarly\ the relevant halides\ tri~ates


and boronic acids facilitate palladium!catalysed ketone synthesis by carbonylative cross!couplingð72TL2758\ 77JA0446Ł\ or by Stille ð67JA2525Ł and Suzuki ð82TL6484Ł methodologies[ Manymonoalkylphenyl aldehydes and carboxylic acids are commercially available and provide obviousbuilding blocks for a variety of the general methods of ketone synthesis already discussed[

2[95[1[2 Dialkyl! and Polyalkylphenyl Ketones

Aluminum trichloride and acid chlorides usually acylate symmetrically "R0�R1# substituteddialkylbenzenes to give ketones largely as isomers "0#\ "1# and "2# respectively and\ as expected\ thereactivity of xylenes increases in the order m!xylene×o!xylene×p!xylene[ When R0�R1 the prod!uct ratios are determined largely by relative steric interactions[ Dealkylative processes or alkyl!substituent rearrangements can occur but\ due to the greater general reactivity of these systems\ toa far lesser extent than with monoalkylbenzenes[ This increased nucleophilic character allows forsuccessful FriedelÐCrafts acylations under a variety of more modern conditions ð61S422\ 67S561\70CB815\ 72CB0084\ 89CL672\ 80S211Ł[ Polyalkylbenzenes\ being even more activated towards elec!trophiles\ are readily acylated under most FriedelÐCrafts conditions as well as with milder methodsutilising mixed anhydrides ð68S292\ 79S028\ 72CB0084Ł or those employing substoichiometric quantitiesof catalysts ð61S422\ 81CL324Ł[ The trimethylbenzenes\ pseudocumene and mesitylene are acylated togive the expected ketones "3# and "4# and hemimellitene\ presumably for steric reasons\ tends to giveproduct mixtures rich in the ketone "5#[ Symmetrical tetra! and pentamethyl benzenes give theexpected products in good yield[

R2

R1

O R3

R2

O R3

R1

R2

R1

R3

O

R

O O R O R

(1) (2) (3) (4) (5) (6)

2[95[1[3 Halophenyl Ketones

Halobenzenes are acylated predominantly in the p!position in the FriedelÐCrafts reaction[ Thehalogen substituents are considerably deactivating and necessitate the use of strong Lewis acids"e[g[\ AlCl2#[ Benzoylations of halobenzenes relative to benzene have been shown to occur withrelative rates decreasing in the order benzene×~uorobenzene× iodobenzene×bromo!benzene×chlorobenzene[ "Trichloromethyl# benzene and aluminum trichloride constitute a par!ticularly active reagent combination which reacts at room temperature to give\ on hydrolysis\benzoylated halobenzenes in high yield ð80S211Ł[ With few exceptions haloalkylbenzenes can beacylated with predictable regioselectivity and\ although very unreactive\ dihalobenzenes can undergosuccessful FriedelÐCrafts acylation ðB!53MI 295!90Ł[ Suzuki ð82TL6484Ł and Stille ð67JA2525Ł couplingreactions tolerate most aryl halide functionality with the exception of aryl bromides ð75AG"E#497Łin the latter methodology\ and haloarylzinc compounds\ prepared by selective metallation of oneof two carbonÐhalogen bonds\ give ketones an exposure to acid chlorides in the presence ofpalladium"9# catalysts ð70CL0024Ł[ Halogens can function as directing groups in ortho!metallationsð89CRV768Ł thus providing a regioselective entry to ketones upon acylation of the correspondingorganometallic species[

2[95[1[4 Phenolic Ketones

Phenol is acylated under FriedelÐCrafts conditions to give ortho!para substituted!ketone mixtures[The para to ortho ratio is maximised by the use of boron tri~uoride as the Lewis acid[ Borontri~uoride and zinc chloride are the best Lewis acids for electrophilic acylations of di! and trihydricphenols\ and generally lead to the ketones expected on the grounds of other known aromaticsubstitutions[ Equation "61# illustrates a reaction in which only 0 mol) of zinc chloride provided


the required acetyl derivative in good yield ð61S422Ł[ In problematic cases the temporary protectionof phenols as the corresponding trimethylsilyl ethers has been recommended ð45AG507Ł[ For obviousreasons the free0OH group is not usually tolerated in acylation reactions of organometallic species[

(72)ZnCl2, 140 °C

70%

OH

OH

+O

O O

OH

OH

O

Of considerable importance in the preparation of phenolic ketones is the Fries rearrangement[This thermal rearrangement of phenolic esters occurs in the presence of FriedelÐCrafts catalysts toprovide the ketones in synthetically useful yields ðB!53MI 295!90\ B!56MI 295!90\ 80COS"1#622Ł[ Thereaction can often be tuned by careful selection of temperature\ solvent and catalyst to provideeither the o! or p!acylphenol with good selectivity[ Various substituents on the aromatic ring aretolerated but electron!withdrawing groups are generally detrimental to the success of the reaction[Equations "62# to "66# ð52CR"145#4483\ 62JOC0813\ 73JCS"P0#0228\ 74JMC0721\ 81T6470Ł detail some litera!ture examples of this transformation[

(73)TiCl4

96%

O

O

OH

O

AlCl3

73%

MeO

OMe

O

O

O

MeO

OMe

O

OH

O(74)

BF3

86%

OMe OH

OMe

(75)

OOMe O

O

OMe

(76)AlCl3

49%N

O

OH

O

N

O

O

O

(77)HF

76%

Ph

OH O

O Ph

O

The Fries rearrangement can also be accomplished in the absence of a catalyst by irradiation withUV light[ Known as the photo!Fries rearrangement ð56CRV488Ł\ both o! and p!adducts can beprepared and some success has been achieved with deactivated aromatic substrates[ Two examplesare shown in Equations "67# and "68# ð51JOC1182\ 75H"13#1400Ł[


(78)hν, benzene

72%

O

But

O

Cl

OH

But

Cl

O

hν, benzene

65%

MeO

O

O

Ph

O

O OH

OMe

O

Ph

OO

(79)

2[95[1[5 Alkoxyaryl Ketones

Anisole is a reactive aromatic substrate and undergoes FriedelÐCrafts acylations under a diverserange of conditions to give p!ketone "6# "the o!isomer is sometimes observed\ e[g[\ ð72CB0084Ł#[Besides the standard reactions with carboxylic acids\ acid chlorides\ or anhydrides and a strongLewis acid\ many less active catalysts "e[g[\ AgClO3\ TiCl3\ AlBr2# are e}ective[ A host of mixedanhydrides and related species readily acylate aryl ethers under mild conditions ð61AG"E#299\ 68S292\79S028\ 70CB815Ł[ Furthermore\ catalytic quantities of iron trichloride\ iodine\ zinc chloride andiron all promote acylations with acid chlorides and anhydrides\ although usually at quite hightemperatures ð61S422Ł[ A number of novel catalytic systems allow for high yielding ketone synthesisusing acid chlorides and anhydrides ð75CL054\ 80CL0948\ 80S0105\ 81CL324\ 82CC0046Ł or carboxylic acidsand their TMS derivatives ð81CL0640\ 82BCJ2618Ł under very mild conditions[ Aryl ethers with afurther alkyl substituent are generally acylated para to the alkoxy group or ortho if that position isblocked ""7# and "8##[ m!Alkyl anisole tends to give mixtures of isomeric products with ratios beingdetermined largely by steric demands[ Ketones "09#\ "00# and "01# are all formed\ usually as the soleproducts\ from the corresponding diethers[ Similarly\ higher ethers give the expected products[ Incases where o!acyl substituents are introduced "e[g[\ "8#\ "00#\ "01## dealkylation of the ether functionmay occur[ Hydrogen bonding in the derived adduct presumably favours this process "Equation"79## ð65LA0403Ł[

OMe

O R

OMe

O R2

OMe

R1

OMe

OMe MeO

OMe

OMe

(7) (8) (9) (10) (11) (12)

OMeR1

R2

O

O R

R

O

R

O

BF3

73%

OMe

OMeMeO

+HO

O O

OMeMeO

OH

(80)

Substitution of groups such as i!propyl and t!butyl by the acyl species occurs in some cases\particularly as the substitution of the aromatic substrate is increased[

Organolithium derivatives of aryl ethers can be prepared by metalÐhalide exchange reactions orby ortho!metallations using the O!alkyl substituents as directing groups ð89CRV768Ł[ Acylations ofsuch species or of compounds derived therefrom provide routes to ketones which would not beaccessible by FriedelÐCrafts methodology[ For instance\ Equation "70# illustrates an example whereo!lithiated anisole is acylated regioselectively to give the ketone product which is usually only


produced in relatively small amounts in the FriedelÐCrafts reaction[ Alkoxy aromatic substituentsare generally quite inert and compatible with most general methods[

Li+

OMe

(81)

OMe

OBn

O

BnON

OMe

O

Me90%

2[95[1[6 Thiophenyl Ketones

Aromatic thioethers behave similarly to the analogous oxygen compounds under FriedelÐCraftsconditions and exhibit similar selectivities ðB!53MI 295!90Ł[ However\ the o\p!directing capability ofsulfur is considerably weaker than oxygen\ and substituents such as alkoxy groups and halogensexert considerably greater electronic e}ects in the course of such reactions[ The sulfur groups arecompatible with most other aryl ketone syntheses\ although sulfur residues often poison catalystsin palladium!mediated reactions\ and oxidation of sulfur is a potential complication in certainoxidative procedures[

2[95[1[7 N!Substituted Phenyl Ketones

Aryl amides tend to form complexes with FriedelÐCrafts catalysts resulting in deactivation andpoor yields of the desired ketones[ In some cases bulky substituents on the aromatic ring or onnitrogen can prevent such interactions and ketones can be produced in moderate yields[ Recently\dimethylaniline has been acetylated in good yield using acetic anhydride and a catalytic quantityof ytterbium"III# tri~ate "Yb"OTf#2# "Equation "71## ð82CC0046Ł[ Acetanilides are less prone tocomplexation with Lewis acids and can be acylated successfully with acid chlorides and aluminumtrichloride[ The acetylation of 0\1\2\3!tetrahydroquinoline "Equation "72## illustrates how di}erent0NH protecting groups can dramatically alter both reaction yields and regioselectivitiesð81JCS"P0#2390Ł[ Equation "73# illustrates another such example used in the synthesis of lysergic acidsð73JA0702Ł[

(82)Yb(OTf)3

76%

O

Me2N

+O

OO

Me2N

AlCl3+

Cl

O

N

RN

R

O

N

R O

(83)+

R = CONHMeR = COCF3

>9810

::

<287

96%13%

AlCl3

60%N

N

O

O

H Ph

OPh

N

OPh

ON HO

Ph

H (84)

Nitro!arenes form very tight deactivated complexes with Lewis acids and generally do not undergoFriedelÐCrafts acylations[ However\ electron!donating substituents can sometimes override this


e}ect\ and the use of an AlCl2:DMF complex provides an isolated example of the FriedelÐCraftsacylation of nitrobenzene itself ð89JOC2850Ł[ In an analogous fashion to the Fries!rearrangement\aryl amides can undergo both Lewis acid catalysed and photochemical rearrangement to thecorresponding acyl anilines in good yields "Equations "74# to "76## ð65TL2106\ 73IJC"B#052\ 75SC374Ł[

NH2

OMe

O Cl

(85)BiCl3

80%

N

OMe

H

O Cl

OH

NH2

O

O

(86)B(OH)3, H2SO4, SO3

63%

Cl

N

O

OH

(87)

O2N

HN Ph

O O2N

NH2

Ph

O

hν, H2O

Amines\ amides and urethanes can serve as directing groups in o!lithiation reactions ð89CRV768Ł\and nitro substitution is tolerated by Stille reaction conditions ð75AG"E#497Ł[ Both methods conse!quently provide alternative direct routes to N!substituted phenyl ketones\ although examples in theliterature are comparatively rare at present[

2[95[1[8 Other Substituents

Aromatic carboxylic acids\ esters\ amides\ and aldehydes and ketones are considerably deactivatedand cannot be acylated under FriedelÐCrafts conditions[ However\ if the deactivating e}ects ofthese groups are o}set by electron!rich substituents\ or if steric interactions with o!alkyl groupsprevent the necessary coplanar orientation required for e}ective deactivating conjugation\ acylationcan occur at positions ortho and para to the activating group ðB!53MI 295!90Ł[ Some of thesefunctional groups\ or derivatives thereof "e[g[\ acetals\ nitriles#\ can be used to direct metallationsand hence control regioselectivity in subsequent ketone forming acylations ð89CRV768Ł[ Further!more\ esters\ nitriles and aldehydes have been shown to be tolerant to various palladium!catalysedreaction conditions\ and the desired ketones can consequently be prepared from\ for example\ therelevant halogenated substrates by carbonylative cross!coupling ð81T1002Ł[

2[95[2 POLYCYCLIC ARYL KETONES

2[95[2[0 Naphthyl Ketones

Naphthalene is readily acylated under FriedelÐCrafts conditions but generally gives isomericmixtures of ketone products[ The relative ratios of these products are highly dependent on factorssuch as the solvent and catalyst used ðB!53MI 295!90Ł[ 0!Alkylnaphthalenes and 1!alkylnaphthalenesare acylated in the 1! and 0!positions respectively\ and dialkylnaphthalenes are usually acylated atan unsubstituted a!carbon[ Heterosubstituted naphthalenes "e[g[\ halonaphthalenes\ naphthols\naphthol ethers\ naphthylamines# can all be acylated in high yields under FriedelÐCrafts conditions\

290Polycyclic Aryl Ketones

although the regioselectivity of ketone formation is once again highly dependent on factors such assolvent and the relative positions of other substituents ðB!53MI 295!90\ 89SC272Ł[ Acylations usingstoichiometric quantities of aluminum trichloride and acid chlorides comprise the majority ofliterature examples\ but catalytic amounts of iron\ ferric trichloride\ zinc chloride and iodine canalso provide the requisite ketones in good to excellent yield "Equation "77## ð61S422Ł[ Many of thegeneral methods "Section 2[95[0# discussed earlier have obvious applicability to the synthesis ofnaphthyl ketones[ For example\ Equation "78# illustrates the palladium!catalysed carbonylativecross!coupling reaction of a naphthyl boronic acid with an iodoarene to give the correspondingketone in high yield ð82TL6484Ł[

(88)

OMeOMe

O R

R Cl

O+

FeCl3 (cat.)

66–90%

(89)

O

+

B(OH)2

O

OI

O

O

CO (1 atm), K2CO3PdCl2(PPh3)2 (3 mol%)

86%

2[95[2[1 Anthryl Ketones

FriedelÐCrafts acylations of anthracene often lead to the formation of mixtures of the 0!\ 1! and8! isomers ðB!53MI 295!90Ł[ The 0! and 1!isomeric ketones have been shown to form by rearrangementof the 8!isomer\ and consequently the 8!isomer can be cleanly isolated by using solvents in which theproduct!Lewis acid complex is insoluble or by applying generally milder methodologies[ Examplesof the latter procedures include tri~uoroacetylation with tri~uoroacetyl tri~ate "Equation "89##ð68JOC202Ł and benzoylation with benzoyl chloride and a catalytic amount of iodine "Equation"80## ð61S422Ł[ Many general methods are potentially applicable to the construction of anthrylketones but literature examples are scarce[

(90)

O CF3

CF3CO2Tf, base

81%

(91)

O Ph

+I2 (cat.)

68%Ph Cl

O

2[95[2[2 Phenanthryl Ketones

The vast majority of phenanthryl ketones have been prepared by FriedelÐCrafts acylationmethods[ The 1! and 2!isomers ""02# and "03# respectively# are usually isolated preferentially\although the 0! and 8!phenanthryl ketones are formed to varying extent in some casesðB!53MI 295!90Ł[Similarly\ most substituted phenanthrenes give more than one ketone isomer on acylation[


(13) (14)

R

O O R

2[95[2[3 Other Polycyclic Aryl Ketones

Higher polycyclic aryl ketones are relatively reactive and usually undergo FriedelÐCrafts acylationsquite readily ðB!53MI 295!90Ł[ In some cases the introduction of a second acyl group occurs and\under su.ciently vigorous conditions\ even tri! and tetra!substitution has been known to occur[Pyrene is acylated selectively at the 0!position to give the ketone "04#[ Chrysene and benzoðcŁphenanthrene give the ketones "05# and "06# respectively[ Once again\ other methods "e[g[\ lithiationof halides# are potentially useful but have little or no literature precedent[

R

O

O R

(17)

R

O

(15) (16)

2[95[3 HETARYL KETONES

This section again\ in order to avoid duplication\ makes little reference to methods of saturatedketone synthesis that are equally applicable to hetaryl ketone synthesis "e[g[\ alkylation of hetarylmethyl ketone enolates#\ and instead highlights methods which exploit the chemical properties ofthe relevant heteroaromatic ring systems[ A further point to note with the synthesis of hetarylketones\ particularly in highly substituted cases\ is that synthesis of the required heteroaromaticring\ from an open!chain or cyclic precursor with the ketone function already intact\ can be a viableroute to a chosen target[ However\ the generality of such reactions is not always entirely clear andthe emphasis on synthesis of the heteroaromatic ring rather than on the ketone function itself haveled to the exclusion of examples using such methodology[

2[95[3[0 Furanyl Ketones

Furan can be acetylated in good yield under a range of FriedelÐCrafts like conditions using aplethora of catalysts ðB!53MI 295!90Ł[ Being less aromatic than pyrrole\ for instance\ furan and simplealkyl furans are cleaved or polymerise when exposed to strong mineral acids or Lewis acids such asaluminum trichloride\ and such conditions should therefore be avoided[ Higher furanyl ketones areaccessible via the FriedelÐCrafts methodology using anhydrides and mixed anhydrides with catalystssuch as tin tetrachloride ð55JOC3141Ł\ boron tri~uoride ð68JOC2319Ł and ion!exchange resinsð71SC0010Ł\ or with acid chlorides under similar conditions ð60JOC2080\ 80LA0254Ł[ However\ theyields in these reactions are often low\ and milder methods such as copper!catalysed acylation withselenoesters "Equation "81## ð79JA759\ 74T3710Ł or similar reactions of thioesters in the presence ofmercury salts "Equation "82## ð89TL0866Ł give better yields of ketones[ The acylation of furan itselfoccurs exclusively at the 1!position but the electronic e}ects of substituents on more complex furansmarkedly in~uence selectivity[ 1\4!Dialkylfurans are acylated at the 2!position\ and 1!monoalkylfurans usually give the 4!substituted product[ If the 1!substituent is electron withdrawing\ reactionat the 3!position becomes more prevalent and product mixtures may result "Equation "83##

292Hetaryl Ketones

ð55JOC3141Ł[ 2!Alkylfurans are also often not acylated with particularly high selectivity underFriedelÐCrafts conditions ð60T2212Ł[

(92)+(CuOTf)2Ph

100%O SeMe

O

( )5

O( )5

O

Hg(OCOCF3)2, MeCN

65%O

OTBDMS-O

H

O

O

OTBDMS-O

H

O

SBut

(93)

+ +SnCl4, benzene

21%O

MeO

O

(n-C5H11CO)2O OMeO

O O OMeO

O

( )4O

( )4

(94)

62 : 38

Acylations of lithiated furans are of considerable contemporary importance and allow for regio!selective and often high yielding ketone syntheses[ Furans can be lithiated selectively at the 1!position using alkyllithium reagents\ and at the 1! or 2!position by lithiumÐhalogen exchange[Furthermore\ lithiation of the 2!position is possible using various functional groups at the 1!position to direct the metallations ð71JCS"P0#0232Ł[ A range of electrophiles including Weinreb amides"Equation "84## ð82TL1354Ł\ dimethylamides ð78SC676Ł\ anhydrides and acids ð58JHC030\ 81AG"E#0924Łhave proved useful\ and transmetallations of the lithium species to the corresponding organocupratesð68TL3466Ł or organomanganates ð81TL4134Ł allow for e}ective acylations with acid chlorides[Stannylated furans and acid chlorides in the presence of palladium"9# catalysts undergo extremelye}ective coupling reactions and constitute a very mild ketone synthesis ð80ACS803\ 80OM255\ 80S132Ł[2\3!Distannyl furans can similarly be mono!acylated and subsequently arylated or vinylated toprovide furanyl ketones which could otherwise prove somewhat di.cult to access "Equation "85##ð81CC545Ł[ Carbonylative cross!coupling reactions of stannyl furans with allyl chlorides\ again inthe presence of a palladium catalyst\ also provide the corresponding ketones in high yields ð73JA3722Łand have been applied to the synthesis of relatively complex ketones "Equation "86## ð77TL0062Ł[An obvious aspect of such reactions is the use of furanyl acid chlorides as the electrophilic partnersin such palladium!catalysed reactions[ A number of such examples are found in the various catalysedand uncatalysed reactions of other organometallic species "e[g[\ Equation "87## ð56T786\ 71CL0448\72TL1340\ 78JOC4191\ 81TL4134Ł[ Anions of cyanohydrins derived from furanyl aldehydes have foundsome use as umpoled synthons for ketone synthesis ð68CB1934\ 73SC632Ł\ and the additions of organo!metallic reagents to furanyl aldehydes with subsequent oxidations of the resulting alcohols is a fairlypopular route to the corresponding ketones[ Oxidations of furan methanols using chromium reagentsð73JA1004\ 75JA0945Ł\ t!butyl hydroperoxide ð82TL6978Ł\ Swern conditions ð89JCS"P0#1566Ł\ bariummanganate "Equation "88## ð74JA4108Ł and manganese dioxide ð76JA2870Ł have all been reported[

OLi

O

OO

O

O

O

N

O

OMe

Me

(95)+79%

i, , PdCl2(PPh3)2

ii, , Pd(PPh3)4

Cl

O

O2N

Br(96)

O

Bu3Sn SnBu3

O

O

O2N


O

SnBu3

TMSCl

OMeMeO

OMeMeO

O

+

O

Pd(acac)2, PPh3, CO (1 atm)

TMS

(97)

OCl

O

+But O I

O Zn, CuCN(LiCl)2, THF

81%O

O

OBut

O

(98)

(99)O

OBn

O-TBDMSOH

OOBn

O-TBDMSO

BaMnO4, CH2Cl2

80%

2[95[3[1 Benzofuranyl Ketones

Benzofurans are only weakly aromatic in nature and they are cleaved by many oxidative andreductive conditions[ They are also prone to polymerisation in the presence of concentrated mineralacids and Lewis acids[ Consequently\ ring synthesis is often preferred ð40JA643Ł to electrophilicsubstitution[ FriedelÐCrafts acylations are possible using acid chlorides in the presence of stannouschloride "Equation "099## ð44JCS2582Ł and stannic chloride ð66JHC750Ł\ although regioselectivitiesare not always high[ The reactions are usually only applicable to 1!substituted derivatives\ whichare more stable to the Lewis acidic conditions required\ thus providing the 2!acyl compounds[1!Acyl derivatives which\ in contrast to indoles\ are the favoured products in electrophilic sub!stitutions of benzofurans\ are e.ciently prepared by ipso!substitution of 1!trimethylsilyl benzofuransusing acid chlorides and tin tetrachloride as the catalyst "Equation "090## ð73T510Ł[ 1\2!Disubstitutedbenzofurans can be acylated on their benzene ring portions\ in moderate yields\ using acid chloridesand aluminum trichloride[ The regiochemical outcome in these reactions is highly dependent on therelative positioning of other substituents ð69BCJ1773\ 69BCJ2385Ł[ Similarly\ benzofurans with elec!tron!withdrawing groups in the 1!position are acylated in high yield on the benzene ring if carboxylicacids or anhydrides\ and boron tri~uoride are used "Equation "091## ð52JOC287Ł[ Benzofuran islithiated selectively at the 1!position using alkyllithium reagents\ and 2!lithio derivatives "althoughthermally unstable# can be prepared by halogenÐmetal exchange[ However\ the application of suchmethodology to the direct synthesis of ketone derivatives is conspicuously lacking[

(100)O

+Cl

O

O

OPh

SnCl2

60%

(101)TiCl4

75%+

But Cl

O

O

But

OOTMS

294Hetaryl Ketones

+HO

O

O

OMe

OEt

O

O

OMe

OEt

O

O

(102)BF3•OEt2

88%

2[95[3[2 Ketothiophenes

Thiophenes have considerable aromatic character but they are also considerably more reactivetoward electrophiles than is benzene[ Consequently FriedelÐCrafts acylations can be e}ected undervarious conditions ðB!53MI 295!90Ł[ Acid chlorides\ anhydrides and carboxylic acids are the mostcommonly used electrophiles\ and the most popular catalysts are aluminum trichloride "e[g[\ð82ACS176Ł# and tin tetrachloride "Equation "092## "e[g[\ ð73JOC1211\ 73TL4328Ł# in the case of acidchlorides^ pyridyltri~ate:TFA ð68S292\ 79S028\ 77BCJ344Ł and protic acids such as ppa for carboxylicacids ð79JHC76Ł^ and iodine ð61S422Ł boron tri~uoride ð37JA756Ł\ perchloric acid ð60HCA242Ł andphosphoric acid ð44OSC"2#03Ł with the corresponding anhydrides[ Thiophene has been similarlyacylated in high yield using selenoesters and a copper catalyst ð79JA759\ 74T3710Ł\ and benzoylatedwith equal facility using trichloromethylbenzene and aluminum trichloride ð80S211Ł[ Fries!rearrangements involving substituted thiophenes are also possible but not particularly general"Equation "093## ð75JCS"P0#496Ł[ Acylations under FriedelÐCrafts conditions are highly selective andgive the 1!substituted products exclusively[ 1!Substituted thiophenes react with similar dis!criminations to give the 1\4!products\ and 1\4!disubstituted thiophenes are acylated at the 2! or3!position as dictated by relative steric and electronic e}ects[ An exception to the latter occurs inthe case of 1\4!dihalothiophenes where the acylating species can substitute for either halogenð70JHC0234Ł[ Finally\ 2!substituted thiophenes react to give 1\2! and 2\4!disubstituted products indistributions which are determined by the nature of the substituent[

(103)SnCl4

CH2Cl2SPh

( )6S

Ph( )6

OMe

O OOMe

O O

Cl+

(104)AlCl3, HCl, CH2Cl2

79%

S

OOMe

O

O

S

OMe

OHO

O

Thiophenes are readily metallated to produce reagents which can be acylated in high yield withcomplete regioselectivity[ Thienyllithium compounds are by far the most popular of such speciesand are readily prepared by halogenÐmetal exchange reactions using butyllithium "e[g[ ð81JHC136Ł#[1!Lithiothiophenes can be prepared by the direct action of strong lithium bases "e[g[ ð80JOC3159Ł#\and directed lithiations are a viable route to 2!lithio species ð89CRV768Ł[ The best general methodfor the direct conversion of thienyllithiums into the corresponding ketones is by reaction withWeinreb amides "Equation "094## ð80JOC1800\ 80JOC3159\ 80TL610\ 81JHC136Ł[

(105)S S

O

Ph

Li

O

Ph

NOMe

Me

+91%

1!Iodothiophenes and organoaluminum compounds have been converted into the corresponding1!keto products by palladium!catalysed carbonylations ð74TL3708Ł\ and the related imino!carbonylative cross!coupling with 8!alkyl!8!BBN derivatives "Equation "095## ð81TL3354Ł has alsobeen reported[ Furthermore\ 1!ethyldi~uorosilyl thiophene and aryl halides undergo similar pal!ladium!catalysed carbonylative cross!coupling reactions to give diaryl ketones "Equation "096##ð78CL1938\ 81T1002Ł[ All of these palladium!catalysed reactions are high yielding and provide anextremely mild methodology for ketone synthesis[ Acid chlorides and other derivatives of thiophenyl


carboxylic acids have been used as electrophiles in the acylations of various organometallic species"Equation "097## ð65JCS"P0#638\ 76TL1942\ 81TL4134\ 82JOC4751Ł to produce the corresponding ketones[

(106)S S

O

I+

9-BBN

+ ButNC

i, Pd(PPh3)4 (5 mol%), K3PO4ii, H3O+

83%

(107)S S

O

Si(Et)F2+

I CHOCHO

CO (1 atm), (η3-C3H5PdCl2) (2.5 mol%)KI, DMI

72%

(108)SS

O

NN

Me

O N

Me

+

+

MgBr

90%

2[95[3[3 Benzothiophenyl Ketones

FriedelÐCrafts acylations of benzothiophene give the 2!acyl products predominantly\ but sel!ectivity varies quite markedly with di}erent catalysts ðB!53MI 295!90Ł[ 1!Substituted benzothiophenesyield the expected 2!acyl products\ and 2!substituted benzothiophenes the corresponding 0!acylderivatives[ Electron!withdrawing groups on the heteroaromatic ring generally activate the carbo!cyclic ring to electrophilic substitution\ as do electron!donating groups on the carbocyclic ring"Equation "098## ð82JCR"S#081Ł[ Rearrangements of the Fries!type have also been reportedð62JCS"P0#0085Ł[

(109)ppa

72%

S

OO

OH

S

O

O

ppa = polyphosphoric acid

As is the case with thiophenes\ 1!lithio derivatives of benzothiophenes are readily prepared bythe action of butyllithium\ and they can be acylated successfully "e[g[ ð79TL1018\ 80TL1992Ł[2!Lithiobenzothiophenes are not thermally stable and have only found limited use in ketonesynthesis[ However\ 2!aroylbenzothiophenes have been prepared in high yields by palladium!catalysed carbonylative cross!coupling reactions of arylboronic acids with 2!iodo benzothiophene"Equation "009## ð82TL6484Ł[

(110)

S

I

+ PhB(OH)2

S

OPhCO (1 atm)

PdCl2(PPh3)2 (3 mol%)

K2CO3

2[95[3[4 Pyrrolic Ketones

The preparation of pyrrolic ketones using FriedelÐCrafts conditions is not always a useful method\as the conditions required for such reactions often result in polymerisation\ particularly in the caseof pyrrole itself[ However\ pyrroles can sometimes be acylated using a Lewis acid "usually aluminumtrichloride# and an acid chloride "Equation "000## ð69LA"622#16\ 82JCS"P0#162Ł[

296Hetaryl Ketones

(111)

NH

O

+ Cl

O

NH

O

O

AlCl3

55%

Selenoesters in the presence of copper catalysts are also an e}ective acylating combinationð79JA759\ 74T3710Ł\ as are dimethylamino! ð74JMC0926Ł and morpholido amides "Equation "001##ð66JOC3137\ 73JOC3192Ł in the presence of phosphorus oxychloride in what amounts to an extensionof VilsmeierÐHaack type formylations[ Although requiring subsequent hydrolysis to the ketone\ theHoubenÐHoesch synthesis has found some utility "Equation "002## ð72JHC0454Ł as have reactionsusing 0\2!benzoxathioyl ð82JCS"P0#162Ł and dialkoxycarbenium tetra~uoroborates ð78JHC0452Ł[N!Alkyl and other N!protected pyrroles can often be acylated "and acetylated in particular# by simplyheating with acid chlorides ð74JMC0926Ł or active anhydrides ð47JOC0271Ł\ and N!phthaloylaminopyrroles can be acylated with acid chlorides using zinc chloride as catalyst ð77JHC406Ł[

(112)NH

+ N

O

NH

O

Ph

OBnO

OBn

POCl3

71%

(113)+ N

NO2

O

ClN

NO2

Cl CNHCl, H2O

53%

Electrophilic acylations of the FriedelÐCrafts type occurs preferentially at the 1!position "Equa!tions "000# to "002##\ but the substitution pattern of the particular pyrrole substrate can markedlye}ect this aspect of the reaction[ If the 1! and the 4!position are blocked\ acylations occur at the2!position "Equation "003## ð79SC662Ł\ and a similar e}ect is noted if only the 1!position bears anelectron!releasing group or if the pyrrole nitrogen is protected with a bulky group ð74S242Ł[ Examplesof the latter include t!butyldimethylsilyl ð74TL4924Ł\ triisopropylsilyl "Equation "004## ð72TL2344Ł\trityl ð72JCS"P0#82Ł\ t!butyl and adamantyl ð79JCR"S#31Ł[ Furthermore\ deactivating N!sulfonyl pro!tection also promotes acylation at the 2!position "Equation "005## ð70TL3788\ 70TL3890\ 72JOC2103Ł^electron!withdrawing groups at the 1!position direct acylation to the 3!position ð68TL1494\ 79CJC1416\77H"16#0744Ł^ and in a somewhat surprisingly general manner 1!keto pyrroles can be isomerised tothe corresponding 2!keto derivatives on exposure to acidic conditions ð70JOC728\ 71JOC2557Ł[ Deliveryof acylating species by tethering to the nitrogen atom can provide 1!keto pyrroles selectively\although mechanistic details are uncertain ð89TL884Ł[

(114)HI

71%

N

OMe

+ (ButCO)2O N

OMe

But

O

(115)

tips = 1,1,3,3-tetraisopropyldisiloxane

N

tips

+

N

O

tips

OEt

OClOEt

O

O

pyridine, CH2Cl2

70%


N

S+

Cl

O

O O

Ph

AlCl3

99% N

O

SO O

Ph

(116)

Pyrroles can be acylated in their C!1 positions using acid chlorides and bases such as sodiumhydroxide ð53AJC0945Ł\ triethylamine ð69LA"622#16Ł and 1\5!lutidine ð61JOC2507Ł[ However\ yieldsare not usually good under such conditions\ and acylation reactions of lithio! and magnesiopyrrolesis far more e}ective[ N!Substituted pyrroles are readily lithiated at the 1!position on exposure toalkyllithiums\ and the lithium species can then be successfully acylated with nitriles ð71SC120Ł\benzamides ð80S0968Ł and lactones "Equation "006## ð70JOC2659\ 72CC529\ 73JOC2492Ł to provide thecorresponding ketones with complete regiocontrol[ Treatment of pyrroles with simple Grignardreagents "e[g[\ MeMgBr# or transmetallation reactions of lithiated derivatives ð70JOC2659Ł providethe corresponding magnesiopyrroles that will then react with acid chlorides ð54JHC362Ł to giveketones in low yields\ or with low regiocontrol\ but are best acylated with pyridyl thioesters togive high product yields "Equation "007## ð70TL3536Ł[ This latter approach is e}ective under mildconditions and has been used in the preparation of a number of functionally complex compounds"Equation "008## ð70JA5858\ 75T5354\ 76JA6442Ł[ Additions of metallated pyrroles to aldehydes andsubsequent oxidation\ usually with manganese dioxide ð72OS"51#000Ł\ of the resulting alcohols havebeen used to prepare some ketones\ and the use of pyrrolic carboxylic acid derivatives as acylatingspecies for organometallic or aromatic substrates has also found utility in the preparation of pyrrolicketones "Equation "019# ð55T"S#130\ 70H"05#288\ 76AP"219#0919Ł[

(117)+DME, 0 °C

62%N

SEM

Li

OO

HO

ON

SEM

SEM = β-trimethylsilylethoxymethyl

(118)+N

MgCl R S N

ONH

R

O

toluene, –78 °C

90–95%

N

MgCl

O

MeO2CHH

H

H

O SPy

O

MeO2CHH

H

H

ONH

toluene, THF, –20 °C

90%+

(119)

NaH

66%N

O

EtO

O

OEt

Me

NOEt

O OEtO

N

O

EtO

Me

N

O

O

O OEt

(120)

298Hetaryl Ketones

2[95[3[5 Ketoindoles

Indoles are considerably nucleophilic and sometimes undergo uncatalysed FriedelÐCrafts acyl!ation reactions with acid chlorides and anhydrides\ particularly on heating with the more reactiveof such compounds ðB!53MI 295!90Ł[ However\ most examples require a Lewis acid catalyst of whichzinc chloride ð61S422Ł\ and especially aluminum trichloride ðB!53MI 295!90Ł\ are the most popularand e}ective[ Acylations with carboxylic acids and protic acid catalysts "Equation "010## ð58JA1231\79H"03#0828Ł or with selenoesters and copper catalysts "Equation "011## ð79JA759\ 74T3710Ł have alsoproved relatively useful\ as has the two!step method utilising 1!substituted!0\2!benzoxathioliumions ð76S200Ł[ In contrast to the analogous reactions of pyrroles\ electrophilic acylations of this typegenerally occur at the 2!position[ However\ when blocked\ acylation at the 1!position occurs withequal facility[ FriedelÐCrafts acylations can occur selectively at the 1!position when the 2!positionis unsubstituted by ipso!substitution of a trimethylsilyl group "Equation "012## ð78JOC3249Ł[ Thistype of reaction has also been used in acylations of the 3!position ð73JOC3398Ł[ Competitive acylationat the 2!position is avoided by acetylation of nitrogen and concomitant deactivation of the hetero!cyclic ring "Equation "013##[ The 3!position can also be acylated electrophilically in indoles bearingan activating group "e[g[\ OMe# at the 4! or 6!position\ and usually also with an electron!withdrawinggroup on either the nitrogen atom or the 1!position ð30LA"438#127\ 66CPB2912\ 73JOC2084Ł[ FriedelÐCrafts acylations of simple indoles are not common at the 4! and 6!positions\ but they can occurwith varying selectivity when electron!withdrawing groups are present at the 1!position ð77CPB1912\89CPB2150Ł[ 5!Acylations can occur in useful yields in the case of N!acetyl indoles ð30LA"438#127\73JOC3398Ł[

(121)

NH

N

O

OH

O H3PO4

85%

NH

NO

O

(122)N

Me N

O

Me

MeSe

O+

CuOTf, benzene

85%

NTMS

S OO

Ph

+ (MeCO)2OAlCl3, CH2Cl2

86%

N

S OO

Ph

O (123)

(124)N

TMS

O

N

O

O Cl

Cl O

Cl+

AlCl3

75%

0!Indolylmagnesium halides are acylated preferentially at the 2!position "e[g[\ ð38RTC4\ 76TL2630Ł#but often only in moderate yields[ 0!Methylindoles ð79JA0346Ł and 0!phenylsulfonylindolesð62JOC2213\ 70JOC1868\ 78JOC2153Ł are selectively lithiated in the 1!position using strong bases\ andcan subsequently be acylated e.ciently using acid chlorides or anhydrides[ In a related manner0!"N!aroylcarbamoyl# indoles\ prepared from 0!"1!oxazolinyl#indole\ give 1!aroyl!0H!indoles\ ontreatment with lithium diisopropylamide "LDA#\ by an intramolecular acyl transfer "Equation "014##ð82H"24#462Ł[ Additions of aldehydes to metallated indoles\ and oxidation of the resulting alcohols\usually with manganese dioxide ð64JOC1502\ 73T2228\ 75T1200\ 89SC2958\ 82T1774Ł\ provide the desiredketones\ and direct oxidation of an a!methylene in substituted indoles can lead directly to ketones


using oxidants such as selenium dioxide "Equation "015## ð80CC0576Ł\ hydroiodic acid ð55JA0938Ł\ddq ð65H"3#0748\ 78JOC1069\ 89T5512Ł and iodine pentoxide "Equation "016## ð70JA5889\ 76CPB3699Ł[

(125)N

ON N

H

Ph

O

i, PhCOCl, 95%

ii, LDA, 73%

N

NH

O

OBnH

H

N

NH

O

OBnH

OH

(126)SeO2, dioxane

43%

(127)N

ClO

NH

N

ClO

NH

O

I2O5, THF (aq.)

65%

2[95[3[6 Pyridyl Ketones

Pyridine is essentially an electron!de_cient aromatic heterocycle and is about a million times lessreactive than benzene towards electrophilic substitution[ Furthermore\ N!acylation and the resultingfurther deactivation generally results in FriedelÐCrafts acylations being of little use in the preparationof pyridyl ketones[ Alkoxy and amino groups can o}set such e}ects to some extent and acylationsof such systems\ particularly of the intramolecular variety\ are known ð65RTC119\ 66JCS"P0#678\89JHC0416Ł[ Readily available pyridyl carboxylic acids and their derivatives can serve as electrophilesin FriedelÐCrafts acylations of electron!rich aromatic substrates providing aryl pyridyl ketones"Equation "017## ð74SC0160\ 75JOC1910Ł[

(128)N

OH

O

FN

O

F

ppa

85%

Direct lithiations of pyridines can be problematic due to the ready addition of alkyllithiums tothe pyridine ring system[ However\ transmetallations of pyridyl bromides are readily achieved atlow temperature\ and the resulting organometallic species can be acylated successfully[ Lithiatedpyridines prepared in this way are acylated in moderate yields with tertiary amides "Equation "018##ð80JOC0711\ 81JOC650Ł\ nitriles ð48JA0827Ł and carboxylic acids ð82SC874Ł[ Grignard reagents showsimilar utility "e[g[ ð82TL2572Ł#\ and they can also be prepared by the reaction of phenyl magnesiumbromide with pyridyl sulfoxides ð75TL2788Ł[ Pyridine N!oxides and some of their derivatives can bedeprotonated at the 1!position and subsequently acylated ð61JOC2473\ 75CB168\ 89H"20#316Ł[ Directlithiation of pyridines is possible with ortho!directing groups such as acylamino ð76CJC0047Ł\ chloroð70JOM"105#028\ 75S775Ł and amido groups "Equation "029## ð79JA0346\ 76T4170Ł[ Directing groups inthe 2!position usually stabilise 3!lithio derivatives\ but in some cases the 1!position can be lithiatedselectively ð70JOM"105#028Ł[

200Hetaryl Ketones

(129)

N

BrCl

O

NMe2

ButLi

57%

N

Cl

O

+58%

MeO

OMe

OMe

NMe2

O

N

Li

NPri2

OMeO

OMe

OMe O

N

NPri2O

(130)

1! and 3!Trimethylstannyl pyridines are acylated in variable yields on direct reaction with acidchlorides ð71CPB1992\ 71H"08#30\ 74JOC4325Ł[ The 2!stannyl compounds require a palladium catalystfor reaction to occur "Equation "020## ð81TL2992Ł\ as do similar reactions between pyridyl zinccompounds and anhydrides ð81TL4262Ł[ Palladium catalysts are also e}ective in promoting iminocarbonylative cross!coupling reactions between bromopyridine and 8!alkyl!8!BBN derivativesð81TL3354Ł\ and between iodopyridine and boronic acids ð82TL6484Ł[ Under somewhat harsherconditions\ a ruthenium catalyst has been shown to promote carbonylative coupling betweenpyridine and alkenes ð81JA4777Ł[ Nucleophilic acyl radicals can add at the 1!position of pyridine togive ketones in good to excellent yield "Equation "021## ð63JCS"P1#0588\ 78H"17#378\ 80JOC1755Ł\ andcyanohydrins derived from pyridyl aldehydes are readily lithiated\ alkylated and _nally hydrolysedto provide the desired ketones ð68CB1934\ 73SC632Ł[ Oxidations of alcohols to pyridyl ketones arebest achieved with relatively mild oxidants such as manganese dioxide ð71JA425Ł and DessÐMartinperiodinane ð82TL220Ł[

+

N

SnMe3

ClO

NO

OBn

O

O

ONO

OBn

O

ON

(131)PdCl2(PPh3)2

48%

(132)+ MeCHOFeSO4, H2SO4 (aq.)

N

O

N

O

O

2[95[3[7 Ketones Derived from Imidazoles\ Thiazoles and Oxazoles

These aromatic heterocycles fail to undergo C!acylation under FriedelÐCrafts conditions due toheteroatom complexation and consequent deactivation[ Two notable exceptions\ 1!hydroxy thia!zoles and N!methyl!1!phenyl!3!benzamino imidazole\ are su.ciently activated to give the desiredketones ð28CB0369\ 60JOC2257Ł[ However\ the 1!keto products are formed on treatment with acidchlorides in the presence of triethylamine[ These reactions are thought to occur via initial heteroatomacylation followed by ylide formation and rearrangement to the product "Equation 022# ð66LA034\67S564\ 73JOC489Ł[ A similar reaction has been observed with dichloroketene ð73JOC2367Ł[ Oxazoles\thiazoles and N!alkyl imidazoles are readily lithiated at the 1!position and react with electrophilessuch as tertiary amides ð73S0937\ 75CPB3805Ł and esters ð80CC0202Ł to give the 1!keto adducts directlyin moderate to excellent yield[ The example shown in Equation "023# proceeded without loss ofstereochemical integrity at the a!chiral centre[ 3!Acyl imidazoles have been prepared by C!1 andN!protection\ followed by selective lithiation at C!3 prior to reaction with acid chlorides "Equation024# ð80S0910Ł "the protecting groups are removed in quantitative yield using dilute HCI#[ Thermalrearrangement of 4!keto imidazoles can give the 3!C adduct ð73JOC4992Ł and acylation of lithiated4!"0\2!dithianyl#oxazole leads to mixtures of two 3!keto!oxazoles after a subsequent Cornforth


rearrangement ð82TL6694Ł[ 1!Trimethylsilyl or 1!stannyl derivatives of oxazoles\ thiazoles\ imi!dazoles and their benzoderivatives can be acylated with acid chlorides ð72JHC0900Ł and in the caseof the silylated compounds\ with ketenes ð70CC544Ł and anhydrides "Equation "025## ð75G022Ł[

(133)+Et3N, benzene

45%N

S

Cl CCl3

O

N

SCCl3

O

+N

SLi

SO

N

O

N

ButO

O

(134)80%

OMeON

O

ButO

O

N

N

SO O

NMe2

TBDMSN

N

SO O

NMe2

TBDMS

O

i, BuLi

ii,

91%

Cl

O(135)

tbaf, THF, benzene

60%

N

S

Cl

TMS +OO O

HO S

N

Cl

O

O(136)

tbaf = tetra-n-butylammonium fluoride


3.07Aldehyde and Ketone FunctionsFurther Substituted on OxygenDONALD A. WHITINGUniversity of Nottingham, UK

2[96[0 CARBONYL YLIDES 202

2[96[0[0 Introduction 2022[96[0[1 Carbonyl Ylides From Oxiranes 204

2[96[0[1[0 Intramolecular cycloadditions^ oxirane to oxyèn heterocycle 2042[96[0[1[1 Intermolecular cycloadditions^ oxirane to oxyèn heterocycle 2062[96[0[1[2 Electrocyclizations leadin` to furans and oxepines 2072[96[0[1[3 Trappin` by hydroxyl functions leadin` to acetals 2082[96[0[1[4 Trappin` by oxyèn leadin` to ozonides 208

2[96[0[2 Carbonyl Ylides From Carbenes 2082[96[0[2[0 Intramolecular cycloadditions^ diazocarbonyl to oxyèn heterocycle 2082[96[0[2[1 Intermolecular cycloadditions^ carbene to oxyèn heterocycle 2192[96[0[2[2 Electrocyclizations leadin` to furans 2102[96[0[2[3 Hydroèn mi`ration leadin` to enol ethers 2122[96[0[2[4 Haloèn mi`ration and decarbonylation reactions 212

2[96[0[3 Carbonyl Ylides From Cycloreversions 2122[96[0[4 Carbonyl Ylides From Elimination Reactions 213

2[96[1 CARBONYL OXIDES 215

2[96[1[0 Other Carbonyl Derivatives 216

2[96[0 CARBONYL YLIDES


Carbonyl ylides are 0\2!dipolar species\ represented by the parent 1!oxatrimethylene structure"0#[ This ylide is conveniently shown in the zwitterionic form\ although calculations show signi_cantdiradical character ð68JA0984\ 68JA0090\ 79JA0493Ł and indicate a preferred nonlinear\ planar geometry"the 9>\ 9> conformation#[ Theoretical studies also suggest that the stability of such ylides would beincreased by substitution by electron!donating groups at one carbon centre and electron!with!drawing groups at the other\ when dipolar zwitterionic character is enhanced and the energy barriersto rotation are lowered[ In an extreme case "1#\ the "9>\ 89># conformation should be favoured[

O+

–

H2N O

H2NCN

CN+

–

(1) (2)H H

HH

202

203 Further Substituted on Oxy`en

Carbonyl ylides are generally encountered as reactive intermediates rather than stable species^they have been observed spectroscopically "at low temperatures and trapped in matrices# in severalcases[ Thus irradiation of tetraphenyloxetanone "2# at wavelengths ×166 nm leads to expulsion ofcarbon monoxide and production of the blue ylide "3#\ identical to that obtained by irradiation oftetraphenyloxirane "4# "Scheme 0# ð69JA0391Ł[ Both thermolysis and photolysis of the 4!oxabicyclo!ð1[0[9Łpentane "5# have yielded the colored\ _ve!membered ring ylide "6# "Equation "0##[ In the caseof the ylide "6#\ when R�Ph\ the species displayed a t0:1 of 7 min[ This relatively long lifetime isascribed to the unfeasibility of thermal ring closure to the highly strained trans!fused bicycle\through the allowed conrotatory process ð69JA0393\ 69PAC412\ 60JHC0986Ł[ A study of the reactionwith acetone of the carbene "7#\ generated by laser photolysis of diazo~uorene\ showed the formationof the ylide "8# "Scheme 1#[ The decay of the intermediate "8# was interpreted as requiring rotationfrom the initial 9>\ 9> conformation to the 9>\ 89> geometry before collapse to the oxirane "09#"Scheme 1# ð74JA6193Ł[ One example is known of a stable carbonyl ylide\ this is "00#\ which existsas a crystalline solid in the 9>\ 89> shape[ The stability of "00# arises from the extreme {push!pull|electronic e}ects ð72JA4818Ł[ One metal complex "01# of a carbonyl ylide has also been reportedð61JOM"35#C18Ł[

Scheme 1

Ph O Ph

Ph Ph

+

–

O

Ph

PhPh

Ph

O

Ph

PhPh

Ph

O

(3) (4) (5)

hν, > 277 nm

77 K

254 nm

77 K

(6) (7)

OPh R OPh R

+

–∆ or hν(1)

Scheme 2

(8) (9) (10)

:

+O–

OMe2CO

Me2N O

CF3

F3CCF3

CF3Me2N

O

Pt CN

CNNC

NC

Ph3P PPh3

+

–

(11) (12)

This review concentrates on synthetic aspects of the carbonyl ylide area[ Historical\ theoretical\and mechanistic aspects are outside the scope of this chapter\ and the reader is referred to majorgeneral reviews of the _eld\ inter alia ðB!73MI 296!90\ 80COS"3#0978\ 80COS"3#0048Ł[ Carbonyl ylides areformed by four general processes] "i# thermal or photochemical carbon0carbon bond cleavage inepoxides^ "ii# carbene additions to carbonyl groups^ "iii# cycloreversion reactions^ and "iv# eliminationprocesses[ The _rst three of these processes are exempli_ed in the formation of the ylides "3#\ "6#\and "8#[ The various subsections of this review will treat each mode of ylide formation in turn\illustrating the transformations observed with examples chosen to highlight the range of reactionsof these reactive novel intermediates[

204Carbonyl Ylides

2[96[0[1 Carbonyl Ylides From Oxiranes

Carbon0carbon bond cleavage of oxiranes\ induced thermally\ photochemically\ or by electrontransfer catalysis\ is a common method of generating carbonyl ylides[ Either conrotatory or dis!rotatory ring openings are possible^ these are formally allowed either thermally "conrotatory# orphotochemically "disrotatory#^ exo!exo or exo!endo ylide conformations result "Scheme 2#[ In prac!tice\ situations are complicated by the thermal interconversion of the two conformations\ and byviolation of orbital symmetry control in the face of acute steric constraints ð60CC0089\ 60CC0081\65TL3532\ 66CC328\ 66CC339Ł[ The overall outcome is dependent on the relative kinetics of ring opening\conformational equilibration\ and the rate of trapping by a dipolarophile[ As a consequence\ varyingdegrees of stereospeci_city have been observed[ The cycloaddition reactions of carbonyl ylides areusually regioselective\ and the regiochemistry can be rationalized by Frontier Molecular Orbital"FMO# theory\ with the HOMO of the dipole dominant for reactions with electron!de_cient species\while the LUMO becomes important for addition to electron!rich alkenes[

OR O R

O R O

Scheme 3

R

+

–

+

–∆, conrotatory

R

H

H

RR

H

R

H

∆, conrotatory

hν, disrotatory

exo-exo

exo-endo

2[96[0[1[0 Intramolecular cycloadditions^ oxirane to oxygen heterocycle

Eberbach and co!workers have accessed an interesting range of heterocycles in which a tetra!hydrofuran moiety is incorporated into di! and trifused!ring systems\ etc[\ including macrocyclicsystems[ Thus irradiation of the "Z#!stilbene oxide "02# yielded the oxabicycle "03# with disrotatoryepoxide opening\ and the same isomer was produced by ~ash thermolysis of the "E#!oxide "04#"Scheme 3# ð73TL0026Ł[ Heating the epoxide "05^ R�H# gave rise to the trans!fused furan "06#\together with its cis!isomer "Equation "1## ð79AG"E#36\ 73CB1046Ł^ intramolecular cycloaddition tothe unactivated alkene was slower than intermolecular trapping with\ for example N!phenyl!maleimide[ A series of similar reactions with the corresponding ylide separated from its reactingpartner by tethers of di}erent length ð79TL3898Ł a}orded a set of macrocyclic ethers\ for instance"05^ R�CO1Me\ n�09# at 129>C\ 09[4 h\ gave mainly the bridged furan "07# with oppositeregiochemistry from that shown by lower homologues[ Trapping of the ylides by cyclic alkenes hasalso proved viable\ as in the transformation of the cyclohex!1!enol derivative "08# to the tetracycle"19# "Equation "2## ð72CB1272Ł[ In another example the 07!membered dioxacycle "11# "2a\ 2\3 transand 2b\ 2\3 cis# was produced by intramolecular trapping by the cinnamate unit in the precursor"10# "Equation "3## ð71TL3554Ł[ Terminal alkynes also act as e}ective ylide interceptors as shown bythe conversion of the propargyl ether "12# into the chromanodihydrofuran "13# "Equation "4##ð80T6602Ł[ The indanone oxides "14# and "16# yielded the bridged tetracyclic products "15# and "17#respectively\ on irradiation "Equations "5# and "6## ð72TL4474Ł[

O PhPh

CO2Me

O PhPh

CO2Me

Scheme 4

OPh

H

Ph

CO2Me

(13) (14) (15)

hν, disrotatory

35%

450 °C, 10 sconrotatory

25%


(2)

(16) (17)

Ph

CN

O

Rn( )

H

H

CN

Ph

( )n

R = H, 175 °C, 9 h

n = 1, 75% (40% conversion)n = 1, 66% (30% conversion)

O

O

MeO2C

CN

Ph

(18)

(3)

(19) (20)

OCN

OPh

O

O

Ph

CN

H

H

H

180 °C, 6 h

90%

(4)

(21) (22)

O

O

O

NCPh

10( )245 °C, 22 h

42% O

O

O

MeO2C

NC

Ph

3 4

MeO2C

(5)

(23) (24)

O

CO2Me

CO2Me

OO

OCO2Me

MeO2C

160 °C, 13 h

76%

(6)

(25) (26)

O

O O

O

300 nm, PhH

65%

(7)

(27) (28)

O

OO

O

300 nm, PhH

34%

206Carbonyl Ylides

2[96[0[1[1 Intermolecular cycloadditions^ oxirane to oxygen heterocycle

An early example of these cycloadditions is a}orded by the thermal C0C bond scission oftetracyanoethylene oxide "18#^ the resulting ylide was particularly reactive\ not only yielding anadduct "29# "49)# with styrene\ but also a product "20# "32)# with p!xylene ð54JA2546Ł[ A cyclicylide is formed on photolysis or pyrolysis of the indenone oxide "21#\ which can be trapped with\for example dimethyl acetylenedicarboxylate "DMAD#\ bicycloð1[1[0Łheptadiene\ or cyclohexanoneto provide the varied products "22#\ "23#\ and "24# respectively "Scheme 4# ð51JA0204\ 53JA2703\53TL0736\ 60CJC2332Ł[

O

CN

CNNC

NC

O

Ph

NC

NC CN

CN

O

H

H

CNCN

CNCN

(30)(29) (31)

(32) (33)

(34) (35)

O

O

R

Ph

O

O

CO2Me

CO2Me

Ph

R

hν, PhH

40%

O

O

OPh

Ph

O

O Ph

Scheme 5

145 °C, 16 h83%hν, 63%

Electron transfer photosensitization o}ers an alternative mode of generating carbonyl ylides fromepoxides[ A sensitizer\ for example dicyanonaphthalene or dicyanoanthracene\ in a photochemicallyexcited state extracts an electron from the oxide\ which then ring opens to the corresponding cationradical equivalent of the ylide before reclaiming an electron ð67CJC1874Ł[ The isomerization of cis!to trans!stilbene oxide\ "25#:"26# "Equation "7##\ can be observed under these conditions\ andthe intermediate can be trapped with fumaronitrile and maleonitrile to yield the correspondingtetrahydrofurans "27# "76)# and "28# "42)# with other minor stereoisomers in each case ð67CJC1874Ł[Interception with maleic anhydride\ and the less reactive 1!butenolide\ has a}orded the bicyclicethers "39# "52)# and "30# "32)# respectively ð89JCS"P0#042Ł[ Attempts to generate a carbonyl ylidefrom bis"3!methoxyphenyl#oxirane "31^ Ar�3!methoxyphenyl# thermally or by direct or tripletsensitized irradiation were frustrated by preferential C0O bond cleavage\ leading to deoxyanisoinand bis"3!methoxyphenyl#ethanal[ However electron transfer sensitization "ET sens# using dicyano!naphthalene\ and through phenanthrene!toluene _lters\ allowed formation of the desired ylide\trapped by DMAD to a}ord "32# "43)# ð89JCS"P0#042Ł[

(8)

(36)

O

Ph Ph

O

Ph Ph(37)

hν, ET sens

The oxirane "33^ Ar�2\3!methylenedioxyphenyl# has been ring!opened on thermolysis to a highlypolarized ylide\ which nevertheless reacted with ethyl acrylate in a nonregioselective manner\ giving


O

CN

Ph Ph

NC

O

CN

Ph Ph

NC

O

O

Ph Ph

H H

O O

O

O

Ph Ph

H H

O

O

Ar Ar

O

MeO2C CO2Me

Ar Ar

(38) (39)

(40) (41) (42) (43)Ar = 4-methoxyphenyl

rise to products "34# and "35# in nearly equal proportions "Equation "8## ð76TL2044\ 89JCS"P0#0082Ł[Related cases were observed\ and the ylide intermediates may have high radical character[

O

ArCN

NO2 OAr1

NCAr2

MeO2C

OAr1

NCAr2

CO2Me

(9)+

(44) (45) (46)

110 °C

75%

Ar1 = 4-nitrophenyl; Ar2 = 3,4-methylenedioxyphenyl

2[96[0[1[2 Electrocyclizations leading to furans and oxepines

Carbonyl ylides generated from butadiene or hexatriene monooxides readily undergo electro!cyclization to a}ord O!heterocycles\ for instance the spirooxirane "36# undergoes ring expansion onheating leading to the bicyclic ether "37# "Equation "09## ð67TL3764Ł[ The cyclic epoxide "38# cleavedto a seven!membered ylide intermediate which was then observed to cyclize to the strained bicycle"49#^ ethene was excised from the latter under the reaction conditions to a}ord 1\2!bis"carbo!methoxy#furan "40# "Scheme 5# ð69PAC412\ 65TL2188\ 65TL2292Ł[ A synthetic route to a variety offuran and g!lactone compounds has been devised which rests on synthesis of the vinyl epoxide "41#and its rearrangement in high yield to dihydrofurans "42# "Equation "00##\ which have proved to beextremely versatile intermediates ð71CC0944Ł[ The oxepine "44# is obtained as a minor product fromthe thermolysis of the hexatriene oxide "43#\ with 0\6!electrocyclization less favoured than the0\4!electrocyclization\ which leads to the major bicyclic furans "45# "Equation "01## ð68TL3938\70CB1868\ 70TL3842\ 74CB3924Ł[

(10)325 °C

65%

O

Ph

NC

O

NC Ph

(47) (48) cis : trans = 9 : 1

(49) (50) (51)

MeO2C

O

CO2Me

O CO2Me

CO2Me

O

CO2MeMeO2C

Scheme 6

390 °C

50%

208Carbonyl Ylides

(11)

(52) (53)

R1 SMe

R2

O SMe O SMe

SMe

R2R1

(12)

(54) (55) 22% (56) 53%cis : trans = 4 : 3

+O

Ph

CO2Me

200 °C, 1 h O

Ph

MeO2C

O

CO2Me

Ph

2[96[0[1[3 Trapping by hydroxyl functions leading to acetals

Carbonyl ylides react with water or alcohols to yield hemiacetal or acetals[ This reaction has beenrarely used but a nice example is provided by the synthesis of the bridged bicyclic acetal "47# byphotolysis "p:p�# of the epoxy hydroxy ionone "46# "Equation "02## ð71HCA1252Ł[ In a relatedreaction an ylide intermediate was formed photochemically from the epoxide "48#^ reaction withmethanol then gave the primary product "59# which subsequently underwent 2\2!sigmatropicrearrangement leading to the cycloheptanone "50# "Scheme 6# ð68HCA0534Ł[

(13)HO

OO

O

O

(57)

O

(58)

254 nm, MeCN

55%

(59) (60) (61)

hν, MeOH [3,3]

43%

OO

O

O

OMe

OO

OMe

Scheme 7

2[96[0[1[4 Trapping by oxygen leading to ozonides

Carbonyl ylide cation radicals\ generated from oxiranes by electron transfer photosensitization\react e.ciently with oxygen\ to form ozonides\ a rare alternative to ozonolysis ð71CC0112\ 72JA552Ł[Thus tetraphenyloxirane "51# gave the ozonide "52# in 53) yield using dicyanoanthracene assensitizer^ this yield was raised to 82) on addition of biphenyl "Equation "03##[

hν, ET sens, O2

64%

OPh

Ph Ph

Ph

(62) (63)

O O

OPh

Ph Ph

Ph

(14)

2[96[0[2 Carbonyl Ylides From Carbenes

2[96[0[2[0 Intramolecular cycloadditions^ diazocarbonyl to oxygen heterocycle

As has been pointed out by Padwa and Hornbuckle ð80CRV102Ł\ reactions of carbalkoxycarbeneprecursors with carbonyl compounds were described as early as 0774 ð0774CB1260Ł\ and the structures


of the dioxolane products were assigned early in the twentieth century ð09CB0913Ł[ The carbeneÐcarbonyl reaction leads to a carbonyl ylide intermediate\ as shown in Equation "04#\ and ylideinterception reactions follow[ From a synthetic standpoint this route allows the formation of acarbonyl ylide from quite di}erent functional assemblies from the oxirane units described above[

O

R2

R1

+R4

R3

:R1 O R3

R2 R4

(15)

+

–

In the 0879s the formation of carbenes from diazocarbonyl compounds catalyzed by rhodium"II#salts\ especially rhodium acetate\ has attracted much attention[ This method allows mild conditions\reactions often taking place at ambient temperature in a few hours[ Thus the diazoketone "53# withrhodium acetate loses nitrogen to form the corresponding ketocarbene^ the carbene then is trappedby the adjacent ester carbonyl functionality to give an ylide which _nally undergoes intramolecularcycloaddition to form the tricyclic furanone "54# "Scheme 7# ð71T0366Ł[ The phthalate derivative"55# under similar circumstances yields the bridged furofuran "56# "Equation "05##^ the intermediatein this reaction can also be intercepted with DMAD ð77JA1783Ł[ The acyclic functional assemblies"57# and "69# undergo related reaction cascades to provide the tricyclic heterocycles "58# and "60#respectively "Equations "06# and "07##^ in the _rst case an isomunchone!like ylide intermediateparticipates ð77TL0566\ 78JOC706Ł^ cf[ ð82TL6742Ł[

(64) (65)

COCHN2

CO2Et O

O

EtO +

–

O

O

EtO2C

Scheme 8

Rh2(OAc)4, 3 h, RT

43%

(16)O

N2

O

O

O

O

ORh2(OAc)4, 25 °C

87%

(66) (67)

N

O

Ph

O

N2

O

N O

O

Ph

O

(69)(68)

( )3Rh2(OAc)4, 110 °C

91%(17)

(18)

(70) (71)

Rh2(OAc)4

N2

O

O

( )3 OO

2[96[0[2[1 Intermolecular cycloadditions^ carbene to oxygen heterocycle

Modern interest in the carbeneÐcarbonyl reaction was awakened by a study of the example shownin Equation "08# by de March and Huisgen ð71JA3841\ 71JA3842Ł[ The involvement of a carbonylylide was indicated by the production of the epoxide "61# with equimolar reactants "61)\ copperpowder\ re~uxing chlorobenzene#\ and by the isolation of the dioxolane "62# with excess

210Carbonyl Ylides

benzaldehyde "01 equivalents\ 014>C\ 45)\ cis ] trans�47 ] 31#[ Trapping by other dipolarophileswas achieved and catalysis by copper metal\ copper acetylacetonate\ copper tri~ate\ and rhodiumacetate was also observed[ Arylmercuric compounds are an alternative source of carbenes[ Thus\heating together bromodichloromethyl phenylmercury\ an aldehyde\ and a suitable ylide co!reactant"Equation "19## a}ords the dihydrofurans "63#\ which eliminate hydrogen chloride under the reactionconditions to form furans "64# in reasonable yield "R�Ph\ 35)# ð71TL4988\ 72JOC0940Ł[

(72) (73)

PhCHO N2

CO2Me

CO2Me+

OPh

CO2Me

CO2Me +O

O

Ph

PhCO2Me

CO2Me

(19)∆, cat.

(20)

(74) (75)

ArCHO + +DMAD

PhH, 80 °CPhHgCBrCl2

OAr

MeO2C CO2Me

Cl

Cl OAr

MeO2C CO2Me

Cl

Two examples of intermolecular reactions of ylides from diazocarbonyl reactants are providedby the work of Padwa and co!workers ð78CC810\ 78TL0380\ 89JA2099\ 82JOC3535Ł[ Thus\ the diazoester"65# with N!phenylmaleimide gave the bridged furolactone "66# "Equation "10##\ while the diazo!ketone "67# reacted with propanal to yield bridged cyclic acetals "68^ X�O# and "79^ X�O#"59)\ 1 ] 0#\ which were deoxygenated to exo! and endo!brevicomin "68^ X�H1# and "79^ X�H1#respectively "Equation "11##[ The last case in this subsection illustrates the scope for intramolecularreactions of carbenes with amide carbonyl groups "70# to form ylides "71#\ which can equilibratewith their isomers "72# through hydrogen transfer^ both of the ylides can be trapped by DMAD"Scheme 8# ð81JA482Ł[

O

O

NO O

Ph

ZR

O

RO

Z

O N2

O

(21)

(76)Z = CO2Et, CN; R = Me, Ph

(77)

Rh2+, 80 °C, N-Phenylmaleimide

75–85%

(22)N2

O

ORh2+, EtCHO

(78) (79)

OO

XEt

OO

X

(80)

Et

H+

Rh2+N

R O

O

N2

(81) (82) (83)

N

R O

O

+

–

N

R O

O

Scheme 9

+

–

2[96[0[2[2 Electrocyclizations leading to furans

Vinyl carbonyl ylides formed from carbenes and a!unsaturated ketones cyclize to furan sub!structures\ as exempli_ed in methodology developed for the elaboration of fused furans by Spencer


and co!workers ð56JA4386\ 56TL0754Ł and used in the synthesis of the diterpene methyl vinhaticoate[The key step\ "73# to "74#\ is illustrated "Equation "12##[ If aryl esters or amides are employed thenisobenzofurans result\ as in the conversion of "75# into "76#^ these new reactive intermediates can inturn be trapped by suitable dienophiles\ as in the formation of dihydronaphthalene "77# "Scheme09# ð72TL1834Ł[ This sequence has been exploited to form 00!oxasteroids\ centred around thetransformation of diazo ester "78# into an isobenzofuran\ which undergoes intramolecular DielsÐAlder reaction leading to the adduct "89# "Equation "13## ð77TL1934Ł[

CuSO4, 160 °C

30%

N2 CO2EtOMe

O

CO2Me

H

H

CO2Me

H

H

O

CO2Et

(23)

(84) (85)

(86) (87) (88)

O

NPri2

N2

O

NPri2

NPri2

CO2Me

CO2Me

OH

Scheme 10

Cu(acac)2 dimethyl maleate

75%

(89) (90)

Cu (F6 - acac)2

MeON2

CO2Me

O

OO

O

MeO

CO2Me

OO

O

HO

(24)

Further variants are o}ered by the cyclization of vinyl carbenes to fused furans[ The diazoketone"80# with an alkyne side chain is converted by rhodium acetate into the corresponding ketocarbene\which cyclizes _rst to the vinyl carbene "81#\ then to the furan "82# through a formal 0\2!dipole"Scheme 00# ð89JOC303Ł[ Parallel chemistry is displayed in the formation of the furolactone "84#from the acyclic diazoester "83# "Equation "14## ð89TL5724\ 82JOC10Ł[

(91) (92) (93)

Rh2(OAc)4

85%

O

N2

O :

O

Scheme 11

(25)

O

R

O

N2

O

O

O

R

O

(94) (95)

Rh2(OAc)4, 80 °C

212Carbonyl Ylides

2[96[0[2[3 Hydrogen migration leading to enol ethers

Carbonyl ylides with suitably disposed hydrogen atoms can rearrange by hydrogen migration tothe anionic site\ as illustrated in Scheme 01[ The enol ether "83# is the major product although alittle ylide is trapped by cyclohexanone to form the dioxolane "84# ð42JOC0929\ 78TL3978Ł[ With1!methylcyclohexanone\ regioselective enolization results ð67JOC0133Ł[ Another example arises inthe decomposition of the diazoketone "85# where 0\2!hydrogen shift in the ylide leads to the furan!2!one "86# "Equation "15## ð80JOC2160Ł[

OO

CO2Et

O

CO2Et

OO

EtO2C+ –

Cu, 90 °C

N2 CO2Et

Scheme 12

+

(94) 43% (95)

(26)

(96) (97)

O

N2

O

EtO OEtO

ORh2+, 25 °C

90%

2[96[0[2[4 Halogen migration and decarbonylation reactions

Ylides derived from halocarbenes can react by way of 0\2!halide shift\ formally generating acarbene which then fragments with a second halide shift to form a 0\0!dihalide and carbon monoxide"Scheme 02# ð63S613\ 67JOC0960\ 72JOC0787\ 72TL1718Ł[ The ylide intermediate in this sequence can\ infavourable cases\ collapse to the corresponding oxirane in good yield ð63JOM"56#230Ł[

ArCHO + PhHgCBrCl280 °C Ar O Cl

Cl

Scheme 13

+

– CO + ArCHCl2

2[96[0[3 Carbonyl Ylides From Cycloreversions

Cycloreversion of carbonyl ylide adducts has been observed in a number of cases[ Examples arelimited to those cases in which a heterocycle fragments to an ylide essentially irreversibly[ The best!known examples are those in which nitrogen is extruded\ such as in the thermolysis of the oxadiazole"87#\ which at 59Ð54>C a}ords the corresponding ylide\ trapped by N!phenylmaleimide with sub!sequent loss of acetic acid to yield the dihydrofuran "88# "Equation "16## ð56TL1578Ł[ Low regio!selectivity in the interception of the ylide oxadiazole "099# by D3!methanol was demonstrated\ withisolation of both the bisacetal "090# and the orthoester "091# "2 ] 6# "Equation "17## ð72CJC508Ł\ andcompetitive 0\3!hydrogen shifts were observed on heating the related oxadiazole "092#\ when theisomeric enol ethers "093# and "094# were formed "Equation "18##] di}erences in product distributionbetween cis and trans "092# indicated that the conformationally di}erent ylides did not equilibratein their lifetime ð78CJC0642Ł[ Thermolysis of the diazaheterocycle "095# is a convenient method of


generating dialkoxy carbenes "096# "Equation "29## ð81JA7640Ł[ Diazirenes pursue a similar reactionpath on heating^ thus the arylchlorodiazirene "097# generates the corresponding carbene at 79>C inacetone\ and subsequent reaction with the solvent a}ords the ylide "098# "Equation "20## ð75TL3272Ł^cf[ ð75TL3272\ 76CL1024\ 76TL0900\ 89JA633Ł[ The bicyclic compound "009# reversibly eliminates dimethylfumarate on heating\ to form the mesoionic isomunchone dipole "000#\ which in the presence ofdimethyl acetylenedicarboxylate undergoes addition followed by elimination of methylisocyanateto form the _nal furan product "001# "Scheme 03# ð64CL388Ł[

(27)

N N

O

Ph

OAc

O

N

Ph

O

OPh

(99)(98)

N-phenylmaleimide, 60–65 °C

51%

(28)

(100) (101) (102)

N N

OMeO MeO O OCD3

D

MeO O D

D3CO+

CD3OD, 80 °C

(29)

(103) (104) (105)

N N

OAcO AcO O+

PhH, 80 °C AcO O

(30)

(106) (107)

N N

ORO

MeO

PhH, 100 °C MeO OR

:

(31)

(108) (109)

Me2CO, 80 °C

N

NAr

Cl

Ar O

Cl

+

–

N

OPh Ar

MeO2C CO2Me

Me O

N

O

Me O–

ArPh+

O

MeO2C CO2Me

ArPh

Scheme 14

DMAD

–MeNCO

(110) (111) (112)

2[96[0[4 Carbonyl Ylides From Elimination Reactions

Heating the thionoacid "002# with acetic anhydride induces cyclodehydration to give the mesoionicheterocycle "003#^ addition to methyl propargylate and elimination of carbonyl sul_de then yieldsthe furan "004# "Scheme 04# ð64AG"E#311Ł[ Sammes and co!workers have exploited the mild elim!ination of acetic acid from 1!acetoxydihydropyran!2!ones to form 2!oxidopyrilium ylides tosynthesize a variety of bridged furans and other O!heterocycles ð71CC0945\ 72CC555\ 72JCS"P0#0150\75JCS"P0#0614\ 76JCS"P0#084Ł[ An example of intramolecular cycloaddition is provided by 0\4!diazabicycloð3[2[9Łnon!4!ene "dbn#!catalyzed elimination from the 2!pyranone "005# at ambienttemperature to a}ord the tricyclic product "007# via the ylide "006# "Scheme 05#[ Substituted relatives

214Carbonyl Ylides

of "007# have been used to synthesize various sesquiterpenoids of the hydrazulene series\ for example"2#!b!bulnesol\ "2#!b!bulnesene\ "2#!cryptofauronol\ "2#!fauronol acetate\ and "2#!valeranone[Intermolecular trapping of these 2!oxidopyrilium ylides by both electron!rich and electron!de_cientalkenes has also been observed[ Thus\ the precursor "008# with triethylamine and ethyl vinyl ethergave the bicyclic ether "019#\ and with 1\2!dimethylbutadiene ð3¦3Ł cycloaddition occurred to yield"010#[ The isochroman derivative "011# reacted with cyclohexenone\ for example\ to provide thestereoisomers "012# and "013# "Equation "21##\ with minor quantities of a regioisomer[ Wender andco!workers have employed the generation of the 2!oxidopyrilium ylide from the pyranone "014#\yielding "015# through intramolecular cycloaddition\ as a key step in the synthesis of a generalprecursor to the tiglianes\ daphnanes\ and ingenanes "Equation "22## ð78JA7843Ł[ This chemistrywas then developed into an elegant total synthesis of phorbol ð78JA7846Ł[ An approach to thetigliane system using a carbonyl ylide strategy has also been reported ð82JOC6524Ł[

N

O

S

Ph

CO2HN

S

+ O Ph

O–

NO Ph

Scheme 15

(113)

MeO2C

(114) (115)

CO2MeAc2O, 80 °C

–COS

(116) (117) (118)

O

O

AcO O

O

+

–O

O

H

Scheme 16

dbn, RT

–AcOH 75%

O

O

AcO

O

O

EtO

(119)O

O

(120) (121)

(32)O

O

OAc

H

H

O

O

O

H

H

O

O

O(122) (123) (124)

+Et3N, RT

cyclohexenone

(33)

(125) (126)

OO

OAc

OAcO-TBDMS

dbu, RT

OAc

O

O

O-TBDMS

dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene; TBDMS = t-butyldimethylsilyl


0\2!Elimination from chloromethyl!a!trimethylsilyl!a!arylmethyl ethers "016# has been shown tolead to the formation of simple aryl carbonyl ylides "017# under mild neutral conditions followingchemistry parallel to that of the nitrogen analogues "Equation "23## ð82TL4832Ł[

(34)

(127) (128)

O

Ar

+

–

TMS O Cl

Ar CsF, RT

Finally an isolatable 2!oxidopyrilium ylide has been obtained from the thiopyrilium perchlorate"018#[ S!Phenylation of "018# followed by treatment with oxygen _rst gave the cyclic peroxide "029#which next rearranged on reaction with hydrogen chloride with loss of thiophenol to form the ylide"020# as a dark red solid "Scheme 06#^ the ylide "020# then gave an adduct with maleic anhydrideð51JA1983Ł[

(129) (130) (131)

SPh

Ph

Ph+

ClO4–

i, PhLi

ii, O2 SPh

Ph

Ph

Ph

O O

OPh

Ph

Ph+

O–

Scheme 17

HCl, Et2O

2[96[1 CARBONYL OXIDES

Carbonyl oxides are generated as reactive species inozonolysis reactions of alkenes ðB!67MI 296!90\B!71MI 296!90\ B!73MI 296!91Ł[ Scheme 07 indicates the accepted general course of events where theinitial molozonide fragments "reverse 0\2!dipolar cycloaddition# into carbonyl oxide and aldehydeor ketone[ This pair may then add together with reverse regiochemistry to form the normal ozonide\but other courses are open to the carbonyl oxide\ including interception by a more reactive carbonylcompound to give a new ozonide\ reaction with alcohols to form an a!methoxy hydroperoxide\dimerization to a cyclic bisperoxide\ or polymerization[ This scheme implies that a speci_c ozonidemay not be formed exclusively from a simple alkene\ and this has been borne out by severalexperimental studies\ for example ozonolysis of neat pent!1!ene at −69>C gave a mixture of allthree possible ozonides\ each as a cisÐtrans pair "Equation 24# ð54JA626Ł[ The intramoleculartrapping of a carbonyl oxide has been demonstrated in the ozonolysis of the unsaturated diketone"021#^ intermediate "022# reacts to yield the bicyclic peroxide "023# "Scheme 08# ð43CB0697\ 57CB352Ł[Criegee et al[ ð64CB0531Ł have shown that a carbonyl oxide has a long enough lifetime to choosebetween two available carbonyl groups in the ozonolysis of the deuteriated compound "024#[ Equalquantities of the two ozonides "025# and "026# were obtained "Equation "25##[ An intramolecularrearrangement of the initial molozonide was ruled out[ Carbonyl oxides have been shown to reactwith suitable dicarbonyl compounds to give either monoozonides or novel 0\1\3\5!trioxepanesð83JCS"P0#532Ł[

(35)O3, –70 °C OO

O

OO

O

OO

O+ +

O3+

O

DD

D

D

D

O

DD

D

D

DO

OO (36)

O

O

O

D3C

O

DD

(135) (136) (137)

216

R1

R1 OMe

OOH

O O

OO

R1

R1R1

R1

OO

O R1

R1

R2

Scheme 18

R1 R1

+ OO–

R1 R1

O OO

O

OO

O

R1

R1R1R1

R1

R1R1

R1

+

MeOHR2CHO

O

O

O

O

O–

+ OO O

Scheme 19

O3

(132) (133) (134)

Sensitized photooxygenation of furans\ for example "027# has been shown to lead to a reactionsequence involving a!unsaturated carbonyl oxides "028# as intermediates "Equation "26##[ The latterdisplay a range of reactions\ including cycloadditions ð83JCS"P0#036Ł[

(37)

OAr

CO2Me

OMe O

CO2Me

CO2Me

Ar

O–

(139)(138)+

hν, O2

2[96[1[0 Other Carbonyl Derivatives

Various analogues of carbonyl oxides can be envisaged\ for instance carbonyl imines "039#\ and{{carbonyl sul_des|| "030#[ The former have attracted theoretical attention\ and calculations haveindicated that such species should be stable enough to be detected ð62JA6176\ 72JCR"S#151Ł[ Howeverno signi_cant experimental work on these and other analogous intermediates has yet been reported[

ONR

R

R

OS(R2)

R

R

+ +– –

(140) (141)


3.08Thioaldehydes and ThioketonesWILLIAM G. WHITTINGHAMZENECA Agrochemicals, Bracknell, UK

2[97[0 INTRODUCTION 229

2[97[1 THIOALDEHYDES 220

2[97[1[0 Alkyl Thioaldehydes 2202[97[1[0[0 Photolysis of phenacyl sul_des 2202[97[1[0[1 Formation of the a C0C bond 2212[97[1[0[2 0\1!Elimination reactions 2222[97[1[0[3 Cycloreversion and related reactions 2232[97[1[0[4 Sulfuration of aldehydes and derivatives 2252[97[1[0[5 Other methods 225

2[97[1[1 a\b!Unsaturated Thioaldehydes 2262[97[1[1[0 Thioaldehydes bearin` an a\b!alkenic bond 2262[97[1[1[1 Thioaldehydes bearin` an a\b!aryl or hetaryl substituent 2392[97[1[1[2 Thioaldehydes bearin` an a\b!alkynic bond 231

2[97[2 THIOKETONES 231

2[97[2[0 Dialkyl Thioketones 2312[97[2[0[0 Dialkyl thioketones by sulfuration of ketones 2322[97[2[0[1 Dialkyl thioketones by direct sulfuration of other compounds 2362[97[2[0[2 Dialkyl thioketones by other methods 238

2[97[2[1 a\b!Unsaturated Thioketones 2412[97[2[1[0 Thioketones bearin` an a\b!alkenic bond 2412[97[2[1[1 Thioketones bearin` an a\b!aryl or hetaryl substituent 2592[97[2[1[2 Thioketones Bearin` an a\b!Alkynic Bond 255

2[97[3 THIOALDEHYDE AND THIOKETONE FUNCTIONS FURTHER SUBSTITUTEDON SULFUR 255

2[97[3[0 Two!coordinate Sulfur Functions 2562[97[3[0[0 Thiocarbonyl ylides 2562[97[3[0[1 Sul_nes 2572[97[3[0[2 Thiosul_nes 2692[97[3[0[3 Thiocarbonyl S!imides 2692[97[3[0[4 Metal complexes of thioaldehydes and thioketones 2692[97[3[0[5 Thiopyrylium salts 2692[97[3[0[6 0\1!Dithiolium salts 2602[97[3[0[7 Nonclassical thiophenes 2602[97[3[0[8 Other heterocycles 261

2[97[3[1 Three!coordinate Sulfur Functions 2612[97[3[1[0 Sulfonium ylides 2612[97[3[1[1 Sulfenes 2642[97[3[1[2 Other simple systems 2642[97[3[1[3 Thiabenzenes 2642[97[3[1[4 0\5\5al3!Trithiapentalenes and related systems 265

2[97[3[2 Four!coordinate Sulfur Functions 2672[97[3[2[0 Sulfoxonium ylides 2672[97[3[2[1 Other simple compounds 2682[97[3[2[2 Thiabenzene S!oxides 268

2[97[3[3 Five!coordinate Sulfur Functions 2792[97[3[3[0 Alkylidene sulfur tetra~uorides 279

218

229 Thioaldehydes and Thioketones

2[97[0 INTRODUCTION

Although the chemistry of the C1S double bond bears many similarities to that of the C1Obond\ there are some signi_cant di}erences[ The C1S bond is much less polarized than the C1Obond\ because of the much smaller di}erence between the electronegativities of carbon "1[49# andsulfur "1[47# than between those of carbon and oxygen "2[33#[ Thus\ whereas the carbonyl bond hasa clear polarization\ with a partial negative charge on oxygen and a partial positive charge oncarbon\ the situation for the thiocarbonyl bond is much less clear cut[ The greater length of theC1S bond also leads to a bond that is more easily polarized by neighboring groups[ This results inlarge variations in the reactivity of di}erent thiocarbonyl groups^ an e}ect that is not seen forcarbonyl compounds[ For example\ electron!withdrawing groups on the thiocarbonyl carbon atom\as in hexa~uorothioacetone\ signi_cantly reduce the electron density on sulfur\ and can reverse theexpected polarity of the C1S bond\ resulting in nucleophilic attack occuring at sulfur rather thancarbon ð54JOC0273Ł[ On the other hand\ conjugative electron!donating groups "as in\ for example\thioesters and thioamides# result in the opposite sense of polarization and hence in compounds witha strongly nucleophilic sulfur atom[

Thiocarbonyl compounds bearing electroneutral groups\ such as carbon and hydrogen\ tend tohave nonpolarized C1S bonds and can thus react in di}erent ways\ depending on the conditions[This results in the very ready oligomerization or polymerization of thioaldehydes and thioketones\and many of these compounds are highly unstable and can only be isolated under special conditions\if at all[ For this reason many simple thioaldehydes and thioketones\ and their derivatives\ havebeen generated and characterized only at very low temperatures\ or in the gas phase[ Although thesecompounds are not strictly within the scope of this review\ their preparation will be detailed whereit demonstrates a useful principle\ or if the method could potentially be applied to the synthesis ofstable compounds[ The same criteria have been applied to those cases where the thiocarbonylcompounds have been generated and then trapped in situ without isolation or characterization[ Thisapproach has been widely used\ not only for the characterization of the thiocarbonyl compounds\but also in a number of synthetic applications[

The C1S double bond is also signi_cantly weaker than the C1O bond "004 kcal mol−0 "370 kJmol−0# against 051 kcal mol−0 "567 kJ mol−0##[ This not only increases the reactivity of thethiocarbonyl group\ it also radically changes the balance of the tautomerism between the thioneand enethiol forms of these compounds[ Thus the enethiol form is often the more stable and\ undersome circumstances\ can be formed exclusively in a reaction or by subsequent equilibration[ Aslightly di}erent manifestation of this e}ect occurs in the case of a!dithiones\ which can tautomerizeto 0\1!dithietes "Equation "0##[ In this case the position of the equilibrium is very dependent on thefurther substitution of the system ð72HCA790Ł[ A similar acyclicÐcyclic tautomerism is possible fora!ketothiones and a\b!unsaturated thiocarbonyls[ In these cases the equilibrium lies completelytoward the acyclic thione tautomer\ unless there is a very strong driving force for formation of theC1C double bond as in\ for example\ monothio o!quinones "Equation "1## and o!thioquinone!methides[ A more detailed analysis of the tautomerism of thiocarbonyl compounds is given bySchaumann in his recent excellent review of the thiocarbonyl group ðB!78MI 297!90Ł and by Duus inan earlier review ð68COC"2#262Ł[ For the purpose of this work\ brief mention will be made of syntheticmethods which result in the exclusive formation of enethiols or cyclic tautomers*further detailscan be found in Chapter 1[03[0[

S

S

R S

R S R

R

(1)

O

S

O

S

(2)

A further notable di}erence between thiocarbonyl and carbonyl compounds is a result of theability of the sulfur 2d orbitals to participate in bonding[ This\ combined with the lower elec!tronegativity of sulfur than oxygen\ results in a rich chemistry of thiocarbonyl compounds that arefurther substituted on sulfur which has no real equivalent in the chemistry of the carbonyl group[A wide range of compounds of this type have been prepared\ and are discussed in Section 2[97[3[

220Thioaldehydes

2[97[1 THIOALDEHYDES

As has been mentioned above\ the low polarization of the thioaldehyde bond means that manyof these compounds are unstable\ often forming cyclic dimers or trimers\ or polymers[ Indeed\ theonly thioaldehydes that can be isolated under normal conditions are those which have stabilizingsteric or electronic interactions[ This has resulted in the chemistry of thioaldehydes being much lesswell developed than that of thioketones\ in which there are two potentially stabilizing groups[ The_rst stable thioaldehyde was only prepared in 0859\ by Woodward et al[ as an intermediate in theirsynthesis of chlorophyll a ð59JA2799Ł[

Signi_cant advances have followed\ notably in the use of reactive thioaldehydes in total synthesisby the in situ trapping of these compounds as they are generated[ In particular\ thioaldehydes reactreadily as dienophiles in the DielsÐAlder reaction\ a technique that has been developed extensivelyby the groups of Baldwin\ Kirby\ and Vedejs[ The use of this method\ and of thiocarbonyl chemistryin general\ for the formation of carbonÐcarbon bonds has recently been reviewed ð81S0074Ł[ Anumber of stable thioaldehydes have been prepared and isolated\ generally in those cases whereelectronic factors allow conjugation and delocalization of the thiocarbonyl bond\ or where extremesteric crowding disfavors polymerization[

2[97[1[0 Alkyl Thioaldehydes

A number of methods for the preparation of simple alkyl thioaldehydes have been developed\some of which have recently been reviewed ð77YGK0038Ł[

2[97[1[0[0 Photolysis of phenacyl sul_des

Vedejs and co!workers have developed the Norrish type II photolytic cleavage of phenacyl sul_desinto a versatile method for the synthesis of thioaldehydes "Scheme 0# ð71JA0334Ł[ A wide variety ofalkyl thioaldehydes\ including several bearing nitrogen substituents ð77JOC1115Ł\ have been preparedand trapped in situ as DielsÐAlder adducts ð75JOC0445\ 77JA4341Ł[ Several dienes have been used asthe trapping reagent\ and the yields for this process are generally good[ This methodology has beenapplied to more complex systems as a key step in the total synthesis of cytochalasans ð73JA3506Łand zygosporin E ð77JA3711Ł[ The intramolecular DielsÐAlder reaction of thioaldehydes generatedin this manner has also been examined "Scheme 1# ð77JOC1119Ł[

S R1

R2OO

S R1

Ph

S R1

Ph OH

hν R2O

Scheme 1

Scheme 2

hν

S

H

HSS

O

Ph

71%

Vedejs and co!workers have used this technique to prepare thiopivaldehyde "0#\ the _rst exampleof a stable simple alkyl thioaldehyde ð72JA0572\ 75JA1874Ł[ Photolytic cleavage of phenacyl neopentylsul_de "1# provided the white insoluble thiopivaldehyde polymer[ The yield of this fragmentationcould be improved to 49Ð59) under optimum conditions "photolysis in benzene solution containingan excess of 1\2!dimethylbutadiene\ using light _ltered through aqueous copper sulfate to removeshort!wavelength radiation that decomposes the polymer#[ Cracking the polymer at 149>C\ andcollection of the volatiles in a liquid nitrogen trap\ provided monomeric thiopivaldehyde "0# as amagenta solid "Scheme 2#[ Addition of an inert solvent and warming to room temperature resultedin a pink solution that was stable for up to 05 h\ depending on the cleanliness of the glassware and


the purity of the solvents used[ Impurities\ especially protic or Lewis acids\ resulted in a more rapiddecomposition to the polymer and trimer[ The thiopivaldehyde was not particularly air!sensitive\and underwent many reactions typical of thioaldehydes[ Other tertiary thioaldehydes can also beprepared as monomers by this method ð75JA1874Ł[

Scheme 3

hν

59%

∆

O

S

Ph

But

S But

(2) (1)

(ButCHS)n

2[97[1[0[1 Formation of the a C0C bond

A uniquely stable group of alkyl thioaldehydes are those in which the C1S bond is conjugatedto an adjacent phosphonium ylide[ Yoshida et al[ have prepared compounds of this type by thecondensation of a triphenyl phosphonium ylide with methyl thionoformate "Scheme 3# ð64BCJ1896Ł[The stability of these compounds is presumably a result of the contribution of the canonical form"2#\ the importance of which is suggested by the occurrence of slowly interconverting geometricisomers of the thioaldehyde "3#[

S–

Ph3P

S

Ph3PCH2Ph3P +HCSOMe

(4) (3)

Scheme 4

Vedejs et al[ have prepared thiopivaldehyde by an alternative route to the photolytic methoddescribed above\ which is conceptually similar to that used for the synthesis of the phosphoniumylide!stabilized thioaldehydes "Scheme 4# ð75JA1874Ł[ Addition of t!butyllithium to ethyl thiono!formate provided the hemithioacetal "4#\ which underwent acid!catalyzed decomposition to thio!pivaldehyde\ which was distilled and trapped as before[ A similar technique has been applied tothe preparation of the highly sterically hindered thioaldehyde "5# by Okazaki et al[ "Equation "2##ð76JA168Ł[ In this case\ reaction of the alkyllithium with ethyl thionoformate gave a 05) yield ofthe thioaldehyde "5#\ a stable crystalline compound which could be puri_ed by chromatographyand recrystallization[ A further product "6# was isolated in 14) yield and is believed to derive fromthe hemithioacetal "7#\ suggesting that an improvement in the yield of the thioaldehyde is possibleif "7# could be decomposed following Vedejs| method[

SH

But OEt

S

But

S

OEt

ButLi

70%

H+, ∆

31%

(5)

Scheme 5

SS

OEt 16%

TMS

TMS

TMS

(6)

(3)

LiTMS

TMSTMS

SH

TMS

TMS

TMS

(8)

OEt

TMS

TMS

(7)

OEt

222Thioaldehydes

A related method has been used by Hartke and Gu�nther to prepare thioformyl acetonitrileð62LA0526Ł[ This compound could not be isolated\ but was moderately stable in solution\ existingexclusively as the enethiol tautomer[

2[97[1[0[2 0\1!Elimination reactions

A widely used approach to the synthesis of thioaldehydes has been 0\1!elimination\ from a suitableprecursor containing a C0S single bond\ to generate the C1S double bond "Equation "3##[ Thisarea has been developed by Kirby and co!workers\ who have demonstrated that base!catalyzedelimination from sulfenyl halides ð72CC312\ 74JCS"P0#0430Ł\ phthalimides "Equation "4## ð72CC0214Ł\Bunte salts "Equation "5## ð73CC811Ł\ and a!sulfonyl disul_des ð73CC0358Ł generated the thioal!dehyde "8#\ which was readily trapped as DielsÐAlder adducts[ Kirby and Sclare have extended thismethod to the preparation of the a!keto thioaldehyde "09# "Equation "6##\ which was reacted in situwith thebaine ð80JCS"P0#1218Ł[ Although these methods have only been applied to the preparationof a very limited range of alkyl and aryl "see Section 2[97[1[1[1# thioaldehydes\ there appears to beno reason why they could not be used to prepare any thioaldehyde bearing a suitable electron!withdrawing group[

R SX

H

R S + HX (4)

N

O

O

S

EtO2CEtO2C S

Et3N

78%

(9)

(5)

EtO2C SEt3N

67%(9)

(6)EtO2C SSO3

– Na+

S

(10)

Et3N, CaCl2

74%(7)S

SO2Tol

O O

A further development of this general method has been reported by Kra}t and Meinke\ who haveused the ~uoride!induced cleavage of a!silyl disul_des "00# to generate a range of alkyl thioaldehydes\which have been trapped by reaction with cyclopentadiene\ in good yields "Equation "7## ð74TL0836Ł[A related approach has been described by Vedejs et al[ "Equation "8## ð77JA4341Ł\ although thismethod has not been applied widely[ These two modi_cations of the 0\1!elimination technique havethe advantage that a wider range of thioaldehydes can be prepared\ as no adjacent activating groupis required[

R1 SCsF or tbaf

58–94%SSR2Me2Si

R1X

(11)

(8)

R SEt2NH

29–77%(9)

SO2Ph

R SAc

A related elimination strategy has been devised which relies on elimination from "or cycloreversionof# a suitably activated dithiolane or derivative[ Thus\ deprotonation of the sulfonium salt "01#forms an ylide which fragments to generate a thioaldehyde "Scheme 5# ð74TL4154Ł[ This method hasbeen used to prepare thioformaldehyde and thioacetaldehyde\ both of which were trapped in situ[


Thiopivaldehyde was also prepared as a polymer\ which could be thermally cracked to the monomeras described above[ A recent modi_cation of this method has also been used to synthesize thio!pivaldehyde "Equation "09## ð89JOC3199Ł[ A variation of the procedure\ the thermolysis of a 0\0!dioxodithiolane\ has been used to generate tri~uorothioacetaldehyde\ which was characterized inan argon matrix and trapped as DielsÐAlder adducts ð78TL3000\ 89CB066Ł[ This thioaldehyde provedto be rather unstable\ forming a polymer in a few minutes at −085>C[

S

S

CO2Me

CO2Me

R R S+

(12)

EtNPri2

24–65%

S

S

CO2Me

CO2Me

R+

Scheme 6

–

But SS

S

O

But

TBDMS-OTf, EtNPri2

39%(10)


Vedejs et al[ have demonstrated that cyanothioformaldehyde can be prepared by the reaction ofdibromoacetonitrile with EtOCS1

−K¦\ a reaction that is mechanistically similar to other 0\1!elimination approaches ð79JOC1590Ł[ The thioaldehyde could be trapped by dienes in low yield"Scheme 6#[ This method could potentially be extended to the synthesis of other thioaldehydes\ butappears to have been superseded by the Norrish type II photofragmentation technique[

S CN

EtO

S

K+ –S OEtS CN

EtOBr2HCCN

15%

Scheme 7

A technique closely related to the 0\1!elimination approach is the thermal rearrangement ofS!alkyl thiosul_nates[ The earliest example of this reaction is the work of Block and O|Connor\who thermally decomposed alkylthiosul_nate esters to generate a sulfenic acid and a thioaldehydeð61JA531\ 63JA2818Ł[ The main aim of these studies appears to have been the preparation andcharacterization of the sulfenic acids\ as little mention of the thioaldehydes was made\ although thereaction of methyl alkylthiosul_nates was shown to generate thioformaldehyde polymer[ Baldwinand Lopez have developed this reaction into a general method for the preparation of thioaldehydes\which were trapped as DielsÐAlder adducts with anthracene "Scheme 7# ð71CC0918Ł[ The methodhas also been used to synthesize a thioaldehyde which underwent intramolecular DielsÐAldercyclization ð72T0376Ł[

Scheme 8

S∆ SSS

O

74%

2[97[1[0[3 Cycloreversion and related reactions

One of the most widely used methods for the generation of simple thioaldehydes is the cyclo!reversion of various precursors[ The ð1¦1Ł cycloreversion reaction of sulfur!containing four!mem!bered rings\ under thermolytic or photolytic conditions\ has been employed to prepare thioaldehydes\and the reaction has been reviewed by Schaumann and Ketcham ð71AG"E#114Ł[ This technique hasbeen used to generate and characterize thioformaldehyde and dideuterothioformaldehyde isolated

224Thioaldehydes

in an argon matrix ð80BCJ0278Ł[ A range of variations of this method have been used ð63CJC2407\71JA2008Ł\ typi_ed by that shown in Equation "00# ð56JPC3000Ł[ The ð3¦0Ł cycloreversion of "02#has been used to prepare monothioglyoxal "03#\ which was isolated and characterized in an argonmatrix "Equation "01## ð72NJC158Ł[ The same technique has been used to prepare dithioglyoxal andt!butyl dithioglyoxal ð67NJC220Ł[

S H2C CH2+HCHS

∆(11)

(12)hν

O

SO

O

S

(13) (14)

The most widely used method of this type involves the retro DielsÐAlder reaction[ As has beendiscussed above\ the trapping of reactive thioaldehydes with dienes\ most commonly cyclo!pentadiene\ is the method of choice for the isolation and characterization of these unstablecompounds[ Heating the DielsÐAlder adducts regenerates the free thioaldehydes\ which can betrapped ð72CC0214Ł or\ in the case of thiopivaldehyde\ isolated in a liquid nitrogen trap "Equation"02## ð77JA4341Ł[ A wide range of thioaldehydes can be generated in this way\ and conventionalchemistry can be used to elaborate the starting DielsÐAlder adducts and hence the _nal thioaldehydes"Scheme 8# ð77JOC1119Ł[ A variety of di}erent adducts can be used to prepare thioaldehydes in goodyield ð72CC312\ 72T0376\ 74JCS"P0#0430\ 89JOC1485Ł[ A particularly useful variant of this reaction hasbeen reported by Lee et al[ "Scheme 09# ð74JOC2105Ł[ In this case the precursor "04# is prepared bya di}erent route\ potentially allowing the synthesis of thioaldehydes not available by other methods[

But S∆

75%(13)

S

But

S

O

CO2Et S

OO

SEtO2C∆

CO2Et

i, NaH, MeIii, NaH, ClCH2C(Me)CH2, NaI

35%

Scheme 9

EtO2C S∆

85%HN

SN

OCCl3

CCl3

EtO2C

Cl3CCO2Et

NH2

SCl2

33%

(15)

Scheme 10

The retro ene reaction of allyl sul_des "Equation "03## ð65CJC426\ 82JA213Ł and a retro ð2¦1Łcycloaddition "Equation "04## ð74TL4154Ł have also been used to generate thioaldehydes[

∆

S SS S (14)

But SN

S

O

Ph

But

Ph

∆

39%(15)


2[97[1[0[4 Sulfuration of aldehydes and derivatives

Although the direct conversion of a carbonyl group into a thiocarbonyl group is the most widelyused procedure for the preparation of stable thioketones "see Section 2[97[2#\ it has received littleattention for the synthesis of thioaldehydes[ This may be because the reagents and conditions thatare routinely used are incompatible with these comparatively unstable compounds[ However\hexamethyl disilathiane "TMS!S!TMS# has been used either on its own ð68ZOB0973Ł\ or in com!bination with boron trichloride ð71JA2093Ł\ n!butyllithium ð77JA0865Ł\ or cobalt chlorideð80JOC6212Ł\ to prepare a range of thioaldehydes which could readily be trapped as DielsÐAlderadducts in good yield[ The n!butyllithium!promoted reaction has also been applied to the dienal"05#^ the thioaldehyde thus formed undergoes intramolecular DielsÐAlder cyclization "Scheme 00#ð78SC1320Ł[

SSO

TMS-S-TMS, BunLi

(16)

54%

H

H

Scheme 11

Aldehyde dimethyl acetals can be converted into the corresponding thioaldehydes by reactionwith "Me1Al#1S^ the products were trapped with phosphonium ylides\ to give alkenes in reasonableyields ð82CE42Ł[

2[97[1[0[5 Other methods

An interesting approach to the synthesis of thioaldehydes\ which may _nd wide application\ isthe reaction of phosphonium ylides with elemental sulfur "Scheme 01# ð77CL0034\ 80BCJ1391\81RHA006Ł[ The thioaldehydes prepared by this method were trapped by reaction with secondaryamines to produce thioamides or enamines[ A modi_cation of this technique\ which allows milderconditions to be employed\ utilizes the cyclic polysul_des "06# or "07# as the sulfur source ð80S674Ł[

MeO2C PPh3 MeO2C SS8 Me2NH

MeO2C S

NMe2

Scheme 12

S S

S

S

S SS

SS

(17) (18)

Another potentially versatile method for the formation of thioaldehydes has recently beendescribed by Dzhemilev et al[ ð81IZV059Ł[ Reaction of the sulfoxide "08# with catalytic Ni"acac#1\triphenylphosphine\ and triethylaluminum\ in the presence of butadiene gave an 71) yield of theDielsÐAlder adduct "19# "Equation "05##[ This technique has been applied to a range of dialkylsulfoxides\ and a number of alternative catalysts have been described ð80URP0579588\ 81URP0609459Ł[Given the ready access to a wide variety of sulfoxides\ this method should prove to be applicable tothe preparation of a range of thioaldehydes[

C6H13 S C6H13

O

S

C6H13

(19) (20)82%

Ni(acac)2, PPh3, Et3Al(16)

226Thioaldehydes

The zirconation of thioketenes has been used for the preparation of stable\ highly stericallyhindered\ enethiolizable thioaldehydes\ as mixtures with the enethiol tautomers "Equation "06##ð80JA6671Ł[

But

ButS

But

ButSH+

But

But •S

i, Cp2ZrCl2. BunLi

ii, 2 equiv. HCl

62%(17)

40% 60%

A number of photolytic and thermal techniques have been used to generate simple thioaldehydesfor characterization in the gas phase or by matrix isolation[ The 0\1!elimination of hydrogenchloride from alkylsulfenyl chlorides discussed above has been carried out thermally to preparethioformaldehyde ð65JA5943Ł and thioformyl cyanide ð80T3816Ł\ and photolytically to producethioacetaldehyde ð80CB1598Ł[ The thermolysis of thiocyanohydrins has also been used to preparethioaldehydes ð77TL4788\ 80T3816Ł[ The thermal elimination of sulfur from 0\1\3!trithiolane has beenemployed in the preparation of thioformaldehyde ð66CC176Ł[ A range of thermal methods for theformation of thioaldehydes has been summarized in a paper by Bock et al[ ð71CB381Ł[

A number of synthetic approaches have been described which selectively produce vinyl thiols "theenethiol tautomers of thioaldehydes#[ These include the addition of hydrogen sul_de to alkynesð52JA852\ 54CJC606Ł and the cleavage of vinyl sul_des ð69RTC482\ 60IJS"B#74Ł and vinyl thiocyanatesð89JCR"S#219Ł[ The vinyl thiols formed\ with the exception of ethenethiol which has a half!life ofbetween an hour and several days ð66CC372Ł\ were stable enough to be isolated\ although a slowtautomerization to the corresponding thioaldehyde\ followed by polymerization\ was observed[ Formore details of these methods\ see Chapter 1[03[0[

2[97[1[1 a\b!Unsaturated Thioaldehydes

Simple a\b!unsaturated thioaldehydes are similar in many respects to the alkyl thioaldehydesdiscussed in the previous section[ Thus\ they are highly reactive species which often oligomerizeunless trapped in situ\ and they have generally been characterized in the gas phase\ at low tempera!tures\ or as stable derivatives such as DielsÐAlder adducts[ In a single case\ that of 1\3\5!tri!"t!butyl#thiobenzaldehyde\ steric protection has resulted in a stable compound ð73TL738Ł[ However\there is the possibility of electronic stabilization of unsaturated thioaldehydes in those cases wherea suitable electron!donating group is conjugated to the C1S double bond[ A number of compoundsof this type have been prepared\ and the resulting vinylogous thioamides or thioesters and het!erocyclic thioaldehydes have proved to be stable isolable compounds[

2[97[1[1[0 Thioaldehydes bearing an a\b!alkenic bond

This section covers the preparation of thioaldehydes containing an a\b C1C double bond[Thioaldehydes that are conjugated to other types of double bond\ such as C1O\ C1S\ or C1P\have been described in Section 2[97[1[0 on alkyl thioaldehydes[

"i# Simple alkenyl thioaldehydes

A number of the techniques used for the preparation of alkyl thioaldehydes have been applied tothe synthesis of thioacrolein and related reactive unsaturated thioaldehydes[ Thus the ~ash ther!molysis of diallyl sul_de ð63CC398\ 65CJC426\ 71JA201Ł or diallyl sulfoxide ð89TL4992Ł yielded thioac!rolein\ which was characterized at low temperature\ as DielsÐAlder adducts with dienophiles\ or asa mixture of its isomeric DielsÐAlder dimers "10# and "11# "Scheme 02#[ Thermolysis of the dimermixture\ which can be readily isolated and puri_ed\ provides a convenient source of pure thioacroleinð71JA201Ł[ Thioacrolein was also produced by the thermolysis of various cyclopropyl sul_desð67JA6325Ł[ The authors postulated a ring opening\ followed by a retro ene or 0\1!eliminationreaction to explain this unexpected result "Scheme 03#[ 0\1!Elimination from a dithiolane ð74TL4154Łor from the reaction product of 1!propen!0!thiol and Ebselen oxide "12# "Scheme 04# ð78JOC0981Łhas been used to generate thioacrolein\ as has the photochemical method of Vedejs ð77JA4341Ł[Direct sulfuration of acrolein has been used to prepare the thioacrolein dimers "10# and "11#


ð72JHC0642Ł\ and the analogous dimers of thiomethacrolein may be the actual products from thetreatment of methacrolein with phosphorus pentasul_de\ rather than the thioaldehydes postulatedð68JOC375Ł[

SS

S

SSS

∆+

(21) (22)

Scheme 13

S

SCl

S

SX SX S–HX

••

Scheme 14

HSS

SeN

O

O

PhNHPh

O

SeS

O

Scheme 15

69%

(23)

"ii# Electronically stabilized alkenyl thioaldehydes

Simple enamino thioaldehydes can be regarded as vinylogous thioamides\ and are stable formonths at room temperature ð70PS"09#0Ł[ The _rst example of this type of compound\ 2!dimethyl!aminopropenethial\ was prepared by treatment of the corresponding aldehyde with P1S4 "Equation"07## ð61OMR"3#310Ł[ Perhaps surprisingly\ this simple method has not been further applied to thepreparation of this type of compound[

Me2N O Me2N SP2S5

(18)

Muraoka et al[ have prepared a series of a!cyano!b!imino thioaldehydes by the condensation ofthe anion of b!imino nitriles with potassium dithioformate "Scheme 05# ð71CL090Ł[

Scheme 16

R S

NH2

CN

R S

NH

CN

R

NH

CN

HCSS– K+, t-C5H11O– Na+

23–96%

A more versatile method for the synthesis of this class of compounds\ in moderate yields\ is amodi_cation of the VilsmeierÐHaack reaction ð74CC0188\ 78JCS"P0#0130Ł[ Thus\ reaction of enamineswith phosphoryl chloride and DMF or N!methylformanilide\ followed by hydrolysis of the resultingVilsmeier salts with methanolic sodium hydrogensul_de\ provided a wide range of stable thio!aldehydes "Scheme 06#[ Proton NMR data showed that these compounds existed exclusively as the

228Thioaldehydes

enamino thioaldehyde tautomer\ rather than the alternative imino thioaldehyde or iminovinyl thiolform ð78JCS"P0#0130Ł[ A related approach has been applied to the synthesis of a diselenovinylthioaldehyde ð77JOC2418Ł[

Scheme 17

POCl3, DMF NaSH

37–87%

R1 S

R2

R3R4N

R1 NMe2

R2

R3R4N

R1

R2

R3R4N

+

An interesting approach to the preparation of enamino thioaldehydes has been developed byHolm and co!workers in connection with the synthesis of tetraaza macrocycles ð62IC1478\ 62JA502Ł[Treatment of the 3!phenyldithiolium cation with one equivalent of a diamine produced the enam!inothial "13# in good yield[ This compound was then cyclized with further diamine to provide thedesired macrocycle "14# "Scheme 07#[ This method has been further developed and applied to simplemonoamines by Quiniou and co!workers ð76BSF406Ł[ These workers have studied the reaction indetail\ in particular the structures of the products and by!products of the reaction[ Isothiazoliumsalts also react with amines to produce enamino thioaldehydes\ although in this case the productsformed depend upon the substitution pattern of the isothiazole and the exact conditions employedð74T0774Ł[ Reaction of the 3!arylthiazolium perchlorate "15# with benzylamine gave only theN!methyl product "16# "Equation "08##[ In contrast\ the 2!phenyl compound "17# gave a mixture ofN!methyl and N!benzyl products when reacted with one equivalent of benzylamine\ and exclusivelythe N!benzyl compound when three equivalents were used "Equation "19##[

N

NH

Ph

HN

N

PhS

NH

PhS

HN

PhS

S+

Ph

H2N NH2

Scheme 18

(25)

H2N NH2

40%

(24)

60–80%

S

NPh

+

NHMe

SPhNH2Ph

51%(19)

(26) (27)

S

N+

NHBn

SNH2Ph

39%(20)

(28)Ph

Ph

3 equiv.

Activated alkynes undergo a ð2¦1Ł cycloaddition with 0\1!dithiole!2!thiones "18# to producethioformylmethylene dithioles "29#\ which were stable enough to be isolated but could not be puri_ed"Equation "10## ð60CJC2188\ 61CR"C#512\ 64BSF"1#0324Ł[ This method can also be applied to benzyne\resulting in the formation of the benzo!fused 0\2!dithiole ð63CR"C#148Ł[ A by!product of theseprocesses is the 0\5\5al3!trithiapentalene\ which can be formed by isomerization of the thioaldehydes"see Section 2[97[3[1[4#[ The use of 0\1!dithiole!2!ones in this reaction results in the formation ofthe 0\2!oxathiole!substituted thioaldehydes ð79BSF"1#429Ł[

dimethylacetylenedicarboxylate

85%

SS

S

Ph

S

S

MeO2C

MeO2C

Ph

S

(30)(29)

(21)


2[97[1[1[1 Thioaldehydes bearing an a\b!aryl or hetaryl substituent

"i# Simple aryl thioaldehydes

Many of the general methods described in the previous sections have been applied to the prep!aration of thiobenzaldehyde "Scheme 08#[ Several substituted thiobenzaldehydes and simple het!erocyclic thioaldehydes have also been prepared\ notably by the 0\1!elimination of Bunte saltsð73CC811Ł or a!sulfonyl disul_des ð73CC0358Ł\ and by the direct sulfuration of aldehydes ð71JA2093\77JA0865\ 80JOC6212Ł or acetals ð82CE42Ł[ In all these cases the products were unstable and werecharacterized at low temperature or in the gas phase\ or trapped as DielsÐAlder or other adducts[The Lewis acid!catalyzed cycloreversion of heterocycles "20# has also been used to generate aromaticthioaldehydes for further reaction ð77MI 297!90Ł[

S

S

O

Ph

SPh SH

Se

N

S+

S

O

O

Ph

CO2Me

CO2Me

Ph SS Ph

Ts

SPh

S

Ph

S

OPh

Ph

O

Ph

S

Ph

Ph

O

TMS-S-TMS, additive

Ph SAc

SAcCl

SSPh

TMS

Ph SS Ph

O

Ph PPh3

TBDMS-OTf

EtNPri2

∆ 75% Et3N

LDA

48%

∆92%

hν

84%

85–96%

Ni(acac)2, Ph3PEt3Al

S8

56%

∆ 97% CsF 90%

Et2NH

15%

39%


Scheme 19

⟨74CC409⟩⟨84CC1469⟩

⟨85TL5265⟩

⟨87JA5549⟩(see also ⟨89JOC1092⟩)

⟨90JOC4200⟩

⟨88JA5452⟩

⟨85TL1947⟩⟨82CC1029⟩

⟨88CL1145⟩

⟨8 2JA3104, 88JA1976,91JOC7323⟩

⟨86JOC1556⟩

⟨83T1487⟩

⟨92IZV160⟩

S NH

SAr Ar

Ar

(31)

The only stable thiobenzaldehyde to have been prepared\ isolated\ and fully characterized is thehighly sterically crowded 1\3\5!tri!"t!butyl#thiobenzaldehyde "21#\ synthesized by Okazaki et al[ bythe addition of an aryllithium to ethyl thionoformate "Equation "11## or the sulfuration of hydrazone"22# "Equation "12## ð71CC0076Ł[ This thiobenzaldehyde is quite stable\ and has been used to studythe reactions of the thioformyl group ð73TL738\ 73TL762Ł[ More recently\ Okazaki and co!workers

230Thioaldehydes

have prepared deuterated 1\3\5!tri!"t!butyl#thiobenzaldehyde in 26) yield by reaction of the aryl!lithium with O!cholesteryl deuterothionoformate ð76BCJ0926Ł[ Crossley and Curran reported thepreparation of thioveratraldehyde from the corresponding aldehyde by reaction with H1S and HCl\but the data presented suggest that this compound was probably not monomeric ð63JCS"P0#1216Ł[

But

But

Li

But

But

But But

S

56%

(32)

S

OEt(22)

But

But But

NNH2

But

But But

SS2Cl2, Et3N

40%

(33) (32)

(23)

"ii# Electronically stabilized aryl thioaldehydes

In contrast to the low stability of simple aryl and hetaryl thioaldehydes\ those compounds inwhich the C1S double bond can be stabilized by interaction with a nitrogen lone pair are oftenperfectly stable compounds[ This exactly parallels the stability of the vinylogous thioamidesdescribed in the previous section[ Thus\ the _rst thioaldehyde to be prepared and isolated was thedipyrrylmethane "23# prepared by Woodward et al[ as an intermediate in the synthesis of chlorophylla ð59JA2799\ 89T6488Ł[ This compound was prepared from the corresponding aldehyde "24# via theiminium salt "25#\ which was hydrolyzed by treatment with hydrogen sul_de and sodium methoxide"Scheme 19#[ The thioaldehyde "23# was remarkably stable\ crystallizing from benzene:cyclohexaneand surviving storage for 29 years with only slight decomposition ð89T6488Ł[

HN

O

HN

CO2Me

O

MeO2C

HN

EtHN+

HN

CO2Me

O

MeO2C

HN

S

HN

CO2Me

O

MeO2C(35) (36) (34)

EtNH2, AcOH

94%

H2S, NaOMe

86%

Scheme 20

Following this precedent\ a number of stable hetaryl thioaldehydes have been prepared usingrelated methods[ Reid and co!workers have developed a modi_cation of the Vilsmeier reactionwhich has proved to be applicable to a number of heterocyclic systems ð55CC390\ 69JCS"C#034\62JCS"P0#546\ 76KGS0583\ 89KGS0174Ł[ As an example\ reaction of the indolizidine "26# with phosphorylchloride and DMF produced the Vilsmeier salt "27#[ This was then treated directly with aqueoussodium hydrogensul_de to produce the thioformyl indolizidine "28# in 75) yield "Scheme 10#ð55CC390\ 69JCS"C#034Ł[ A modi_cation of this procedure\ utilizing dimethyl thioformamide in placeof DMF\ has proved to give better results in some cases ð58JCS"C#802Ł[ McKenzie and Reid alsodemonstrated that the thioaldehydes could be prepared via an enol ether\ although the thiolysisonly proceeded in 22) yield ð55CC390\ 69JCS"C#034Ł[

Direct sulfuration of heteroaromatic aldehydes has been employed for the preparation of stablethioaldehydes[ McKenzie and Reid _rst described the reaction of formyl indolizidines with P1S4 asan alternative to the Vilsmeier synthesis\ the thioaldehydes being formed in good yield "Equation"13## ð69JCS"C#034Ł[ Becher et al[ have demonstrated that treatment of o!amino heteroaromatic


N

(37)

N

(38)NMe2

N

(39)S

+

POCl3, DMF NaSH

86%

Scheme 21

aldehydes with either hydrogen sul_de:hydrogen chloride or Lawesson|s reagent generated thecorresponding stable thioaldehydes "Equation "14## ð80S598Ł[ They also showed that these com!pounds could be prepared in good yield by the one!pot reaction of o!azido aldehydes with hydrogensul_de\ _rst in the presence of piperidine to catalyze reduction of the azide\ then with an excess ofhydrogen chloride to catalyze the thionation of the aldehyde[

N

O

N

S

P2S5, C5H5N

59%(24)

NN NH2

Ph O

NN NH2

Ph SH2S, HCl

55%(25)

2[97[1[1[2 Thioaldehydes bearing an a\b!alkynic bond

The only example of an a\b!alkynic thioaldehyde reported is propynethial\ which was preparedby the gas phase pyrolysis of dipropynyl sul_de\ a reaction optimized by Korolev and co!workersð76IZV1210\ 76IZV1287\ 81MC56Ł[ The compound has been characterized in the gas phase\ and as itsDielsÐAlder dimer ð72PS"06#36Ł[ The 23S compound has also been prepared ð71AJC0636Ł[

2[97[2 THIOKETONES

Thioketones are generally more stable than the corresponding thioaldehydes[ This is particularlyso for diaryl thioketones in which the C1S electron density is delocalized through both aromaticrings[ Even the simplest of this class of compound\ thiobenzophenone\ is a relatively stable molecule\and diaryl thioketones have been known for many years[ However\ simple thioketones which arenot stabilized by electronic or steric factors are still highly reactive compounds which have frequentlybeen generated and trapped in situ\ or characterized at low temperature or in the gas phase[

One consequence of the greater stability of thioketones than thioaldehydes is that rather morevigorous methods can be used for their formation without signi_cant decomposition of the products[This\ combined with the very ready availability of ketones\ means that the predominant method forthe preparation of thioketones is the direct conversion of a carbonyl group\ or a simple carbonylderivative\ into a thiocarbonyl[ Various other methods have been used to synthesize thioketones\but they tend to have been applied to only a few speci_c cases rather than being of general utility[

Early work in this area has been reviewed by Campaigne ðB!55MI 297!90Ł[

2[97[2[0 Dialkyl Thioketones

Mayer et al[ ð53AG"E#166Ł and Paquer ð61IJS"B#158Ł have reviewed the early progress in this areaand have discussed the preparation and physical and chemical properties of aliphatic thioketones[

232Thioketones

2[97[2[0[0 Dialkyl thioketones by sulfuration of ketones

"i# Usin` hydroèn sul_de

The most widely used method for the conversion of aliphatic ketones into thioketones is reactionwith hydrogen sul_de in the presence of HCl[ However\ if this reaction is carried out at ambienttemperature the major product is often a èminal dithiol[ These compounds can be isolated andthermolyzed to give the thioketone "see Section 2[97[2[0[2[i#\ but more conveniently their formationcan be suppressed by conducting the reaction at low temperature\ generally −69>C to −79>C"Scheme 11# ð56CB82Ł[ Working at low temperature has the added advantage that the thioketonesare usually formed as monomers rather than trimers\ the formation of which is catalyzed by acid athigher temperatures ð62BCJ1142Ł[ The amount of trimer formed is also dependent on the substrateused\ with greater steric hindrance favoring formation of the monomer[ Thus\ reaction of cyclo!butanone with H1S and HCl gave exclusively a trimer\ whereas a series of relatively stable\ mono!meric 1\1!dimethylcyclobutanethiones were prepared under identical conditions "Equation "15##ð67RTC010Ł[ Increased steric hindrance also favors the formation of the thioketone rather than thedithiol[ Dimers can sometimes be formed\ especially in those cases where steric hindrance results ina slow reaction and disfavors trimer formation ð67T1178Ł[ A systematic study of the di}erentproducts formed in the reaction of a series of aralkyl ketones has been conducted ð51JOC2659Ł[

H2S, HCl, –80 °C

55%

H2S, HCl, –25 °C

32%

HS SH SO

Scheme 22

H2S, HCl, 0 °C

40%(26)

O S

The reaction is commonly performed in methanol or ethanol\ but co!solvents such as ether canbe used[ Additives such as trialkyl orthoformates have also been employed\ and appear to allow thereaction to be conducted at higher temperature without the formation of dithiols ð63JCS"P0#0683\68TL1566Ł[ In the reaction of adamantanone with H1S and HCl in ethanol at −44>C an alternativeproduct\ the èminal ethoxythiol "39#\ was formed in reasonable yield ð58CJC2604\ 69CJC2429Ł[ Thiswas converted into adamantanethione in excellent yield by heating under vacuum "Scheme 12#[

Scheme 23

100 °C, 15 torr

93%

H2S, HCl, EtOH, –55 °C

57%

O S

SH

OEt

(40)

When applied to ketones bearing one or more a!hydrogen atoms there is the possibility of theformation of the enethiol tautomer of the product thioketones[ With simple thioketones the enethiolsare not generally seen ð67RTC010Ł\ although the reaction of naltrexone is reported to give thecorresponding enethiol ð80JMC0181Ł[ The situation with b!oxothioketones is considerably morecomplex "see below#[

A somewhat less acidic variant of this technique\ which uses anhydrous zinc chloride instead ofHCl\ has been applied to a series of bicyclic ketones by Vialle and co!workers ð79JOC1406Ł[ Theproduct formed was dependent on which isomer of the starting material was used\ with some of theinitially formed thioketone products undergoing rearrangement under the reaction conditions[

When applied to diketones this method can yield either monothio or dithio products\ dependingupon the precise conditions used[ Thus\ the monothiodiketone "30# was prepared from the diketoneby reaction with H1S and HCl at −69>C for 1[4 h "Equation "16## ð65TL3186\ 66T2978Ł[ Reaction ofvarious cyclobutanediones with H1S in the presence of HCl and zinc chloride produced either the


dithiones selectively ð60JOC2774Ł\ or a mixture of the mono! and dithiones ð76JOC1043Ł\ dependingupon the exact conditions used[

H2S, HCl, –70 °C

35–65%

O O O S

(41)

(27)

Enolizable b!oxo thioketones can also be prepared by this technique\ thioacetylacetone beingformed from acetylacetone in excellent yield under carefully controlled conditions ð66ACS"B#39Ł[Interesting selectivity was observed when the same conditions were applied to nonsymmetricaldiketones ð66JOC2012Ł[ 1!Acetylcyclohexanone reacted selectively at the endocyclic carbonyl "Equa!tion "17##\ whereas the analogous cyclopentanone gave the exocyclic thione as the only product inlow yield "Equation "18##[ The selectivity for the endocyclic carbonyl in cyclohexanones appears tobe general for several substituted compounds ð75JA529Ł[ b!Keto esters ð61T4812\ 63T2642\ 65RTC061Ł\b!keto thioesters ð57T4212Ł\ b!keto dithioesters ð62BSF"1#0862Ł\ and b!keto lactones and thiolactonesð58T4692Ł react selectively at the ketone carbonyl to give good yields of the b!thioxo compounds[These b!oxo thioketones can exist in a number of tautomeric forms\ the relative amounts of whichdepend upon a number of factors\ including solvent\ temperature\ and molecular structure[ Thedi}erent tautomers can be interconverted by photolysis at suitable wavelengths "Equation "29##ð68JCS"P1#0421Ł[ This area has been extensively investigated by Duus and co!workers\ who havestudied the tautomerism in detail and proposed a model to explain the observations ð71JA4811\72JCS"P1#0210\ 75JA529Ł[ A more detailed discussion of this complex area is given in the review of thethiocarbonyl group by Duus ð68COC"2#262Ł[

H2S, HCl, –40 °C

30–39%(28)

O O S O

H2S, HCl, –40 °C

4.5%(29)

O OO S

hν (353 nm)S O S OH H

(30)hν (288 nm)

Hydrogen sul_de will also react with ketones under basic conditions[ The usual product formedin this case is the dithiol\ but some ketones give low yields of thioketones "Equation "20##ð52AG"E#269Ł[ 0\2!Diketones react to give the corresponding monothiodiketones\ predominantly inthe enethiol form\ but 0\1!diketones are reduced to either the a!hydroxy ketone or the monoketone[

(31)

O S

H2S, BunNH2, DMF

22%

"ii# Usin` phosphorus!based rea`ents

Another widely used reagent for the conversion of ketones into thioketones is phosphoruspentasul_de[ The most commonly used conditions for this reaction involve heating the ketone andP1S4 in pyridine[ Good yields of the thioketone are generally obtained\ although the quantity ofP1S4 used must be calculated carefully\ as an excess can cause decomposition of the productsð69CJC2429Ł[ Other solvents have also been employed e}ectively\ including toluene ð54MI 297!90Ł\xylene ð81CJC863Ł\ and ethers such as DIGLYME ð62S038Ł[ The use of a polar solvent such asDIGLYME generally results in a more rapid reaction\ suggesting the participation of a polar

234Thioketones

intermediate[ The addition of bases such as sodium hydrogencarbonate ð62S038Ł further acceleratesthe reaction\ providing support for an anionic species being the active reagent[ A wide range ofaliphatic thioketones have been prepared using variations of this method^ a selection is shown inTable 0[

Table 0 Aliphatic thioketones prepared using phosphorus pentasul_de[

Thioketone Conditions Yield(%)

Ref.

Pyridine90 °C, 11 h

90 70CJC3530


93 91JOC5932

DIGLYME, NaHCO3120 °C, 5h

70 73S149

Pyridine110 °C, 30 min

69 75JCS(P1)2513

S

DME, NaHCO3RT, 65 h

S

85

F

80CB2255

S


SO2

S

15 83JOC214

S

DIGLYME, NaHCO3110 °C, 2 h

S

20S

83JOC214

S

EtO2C CO2EtPyridine

110 °C, 1 h60 (Diels–Alder adduct) 90JCS(P1)3175

As is the case with other reagents\ the reaction of P1S4 with diketones can result in the formationof either monothio or dithio compounds\ depending upon the conditions used[ Thus the sulfurationof cyclobutanedione "31# gave either the monothiodione "32# or the dithione "33# as the majorproduct\ depending on the amount of P1S4 used and the reaction time ð56JOC0451Ł[ A by!product\the thione "34#\ was formed in one of the reactions "Scheme 13#[ Similar mixtures of mono! anddithiodiketones have been observed in other systems ð81CJC863Ł[ An interesting example is thereaction of P1S4 with a 1!keto!0\2!diamide[ The major product from this reaction was the ketodithio!amide\ but a small amount of thioketone was also produced ð72LA0583Ł[

The preparation of the thioketone "35# has been reported by Lipkowitz and Mundy ð66TL2306Ł[This compound could be prepared by reaction of the corresponding ketone with P1S4 ð68JOC375Ł\but was also one of the products formed in the reaction of methyl vinyl ketone with P1S4 in pyridine\together with a smaller amount of the regioisomer "36# "Equation "21##[ Presumably the reaction


initially produces methyl vinyl thioketone\ which then undergoes a DielsÐAlder reaction withunreacted ketone[

O OS O S S + S

SS

SS

(42)(43) (44) (45)

P2S5 (1 equiv.)90 min

50%

P2S5 (0.45 equiv.)40 min

40%

Scheme 24

(32)P2S5, pyridine

(46) 13%

OO O

S

S

+

(47) 1%

Although P1S4 is a versatile reagent for the synthesis of thioketones\ in some circumstances theconditions required for the reaction to proceed are such that the initially formed thioketonedecomposes or undergoes further reaction[ In this way\ treatment of the diketone "37# with P1S4 inre~uxing pyridine did not give the desired dithioketone\ but the dithiolactone "38# "Equation "22##ð72JOC3371Ł[ In contrast\ the dithioketone could be prepared\ in 69) yield\ by using H1S\ HCl\ andzinc chloride[ A similar rearrangement product was isolated from the reaction of P1S4 with thecyclobutanedione "31# ð56JOC0451Ł[ Interestingly\ this product could be converted into the desiredcyclobutanedithione "33# by photolysis in nonprotic solvents ð79CC132Ł[

(33)O O

SS

P2S5, pyridine

(48) (49)

Lawesson|s reagent "49# has also been used for the conversion of ketones into the correspondingthioketones ð67BSB112\ 79CB1144\ 80TL0676Ł\ and its use has been reviewed ð74T4950Ł[ In some cases\enethiols can be formed ð71T882Ł\ and di!t!butyl dithiet "40# was formed in the reaction of "49# withthe monothiodiketone "41# "Equation "23## ð71JCR"S#203Ł[ Interestingly\ neither the dithiet "40# northe thioketone "41# could be prepared directly from the diketone ð67NJC220Ł[

SP

SP

S

S

MeO OMe

(50)

S SO

But But

S

But But

(52) (51)

(50), ∆

45%(34)

"iii# Usin` other rea`ents

A number of other sulfuration reagents have been employed in the synthesis of simple thioketones\although they have not been widely utilized[ Bis"trimethylsilyl# sul_de\ in combination with eitherboron trichloride ð71JA2093Ł or trimethylsilyl tri~ate ð80JOC6212\ 82TL762Ł\ has been used to prepare

236Thioketones

a range of thioketones in good yield[ Several tin sul_des have also been used in conjunction withboron trichloride ð71JA2093Ł[

A slightly di}erent approach has been applied to the synthesis of thiodimedone from dimedoneð63ACS"B#0966Ł[ Reaction with PCl2 gave the vinyl chloride "42#\ which\ upon reaction with sodiumsul_de and acidi_cation\ gave thiodimedone "43#\ which exists exclusively as the conjugated enethioltautomer in solution "Scheme 14#[ The same method has also been used for the formation of acyclicb!thioketo aldehydes ð62ZOR0606Ł[ A related technique has been applied to the preparation ofthioketones conjugated to a phosphonium ylide "Scheme 15# ð81TL4844Ł[

OH

O

Cl

O

SH

O

PCl3 i, Na2Sii, HCl

95%

(53) (54)

Scheme 25

Scheme 26

(TfO)2O

70%

Na2S

82%But

O

PPh3

But

OTf

+PPh3

But

S

PPh3

Tf = trifyl

2[97[2[0[1 Dialkyl thioketones by direct sulfuration of other compounds

"i# Acetals and enol ethers

A range of simple thioketones has been prepared by the reaction of dimethyl or diethyl ketalswith H1S in the presence of HCl\ tosic acid\ or zinc chloride ð52CB2985\ 61CJC2812\ 81TL5040Ł[ Thismethod is particularly mild\ and gives the pure thioketones not containing any of the enethiol formð81TL5040Ł[ Similar reaction conditions can also be applied to enol ethers ð52CB2985Ł[

"ii# Hydrazones

Hydrazones have proved to be useful intermediates in the conversion of ketones into thioketones\and have found particular application to the preparation of highly sterically hindered thioketones[The thermal decomposition of triphenylphosphorylidene hydrazones "easily prepared from thehydrazone itself# in the presence of elemental sulfur was used by de Mayo et al[ to prepare severalthioketones\ in varying yields "Scheme 16# ð67TL3510Ł[ However\ in a number of cases this methodfailed\ particularly with enethiolizable compounds[

But But

NNH2

But But

NN

But But

S

PPh3

Scheme 27

But But

O Ph3PBr2, Et3N S8, ∆

83%

H2NNH2, ∆

An alternative method which has found wider application to the formation of sterically hinderedthioketones has been developed by Okazaki et al[ ð68TL2562\ 70BCJ2430Ł[ Reaction of hydrazoneswith S1Cl1 provides thioketones directly\ probably via an unstable thiosul_ne "44# which eliminates


sulfur in situ "Scheme 17#[ The yields of this process are generally good\ and it has been usedto prepare various thioketones as intermediates in the synthesis of hindered alkenes ð72TL4750\73CB166Ł[

S2Cl2, Et3N

66%But But

NNH2

But But

SS

(55)

But But

S

Scheme 28

"iii# Imines

The reaction of N!phenylimines with H1S in the presence of benzoic anhydride provides purethioketones in good yield ð64ZN"B#659Ł[ b!Keto thioketones can be prepared from the correspondingb!keto imines by this method[ The lithium or sodium salts of imines react with carbon disul_de toform thioketones in good yield[ This method has been applied to the preparation of di!t!butylthioketone "Equation "24## ð63JCS"P0#0683\ 64BCJ1392Ł and other hindered thioketones ð66JCR"S#035\73CB166Ł[

But But

S i, MeLiii, CS2

100%But But

NH

(35)

"iv# Enamines

Enamines can be converted into thioketones in good yield by reaction with H1S ð59BCJ0632Ł[ Thismethod can be used to prepare\ in monomeric form\ thioketones "e[g[\ cyclohexanethione# whichtend to form trimers under other conditions[ The reaction has been extended to the synthesis of b!thioxo esters*in this case tri~uoroacetic acid is used as an additive ð68JOC2160Ł[

"v# Miscellaneous compounds

An interesting approach to the preparation of isotopically labeled thioketones from labeledelemental sulfur has been developed by Klages and Voss ð66AG"E#614Ł[ Heating a selenoketone withelemental sulfur in an ampoule results in formation of the thioketone by sulfurÐselenium exchange[Direct sulfur exchange of thioketones with labeled sulfur is also possible under similar conditions*an equilibrium mixture is obtained\ so the use of an excess of labeled sulfur should allow a goodconversion to the labeled thioketone[

Middleton et al[ have developed several novel methods for the preparation of per~uorothioketonesð50JA1478\ 54JOC0264Ł[ Reaction of bis"per~uoroisopropyl#mercury with re~uxing sulfur vapour gavea 59) yield of hexa~uorothioacetone\ a reasonably stable but highly reactive compound whichdimerizes in the presence of a base "Scheme 18#[ This type of compound can also be prepared invery good yield by the reaction of per~uoroalkyl iodides with phosphorus pentasul_de at re~ux"Equation "25##[

S8, ∆

60% F3C CF3

Sbase

S S

F3C CF3

F3C CF3

Hg

F3C

CF3

CF3

F

CF3F

Scheme 29

238Thioketones

F3CCF3

S

FF

F3CCF3

FF

IF

P2S5, ∆

92%(36)

A number of a\a!dioxo thioketones have been generated by the reaction of b!diketones withdithiobissuccinimide and pyridine[ The resulting thioketones were not stable\ but could be trappedas DielsÐAlder adducts ð76JOC058Ł[

2[97[2[0[2 Dialkyl thioketones by other methods

Although the techniques described above are by far the most widely used for the synthesis ofthioketones\ a number of other methods have also been employed\ including several that have beendeveloped primarily for the formation of thioaldehydes "see Section 2[97[1[0#[

"i# 0\1!Elimination reactions

An early example of this approach to the synthesis of thioketones was the dehydro~uorinationof a per~uorothiol to produce\ in quantitative yield\ the per~uorothioketone "45# "Equation "26##ð54JOC0264Ł[ Geminal dithiols eliminate H1S on heating\ and a range of aliphatic thioketoneshave been prepared by this method ð55CB0660Ł[ Similarly\ elimination of ethanol from a `eminalethoxythiol has been used to synthesize adamantanethione "see Scheme 12# ð58CJC2604\ 69CJC2429Ł[The reaction of a suitably activated Bunte salt with base has been used by Voss and co!workers toprepare stable a!oxothioketones ð70LA09\ 72LA0583Ł\ and by Kirby and McGregor to synthesizediethyl thioxomalonate ð89JCS"P0#2064Ł[ Diethyl thioxomalonate has also been prepared "as its dimer#by the triphenylphosphine!promoted elimination from an a!chlorosulfenyl chloride ð68JOC0625Ł[

F3CCF3

S

FF

F3CCF3

FF

FSH

NaF

100%(37)

(56)

The most widely used variant of the 0\1!elimination technique has been the cycloreversion of 1\1!disubstituted 0\2!dithiolanes or derivatives\ under basic or pyrolytic conditions[ In general\ theproduct from the reaction of a thioketal with butyllithium is the corresponding thiol\ formed by thereduction of the _rst!formed thioketone by butyllithium ð71JOC2208Ł[ However\ in the case ofcamphor thioketal the major product is thiocamphor\ apparently because this thioketone undergoesdeprotonation to form an enethiolate rather than being reduced[ Base!induced elimination from 0\0!dioxo!0\2!dithiolane "46# has been employed by Schaumann and co!workers to prepare thiocamphor"Equation "27## ð71AG52\ 72AG"E#44Ł[ Several of the methods used to generate thioaldehydes describedin Section 2[97[1[0[2 have also been applied to the preparation of thioketones "see Scheme 5 andEquation "09## ð77CB0048\ 89CB066\ 89JOC3199Ł[ A related method\ the reaction of a\a!dibromo!carbonyl compounds with EtOCS1

−K¦\ has been used to prepare reactive a!oxo thioketones whichcan be trapped as DielsÐAlder adducts ð64CB562\ 67ZN"B#306\ 70TL1860\ 89JCS"P0#2064Ł[

LDA

47%(38)S

S

S

O O

(57)

"ii# Formation of the a C0C bond

The Claisen condensation between a ketone and a thionoester has been widely employed for thesynthesis of b!oxo thioketones "Equation "28##[ Sodamide is commonly used as the base\ and the


reaction has proved to be applicable to aryl methyl ketones and some aliphatic ketones ð66JCS"P0#0016\66JOC2012\ 66S145Ł[ However\ for some aliphatic ketones the reaction is unsuccessful\ and t!butyl!lithium is used as the base in order to achieve satisfactory results ð74S561\ 75JA529Ł[ The self!condensation of ethyl thionoacetate produces a b!thioketo thionoester\ which exists largely in theenethiol form ð61AJC146Ł[ The anion of acetonitrile can also be employed in this type of reaction\the product being a rather unstable enethiol ð62LA0526Ł[

i, NaNH2ii,

(39)R1 R2

O S

R1

OEtO R2

S

An interesting alternative approach has been reported by Hayashi and Midorikawa ð62TL1350\64JAP"K#6438140Ł[ In this case\ condensation of the anion of ethyl trimethylsilylthioacetate with anaromatic aldehyde produced the a!thioketo ester "47#\ which existed exclusively as the enethiol form"48# "Scheme 29#[

i, NaH, PhCHOii, HCl

PhCO2Et

S

63%

(58)

PhCO2Et

(59)

SHS

CO2Et

TMS

Scheme 30

"iii# Rin` openin` of heterocycles

Rhodanine "59# can be condensed with aldehydes to produce heterocycles "50#[ These compoundsundergo ring opening upon treatment with base to give thiopyruvic acids "51# in excellent yields"Scheme 20#[ This approach has been applied to the synthesis of aromatic ð24JA0015Ł and hetero!aromatic ð49JOC70\ 89EUP9268868Ł substituted thiopyruvic acids[ A similar fragmentation occurs withthiazolidinediones ð37BSF0019Ł[ The cleavage of oxathiolanone "52# with sodium methoxide producesthe enethiol tautomer of methyl thiopyruvate "53# "Equation "39##[ This reaction is applicable toaliphatic systems which cannot be accessed via rhodanine derivatives\ and has been applied to thepartial synthesis of the antibiotic griseoviridin ð74JOC2565Ł[

Scheme 31

RCHO

(61) (62)(60)

NaOHS

NH

O

SS

NH

O

S

R RCO2H

S

(63) (64)

NaOMeS

O

O

PhPh

CO2Me

SH(40)

1!Alkyl 0\2!thiazines undergo hydrolysis under very mild conditions to produce the enethioltautomers of b!thioketoamides in reasonable yields ð72CPB0818Ł[

240Thioketones

"iv# Reduction of sul_nes

In the reaction of di!t!butyl sul_ne with Grignard reagents\ di!t!butyl thioketone was formed\ invarying yield depending on the Grignard reagent used[ The best result was obtained witht!butylmagnesium chloride\ which gave 36) of the thioketone ð68JOC1133Ł[ Phosphorus pentasul_decan also be used as the reducing agent in these reactions ð72CB55Ł[

"v# Cycloreversion and related reactions

Although not as widely employed as in thioaldehyde chemistry\ DielsÐAlder adducts provide avaluable source of thioketones for further reaction ð65JPR016\ 68TL1566\ 89JCS"P0#2064\ 89TL5072Ł[The photolytic retro ð3¦0Ł reaction of a dithiolane has been used to prepare t!butyl thioglyoxalð67NJC220Ł[

Retro ð1¦1Ł reactions\ often of thioketone dimers\ have also been used to prepare monomericthioketones ð54JOC0264\ 62BCJ2174\ 75JA2700Ł^ this area has been reviewed ð71AG"E#114Ł[ Cyclic trimersof thioketones can be pyrolyzed to give the monomeric compounds in good yield\ sometimes asmixtures with the enethiol tautomer ð63JOC1498Ł[ The retro ene reaction of allyl sul_des is also aconvenient source of reactive thioketones ð63CC398\ 65CJC426\ 89TL5072Ł[ The hetero!Cope rearrange!ment of the disul_de "54#\ readily formed by the oxidation of thiocamphor with chloramine T\ gavethe dithione "55# as a single isomer in excellent yield "Scheme 21# ð62JCS"P0#1755Ł[ This reactionprovides a novel method for the a\a?!coupling of thioketones[ The thio!Claisen rearrangement hasalso been employed in the formation of a C0C bond a to a thioketone[ Thus the reaction ofthioketones with allyl bromide and sodium hydride gives allyl vinyl sul_des\ which upon heatingrearrange to a!allyl thioketones ð66BSF577Ł[ An allenic thioketone was produced by a similarsequence of reactions using propargyl bromide[

H

Scheme 32

SS S

chloramine T

50%

(65)

S

S

(66)

∆

88%

H

"vi# Miscellaneous methods

The reaction of sulfur vapour with hexa~uoropropene at elevated temperature provides ane.cient synthesis of hexa~uorothioacetone\ largely as a monomer ð53JCS1833Ł[ Vedejs has appliedthe photofragmentation reaction of phenacyl sul_des to the preparation of a macrocyclic thioketoneð73ACR247Ł[ 0\1!Dithiones have been prepared by the photolysis of cyclic polysul_des\ the productbeing trapped with dienophiles "Scheme 22# ð76TL3722\ 78TL1844Ł[ Photolysis of the correspondingcyclic selenopolysul_de produced a mixture of the 0\1!dithione and 0\1!selenoxothione[ A numberof thermolytic methods have been applied to the synthesis of aliphatic thioketones ð71CB381\ 89TL2460\80T3816Ł[

O O O

S S

S

SS

S

SS

S

CNhν CN

85%

Scheme 33

An unusual spirocyclic thioketone was obtained as one product from the reaction of a polycyclicdithietane with triphenylphosphine ð89JA2918Ł\ and an interesting trithiocarbonyl compound wasformed from the reaction of a dithiomalonamide with an azodicarboxamide ð81LA816Ł[ A numberof other rearrangement reactions have given thioketones as products ð66AG"E#611\ 72JA5040\ 80CB0636\


82CB62Ł\ occasionally in good yield\ but none appear to be generally applicable[ The electrolysis ofalkenes using a sulfurÐcarbon cathode produces a range of products\ including thioketones\ butagain this technique appears to be of limited synthetic use ð89BSF316Ł[ The photolysis of thiocarbonylcompounds has been extensively studied\ and in several reactions new thioketones form at leastsome of the products[ However\ these reactions appear to be more of theoretical interest than usefulsynthetic methods\ and the reader is referred to a review of this work by Coyle for further detailsð74T4282Ł[

The enethiol tautomers of thioketones have been prepared by the cleavage of vinyl sul_des withalkali metals in ammonia ð69RTC482Ł\ and by the addition of H1S to alkynes ð52JA852Ł[ The reactionof alkynes with elemental sulfur has been used to prepare a number of 0\1!dithietes\ which appearto exist in the cyclic form rather than as 0\1!dithiones ð59JA0404\ 50JA2323\ 68H"01#0042\ 82TL004Ł[

2[97[2[1 a\b!Unsaturated Thioketones

As is the case for alkyl thioketones\ the most widely applied method for the synthesis of a\b!unsaturated thioketones is the direct conversion of a carbonyl group or a derivative into a thio!carbonyl group[ However\ given the generally greater stability of the unsaturated\ and particularlydiaryl\ compounds\ the phosphorus!based reagents P1S4 and Lawesson|s reagent are more commonlyused than the milder\ but less convenient\ combination of H1S and HCl[

2[97[2[1[0 Thioketones bearing an a\b!alkenic bond

As in Section 2[97[1[1[0\ this section covers only those thioketones conjugated to a C1C doublebond^ molecules in which the thioketone is conjugated to other types of double bond are coveredin Section 2[97[2[0 above[

Simple acyclic unsaturated thioketones are very reactive compounds which readily undergo DielsÐAlder dimerization[ Cyclic enethiones which cannot self!condense in this manner tend to be rathermore stable\ and can usually be isolated\ especially if the thiocarbonyl group is sterically hindered[As is the case for the corresponding thioaldehydes\ the presence of one or two vinylic atoms whichcan donate a lone pair into the C1S bond results in relatively stable compounds "vinylogousthioamides\ thioesters\ and dithioesters#[ A special class of this kind of molecule is typi_ed bypyridin!3!thione^ in this compound the thiocarbonyl group is cross!conjugated to a heteroatom\resulting in a highly stable system\ many examples of which have been reported[ In this section thesynthesis of these three classes of compound will be discussed separately\ although many of themethods utilized are common to all three[

"i# Simple alkenyl thioketones

Early work in this area has been described in a review by Paquer ð61IJS"B#158Ł[ Hydrogensul_de:hydrogen chloride has been used for the synthesis of a number of unsaturated cyclic thio!ketones containing three! to six!membered rings ð61BSF2027\ 74RTC8Ł[ As described above "seeSection 2[97[2[0[0[ii\ Equation "21##\ the reaction of methyl vinyl ketone with P1S4 in pyridineresulted in the formation of a mixture of DielsÐAlder adducts\ each containing one molecule of thestarting material and one molecule of the thioketone ð66TL2306Ł^ a similar result has been observedin the reaction of a dialkenyl ketone ð77CL606Ł[ However\ P1S4 in a variety of solvents has beensuccessfully applied to the preparation of a number of cross!conjugated thioketones derived fromsteroids "Equation "30## ð64CC446\ 68JCS"P0#0055Ł\ as well as to simple acyclic enethiones ð77JOC221Łand diphenyl cyclopropenethione ð53BCJ0786Ł[ Tropothione\ and several more stable analoguesbearing a lone pair!donating substituent at C!1\ have been synthesized using P1S4\ alone or incombination with triethylamine ð65HCA636\ 76TL192\ 89CL452Ł[ P1S4 in toluene at room temperaturehas been used to prepare unsaturated thioketones in good yield from propargylic alcoholsð76CL0188Ł[ This process is selective for reaction and rearrangement of the propargylic alcoholrather than reaction of a ketone also present in the molecule "Equation "31##^ the mechanism of theprocess is not clear[

242Thioketones

O

O

H

H H

S

O

H

H H

P2S5, RT

70%(41)

(42)P2S5, RT

85% PhPh

O

SPh

Ph

O

Ph

OHPh

Lawesson|s reagent "49# has been employed extensively for the formation of a\b!alkenyl thio!ketones[ The reaction is generally conducted in toluene at or above room temperature\ and proceedsin good yield ð71T882\ 89JMC456\ 89SC602Ł[ THF has also been used as the solvent ð81S640Ł[ Whenapplied to acyclic systems the products are often isolated as dimers ð81MI 297!90Ł[ Davy|s reagent"56# has been used with some success "Equation "32##^ the dithione can also be prepared by using alonger reaction time ð80CB0286Ł[ The combination of "TMS#1S and TMS!OTf can be used tosynthesize acyclic and cyclic enethiones in moderate yield ð82TL762Ł[ Thioacetic acid has also beenused as a sulfuration reagent in combination with a strong acid catalyst ð70S25Ł[ The mechanism ofthis process is not certain\ although performing the reaction in an alcoholic solvent resulted in theisolation of a bis"thioester#\ which could then be converted into the thioketone in good yield usinga strong acid in dichloromethane[

O

OPh

Ph Ph

Ph

S

OPh

Ph Ph

Ph

(43)(67), PhMe, ∆, 1 h

58%

SP

SPMeS SMe

S

S

(67)

A number of other methods have been used for the formation of a\b!alkenyl thioketones\ althoughnone has found wide application[ As mentioned above\ acyclic thioketones of this type readilydimerize\ and these dimers have been employed as sources of the monomers by the retro DielsÐAlder reaction*the monomers can then undergo further reaction "Scheme 23# ð81MI 297!90Ł[ Thereaction of the ketone "57# with an excess of P1S4 resulted in the formation of the phosphorus!containing bicycle "58#[ Thermolysis of this compound generated an alkenyl thioketone\ which couldbe trapped with dienophiles "Scheme 24# ð71TL0152\ 77CL606Ł[

S

Ar

Ar

O(50)

35–44% 37–50%[dimers]

Scheme 34

Ando and co!workers have developed a novel Lewis acid!promoted rearrangement of alkenicepisul_des which forms cyclopentenethiones in moderate yield "Equation "33## ð78JOC3559Ł[ Theyhave also applied a similar rearrangement to the preparation of an allenic cyclobutanethione in lowyield ð78TL3160Ł\ and to other systems ð78TL3714Ł[ A number of other rearrangement processes havegiven rise to alkenic thioketones ð79JA5523\ 79NJC692\ 70AG"E#469Ł[


SP

Ph

But SBut

Ph

S

Ph But

O

S

Ph

But

CN

(68) (69)

P2S5, Et3N, CS2

20%

CN, ∆

96%

Scheme 35

S

S

TMS

TMSPh

PhPh

PhBF3•Et2O

35%(44)

a\b!Alkenyl thioketones have also been prepared from thioketones by aldol reaction with analdehyde followed by dehydration ð54MI 297!90Ł\ but as this reaction does not involve formation ofthe thioketone function\ these reactions will not be discussed in detail in this chapter[

"ii# Electronically stabilized a\b!alkenyl thioketones

A wide range of compounds in which the thioketone is stabilized by conjugation to a heteroatomhave been reported^ the synthesis and properties of enamino thioketones ð77ZC234Ł and routes tostabilized cyclohexenethiones ð75MI 297!90Ł have recently been reviewed[ An area that has receivedconsiderable attention is that of derivatives of squaric acid\ for example the dithione "69#\ preparedby sulfuration of the corresponding diketone "Equation "34## ð63S467Ł[ This is a complex area\ afull description of which is beyond the scope of the current work^ for a detailed overview of thearea\ the review by Schmidt should be consulted ð79S850Ł[

P2S5(45)

NMe2

NMe2

O

O

NMe2

NMe2

S

S

(70)

Another complex area is that of linear multisulfur systems and related compounds[ The simplestof this class of molecules\ 0\5\5al3!trithiapentalenes\ can be regarded either as bicyclic systemscontaining tetravalent sulfur "60# or as a mixture of the isomers "61# and "62# in equilibrium"Equation "35##[ For the purpose of this review the structure "60# will be taken as the best descriptionof these molecules\ the synthesis of which is discussed in Section 2[97[3[1[4[ The situation is morecomplex with four! and _ve!sulfur systems\ for example "63#\ prepared by the action of P1S4 on thecorresponding ketone "Equation "36## ð60BSF3318\ 66CC740Ł\ the structures of which show signi_cantSÐS interaction ð69ACS0353\ 60ACS2466\ 62ACS1406Ł[ For a detailed discussion of the structures\ reac!tivity\ and synthesis of this type of compound\ the review by Lozac|h should be consultedð73CHEC"5#0938Ł[

S SS

(71)

S S

(73)

SSS

(72)

S(46)

244Thioketones

S SPh

SSSPh

S SPh

OSSPh

(74)

(47)P2S5

63%

Phosphorus pentasul_de has been used to prepare a variety of electronically stabilized thioketones\including vinylogous thioamides "Equation "37## ð60BAP438\ 78MI 297!91Ł\ doubly vinylogous thio!amides ð80KGS0321Ł\ and triply vinylogous thioamides "Equation "38## ð70HCA1258Ł[ Compoundsstabilized by the presence of two vinylic heteroatoms have also been prepared by this methodð71BRP1970694\ 80AG"E#760Ł\ as have various squaramide derivatives ð65S334\ 66CB1495\ 68S250Ł andcyclopropenethiones ð73AG"E#618Ł[

Me2N O Me2N SP2S5

22%(48)

P2S5, Et3N

10%(49)

O

NPri2

S

NPri2

Lawesson|s reagent "49# has been applied to the synthesis of enamino thioketones ð68S830\76TL5350Ł\ and its use has been reviewed ð74T4950Ł[ The optimum conditions for the formation ofthis type of compound appear to be reaction at room temperature with dimethoxyethane as thesolvent\ although heating in toluene has also proved to be e}ective ð81MI 297!91Ł[ A number ofstabilized dithioketones have been prepared by Sandstro�m and co!workers by reaction of thedioxygen analogues with Lawesson|s reagent "Scheme 25# ð80JOC0891\ 80JOC3808Ł[ These compoundsare highly polarized\ with signi_cant electron transfer from nitrogen to sulfur taking place\ and maybe better described by formula "64#\ especially as "65# is reported to have a large twist angle aboutthe nominal C1C bond ð80JOC0891Ł[ These workers have also developed a sulfur analog "66# ofLawesson|s reagent which they claim to be more stable and easier to handle ð80JOC0891Ł[

N N

O O

PriBnN N

S S

PriBnN N

S S–

PriBn+

(50)

82%

(76) (75)

Scheme 36

SP

SP

S

S

MeS SMe

(77)

Ethoxycarbonyl isothiocyanate has been used to prepare monothio derivatives of squaric aciddiamides "Equation "49## ð67S720Ł[ This reaction is unsuccessful for compounds containing free NHgroups\ as in this case heterocycles are formed\ but the reagent may be of wider utility than hasbeen demonstrated to date[

O

O

NMe2

Me2N

O

S

NMe2

Me2NEtOCONCS, MeNO2

54%(50)


Iminium salts can be hydrolyzed e.ciently by reaction with H1S and catalytic amine base toproduce the corresponding thioketone ð67ZOR555\ 68ZOR71Ł[ This reaction has been used in thepreparation of amine!stabilized cyclopropenethiones "Equation "40## ð65S581\ 80CB554Ł and of dithio!vinyl thioketones ð64JPR026Ł[ The additionÐelimination reaction of vinylic chlorides with sodiumsul_de has also been applied to the formation of cyclopropenethiones ð62JA2932Ł and acyclicenaminothione "67# "Equation "41## ð80LA000Ł[

H2S, pyridine

83%(51)

NMe2

NMe2Ph

S

NMe2Ph

+

Na2S

60%(52)

Me2N NMe2

Cl

Me2N NMe2

S

+

(78)

A number of the methods described in detail in Section 2[97[1[1[0[ii have been employed toprepare stabilized thioketones[ Isothiazolium salts can be opened by hydride reagents to giveenamino thioketones in good yield "Equation "42## ð77SC0736Ł^ a similar compound has beenobserved as a by!product in the preparation of pentalenes ð68JCS"P0#1239Ł[ The thiazolidine derivative"68# can be opened with an enaminonitrile to produce the cyclic thione "79# "Equation "43##ð89JCS"P0#2992Ł[ A closely related reaction has been applied to the synthesis of pyridin!3!thionesð73JHC0334Ł[ The cycloaddition reaction of 0\1!dithiole!2!thiones with alkynes has also been suc!cessfully used for the synthesis of thiocarbonylmethylene dithioles "Equation "44## ð61JCS"P0#30\79BSF"1#429\ 81MI 297!92Ł[

SN+

EtEtHN SNaBH4, –20 °C

90%(53)

NH

S

S

S

Ph

NH

SPh

NCNCNH2

KOBut,

68%(54)

(79) (80)

SS S

S

S

Et

CO2Me

CO2Me

Et

SDMAD

65%(55)

DMAD = dimethyl acetylenedicarboxylate

Carbon monosul_de undergoes cycloaddition with ynamines to produce amino cyclo!propenethiones in reasonable yield ð73AG"E#618Ł[ Several other methods give rise to electronicallystabilized thioketones\ but none have been widely applied ð63ACS"B#256\ 63CL0090\ 80SUL102\ 80TL4908Ł[Enamino thioketones can also be formed from the reaction of amines with b!thioxo aldehydes"Equation "45## ð62ZOR0606\ 89ZC136Ł[ The compounds can be isomerized by heating "Equation "46##\the reaction proceeding through an intermolecular mechanism ð78ZOR0754Ł[

ButNH2(56)F3C NHBut

S

Ph

F3C

Ph

CHO

SH

100 °C(57)

F3C

S NH2

F3C

SNH2

246Thioketones

"iii# Cross!conju`ated electronically stabilized thioketones

Pyridin!3!thiones\ pyran!3!thiones\ and thiopyran!3!thiones are stable thioketones in which theC1S bond is stabilized by cross!conjugation with the heteroatom lone pair[ These compounds bearmany similarities to the simple electronically stabilized thioketones considered above\ but have beenvery widely studied and are thus worthy of separate consideration[

The compounds are most commonly prepared from the corresponding oxo species by reactionwith P1S4[ N!Alkylpyridones have been popular starting materials\ the reaction being performed byheating in the absence of solvent ð47JCS2509\ 53JCS1659\ 89JAN0049Ł\ in pyridine ð80EUP9351420Ł\ orxylene ð64JCS"P0#521Ł[ The free NH compounds have also been employed successfully ð80DP038Ł[ Anumber of 3!thiopyrones have been prepared^ in this case benzene has been the favoured solvent"Equation "47## ð40JA299\ 48JCS1477\ 51JCS0746\ 67BCJ068Ł[ 3!Thiothiopyrones have also been syn!thesized by this method ð56JOC2039Ł[ Silicon disul_de ð64JCS"P0#0224Ł and dimethyl thio!formamide:acetic anhydride ð81JHC730Ł have been utilized for the conversion of 3!pyrones into3!thiopyrones[ This transformation has also been achieved via the dichloride "70# "Scheme 26#\ amethod which has been demonstrated to give better results than the direct reaction with P1S4 insome cases ð47JA5201Ł[ Pyridin!3!thiones have been formed from 3!halopyridines by treatment withsodium or potassium hydrogensul_de "Equation "48## ð58ACS0864\ 65JOC2673\ 89EUP9265613\ 80CPB561\80EUP9398053Ł[

O

O

O

S

P2S5, PhH

85%(58)

O

O

PhPh O

S

PhPhO PhPh

Cl Cl

MeCOSH

47%

Scheme 37

SOCl2

(81)

N

S

NH2H2NN NH2H2N

(59)NaSH

66%

H

NH2

Cl

NO2

3!Thiothiopyrones have been synthesized by the reaction of alkynes with 4!unsubstituted 0\1!dithiole!2!thiones ð79BSF"1#429Ł or 0\1!dithiole!2!iminium iodides and NaSH "Equation "59##ð79BSF"1#428Ł[ This latter process may occur by rearrangement of a _rst!formed trithiapentalene\ asit has been shown that these compounds rearrange to the thiopyran!3!thiones upon treatment withNaSH or Na1S ð57CC752Ł[ Reductive ring opening of a suitably substituted dithiolium salt withpotassium borohydride gave a 3!thiothiopyrone as the _nal product\ formed by cyclization of theintermediate enamino thioketone ð70TL3496Ł[

(60)

S

S

NEt2Ph

MeCCNEt2, NaSH

55%

SS

Ph NEt2+

The cycloaddition of diphenyl cyclopropenethione with heterocycles has been utilized as a con!venient synthesis of pyridin!3!thiones ð62CC722\ 63T3914\ 64JCS"P0#521\ 65JOC707Ł[ This reaction pre!sumably involves initial 0\2!dipolar cycloaddition to give the intermediate "71#\ which then fragmentswith loss of carbon oxysul_de to give the observed product "Scheme 27#[ Other heterocycles havealso been shown to undergo fragmentation and rearrangement to produce pyridin!3!thionesð73H"11#652\73JHC0334Ł[ Alternative condensation reactions have produced 3!thiopyrones ð80EGP183830Ł and


3!thiothiopyrones ð65TL3172Ł\ but these appear to be limited in their applicability[ Pyridin!3!thionescan be formed in reasonable yield from the corresponding 3!thiopyrones by reaction with ammoniað67BCJ068Ł[

N

S

Ph

Ph

Me

Ph

S

NMe

O

PhPh

Ph

SS

PhPhN+

SPh

Me O– 20%+

Scheme 38

(82)

"iv# Thioquinones and thioquinone methides

A number of attempts to synthesize dithio!o!benzoquinone have been made using various cyclo!reversion reactions^ in each case only the benzodithiet tautomer "72# was observed "Scheme 28#ð71JOC0868Ł[ A steroid!derived benzothiet has been prepared by a retro DielsÐAlder reaction andfully characterized ð64CC645\ 66JCS"P0#404Ł[ Similar results have been reported by de Mayo et al[\although they describe the DielsÐAlder trapping of both mono! and dithio!o!benzoquinones withdienes ð68JOC0866Ł[ The photolytic retro ð3¦0Ł reaction of the dithiolanone "73# produces thedithioquinone "74#\ which interconverts with the trisdithiet "75# "Scheme 39#[ None of the cyclo!hexanehexathione tautomer was observed ð81CB154Ł[ Dithio!p!benzoquinone and monothio!p!benzoquinone have been prepared by pyrolysis of bis"allylthio# and allyloxy allylthio benzeneprecursors and characterized in an argon matrix\ but decomposed on warming ð72CB162Ł[ An earlyreport of a diamine!stabilized dithio!p!benzoquinone ð92JCS0190Ł proved to be mistaken\ the productbeing in fact a dithio!o!benzoquinone dimer ð76JOC0763Ł[

S

S

S

S

SS

S

S

SO

O

720 °C

690 °C

540 °C(83)

Scheme 39

S

S

S

SO

(86)

SS

SS

O

O

SS

SS

S

SS

S

S

S

(84) (85)

hν hν

hν

Scheme 40

In contrast to the reactivity of monothio!p!benzoquinone\ monothioanthraquinone "76# has beenprepared by reaction of the diazo compound "77# with elemental sulfur "Equation "50##\ and is astable solid ð68JOC521Ł[ Compound "76# has also been synthesized by the reaction of anthrone witha bis!succinimido disul_de ð76JOC058Ł[ Dithioanthraquinone\ however\ appears to be a much lessstable compound\ prone to polymerization\ and attempts to prepare it by the reaction of anthra!quinone with Lawesson|s reagent have met with limited success ð75BSF172\ 75JOC300Ł[

248Thioketones

O

S

(61)

(87)

O

N2

S, 150 °C

57%

(88)

o!Thiobenzoquinone methide "78# has been generated by photolysis of a dithiole dioxide "89#ð67JOC2263Ł or a retro DielsÐAlder reaction ð80TL1902Ł\ but is more commonly produced by ther!molysis of benzothiet "80# ð75TL4692Ł[ The compound has been characterized from photolysis of"80# in an argon matrix ð78JST"087#296Ł\ but cannot be isolated\ and has been trapped as DielsÐAlderadducts ð76AG"E#0935\ 89CB0032\ 80JHC462Ł or a ð3¦3Ł dimer "81# "Scheme 30#[ o!Thiobenzoquinonemethides stabilized by a dithiole ring have been prepared by the photolytic reaction of benzodithiole!thione "82# with alkenes ð63CC766\ 63CL0328Ł^ these compounds cannot be obtained pure\ but existin equilibrium with their head!to!head dimers "83# "Scheme 31#[ The monomers can be trapped bythe DielsÐAlder reaction with dienophiles ð66CJC2652\ 68BCJ385Ł[ The related thionaphthoquinonemethide "84# has been prepared\ and is a stable monomer "Equation "51## ð65TL2704\ 71BCJ132Ł[Thiobenzoquinone methides bearing nitrogen and oxygen\ as well as sulfur\ stabilizing groups havealso been prepared ð68BCJ2539\ 71LA03Ł[ A nitrile!substituted thiobenzoquinone methide has beenpostulated as a decomposition product of an azidobenzothiophene\ and has been trapped withalkenes ð74CC0330Ł[

SS

S

N

SS

S

O

O

O

O

Ph

H

H

S

N

O

O

Ph

(89)

(90)

(91) (92)

43%

hν

∆

Scheme 41

SS

S S

S

S

S

S S

S S

S

(93) (94)

, hν

90%

Scheme 42

SS

S

S

S

S

cyclohexene, hν

100%

(95)

(62)


2[97[2[1[1 Thioketones bearing an a\b!aryl or hetaryl substituent

The chemistry of diaryl thioketones has been thoroughly explored\ and the early work in thisarea has been reviewed ðB!55MI 297!90\ 62IJS062Ł[ Alkyl aryl thioketones are in many cases similar\although less stable\ and the same methods of preparation can be applied as to diaryl compounds[The synthesis of these compounds is discussed in Section 2[97[2[1[1[iv[ Aryl thioketones bearing ana\b!alkenyl bond are generally more closely related to the alkenic compounds covered in Section2[97[2[1[0 than to other aryl thioketones\ and will be covered separately in Sections 2[97[2[1[1[iÐiii[Thioanthraquinones and naphthoquinone methides\ although strictly aryl thioketones\ have beendiscussed with their benzo analogs in Section 2[97[2[1[0[iv[

"i# Simple alkenyl aryl thioketones

The reaction of simple alkenyl aryl ketones with P1S4 or Lawesson|s reagent ð67JOC3036\ 71CL682Łproduces the DielsÐAlder dimer of the initially formed thioketone[ In the presence of an excess ofP1S4 a phosphorus!containing product "analogous to "58# in Scheme 24# is formed ð71TL0152\74BCJ556Ł[ Heating either the dimer or phosphorus!containing adduct regenerates the unsaturatedthioketone monomer\ which can be trapped as a DielsÐAlder adduct with dienophiles[ This techniquefor the retro DielsÐAlder generation of reactive alkenyl aryl thioketones\ and their trapping with awide range of dienophiles\ has been pioneered by Motoki and co!workers ð68JOC3040\ 79JOC816\75BCJ2168\ 80JCS"P0#1170\ 81BCJ812\ 81JCS"P0#1832Ł[ Thioketones of this type can be trapped intra!molecularly by a double bond\ although in circumstances where the intramolecular DielsÐAlderreaction is slow\ dimers can still be formed ð89CC0554Ł[ Interestingly the thioketone "85# has beenprepared in monomeric form by sulfuration with rearrangement of a propargyl alcohol "Equation"52## ð76CL0188Ł[ Presumably the product is su.ciently sterically hindered to disfavor dimerization[

(63)

Ph Ph

Ph SPh

Ph

OHPh

(96)

P2S5

23%

"ii# Electronically stabilized alkenyl aryl thioketones

A number of compounds of this type have been prepared by treatment of the correspondingketones with P1S4 ð54JCS21\ 70JCS"P0#1841Ł or Lawesson|s reagent ð70T086\ 78CZ189Ł[ Perhaps surpris!ingly\ reaction of the phenylthio ketone "86# with either of these reagents produced a dimer "87#\which on further heating rearranged to the more stable isomer "88#\ presumably by a retro DielsÐAlder ]DielsÐAlder route ð75BCJ224Ł[ Clearly the phenylthio substituent has only a weak stabilizinge}ect upon the thioketone in this case[ The dimer "87# can function as a source of the monomericthioketone for further reaction "Scheme 32# ð78MI 297!92Ł[

SPh

SPh

Ph

S

SPh

(99)

SPh

SPh

CO2Me

SS

Ph

SPhPh

SPh

OPh

SPh

(97)

(50)

46%

∆

78%

CO2Me

56%(98)

, ∆

Scheme 43

The additionÐelimination reaction of sodium sul_de or sodium hydrogensul_de with iminovinylchlorides or ethers has been used to prepare enamino aryl thioketones ð64ZOR0834\ 79JOC3746\

250Thioketones

77JPR554Ł[ In a novel variant of this type of reaction\ the enone "099# was oxidatively sulfurated byreaction with sodium sul_de and elemental sulfur to produce the b!oxo thioketone "090# "Equation"53##\ which exists as a rapidly equilibrating mixture of tautomers ð78CC494Ł[ Iminium salts can behydrolyzed with H1S to produce stabilized thioketones ð79ZOR0731Ł[

(64)

(101)

Na2S, S8, NaOH

65%

O

OO

O

OO

S

(100)

As described in Section 2[97[2[1[0[ii\ the reaction between a 0\1!dithiole!2!thione and an alkynegives rise to a dithiole!stabilized thioketone "Equation "54## ð58CJC1928\ 61JCS"P0#30\ 80JHC0134Ł[ Insome cases the product is mixed with a small amount of the isomeric trithiapentalene ð65BSF"1#019\67ZOR1348\ 79ZOR772Ł[ The analogous reaction with alkenes also gives stabilized thioketones in goodyield ð61CL8\ 64JCS"P0#169\ 66ZOR1901\ 79ZOR332Ł[ Nucleophilic attack on 0\1!dithiolium salts ð54JCS21\57CJC0744Ł or isothiazolium salts ð61JCS"P0#1294\ 62CJC2970\ 74T0774Ł produces enamino aryl thio!ketones[ An interesting intramolecular variant of this reaction has been observed "Equation "55##ð64TL1572Ł[ 0\1!Dithioles can be opened with amines to produce thioacyl ketene aminals "Equation"56## ð68BCJ2539\ 75CB051Ł[ The same class of compounds has been prepared by the reaction of anamidine with an aryl aldehyde and sulfur in a variant of the WillgerodtÐKindler reaction "Equation"57## ð71T0562Ł[ Enamino aryl thioketones can also be formed by the reaction of amines with arylthioketones bearing a b!aldehyde group ð66ZC82Ł[

(65)

O O

S S

S

S

S

S CO2Me

CO2Me

DMAD, ∆

64%

N

Ph

S

Ph N

S

Ph

290 °C

90%+

(66)SS

Ph

S

Ph N

N

Me

, ∆SS

Ph S

Me

MeHNNHMe

(67)62%

S

Ar

(68)5–38%

N

N N

HN

Me Me

ArCHO, S8, ∆

"iii# Cross!conju`ated electronically stabilized aryl thioketones

Aryl fused ring analogs of pyridin!3!thiones\ pyran!3!thiones\ and thiopyran!3!thiones are well!known compounds\ many examples of which have been reported in the literature[ They are com!monly prepared by reaction of the oxo compounds with P1S4 ð70JHC752\ 89SC2974Ł or Lawesson|sreagent ð80BSF865\ 81JCR"S#052\ 81JCS"P0#240Ł[ The yields for the reaction are generally good^ illustrativeexamples are shown in Equations "58# ð89SC2974Ł and "69# ð81JCR"S#052Ł[ Boron sul_de and silicondisul_de have also been applied to the preparation of a variety of systems of this type\ and areclaimed to be superior to P1S4 ð58JCS"C#1081Ł[ P1S4 has also been used to prepare the chromene


thione "091# by concomitant sulfuration and cyclization "Equation "60## ð72PS"03#028Ł[ 3!Thio~avonehas been synthesized by the reaction of a ~avone imine with H1S ð52JA2878Ł[ Oxidation of acridineswith elemental sulfur gives excellent yields of acridine!8!thiones ð90JPR071\ 51JOC3235Ł[ Lithiation ofa bisthiophene ketal\ followed by reaction with sulfur\ unexpectedly gave a cyclized thione as oneproduct ð63T2510Ł[

N

S

H

P2S5, Na2CO3

96%(69)

N

O

H

(70)

O Ph

Ph

S

AcOO Ph

Ph

O

AcO

(50), ∆

68%

(71)

O

S

P2S5, pyridine

75%

(102)

OH O

O

This type of compound can also be formed by the reaction of chloro compounds with NaSH"Equation "61## ð49JOC599\ 65JOC2673\ 67JOC3809Ł or thiourea ð49JOC599\ 55TL5288\ 78MI 297!93Ł[ Thereaction of H1S with 8!amino derivatives of acridine has been employed for the preparation ofacridine!8!thione ð37JCS0070Ł[ Xanthane dichloride has been converted into xanthane thione inexcellent yield by reaction with EtOCS1

−K¦\ followed by basic hydrolysis ð57CB605Ł[ Other reportedmethods include the cyclization of the enamine "092# to produce the thione "093# in good yield"Equation "62## ð80JHC0134Ł\ and the cleavage of dialkyl thioquinanthrenes with H1S to formquinoline thiones ð81H"23#136Ł[

EtO2CNH NH

S

NN

N

OHO

OH OH

EtO2CNH N NN

N

OHO

OH OH

Cl

(72)NaSH, DMF

65%

N

SO

H

(104)

SMe

N

SO

H

(103)

Ph2O, ∆

76%(73)

"iv# Alkyl aryl and diaryl thioketones

"a# Sulfuration of aryl ketones[ The direct conversion of a carbonyl into a thiocarbonyl grouphas been widely used for the preparation of aryl thioketones[ Similar conditions to those used toform dialkyl thioketones have generally been used "see Section 2[97[2[0[0#[ Thus the combinationof H1S and HCl gives good yields of the desired products\ especially if precautions are taken toavoid the formation of dithiols ð63JCS"P0#1448Ł[ Trimer formation is not a signi_cant problem for

252Thioketones

these compounds\ presumably due to a combination of steric and electronic factors[ The use of H1Swith anhydrous HF as the solvent has been advocated as a more e.cient method in some cases\although a careful choice of co!solvent is required ð53JOC0244Ł[ The use of H1S under basic conditionsis not a good method for the synthesis of aryl thioketones*benzophenone does not react\ andthioacetophenone is only formed in poor yield ð52AG"E#269Ł[

P1S4 has also been widely used to e}ect this transformation\ using a variety of solvents and basicadditives ð58BSF716\ 62S038\ 65IJC"B#888\ 65JA5107Ł[ In general the yields tend to be rather lower for theformation of enolizable alkyl aryl thioketones than for the diaryl compounds ð62S038Ł[ Acyl and0\0?!diacyl ferrocenes can be converted into the thioacyl derivatives using P1S4 in nonpolar solvents"Equation "63## ð89JCS"D#2586\ 89JOM"274#258\ 80JCR"S#33Ł[ Lawesson|s reagent has also been exten!sively employed for the synthesis of aryl and hetaryl thioketones ð56TL1852\ 67BSB112\ 89H"29#894\80CPB378Ł^ the mechanism of the reaction has been investigated ð75TL2334Ł[ A range of aryl thio!ketones has been prepared\ including unstablea!hydrazones "Equation "64##ð80S432Ł and diferrocenylthioketone ð81JOM"329#094Ł[ Again\ diaryl thioketones seem to be formed in higher yield than alkylaryl analogs ð80JCS"P0#072Ł\ and a range of products were formed in the reaction with some diketones"Equation "65## ð89JOC1310Ł[ A number of other reagents have been used to prepare aryl thioketoneswith good results] "TMS#1S:BCl2 ð71JA2093\ 89JOC1310Ł\ "c!Hex2Sn#1S:BCl2 ð71JA2093Ł\"TMS#1S:TMS!OTf ð80JOC6212Ł\ and "Et1Al#1S ð60MI 297!90Ł[

P2S5, Et2O

39%

Fe

But

But

But

O

But

Fe

But

But

But

S

But

(74)

(50)

50%PhN

NMe2

O

PhN

NMe2

S(75)

SSPh PhS

P h O O Ph Ph X Y Ph SPh Ph

S(50), PhMe, ∆

62%(76)++

68% 3% 8%(X = Y = S)(X = S, Y = O)21%

As described in Section 2[97[2[1[1[i above\ the sulfuration of simple alkenyl aryl ketones resultsin the formation of DielsÐAlder dimers "88#\ which are themselves alkyl aryl thioketones[

"b# Sulfuration of aryl ketone derivatives[ A number of carbonyl derivatives have been convertedinto aryl thioketones[ The Vilsmeier approach developed by McKenzie and Reid for the preparationof heteroaryl thioaldehydes can also be applied to thioketones "Scheme 33# ð55CC390Ł[ The reactionof imines with carbon disul_de has also been shown to produce diaryl thioketones in good yieldð58TL2500\ 69T706Ł^ dimethylthioformamide can be used in place of carbon disul_de\ although theyields are lower ð58TL2500Ł[ The hydrolysis of enamines with H1S has been used for the preparationof b!oxo ð68JOC2160Ł and b!thioketo ð61IJS"A#105Ł thioketones[ The reaction of hydrazones withS1Cl1 has also been demonstrated to produce thiobenzophenone ð68TL2562\ 70BCJ2430Ł\ but it givesrise to cyclic adducts when applied to the monohydrazone of a diketone "Equation "66##\ presumablyby intramolecular trapping of the intermediate thiosul_ne ð81CC6Ł[ An interesting reaction is thecycloaddition of diphenyldiazomethane with the thioketone "094#\ which gave thiobenzophenoneand the episul_de "095# as products ð80MI 297!90Ł[ These products presumably arise from the twodi}erent orientations possible for the cycloaddition "Scheme 34#\ or\ in the case of "095#\ by thecyclization of a thiocarbonyl ylide[ Diaryl thioketones can also be prepared from the corresponding`em!dichlorides by reaction with "TMS#1S ð61ZOR0711Ł or with t!butyl thiol and TFA ð67BSB112Ł[The reaction of a phosphonium ylide with cyclic polysul_des "see Section 2[97[1[0[5# has been usedto form ~uorene thione\ although this compound was trapped as a DielsÐAlder adduct rather thanbeing isolated ð80S674Ł[ Diaryl thioketones can also be prepared by the oxidative sulfuration ofthe corresponding diarylmethanes ð18CB2937\ 34JCS747Ł or aminodiarylmethanes ð91CB264Ł withelemental sulfur[ The reaction of a polycyclic ethoxy compound with NaSH produced the cor!responding thioketone ð74S528Ł[ A related additionÐelimination approach has been applied to thepreparation of phosphonium ylide!stabilized aryl thioketones "see Scheme 15\ But�Ph# ð81TL4844Ł[


N+

Me2N

N

S

N

dimethylacetamidePOCl3 NaSH

66%

Scheme 44

SSNOPh Ph

OPh Ph

NH2

S2Cl2, Et3N

56%(77)

S

But TMS

S

NN

PhPh

But

TMS

S

Ph

PhBut

TMS

NS

NBut

TMSPh Ph

S

Ph Ph

N2

But TMS+

Ph2CN2

+ N2

(105)Ph2CN2

Scheme 45

(106)

"c# Formation of the a C0C bond[ Phosphonium ylide!stabilized aryl thioketones have beensynthesized by the condensation of methylene triphenylphosphorane with methyl dithiobenzoateð64BCJ1896Ł[ A sulfoxonium ylide!stabilized aryl thioketone has been prepared by a similar routeinvolving the reaction of dimethylsulfoxonium methylide with thiobenzoyl chloride "see Equation"019## ð65BCJ2017Ł[ The reaction of Grignard reagents with chloro dithioformates did not producethe expected dithioesters\ and instead thioketones were formed[ A possible mechanism for thisreaction\ involving initial thiophilic attack by the Grignard reagent\ has been proposed "Scheme 35#ð64RTC0Ł[ Symmetric thioketones can be prepared by the FriedelÐCrafts reaction of electron!rich aromatics ð0784CB1758Ł or heteroaromatics ð58AJC128Ł with thiophosgene "Equation "67##[Thiobenzoyl chlorides can also be used in this reaction to give mixed thiobenzophenones in reason!able yields ð57CB2406Ł[ By direct analogy with the preparation of other b!oxo thioketones\ thecondensation of enolizable ketones with O!alkyl thiobenzoates has been used to synthesize a widerange of b!oxo aryl thioketones ð54AG"E#043\ 66JCS"P0#0016\ 66S145\ 74S561Ł[

S

PhPhS

SEt

S

PhPhS

ClEtS

S

EtS Ph

S

EtS Cl

EtS Cl

SPh

–

EtS–

31%

PhMgBr

PhMgBr

Scheme 46

N N

S HH

N

H

CSCl2(78)

254Thioketones

"d# 0\1!Elimination reactions[ The 0\1!elimination reaction "see Section 2[97[1[0[2# has been usedextensively for the formation of aryl thioketones[ Bunte salts have been widely employed as thestarting materials\ base!catalyzed elimination giving rise to a variety of a!oxo aryl thioketones\including monothiobenzils ð68CB1633\ 79JHC0544\ 70LA09Ł[ In some of these reactions the initiallyproduced thioketones were unstable and rapidly formed dimers ð64TL426\ 66JCR"S#133\ 66JOC1710\73JOC3641Ł[ 0\1!Elimination reactions from thiocyanates ð55CC475Ł\ phenyl disul_des ð57CC613\69JCS"B#214Ł\ a!chlorosulfenyl chlorides "Equation "68## ð68JOC0625Ł\ and thiosulfonates ð74JOC21Łhave been used to prepare diaryl thioketones[ The product of the reaction between `em!dichloridesand EtOCS1

−K¦ undergoes 0\1!elimination upon treatment with aqueous alkali to give diarylthioketones in excellent yield ð57CB605Ł[ The reaction of thioacids with imines ð48MI 297!90Ł\ oximes\and nitrones ð66BCJ1640Ł gives rise to addition products which spontaneously undergo 0\1!elim!ination to produce diaryl thioketones in good yield[

PhPh

S

O

PhPh

O

ClSCl Ph3P

72%(79)

A number of 0\2!dithiolane derivatives have also been used to generate alkyl aryl and diarylthioketones by 0\1!elimination "or cycloreversion# ð71AG52\ 72AG"E#44\ 77CB0048\ 89CB066\ 89JOC3199Ł*these methods have been discussed in detail in Section 2[97[2[0[2[i[ An interesting reaction of thisgeneral type is the reaction of dithioketals with tungsten hexacarbonyl[ This process usually givesalkenes by coupling of two molecules of the dithioketal\ but in highly hindered systems thioketones\postulated to be intermediates in the coupling reaction\ can be isolated in modest yield ð89JOC0763Ł[

"e# Reduction of sul_nes[ Thermolysis of thiobenzophenone S!oxide produces small quantitiesof thiobenzophenone ð66ACS"B#568Ł[ A much more e}ective technique for this reduction has beendeveloped by Zwanenburg and co!workers\ who demonstrated that P1S4 or PSBr2 reduces a varietyof diaryl sul_nes to diaryl thioketones in excellent yield ð70S184Ł[ This technique\ combined with anumber of methods for the preparation of sul_nes that do not involve thioketone oxidation\ makethis a practical synthetic method for the preparation of thioketones[

"f# Other methods[ A number of cycloreversions and related reactions have been used to syn!thesize aryl thioketones[ Ku�sters and de Mayo have prepared the substituted dithiobenzil "096# byphotolysis of "097# "Equation "79##[ Compound "096# was found to exist mostly as the dithione\ notthe tautomeric dithiet ð62JA1272Ł[ It was not possible\ however\ to prepare the unsubstituted parentcompound by this method ð63JA2491Ł[ An attempt to prepare acenaphthenedithione by the samemethod did not lead to the desired product\ although it could be trapped by the DielsÐAlder reactionwith dienophiles ð74JOC0449Ł[ The thio!Claisen rearrangement of allyl "0!arylvinyl# sul_des has beensuccessful in forming alkyl aryl thioketones ð61CC51\ 78CPB0888Ł[ As the starting material can bemade by S!allylation of thioketones\ this technique provides a method for the C!allylation ofaryl thioketones[ The dimers of aryl thioketones\ such as monothiobenzil\ can undergo ð1¦1Łcycloreversion to generate the monomeric compound on heating or irradiation ð79ZN"B#261Ł[

(108)

Me2N

S

S

Me2N

Me2N

Me2N

S

SO

hν(80)

(107)

50%

An interesting formation of an aryl thioketone is the reaction of the sulfoxide "098# with tosylisocyanate to produce "009#\ an imino analog of monothiobenzil "Equation "70## ð74JOC0096Ł[

(81)TsNCO

28%

(109) (110)

S

O

Ph Ph

S

PhPh

NTs


Aryl hetaryl thioketones can be prepared by forming the heteroaromatic ring\ as in the synthesisof thiobenzoyl thiophenes developed by Mollier and co!workers involving cyclization of a dienenitrile with elemental sulfur "Equation "71## ð60CR"C#167\ 63BSF"1#360Ł[ The diene nitrile can be formedin situ by the reaction of cinnamaldehyde with ethyl cyanoacetate[

(82)Et3N, S8, 100 °C

63% S

CO2Et

NH2

S

Ph

CO2Et

CN

Ph

Several photolytic syntheses of aryl thioketones have been reported "Equations "72# ð56JA1682\69JOC3113Ł\ "73# ð61CC521\ 62JCS"P0#0479Ł\ and "74# ð63ZC06\ 73JOC0726Ł#\ although these have not beengeneralized[ Photolytic ð61TL4102Ł or cathodic ð63AG"E#238Ł reduction of a 2\4!diphenyldithioliumsalt gives rise to dithiobenzoyl methane[

SS

PhPh

O

O

PhPhPh

O

Ph

O(83)

hν

56%

S

Ph

Ph

(84)But

OHhν

37%

S

OPh But

Ph

(85)S

PhNH

hν

95%

Ph

OS

NPh

O

Ph

The enethiol tautomer of b!oxo aryl thioketones has been prepared by the Michael addition ofthioacetic acid to aroylphenylalkynes ð54LA"571#077Ł[ Elemental sulfur can be added to phenylalkynesto provide the dithiet isomers of alkyl phenyl a!dithiones ð82TL004Ł[

A number of other reactions have produced aryl thioketones ð65TL1850\ 73AG"E#799\ 77JPR24\89TL6530\ 82CB62Ł\ but none appear to be of general synthetic utility[

2[97[2[1[2 Thioketones Bearing an a\b!Alkynic Bond

No reports of the preparation and isolation of alkynyl thioketones have appeared in the literature[However\ methyl phenylethynyl thione has been observed in the attempted methylation of a thio!amide ð67CPB1981Ł[ A bisalkynyl dithioketone\ existing as a cyclic tautomer\ has been isolated fromvarious plant species ð54CB2970Ł[

2[97[3 THIOALDEHYDE AND THIOKETONE FUNCTIONS FURTHERSUBSTITUTED ON SULFUR

The availability of sulfur d orbitals to participate in bonding results in there being a widevariety of relatively stable compounds in which the sulfur atom of a thiocarbonyl group is furthersubstituted[ As well as many simple compounds of this type\ there exist a wide range of heterocyclicspecies which can be regarded as containing a C1S bond[ The extent to which these compoundscan be considered as derivatives of thioaldehydes and thioketones is a matter of judgement^ for thepurpose of this review only those compounds for which the usual representation contains a C1Sbond will be discussed "thus\ for example\ thiophenes are not included but 0\1!dithiolium salts are#[

Another area of uncertainty is that of sulfur ylides and related compounds\ which can be regardedas charge!separated species "000# or as containing a C1S double bond "001#[ Although the dipolar

256Further Substituted on Sulfur

representation in some cases describes the properties of these compounds more satisfactorily\ forthe purposes of this work they will be considered as containing a C1S bond\ and will be discussedin the relevant section below[

S S– +

(111) (112)

Given the wide range of compound types which fall within the scope of this section\ it is impossible\in the available space\ to give a fully comprehensive account of all the preparative methods thathave been used[ This survey will attempt to give a brief summary of the key synthetic methods foreach compound type\ and also refer to important reviews and other leading references from whichmore detailed information can be obtained[ For the many heterocycles which will be mentioned\ itis recommended that Comprehensive Heterocyclic Chemistry be consulted for a more detailedconsideration of the synthesis and properties of these compounds[

In the sections below\ the compounds will be divided according to the coordination state of thesulfur atom[ Within each section\ simple compounds will be discussed _rst\ followed by heterocyclescontaining a C1S bond[

2[97[3[0 Two!coordinate Sulfur Functions

2[97[3[0[0 Thiocarbonyl ylides

Simple thiocarbonyl ylides bearing no stabilizing groups are highly reactive compounds whichcannot be isolated\ but are generated and trapped in situ\ generally by 0\2!dipolar cycloaddition[The most widely used technique for the generation of these species is by elimination of nitrogenfrom a D2!0\2\3!thiadiazoline "002#\ which is prepared by the reaction of a diazo compound with athioketone "Scheme 36# ð72TL3070\ 74JCS"P0#0050Ł[ The addition of the diazo compound to thethioketone can occur in two orientations\ depending upon the structures of the reacting speciesð78TL6934Ł[ The mechanism of this reaction\ and of the reactions of the thiocarbonyl ylide products\have been investigated ð70JA6921\ 78TL6930Ł[

Thiocarbonyl ylides which have substituents which stabilize the charge!separated form of thecompounds\ for example "003#\ are often stable species[ However\ thiocarbonyl ylides in which theelectron!donating groups are vinylic to the C1S bond "a similar e}ect to that seen with thevinylogous thioamides described in Section 2[97[2[1[0[ii# have been prepared and isolated "Equation"75## ð66AG"E#755Ł[ This equation provides an example of another widely applied method for theformation of thiocarbonyl ylides\ the reaction between an iodonium ylide and a thioketone[ Afurther approach which has found some application is the generation of thiocarbonyl S!methylidesfrom the corresponding thioketone and trimethylsilylmethyl tri~ate ð76CL0740Ł[

N N

SPh

PhPh

Ph S

Ph

Ph S H2CN2, –78 °C –45 °C

>95%

(113)

Scheme 47

Me2N CN

SMe2N CN

Me2N CN

SMe2N CN

+ –

(114)


Pri2N

Pri2N

CN

CN

NC

IPh

CN

CN

NC

SPri2N

NPri2

S

+CHCl3, ∆

86%(86)

The preparation\ properties\ and reactions of thiocarbonyl ylides have been reviewed ð61JOC3934\65T1054\ 68COC"2#262Ł[

2[97[3[0[1 Sul_nes

Sul_nes\ or thiocarbonyl S!oxides\ are well!studied compounds\ and many stable examples havebeen prepared[ By far the most widely used method for the synthesis of sul_nes is oxidation of thecorresponding thioketone[ The oxidation of thioketones by molecular oxygen is a reaction ofconsiderable mechanistic interest\ and has been the subject of detailed investigation\ notably byRamamurthy and co!workers ð71JOC016\ 72JOC103Ł[ Of more importance as a preparative method isthe use of peroxy acids or hydrogen peroxide as the oxidant[ m!Chloroperoxybenzoic acid is themost commonly employed\ and in general good yields are obtained "Equation "76## ð62JCS"P0#62Ł[A report has extended the scope of this reaction to enethiolizable thioketones ð80TL636Ł[ Mono!peroxyphthalic acid has also proved to be an e}ective oxidant ð66LA0418Ł[ In these reactions theconditions must be carefully controlled to avoid over!oxidation and formation of the ketoneð69JOC0605\ 60JCS"B#0436Ł[ A similar problem is encountered when ozone is used as the oxidant\although this method is e}ective for the preparation of sterically hindered sul_nes ð62S506Ł[ Dimethyldioxirane has also been used with some success ð80JCS"P0#2932Ł[

S SOmcpba

75%(87)

A conceptually di}erent approach is the alkylidenation of sulfur dioxide[ This can be achievedby the reaction of SO1 with phosphonium ylides "Equation "77## ð67TL796Ł\ or by a Peterson reactionusing an a!silyl carbanion[ The latter approach may be more versatile\ as the silyl component canbe readily prepared by silylation of an active methylene compound\ the overall reaction proceedingin good yield "Scheme 37# ð67TL700Ł[ An alternative approach to the generation of the anion is byaddition of a nucleophile to a vinyl silane\ although the yields for this method are generally ratherlower ð67TL2272Ł[ In situ generated sulfur monoxide will also react with ylides to produce sul_nes\although the yields are very substrate!dependent ð68JCS"P0#0619Ł[ The reaction between sulfur mon!oxide and diazoalkanes also generates sul_nes in modest yield ð58TL3350\ 65CC320Ł[

PPh3 SO

SO2, PhH, 60 °C

80%(88)

O O O

TMS SO

i, BunLiii, TMS-Cl

i, BunLiii, SO2

80%

Scheme 48

The base!promoted elimination of HCl from sul_nyl chlorides was one of the earliest methodsused for the synthesis of sul_nes "Equation "78## ð53JA0780Ł[ More recently\ a convenient one!potapproach for the preparation and elimination of the sul_nyl chloride has been described "Scheme38# ð73CC491\ 73TL4836\ 78T2630\ 81CJC853Ł[ This 0\1!elimination approach\ analogous to that widelyemployed for the formation of thioaldehydes\ has been extended to other types of substrate and hasbeen the subject of extensive study by Kice and co!workers ð80JOC0313\ 80JOC0320Ł[ A novel variant


of this method is the elimination of chloroform from allyl or benzyl trichloromethyl sulfoxides toproduce vinyl or aryl thioaldehyde S!oxides "Equation "89## ð83TL842Ł[

S SOCl O

Et3N

75%(89)

O-TMS O

S

Cl

O

O

S

O

SOCl2

48%

Scheme 49

Ph SCCl3

O

Ph S

ODABCO

95%

DABCO = 1,4-diazabicyclo[2.2.2]octane

(90)

The retro DielsÐAlder reaction of a variety of precursors has been employed to prepare a!oxo!and a!iminosul_nes "Scheme 49# ð77CB722\ 89JCS"P0#2064\ 89TL4614\ 80NJC422\ 80PS"48#308Ł[ The thio!Claisen reaction of allyl vinyl sulfoxides is a rapid reaction leading to the formation of sul_nes inexcellent yield "Equation "80## ð74JA5620\ 80JCS"P0#2088\ 81JOC2019\ 81SL898Ł[ Retro cyclization of adithiolane trioxide has also been used to prepare sul_nes ð89CB066Ł[

S

N

Tol

O

O

Ph

PhMeN +O N

S

Tol

PhMeN

Ph

ORT

96%O

SPhMeN

Ph

O

Scheme 50

0 °C

98%

S

O

Ph

S

O

Ph

(91)

Many simple sul_nes are unstable and have either been generated and trapped in situ or char!acterized in the gas phase[ This is particularly true of sul_ne itself\ which has been the subject ofdetailed study[ The usual way of generating sul_ne and simple analogs is the retro ð1¦1Ł cyclizationof a suitable precursor "Equation "81## ð65JA0153\ 71JA2008\ 89JST"127#60Ł^ this type of reaction hasbeen reviewed ð71AG"E#114\ 73CHEC"6#338Ł[

(92)500 °C

S S O SO

A number of other approaches have given rise to sul_nes\ although none has been widely used[These include the oxidation of certain thiophenes with singlet oxygen ð69TL680Ł or peroxy acidsð89CB1954Ł\ and the desilylation of alkyltrimethylsilylsul_nes to produce thioaldehyde S!oxides\which are di.cult to prepare by other routes ð75CC853\ 89JOC2633Ł[ For further details of these andother methods for the formation of sul_nes\ the many reviews of the area should be consultedð56AG"E#096\ 69QRS68\ 68COC"2#262\ 71RTC0\ 78PS"32#0Ł[


2[97[3[0[2 Thiosul_nes

In contrast to their oxygen analogs\ thiosul_nes are highly reactive species which have so fareluded isolation[ However\ there is considerable evidence for their existence\ from both mechanisticarguments and trapping experiments ð76JA891\ 81CC300\ 81CC599Ł[ For a discussion of the chemistryof these transient species\ other reviews should be consulted ð78PS"32#52\ 89SUL72Ł[

2[97[3[0[3 Thiocarbonyl S!imides

A number of thiocarbonyl S!imides have been prepared and characterized[ However\ many ofthese compounds are unstable\ readily undergoing cyclization and loss of sulfur to produce thecorresponding imines ð66TL1828Ł[ This process is retarded by steric hindrance\ and many of themore stable compounds of this type are those bearing bulky substituents[ Four major methods havebeen employed for the preparation of these compounds] the 0\2!elimination of HCl from a!chlorosulfenamides "Equation "82## ð62JA168\ 63JOC1774\ 66ACS"B#789\ 89CB0364Ł\ the reaction of a thioketonewith chloramine T ð66TL148\ 68RTC016Ł\ the alkylidenation of sul_nyl amines using either a phos!phonium ylide ð66JOC2811Ł or an a!silyl carbanion "Equation "83## ð72JOC3471Ł\ and the reaction ofa sul_ne with an amine anion ð72JOC3471Ł[ The chemistry of thione S!imides has been reviewedð73SR22Ł[

O

Cl

S Cl O

SNButButNH2

73%(93)

(94)

TMS SN

Ar i, BunLiii, ArNSO

76%

2[97[3[0[4 Metal complexes of thioaldehydes and thioketones

The coordination chemistry of thiocarbonyl compounds\ and of thioaldehydes in particular\ hasbeen extensively studied\ and many stable complexes have been prepared\ often of thioaldehydesthat cannot otherwise be isolated[ In the case of stable thiocarbonyl compounds\ the complexes aregenerally formed by direct reaction of the compound with a suitable metal salt^ for unstable speciesa wide variety of approaches have been used[ A detailed discussion of the preparation of thesecomplexes is inappropriate in this review*other works ð77JA2060\ 81IC612Ł and the references thereinshould be consulted for further information[

2[97[3[0[5 Thiopyrylium salts

Thiopyrylium salts\ which nominally contain a C1S double bond\ have been prepared andisolated as stable compounds[ They can be prepared by hydride abstraction from thiopyransð64JCS"P0#1988Ł[ An alternative route to these molecules is by ring formation "Scheme 40#*theinitially formed thiopyran disproportionates to the thiopyrylium salt and a dihydrothiopyran ð55T6\63TL2800Ł[ Reynolds has reported two e.cient syntheses of aryl!substituted thiopyrylium salts\starting from the corresponding pyrylium salt or from a 3!ketotetrahydrothiopyran ð64S527Ł[ Adi}erent approach to these compounds is by the S!methylation of thiopyran!3!thiones


ð69JCS"C#0191Ł[ Further details of these and other routes to thiopyrylium salts may be found in thereview by Ingall ð73CHEC"2#774Ł[

SSS

50%

S

50%

O

+

HClO4

71%+

Scheme 51

The related thiophenium ions can be formed by the direct protonation of thiophenes with~uorosulfonic acid ð62TL2818Ł[

2[97[3[0[6 0\1!Dithiolium salts

0\1!Dithiolium salts are well!known compounds which have been very widely employed assynthetic intermediates[ Many di}erent synthetic methods have been used for their formation^ fora comprehensive coverage of these\ and a discussion of the reactivity of these compounds\ see thereview by McKinnon ð73CHEC"5#672Ł[

A versatile reaction is the sulfurationÐcyclization of b!diketones\ commonly carried out usingP1S4 ð54LA"571#077Ł\ or hydrogen polysul_des\ H1Sx "x�1Ð4#\ in the presence of acid ð51JCS4093\57CB166Ł[ A more recent modi_cation of this method is the use of hydrogen sul_de in combinationwith FeBr2 and bromine "Equation "84## ð68BCJ0124Ł[

SS+

Ph Ph

O O

Ph Ph

H2S, Br2, FeBr3

62%(95)

The peracetic acid oxidation of 0\1!dithiole!2!thiones is also a widely used technique "Equation"85## ð50JA1823\ 57CJC0744Ł[ Acid!promoted cyclization of thioketones bearing a suitably positionedthiocyanate group has proved to be a useful method for the formation of a range of fused ringdithiolium salts "Equation "86## ð89JCS"P0#1770Ł[ Dithiolium salts can also be formed by the ringopening of trithiapentalenes and related compounds\ brought about by protonation ð64JCS"P0#1986Łor alkylation ð57JOC1804Ł[

SS+

PhMeCO3H

61%(96)

SS

PhS

HClO4

93%(97)

MeO

S SCN

OMe MeO OMe

S+ S

2[97[3[0[7 Nonclassical thiophenes

This fascinating class of compounds\ of general structure "004#\ has been the subject of extensivestudies\ notably by the groups of Potts and Cava[ They can be regarded as cyclic thiocarbonylylides\ and much of their chemistry is similar\ the compounds readily undergoing 0\2!dipolarcycloaddition[ However\ a large number of nonclassical thiophenes are stable compounds that canbe easily isolated and characterized[ The structure of this class of compound is of theoretical interestand has been discussed in detail ð67JOC2782\ 73CHEC"3#602\ 73CHEC"3#0926\ 73CHEC"5#0916Ł[ Moleculeswith a wide variety of rings fused to the thiophene have been prepared\ including "005# ð58JA2841Ł\


"006# ð63JA0706Ł\ "007# ð58JA5780Ł\ "008# ð61JA5104Ł\ "019# ð68CB159Ł\ and "010# ð66H"5#0062Ł\ as wellas several polycyclic systems[

SX

YZ

(115)

SN

ON

Ph

Ph

SSN

Ph

Ph

Ph

SPhNN

Ph

Ph

SN

SN

Ph

Ph

SMeN

Ph

Ph

Ph

Ph

SS

(121)(116)

Ph

Ph

(120)(119)

Ph

Ph

(118)(117)

The most widely utilized method for the preparation of this class of compound is the reaction ofa diketone with P1S4 "Equation "87## ð63JA3157Ł[ This reaction is versatile and has been employedin the synthesis of many nonclassical thiophenes[ An alternative\ somewhat milder\ technique is thedehydration of sulfoxides\ usually with acetic anhydride "Equation "88## ð58JA2841Ł[ The early workin this area has been reviewed ð64ACR028Ł^ more recent reviews are provided in ComprehensiveHeterocyclic Chemistry ð73CHEC"3#0926\ 73CHEC"5#0916Ł[

SS

Ph

Ph

Ph

Ph

S

Ph

Ph

O

Ph

O

Ph

P2S5, pyridine

83%(98)

SS

Ph

Ph

Ph

Ph

SS

Ph

Ph

Ph

Ph

Ac2O

87%O (99)

The analogous six!membered ring system has been prepared in 72) yield by the reaction of adiketone with P1S4 in pyridine ð58JA2842Ł[

2[97[3[0[8 Other heterocycles

A number of unusual heterocycles containing a C1S1N unit have been prepared ð45JCS2078\76JCS"P0#196\ 78JCS"P0#1378Ł[

2[97[3[1 Three!coordinate Sulfur Functions

2[97[3[1[0 Sulfonium ylides

Sulfonium ylides bearing two carbon!based groups on sulfur are versatile reagents that havebeen widely utilized in organic synthesis[ The simplest compound of this type\ dimethylsulfoniummethylide\ has found extensive use for epoxide formation from ketones since its introduction byCorey and Chaykovsky in 0854 ð54JA0242Ł[ Simple sulfonium ylides of this type\ which havehydrogen or alkyl groups on carbon\ are usually generated and used directly\ as they are reactiveintermediates which decompose rapidly at room temperature[ In contrast to this reactivity\ sul!fonium ylides bearing anion!stabilizing groups on carbon are stable compounds that can beprepared\ isolated\ and stored without special precautions ð55JOC0074Ł[ An interesting stabilized


ylide is dimethylsulfonium cyclopentadienylide "011#\ where the stabilization comes from the canoni!cal form "012# in which the ring attains aromaticity ð54TL0646Ł[

S

(122)

S

(123)

–

+

A number of methods have been employed for the formation of sulfonium ylides\ the most widelyused\ especially for unstabilized ylides\ being deprotonation of the corresponding sulfonium salt[The base used depends upon the type of ylide being formed[ For stabilized ylides\ weak bases suchas triethylamine are generally used[ For simple sulfonium ylides\ stronger bases are required\ andthe precise choice of base and reaction conditions can be critical for the successful formation of theylide ð56TL1214Ł[ A number of modi_cations to the conditions for deprotonation have beensuggested\ including the use of heterogeneous reaction conditions ð76T2834Ł and a polymericallysupported reagent ð68TL192Ł[

Another versatile method for the formation of sulfonium ylides is the reaction of a diazo com!pound with a sul_de under photolytic\ thermal\ or metal!catalyzed conditions "Equation "099##ð61JOC0610Ł[ A wide range of structural types have been prepared by this method\ includingcyclopentadienylides ð56CI"L#007Ł\ thiophenium ylide "013# "Equation "090## ð67CC72\ 68JCS"P0#1513Ł\dicyanomethylidene ylides ð65LA530Ł\ and cyclic ylides "Equation "091## ð76TL260Ł[ Some earlyexamples of this technique have been reviewed by Ando ð61IJS"B#078\ 66ACR068Ł[

N2

MeO2C CO2Me

S

MeO2C CO2Me

Me MeS

Me Me, hν

88%(100)

(101)N2

MeO2C CO2MeS

MeO2C CO2Me93%

thiophene, Rh2(OAc)4

(124)

(102)67%

Rh2(OAc)4

S

O

CO2Et

PhN2

O

CO2Et

SPh

Stabilized sulfonium ylides can also be prepared from the corresponding active methylene com!pounds by reaction with sulfoxides\ or ethoxysulfonium salts\ under a variety of conditions "Equa!tion "092## ð56T3168Ł[ The yields for this process are generally modest\ although in some cases\which appear to be substrate!dependent\ better results have been obtained ð57JA639Ł[ Variousmodi_cations to the method have been reported to give improved yields ð67S567Ł[ b!Hydroxyketones can be directly converted into diketosulfonium ylides by oxidation in the presence of DMSO"Equation "093## ð72JOC0888Ł[ A similar result has been obtained using the CoreyÐKim reagent"014# ð77S067Ł\ and this reagent has also been used to convert active methylene compounds intodimethylsulfonium ylides in good yields "Equation "094## ð78CL862Ł[ Active methylene compoundscan be transformed into vinylic sulfonium ylides by reaction with a base and an enaminosulfoniumsalt "Equation "095## ð68CB2996Ł[

O O O O

SPhO

SPh Me , Ac2O, 100 °C

44%(103)


R1

N

H OH

N

O

R2

H

R1

N

H O

N

O

R2

HSDMSO, Et3N, SO3•C5H5N

90–97%(104)

N

O

O

S+

(125)

Ph

O O

Ph

O O

S(125), Et3N

96%(105)

EtO2C CO2Et

S

Me2NCO2Et

S NC+

EtO2C CN, NaH

70%(106)

The addition of a nucleophile to a vinyl! or polyvinylsulfonium salt has been used to prepareseveral sulfonium ylides "Equation "096## ð62TL3922\ 64TL1974Ł[ A number of other techniques havegiven rise to sulfonium ylides\ but none has received wide application ð69CPB389\ 63TL0960\ 64JOC2746\66CL614Ł[ Sulfonium ylides can also be functionalized to form more complex sulfonium ylides byalkylation\ acylation\ or other processes "Equation "097## ð57JOC2406\ 69TL4186\ 63BCJ898\ 64CC178\65JCS"P0#0577Ł[

OS+

OSN

piperidine(107)

S

O

O

MeO2C

MeO2C S

DMAD

100%(108)

A number of reviews have discussed the synthesis and properties of sulfonium ylides ðB!55MI 297!91\B!64MI 297!90\ 68COC"2#136Ł[

Several S!aminosulfonium ylides have also been prepared\ either from an active methylenecompound ð65S209\ 67ZOR0548Ł or from a thioketone S!imide ð63JOC1774Ł[ An interesting reactionis shown in Equation "098#\ although it is not clear whether this could be developed into a generalmethod ð80ZOR106Ł[

CO2Et

SAr

O CO2Et

S

O

Ar N

O

O

NBS–(109)


There are a number of species that are structurally related to sulfonium ylides\ notably the anionsof sul_limines and sulfoxides[ These species are almost exclusively formed by deprotonation andreacted in situ\ although it is possible to isolate the anions if required ð79JA1359Ł[ They will not beconsidered further here[

2[97[3[1[1 Sulfenes

Sulfenes\ or thiocarbonyl S\S!dioxides\ have been the subject of intense study[ However\ despitethis interest\ no stable sulfene has yet been isolated[ They have been prepared and trapped in situ\and are implicated as intermediates in several common reactions^ for example\ the reaction of abase and methanesulfonyl chloride is believed to generate sulfene\ which then reacts with alcoholsto form mesylates[ A number of experiments have been reported in which sulfene has been generatedand studied in the gas phase or at low temperature ð58CJC3498\ 60JA5293\ 63JA1853Ł[

Tertiary amines interact with sulfenes generated by base!induced elimination of HCl from sulfonylchlorides ð65CJC1541Ł\ but it is not clear whether the adduct is a zwitterion "015# or the sulfeneinteracting noncovalently with the amine "016# "Scheme 41#[ However\ Sundermeyer and co!workershave reported the isolation of an adduct between bis"tri~uoromethyl#sulfene and quinuclidine"Equation "009## ð78AG"E#110\ 89CB484Ł[ The x!ray crystal structure of this adduct suggests that theSÐN interaction is relatively weak and the C0S bond has considerable double bond character[

Ph SO

O

Ph SO

O

Ph SO

O

Ph SO2ClNR3 NR3

–R3N R3N

(126) (127)

+

Scheme 52

NS

S

O O

S

F3C

F3C

O

O

F3C

F3C CF3

CF3quinuclidine

74%(110)

For a detailed examination of sulfene generation and chemistry the review by King and Rathoreshould be consulted ðB!80MI 297!91Ł[

2[97[3[1[2 Other simple systems

Iminosulfenes have been postulated as reactive intermediates\ and trapped ð69JA2704Ł[A single example of a simple S\S!dimethoxy thioketone has been reported ð66ACS"B#789Ł[ This

compound\ formed unexpectedly in the reaction of sodium methoxide with an a!chlorosulfenylchloride "Equation "000##\ could be isolated\ but gradually decomposed\ even at −08>C[

O

Cl

SClO

SOMe

OMe

NaOMe

71%(111)

A number of metal complexes of thioaldehydes and thioketones have been reported in which twometal atoms are coordinated to the thiocarbonyl sulfur[ A discussion of the structure and formationof these complexes is beyond the scope of this review^ for an example and further references a paperby Werner and Paul should be consulted ð73AG"E#47Ł[

2[97[3[1[3 Thiabenzenes

Thiabenzenes\ and their polycyclic analogs\ are an interesting class of compounds which bearmany resemblances to simple sulfonium ylides[ Much of the early work in this area\ which involvedthe preparation of thiabenzenes by the addition of phenyllithium to thiopyrylium salts\ has been


called into question by the detailed studies of Mislow and co!workers ð63JA4537\ 63JA4549\ 63JA4540\64JA1607Ł and by Hortmann et al[ ð63JA5008Ł[ However\ this technique can\ in some circumstances\be successfully applied to the synthesis of thiabenzenes and 1!thianaphthalenes ð64JA1607Ł[ A muchmore widely applicable method is the deprotonation of thiinium salts "Equation "001## ð64JA1607Ł[Thiabenzenes are somewhat unstable\ and tend to undergo decomposition or rearrangement readily[However\ they can be stabilized by the presence of electron!donating groups on sulfur ð65JA2504Ł\or electron!withdrawing groups on carbon ð67TL140\ 79JOC1357Ł[ The chemistry of thiabenzenes hasbeen reviewed ð73CHEC"2#774\ 76YGK121Ł[

S+

Me

Ar

SMe

Ar

NaOMe

37%(112)

An example of a four!membered analog\ a thiacyclobutadiene\ has been reported ð63TL2800Ł[

2[97[3[1[4 0\5\5al3!Trithiapentalenes and related systems

A wide range of compounds of the general structure "017# has been prepared[ As mentioned inSection 2[97[2[1[0[ii\ these compounds can be regarded either as the bicyclic species "017# or asmonocyclic[ The choice of which representation is most accurate is complex\ and depends upon theidentity of X\ Y\ Z\ and A[ For the purposes of this review\ all of these compounds will be consideredin this section[ In the space available it is not possible to give a comprehensive account of thepreparation of each of these compounds\ and only a brief summary of the key methods will begiven[ More detailed information is available in the review by Lozac|h ð73CHEC"5#0938Ł[

SA

ZYX

(128)

The starting materials for many syntheses of these heterocycles are 0\1!dithioles or derivatives[The reaction of a 0\1!dithiole!2!thione with an alkyne\ described in Section 2[97[1[1[0[ii as a methodfor the synthesis of electronically stabilized alkenyl thioaldehydes\ also produces variable amountsof trithiapentalenes[ In general the yields of pentalenes are low\ but this depends on the substratestructure ð65BSF"1#019Ł\ and alteration of the reaction conditions can also result in a higher yield ofthe bicyclic system ð67ZOR1348Ł[ 4!Alkyl!0\1!dithiolium salts react with dimethyl thioformamide inacetic anhydride or phosphoryl chloride to produce Vilsmeier salts[ When treated with NaSH theseare hydrolyzed and cyclize to form trithiapentalenes "Scheme 42# ð57JCS"C#1432\ 58JCS"C#802Ł[A related approach is the preparation of enaminodithioles\ followed by hydrolysis "Scheme43# ð69JCS"C#0191Ł[ Acylmethylenedithioles\ available by a similar route\ can be converted intotrithiapentalenes by reaction with P1S4 in pyridine ð52JA2133\ 53CI"L#350Ł[ Related approachescan be employed to give trithiapentalenes directly from dithiolium salts ð63CR"C#682\ 63JCS"P0#611Ł[Diazadithiapentalenes are also prepared from 4!alkyl!0\1!dithiolium salts\ by coupling with arenediazonium salts "Equation "002## ð65JCS"P0#117Ł[

S SSSS+

SS+

Me2NMe2NCHS, POCl3 NaSH

59%

Scheme 53

S SSS S

+

KSH

Ph Cl+

NS S

+

Ph

N Ph

Scheme 54


SN

NSS S+

ArN2+

90–99%

Ar

(113)

Various structural types can be formed by the cyclization of appropriate precursors "Equations"003# ð63JCS"P0#131Ł and "004# ð68JCS"P0#1239Ł#[ This method for the formation of these compoundshas been exploited in the conversion of one ring system into another[ Thus\ in several cases\substitution reactions on the heterocycles are accompanied by rearrangement to produce an alter!native heterocyclic system "Equation "005## ð63JCS"P0#611\ 65JCS"P0#779Ł[

S NNN S

Me

+

Me

SMeMeNH2

50%

Me

(114)

SN

ONN S

Me

N

OHMe

+Na2CO3

87%(115)

S SON Ph

OHC

S SONaNO2

60%Ph (116)

Pyran!3!thiones can be rearranged oxidatively to dioxathiapentalenes by reaction with thal!lium"III# tri~uoroacetate^ a mechanism has been proposed for this transformation "Scheme 44#ð64JCS"P0#664Ł[ Dilute sodium sul_de in combination with potassium ferricyanide brought about thesame conversion\ whereas a more concentrated solution of Na1S introduced an extra sulfur atom\to produce "018# ð61JCS"P0#0336\ 64JCS"P0#0224Ł[ These authors also report the conversion of thedioxathiapentalene "029# into the trithiapentalene "020# "Scheme 45#\ a process that presumablytakes place via ring!opened intermediates[

O O

S STlL2

+OH

STlL2

O

S OOOH S OTlL2

Tl(O2CCF3)3 H2O

61%

≡

Scheme 55

O

O

S

O

O

O

OSO

O

O

SSS

O

O

OSS

(130) (131)

(129)

P2S5

Na2S (dil.), K3Fe(CN)6

Na2S (conc.), K3Fe(CN)6

Scheme 56


Trithiapentalenes and derivatives have also been prepared from acyclic precursors[ Thus\ 0\2\4!triketones\ upon reaction with P1S4\ undergo sulfuration and cyclization to trithiapentalenesð52JA2133Ł[ The bisoximes of b!diketones react with SCl1 or S1Cl1 to produce a mixture of diaza!pentalenes "Equation "006## ð61TL0724\ 68BSF"1#088Ł[ The use of S1Cl1 favors formation of the dithiacompound "021#\ whereas the dioxa compound "022# is the major product from the reaction withSCl1[ Bishydrazones react under the same conditions to produce tetraazathiapentalenes in reasonableyield ð68BSF"1#194Ł[ Trithiapentalenes have also been prepared from acylalkynes by reaction withthioacetic acid ð54LA"571#077Ł[

N N

OHOH SON N

SSO

N NO

SCl2 or S2Cl2+ (117)

(132) (133)

Related systems containing four or _ve sulfur atoms in a linear array have also been prepared[They are commonly made by sulfuration of a ketone\ either directly "see Equation "36## or withrearrangement "Equation "007## ð60BSF3318\ 66CC740Ł[

SSS SSBut But

SS

But

SSBut

O

P2S5(118)

2[97[3[2 Four!coordinate Sulfur Functions

2[97[3[2[0 Sulfoxonium ylides

Sulfoxonium ylides\ like their sulfonium counterparts\ have been very widely used as reagents fororganic synthesis[ Dimethylsulfoxonium methylide was introduced by Corey and Chaykovsky atthe same time as dimethylsulfonium methylide ð54JA0242Ł\ and has been extensively employed forthe preparation of epoxides from ketones[ The sulfoxonium ylide is signi_cantly more stable^solutions only decompose slowly at room temperature and are stable inde_nitely at low temperatureunder an inert atmosphere[ For this reason\ dimethylsulfoxonium methylide has\ despite its lowerreactivity\ been more frequently used than the equivalent sulfonium ylide\ and its use has beenreviewed ð76T1598Ł[ There are some interesting di}erences in reactivity between these two ylides\which are discussed by Corey and Chaykovsky ð54JA0242Ł\ and have been the subject of furtherstudy ð60JA4292\ 62JA6313Ł[

The main methods for the formation of sulfoxonium ylides are analogous to those employed forsulfonium ylides[ Thus\ dimethylsulfoxonium methylide is prepared by the deprotonation of atrimethylsulfoxonium salt by treatment with a strong base\ typically sodium hydride[ More complex\and in particular carbonyl!stabilized\ sulfoxonium ylides have been prepared by the reaction ofdiazo compounds with dimethyl sulfoxide "Equation "008## ð61IJS"B#078\ 61JOC0610\ 66ACR068Ł[ Sul!foximines can replace DMSO in this reaction ð66TL2522\ 68T206Ł[

S

CO2Et

Me OMe

N2

CO2Et

DMSO, CuSO4

50–65%(119)

A widely employed method for the preparation of sulfoxonium ylides is the elaboration ofdimethylsulfoxonium methylide[ This simple ylide can be acylated by reaction with ketenes oranhydrides\ or carbamoylated with isocyanates[ These reactions can also be combined to give doublyfunctionalized ylides "Scheme 46# ð54CB2622Ł[ Thiocarbonyl!stabilized ylides can also be prepared"Equation "019## ð65BCJ2017Ł[ Dimethylsulfoxonium methylide will also undergo Michael additionto activated alkynes ð55TL0676Ł\ and additionÐelimination reactions "Equation "010## ð63JCS"P0#0014\63JOC2064Ł to produce vinylic ylides in moderate yields[ The reaction with imidoyl and related


chlorides has been successfully applied to the synthesis of a number of sulfoxonium ylides "Equation"011## ð66JCS"P0#0085\ 77CB0994Ł[

SMe O

MePhNCO

80%

O

SMe O

MeAc2O S

Me OMe

O

NHPh

O

Scheme 57

SMe O

Me

S

Ph

SMe O

MePhCSCl

30%(120)

O

Cl

O

SMe

Me

O

S

O

Me

Me+28%

(121)

N

N

Cl

O

SMe

Me N

N

S

O

Me

Me+52%

(122)

A number of other species bear close structural and chemical similarities to sulfoxonium ylides[Anions derived from sulfones can be regarded as containing a C1S double bond\ and have beenwidely used in synthesis[ They are generated by deprotonation of the sulfone\ and are almostinvariably reacted in situ without isolation[ The anions produced by deprotonation of sulfoximineshave also proved to be useful reagents\ their reactivity being similar to that of sulfoxonium ylidesð80TL0164Ł[ They are reasonably stable in solution ð62JA3176Ł\ and have been used in a number ofsynthetic applications[ These reagents are again formed by deprotonation of the precursor with astrong base and reacted immediately[ Their use has been pioneered by Johnson\ who has reviewedthe area ð62ACR230\ 74MI 297!90Ł[

2[97[3[2[1 Other simple compounds

A structurally novel compound is the alkylidenesulfur di~uoride oxide "023#\ prepared by con!trolled hydrolysis of alkylidenesulfur tetra~uoride "024# "Equation "012## ð77CB0866Ł[ This reactionis interesting in that hydrolysis of the SF3 group occurs before that of the acyl ~uoride[ Compound"023# exists as a mixture of isomers at low temperature[

OS

O

F FF

OS

F FF

FF

H2O

39%

(135) (134)

(123)

Many metal complexes of sulfur ylides have been prepared\ and although the precise nature ofthe bonding in many of these species is unclear\ in some cases a C1S bond may\ at least nominally\be present[ This area of chemistry has been reviewed by Weber ð72AG"E#405Ł[

2[97[3[2[2 Thiabenzene S!oxides

Thiabenzene oxides are generally stable compounds which can be isolated and characterized[ Anx!ray crystal structure of one of these compounds\ which showed both C0S bonds to be of similar


length and intermediate in character between single and double bonds\ has been reported ð67CC086Ł[The compounds are readily prepared by the addition of dimethylsulfoxonium methylide to anacylalkyne and cyclization "in situ or as a separate step# of the intermediate ylide "Scheme 47#ð60JA1360Ł[ More highly functionalized compounds can be prepared by a related approach "Equation"013## ð63JOC2408\ 77CB0994Ł[

69% S

Ph

OMeO

PhS

O

MeMe

+NaOMe

84%Me SO

Ph

OMe

Scheme 58

33%

SOMe

S

O

MeMe

+ (124)

O

EtO O

O

2[97[3[3 Five!coordinate Sulfur Functions

2[97[3[3[0 Alkylidene sulfur tetra~uorides

A number of compounds containing the C1SF3 group have been prepared and characterized bySeppelt and co!workers[ The simplest of these\ methylenesulfur tetra~uoride\ was prepared frombromomethylsulfur penta~uoride by halogenÐmetal exchange\ followed by elimination of lithium~uoride "Scheme 48# ð67AG"E#405\ 72CB534Ł[ This compound is a stable gas\ and structural studieshave shown that it contains a C1S double bond with less charge separation than in sulfur ylidesð68AG"E#833Ł[ The compound has also been prepared by the decomposition of metal sulfur pen!ta~uoride complexes ð78ZAAC"467#009Ł[ Several other compounds of this class have been preparedusing the same metal!promoted elimination route ð71IC2036\ 73CB2144Ł\ and a crystal structure ofone has been obtained ð80JA122Ł[ An interesting molecule of this class\ "024#\ has been synthesizedby the thermal isomerization of the ketene "025# in the presence of glass "Scheme 59# ð76AG"E#688\77CB0866Ł[

BunLi, –110 °CBr SF5 Li SF5 H2C SF4

–70 °C

Scheme 59

Scheme 60

glass, 270 °C

50%HO2C SF5 • SF5

P2O5

70%

O

(136) (135)

SF4O

F


3.09Seleno- and Telluroaldehydesand -ketonesFRANK S. GUZIEC, Jr and LYNN J. GUZIECNew Mexico State University, Las Cruces, NM, USA

2[98[0 OVERVIEW 270

2[98[1 SELENOALDEHYDES "SELENALS#\ RHC1Se 271

2[98[1[0 Simple Selenoaldehydes 2712[98[1[1 Metal!stabilized Selenals 2752[98[1[2 Conju`atively Stabilized Selenals 277

2[98[2 TELLUROALDEHYDES "TELLURALS#\ RHC1Te 278

2[98[3 SELENOKETONES "SELONES#\ R1C1Se 280

2[98[3[0 Simple Selones 2802[98[3[1 Metal!stabilized Selones 2852[98[3[2 Resonance!stabilized Selones 287

2[98[4 TELLUROKETONES "TELLONES# 399

2[98[0 OVERVIEW

Despite a number of early reports describing the synthesis of selenium and tellurium analoguesof simple aldehydes and ketones\ the preparation of well!characterized derivatives of these classesof compounds only dates from the mid!0869s[ Careful examination of the earlier reports suggeststhat researchers were initially often led astray by signi_cant limitations in analytical techniques[ Thedesired seleno! and tellurocarbonyl compounds were often unstable under the preparative conditionsused and decomposed during the attempted synthesis[ In many cases dimeric and trimeric derivativesof the desired compounds were obtained\ adding to the confusion[ The early di.culties associatedwith the attempted preparation of seleno! and telluroaldehydes and !ketones have been reviewedðB!62MI 298!90Ł[

Despite these early problems\ advances in methodology in the late 0879s\ and the introduction ofa variety of novel reagents\ have made these seleno! and tellurocarbonyl derivatives much morecommon[ It should be noted that\ in general\ these classes of compounds are not stable enough tobe isolated at room temperature unless the seleno! or tellurocarbonyl functional group is shieldedsterically\ is stabilized by complexation to a metal center\ or is conjugated in a vinylogous mannerto other stabilizing functions[ A number of reviews concentrating on aspects of the preparation andreactions of seleno! and telluroaldehydes and !ketones have been published ðB!75MI 298!90\ B!76MI298!90\ B!76MI 298!91Ł[

Finally\ the di.culties associated with the nomenclature of seleno! and tellurocarbonyl analoguesof aldehydes and ketones should be noted[ The terms selenoaldehyde\ selenoketone\ telluroaldehyde\and telluroketone in the literature often refer to carbonyl compounds with selenium or telluriumsubstituents[ Better terms for these compounds are selenal\ selone\ tellural\ and tellone\ respectively[

270

271 Seleno! and Telluroaldehydes and !ketones

It should also be noted that the terms selenone and tellurone are occasionally used incorrectly inthe literature to describe selenium and tellurium analogues of ketones[ These names\ in fact\ referto the selenium and tellurium analogues of sulfones[ The detailed nomenclature of seleno! andtellurocarbonyl compounds has been discussed ðB!76MI 298!91Ł[

2[98[1 SELENOALDEHYDES "SELENALS#\ RHC1Se

2[98[1[0 Simple Selenoaldehydes

Despite descriptions of the preparation of selenoaldehydes "selenals# dating back to the nineteenthcentury\ well!characterized preparative routes to these compounds have only been reported sincethe mid twentieth century[ Many of these early routes to selenals involved reaction of an aldehydewith hydrogen selenide in the presence of acid ðB!62MI 298!90Ł[ These reactions generally lead tocyclic trimers of the desired selenal "Scheme 0# ð49JCS0260Ł[ The trimeric nature of {{seleno!formaldehyde|| "0# ð54JCS796Ł and {{selenoacetaldehyde|| "1# ð56JCS"B#006Ł were con_rmed byx!ray analysis[ Trimeric {{selenobenzaldehyde|| "2# ð21RZC169Ł and linear polymeric {{seleno!formaldehyde|| ð54JPS"B#470\ 55JPS"A#137Ł have also been reported[ It should be noted that the presenceof true monomeric selenal intermediates has not been established in these preparations[ Vacuumpyrolysis of these cyclic trimers at very high temperatures did a}ord the monomeric selenals astransient species "Equation "0##\ where FVP represents ~ash vacuum pyrolysis ð73CB076Ł[

O

R+ H2Se

H+ Se

Se

Se

R

RRSeH

HO

R

R = H, alkyl, aryl,

–H2O

(1) R = H(2) R = Me(3) R = Ph

Scheme 1

Se

RSe

Se

Se

R

RR

R = H, Me

FVP

1000–1100 K(1)

Selenoformaldehyde "0# has also been generated as a transient species by reaction of methylenewith a selenium mirror "Scheme 1# ð57CC348Ł or by FVP of dimethyl selenide "Equation "1##ð73JA4395Ł[ Irradiation of selone "3#\ isolated in an argon matrix by pyrolysis of a selenadiazole\a}orded propyneselenal "4# which was characterized spectroscopically "Scheme 2# ð74JOC432Ł[

CH2N2 [CH2] + SeSe Se

Se

Se

H

H

(1)

Scheme 2

Me2SeFVP

700 °CSe

H

H+ CH4 (2)

272Selenoaldehydes

FVP

700 °CSeN

N• • Se

Se

matrix isolation12 K(4)

matrix isolation12 K(5)

hν

[1,3]-shift

Scheme 3

Despite the extreme reactivity of unstabilized selenals\ they can be readily prepared as transientspecies\ and these intermediates trapped as DielsÐAlder adducts "6# by ~uoride!induced eliminationof cyanide from a!silylselenocyanates "5# "Scheme 3# ð75JA0203Ł[ This was the _rst general\ con!venient preparative method for selenals[ In this procedure an aldehyde is treated with phenyl!dimethylsilyllithium and the intermediate alkoxide is trapped with p!toluenesulfonyl chloride[Treatment of the resulting a!silyl tosylate with potassium selenocyanate a}ords the requireda!silylselenocyanate[ DielsÐAlder adducts of the intermediate selenals are isolated in 28Ð78) yield"Table 0#[

O

R

SiPhMe2

R OTs

SiPhMe2

R SeCN

Bun4N+ F –

(7)(6)

(6)

i, PhMe2Si– Li+

ii, TsCl

KSeCN

18-C-6

Se

R

Se

R

SiPhMe2

R SeCN

Scheme 4

Table 0 Generation of selenals "RCHSe# viaa!silylselenocyanates "5# to "6#[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry R Yield a

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 H 551 Me 722 Et 673 Pr 654 Ph 705 PhCH1 786 But 28*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Isolated yield of selenal DielsÐAlder adducts "6#[

The _rst stable isolable selenal\ 1\3\5!tri!t!butylselenobenzaldehyde "7#\ was prepared using theabove mentioned a!silylselenocyanate method ð78JA4838Ł[ This selenal is a reasonably stable bluecrystalline compound\ which in solution is very sensitive to oxygen even at low temperatures"−49>C#\ rapidly a}ording the corresponding aldehyde under these conditions[ The selenocarbonylcompound is also quite reactive\ undergoing thermal cyclization to the benzoselenane "8# at 69>C"Equation "2##[ This cyclization con_rmed the intermediacy of the selenal "7# in the reaction of tri!t!butylphenyllithium with hindered selenoformates "Scheme 4# ð75CC60Ł[

But

But

But

Se

(8)

Se

But

But

(9)

70 °C(3)


But

But

But

Li +Se

But

But

Se

OBut But

But

But

Se

(9)(8)

Scheme 5

Another route to an uncomplexed selenal involves 0\1!elimination of various selenenyl derivatives"Scheme 5# ð75CC0041Ł[ In this approach\ ethyl bromoacetate was converted to a {{seleno Buntesalt|| "09# which could be oxidized to the corresponding diselenide "00#[ Cleavage with sulfurylchloride and displacement with potassium phthalimide a}orded the key intermediate phthalimidoderivative "01# as a crystalline solid "Scheme 5#[ Treatment of "01# with triethylamine in benzeneunder re~ux in the presence of an appropriate diene a}orded the DielsÐAlder adduct "03# of theintermediate selenal "02# "Scheme 6#[ Other selenyl derivatives behaved similarly\ although theya}orded more complex mixtures containing the selenal adducts[

RO2C Br RO2C SeSO3K RO2C Se

(10) (11)

Scheme 6

R = Me, Et

RO2C SeCl N

O

O

Se

(12)

N

O

O

K

K2SeSO3

H2O–ROH

I2

H2O, EtOH

RO2C

SO2Cl2

benzeneSe CO2R

R = Me, Et

N

O

O

Se

(12)

RO2C

Et3N Se

RO2C

(13)

Se

CO2R

(14)

Scheme 7

Another route to the generation of monomeric selenal intermediates involves the thermal reactionof a Wittig reagent with selenium in an inert solvent "Scheme 7# ð76TL5538Ł[ Stabilized Wittig speciessuch as "04# react with elemental selenium at elevated temperatures a}ording intermediate unstableselenals "05#\ which further react with "04# ultimately leading to the corresponding symmetricalalkenes[ The intermediate selenals can also be trapped by dienes\ a}ording the corresponding DielsÐAlder adducts[

Ph3PCO2Me

SeCO2Me

+ Ph3P Se

(15)

+ SeCO2Me

(16)

MeO2Ctoluene

105 °C

(15)

74%

Scheme 8

274Selenoaldehydes

These reactions also proceed with unstabilized alkyl!substituted ylides "Scheme 8# ð77JA513Ł[ Theselenal anthracene DielsÐAlder adducts "06# are particularly interesting compounds since\ uponmild thermolysis\ the selenals can be regenerated by retrocyclization and trapped by other reagents"Scheme 09#[

Se

R

Se

R

PPh3

R+ Se

90 °C

R = Ph, Et, Bun

21%

(17)

Scheme 9

Se

R

Se

R

R = Ph, Et, Bun, Ph

75 °C

(17)

–Se

R

Scheme 10

A number of reagents have been developed in the 0879s which can be used to introduce seleniuminto molecules directly\ converting a carbonyl group into a selenocarbonyl moiety[ Bis"trimethylsilyl#selenide "07# reacts with aldehydes in the presence of a catalytic amount of n!butyl lithium togenerate a selenal which can be trapped in a variety of ways "Scheme 00# "Table 1# ð77JA0865Ł[ Thedriving force for the reaction is the large energy di}erence between the selenide "07# and its oxygenanalogue disiloxane[

Se

R

O

R

Se

R

TMSSe

TMS

Scheme 11

+ TMSO

TMS+

(18)

BunLi (cat.)

THF 45–85%

Table 1 Direct generation of selenals "RCHSe#from aldehydes using bis"trimethylsilyl#

selenide "07#[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry R Yield a

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 Ph 621 3!ClPh 612 1!furyl 743 Prn 604 Pri 705 But 34*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Isolated yield of selenal DielsÐAlder Adducts[

Appropriately substituted selenals can be generated using this method and trapped intra!molecularly in a DielsÐAlder process "Scheme 01# ð77TL5854Ł[

Bis"dimethylaluminum# selenide "08# is reported to react with acetals to a}ord selenals which canbe trapped with Wittig reagents to a}ord the corresponding alkenes "Scheme 02# ð82CE42Ł[

Trimethylselenophosphate "19# reacts with v!H!per~uoroalkanals to a}ord the correspondingselenals which can be trapped under normal conditions "Scheme 03# ð80ZOR397Ł[


+ BunLi (cat.)

THFTMS

SeTMS Se

R

( )n

Se

R

( )n

O

R

( )n

Scheme 12

R1

R2Se

R1 PPh3

R2(Me2Al)2Se(19)

R1

OMe

OMe

R1 = PhCH2, Ph, C7H15 Scheme 13

O

(CF2)nH

Se

PMeO OMe

OMe

O

PMeO OMe

OMe

Se

(CF2)nH

Se

(CF2)nH ++

49–52%

(20)n = 4, 6

Scheme 14

2[98[1[1 Metal!stabilized Selenals

As previously mentioned\ selenals can be stabilized by complexation to metal centers[ Metalcomplexes of selenobenzaldehydes "11# can be prepared from the reactions of the correspondingbenzylidene metal complexes "10# and selenocyanate ion "Equation "3## ð73AG"E#615\ 78JOM"266#094Ł[These complexes have a variety of isomeric forms which are in equilibrium in solution "Scheme 04#[The complexes can undergo a variety of transformations without a}ecting the selenal ligand"Equation "4## ð76CB0894Ł[

(CO)5M

R

(21)

+ [Et4N]+ C[N Se]–(CO)5MSe

R

(22)

–Et4NCN

M = W, CrR = H, OMe, CF3

(4)

(CO)5W SePh

+ 2 But ]2 W (CO) [ But SePh

(5)

The metal complexes can react spontaneously in solution with elimination of the selenal to a}ordrelated bimolecular metal complexes "12# "Equation "5## ð74JOM"178#C10Ł[ Fischer et al[ have utilizedthe ability of these metal complexes to act as a stable source of selenals in order to carry out avariety of synthetic transformations of transient selenal species under very mild conditions ð76CC448\77JOM"247#118\ 78CC556\ 78JOM"253#044\ 89JOM"273#294\ 81CC452Ł[

276Selenoaldehydes

CO

M

CO

OC

OC

CO Se

H C6H4R

η2

CO

M

CO

OC Se

OC

CO

C6H4R

:

+–

(E)-η1

CO

M

CO

OC Se

OC

CO

:

+–

(Z)-η1

C6H4R

Scheme 15

Se

R

2 (CO)5W Se

R

R = H, OMe, CF3

Se

R

H(CO)5W

W(CO)5

(23)

+ (6)

Some formal metal complexes of selenoformaldehyde "13# and "14# can be prepared by dis!placement reactions on diiodide complexes "Equations "6# and "7## ð72AG"E#205\ 73AG"E#47Ł[ The lattercomplex can also be prepared by extrusion of carbonyl selenide from an osmiumÐdiselenocarbonatecomplex "Equation "8## ð72JOM"133#C42Ł[

SeCpLRh

I

I

CpLRhNaHSe

L = Me3P (24)

(7)

SeL2(CO)2Os

I

I

L2(CO)2OsNaHSe

(25)

(8)

SeL2(CO)2Os

(25)

(9)O

L2(CO)2OsSe Se

–COSe

∆

The electron!rich osmium methylene complex "15# reacts with elemental selenium to form theselenoformaldehyde complex "16# "Equation "09## ð72JA4828Ł[ Selenoformaldehyde can also act asa bridging ligand in organometallic complexes[ Reactions of the selenium complexes "17# or "18#with diazomethane a}ord the bridged complex "29# "Scheme 05# ð72AG"E#203Ł[

SeOs

L

L

NO

ClOs

L

L

NO

ClSe

(26) (27)L = PPh3

(10)


M M

Se Se

M

M

CH2N2

–N2

MSe

SeMCH2N2

–N2

(28) (30) (29)

Scheme 16

M = (η−C5Me5)Mn(CO)2, (η-C5H5)Mn(CO)2

2[98[1[2 Conjugatively Stabilized Selenals

A number of selenal derivatives which exhibit particular stability because of resonance interactionshave also been prepared[ The fact that these compounds can be readily isolated suggests that specialvinylogous or resonance interactions lower the carbonÐselenium double bond character of theselenocarbonyl moieties[

It has been reported that the selenal "20# could be prepared directly from the formyl derivativeby treatment with phosphorus pentaselenide "Equation "00## ð43GEP809088Ł[ It should be noted\however\ that phosphorus pentaselenide is not a particularly useful selenating agent in most casesðB!76MI 298!92Ł[

N

R

Me

O N

R

Me

Se

P2Se5(11)

(31)

Other related stabilized selenals "21#Ð"23# can be prepared from heterocyclic amines by a VilsmeierÐHaack transformation followed by sodium hydrogen selenide treatment "Equation "01##ð68JCS"P0#1223Ł[ These selenal compounds can also be prepared from the corresponding formylderivatives by treatment with phenylselenophosphonic dichloride "24# "Equation "02## ð77CC0383Ł[

N

R

R

R

R

R

R

R = H, alkyl

N

R

R

R

R

R

R

Se

i,

ii, NaHSe

PO2Cl2–NMe2

Cl+

(32)

28–46%

(12)

N

SR

Se

(33)

N

SR

(34)

Se

N

R1

R2R3

CHO

R4

N

R1

R2R3

R4

Se

PPh Cl

Cl(35)

62–81%(13)

Se

278Telluroaldehydes

The _nal class of stabilized selenals includes compounds which formally contain a selenocarbonylmoiety in a contributing resonance form such as "25#\ but which are probably better described ashypervalent sulfur "26# or selenium "27# species ð60JCS"C#2076Ł[ Compounds of this type can beprepared by selenation of the corresponding aldehyde using phosphorus pentaselenide ð55JA4934Ł\or more e.ciently by using phenylselenophosphonic dichloride "24# "Scheme 06# ð77CC0383Ł[ Theunsubstituted derivative "27# can be prepared via a displacement and oxidation sequence "Scheme 07#ð60JCS"C#2076Ł[

Se

PPh Cl

Cl

S SeSPh

Ph

SSPh

Ph

O SSPh

Ph

Se S Se

Ph

(37)

Ph

S

(35)

(36)

Scheme 17

Se SSe SeSeSSe S

(38)

SeS

Se

iii, K3Fe(CN)6

i, Na2S ii, Se2–

Scheme 18

2[98[2 TELLUROALDEHYDES "TELLURALS#\ RHC1Te

The preparation of telluroaldehydes "tellurals# very much parallels the previously describedchemistry of selenals\ although signi_cantly less has been published on this topic[ In general\tellurals*like selenals*cannot be isolated in their free state unless they are stabilized[ In the caseof tellurals\ only metal complexation has led to successful stabilization of these compounds[

The preparation of gaseous monomeric telluroformaldehyde "28# via the reaction of a telluriummirror with methylene generated by thermal decomposition of diazomethane or photolysis of ketenehas been reported ð23JA1270\ 27JCS398Ł[ This material trimerizes to tritelluroformaldehyde "39#"Equation "03## ð57CC348Ł[

Te Te

Te

(40)

Te

H

H

CH2Te +

(39)

(14)

Tellurobenzaldehyde "31# can be prepared as a transient intermediate by the thermal reactionof the Wittig reagent "30# with tellurium[ The tellural can be trapped by a diene "Scheme 08#ð78AG"E#068Ł[ If only a catalytic amount of tellurium is used\ the corresponding {{dimerized|| alkeneis isolated[ This is due to the fact that the by!product triphenylphosphine telluride is thermallyunstable\ regenerating the elemental tellurium "Scheme 19#[

(41)

TePh

(42)

PPh3

Ph Te

toluene105 °

Te

Ph

Scheme 19

11%

Bis"dimethylaluminum# telluride "32# acts as an e}ective direct tellurating agent for the prep!aration of tellurals from the corresponding aldehydes[ The transient intermediate tellurals can be


TePh

PPh3

Ph PPh3

Ph

Scheme 20

Ph

Ph

Te+ Ph3P

Te Ph3P

61%

Te

cat.100 °C

Ph3P + Te100 °C

trapped as their DielsÐAlder adducts "Scheme 10# ð78JA7638Ł[ The key tellurating agent bis"dimethyl!aluminum# telluride "32# can be readily prepared via transmetallation of bis"trimethyltin# telluride"Equation "04## ð78JA7638Ł[ It should also be noted that bis"trimethylsilyl# telluride "33# was not ane}ective tellurating reagent\ in contrast to its selenium analogue "07# which acts as a convenientselenating agent "cf[ Scheme 00#[

Te

R

Te

RR

OAlMe2

TeAlMe2

O

R(Me2Al)2Te +

dioxane –(Me2Al)2O

Scheme 21

44–62%

(43) R = Ph, Prn, But

Bu3SnTeSnBu3 + 2Me3Al (Me2Al)2Te + 2Bu3SnMe

(43)

toluene

90 °C(15)

(Bu3Si)2Te

(44)

A number of metal complexes of tellurals have also been reported[ The tungsten pentacarbonylcomplex of tellurobenzaldehyde "34# can be prepared by tellurium insertion into the metal carbenecomplex "Equation "05## ð80JOM"304#100Ł[ These complexes have structures analogous to the selenalcomplexes previously mentioned "cf[ Scheme 04#[ Thermolysis of "34# a}ords the free tellural as atransient species which can be trapped by dienes "Scheme 11#[

(CO)5W (CO)5WTe+ [Et4]+ [N=C=Te]–

–Et4NCN

18%

(45)

(16)

(CO)5WTe

(45)

Te Te

Ph

∆

Scheme 22

A number of formal complexes of telluroformaldehyde have been reported[ Treatment of the m2!tellurium complex "35# with diazomethane a}ords the bridged complex of telluroformaldehyde "36#"Equation "06## ð72AG"E#203Ł[

280Selenoketones

Te

H

H

M

M

CH2N2

–N2

(47)

M = (η−C5Me5)Mn(CO)2, (η-C5H5)Mn(CO)2

M

TeM M

(46)

(17)

The electron!rich osmium complex "37# also reacts with elemental tellurium to a}ord the osmiumcomplex of telluroformaldehyde "38# "Equation "07##[ Finally\ the diiodorhodium complex reactswith sodium hydrogen telluride to a}ord the telluroformaldehyde complex "49# "Equation "08##ð72AG"E#205Ł[

TeOs

L

L

NO

ClOs

L

L

NO

ClTe

(48) (49)L = Ph3P

(18)

TeCpLRh

I

I

CpLRhNaHTe

L = PMe3 (50)

(19)

2[98[3 SELENOKETONES "SELONES#\ R1C1Se

2[98[3[0 Simple Selones

As previously described for selenals\ early reports of the preparation of selenoketones "selones#by acid!promoted reaction of a ketone with hydrogen selenide are in fact incorrect[ Under theseconditions the presumed intermediate selone "40# was reduced further to the selenol\ which wasoxidized in air to the diselenide "41# upon work up "Scheme 12# ð46JCS688Ł[ These unsuccessfulattempts at the preparation of simple selones have been reviewed ðB!62MI 298!90Ł[

O

R R R R

HO SeH Se

R R

(51)

R R

SeHSe

R

R

Se

R

R

H+ –H2O H2Se+ H2Se

[O]

(52)

Se +

Scheme 23

The _rst preparation of a monomeric selone\ not stabilized by metal complexation or resonanceinteractions\ involved thermolysis of a phosphoranylidene hydrazone "42# in the presence of seleniumpowder "Scheme 13# ð64CC428Ł[ The required phosphoranylidene hydrazones are readily availableby treatment of a hydrazone with triphenylphosphine dibromide in the presence of a tertiary aminebase ð50CB1366Ł[ As well as the selone\ molecular nitrogen and triphenylphosphine selenide are alsoformed[ The method remains a general one for the preparation of sterically hindered stable selonesð65CC194\ 65JCS"P0#1968\ 65JPC0890\ 79JOC1789\ 70TL3452\ 71JOC2452Ł[ Less hindered ketones such asbenzophenone and camphor do not a}ord selones under these conditions[ Instead\ only thecorresponding diazo compound decomposition products and dimeric alkenes are obtainedð65JCS"P0#1968Ł[ These products can also predominate in more hindered cases if the reaction con!ditions are not carefully controlled[

The phosphoranylidene hydrazone reaction probably occurs via the reaction of an intermediatediazo compound "43# with a reactive form of selenium[ If the reaction temperature is too high\ diazocompound decomposition occurs[ If the selone cannot be readily removed from the reaction mixture\


NNH2 + Ph3PBr2

But

But

N

But

But N PPh3

Se +But

ButEt3N

N2 + Ph3P Se

(53)

Se (excess)

29–75%

Scheme 24

a cycloaddition reaction of the diazo compound with the selone can occur as the latter is formed\a}ording the alkene via a twofold extrusion reaction[ Attempts at preparation of selones via directreaction of diazo compounds with selenium were generally limited by this process "Scheme 14#ð74T3732Ł[

+ Se + N2

Scheme 25

N

N PPh3

N2

(54)

Se

N2

Se∆

Generally\ a more convenient method for the preparation of sterically hindered selones involvesthe reaction of the hydrazone with selenium"I# bromide in the presence of triethylamine "Scheme 15#ð73JOC078Ł[ A related alternative route uses the hydrazone dimagnesium salt with selenium"I#chloride ð72CC0318\ 77BCJ750Ł[ Both reactions presumably involve nitrogen extrusion from an inter!mediate N!selenonitrosimine "44#[ Again\ no selones could be obtained from unhindered ketones[

N

N Se

SeNNH2 68%+ Se2Br2

SeN

N2Et3N –N2

Scheme 26

(55)

Aryl selones such as "45# and "46# are less stable than hindered aliphatic selones[ They can beprepared using a modi_ed selenium"I# chloride route "Equation "19## ð81CL1178Ł[ The attemptedpreparation of selones from the hydrazone "47# failed\ a}ording the cyclic di! and triselenides "59#and "50#[ These are presumably formed via reactions of the intermediate selone "48# "Scheme 16#[

SePh PhOSePh PhSeH2NN NNH2Ph

(57)

Ph

(56)

+

33:14

+ Se2Cl2Bun

3N, PhH(20)

The reaction of fenchone with bistricyclohexyltin selenide "51# and boron trichloride is reportedto a}ord selenofenchone "53# in 89) yield[ It is believed that this reaction proceeds via a non!aggregated form of boron selenide "52# "Scheme 17# ð71JA2093Ł[ A comparison of the above methodsfor the preparation of stable sterically hindered selone has been compiled ð74T3732Ł and is sum!marized in Table 2 ð74T3732\ 77BCJ750Ł[

A useful method for the in situ generation of selones involves base!promoted elimination of HCNfrom selenocyanates[ This route proved convenient for preparation of an intermediate seleno!

282Selenoketones

H2NN NNH2PhPh Ph PhSeSe

+

Ph Ph

(60)

Se

Ph PhSeSe

(61)

Se2Cl2

(58)

Se2Cl2

Se

(59)

Se

Scheme 27

Table 2 Comparison of methods of preparation of sterically hindered selones[

Entry Selone Method Yield e

(%)

1abc

6558

2abc

758082

3ab

5370

4abc

546818

5

Se

But

But

ab

4073

6

Se

Se

Se

Se

Se

Se

Se

But

abcd

25762490

7 c 53

8 c 43

a Via phosphoranylidene hydrazone–selenium pyrolysis.b Via selenium(I) bromide–hydrazone.c Via selenium(I) chloride–hydrazone dimagnesium salt.d Via bis(tricyclohexyltin) selenide.e Isolated yields of purified products.

29–(75)


Se

O

(C6H11)3SnSe

Sn(C6H11)3

(62)

+ BCl3 [B2Se3]

(64)(63)

90%

Scheme 28

~uorenone "54# which could be trapped as its DielsÐAlder adduct "Scheme 18# ð76TL2776Ł[ Themethod has been extended to the preparation of a variety of selones containing electron!withdrawingsubstituents "56# "Table 3#[ The key selenocyanate intermediates "55# can be readily prepared viadisplacements on the corresponding halides "Scheme 29# ð77JA7568Ł[

SeCN Se

(65)

Se

98%

Et3N

Scheme 29

Table 3 Generation of selones "R1C1Se# via selenocyanates "55#[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry R0 R1 Yielda

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 CO1Et PO"OEt#1 521 CO1Et Ph 432 CO1Et Me 513 PhCO Me 344 Ph CN 845 PhSO1 Me 746 CO1Et CO1Et 547 Ph Ph 69*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Yields of isolated DielsÐAlder adducts[

X

R1 R2

SeCN

R1 R2

Se

R1 R2

Se

R1

R2

(66) (67)

Et3NKSeCN

Scheme 30

A number of other methods previously described for the generation of transient selenals can alsobe used for the preparation of selones[ Wittig reagents react with elemental selenium to a}ordtransient diarylselones "57# which readily dimerize to the 0\2!diselenacyclobutane "58# "Scheme 20#ð89AG"E#0956\ 80CL0942Ł[ The dimer is in equilibrium with the monomeric selone in solution[ Theintermediate selone can be trapped by dienes or reduced to the corresponding diselenide "Scheme 21#ð76TL5538Ł[ The selone also reacts with dimethyl acetylenedicarboxylate to a}ord the heterocyclicderivatives "69# and "60#[ The alkene generated by reaction of the selone with the Wittig reagent isalso observed "Scheme 22# ð81TL0222Ł[

Selenoketones can also be prepared by reactions of ketones with selenating agents[ Althoughbis"trimethylsilyl# selenide "07# was a useful reagent for selenating aldehydes "cf[ Scheme 00#\selenation failed in the case of ketones[ Bis"dimethylaluminum#selenide "61#\ however\ proved to bean e.cient reagent for the preparation of selones "Scheme 23# ð78TL1984Ł[ A variety of aryl andalkyl derivatives could be prepared using this method "Table 4#[

Hexa~uoroselenoacetone "64# can be prepared as an unstable deep purple oil via pyrolysis of the

284Selenoketones

Se

Se

Ph

Ph

Ph

PhSe

Ph

PhSe +Ph3PPPh3 + 2Se

Ph

Ph

(68) (69)

Scheme 31

Se

Ph

Ph

Se

Ph

Ph

Se

PhPh

SeSe

Ph

Ph

Ph

Ph

i, NaBH4

ii, O2

Scheme 32

Se

Ph

PhSe Ph3PPPh3

Ph

Ph PPh3 Ph

Ph

Ph

Ph Ph

Ph

Se

Ph

CO2Me

CO2Me

Sen

Se

Ph

MeO2CCO2Me

PhPh

Scheme 33

+

+

MeO2C CO2Me

(70) (71)

O SeSe

+ (Me2Al)2Setoluene

reflux 53%

(72)

Scheme 34

0\2!diselenetane "62# as well as by reaction of bis"per~uoroisopropyl# mercury "63# with diethyl!aluminum iodide "Scheme 24# ð80CB312Ł[ This selone can also be generated by reaction of hexa!~uoropropene "65# with selenium and caesium ~uoride\ and trapped by anthracene or other dienes"Scheme 25#[ The seloneÐanthracene adduct "66# is thermally unstable\ regenerating the selone in amild retrocyclization[ The resulting free selone can be trapped by other dienes "Scheme 26#[


Table 4 Generation of selones via selanation of ketones using bis"dimethylaluminum# selenide[

Entry Selone Yield a

(%)

1 77

2

Se

Se

Se

Se

Ph

Se

Ph TMS

Se

63

3 53

4 55

5 44

6 72

a Isolated yields of selone Diels–Alder adducts with cyclopentadiene.

Se

Se

F3C

F3C

CF3

CF3

(73)

+ HgF2

KF

DMF100 °C

Hg[SeCF(CF3)]2

(74)

Se

F3C

F3C

(75)

Et2AlI

∆

Scheme 35

(76)

+ Sen Se

F3C

F3C

F

F3C F

F

Se

CF3F3C

CsF

DMF

(77)

Scheme 36

2[98[3[1 Metal!stabilized Selones

Metal!stabilized selones can be prepared by many of the same methods used for the preparationof selenals[ Reaction of the chromium or tungsten carbene complexes "67# with phenylisocyanateor potassium selenocyanate a}ords the corresponding selone pentacarbonyl metal complexes "68#

286Selenoketones

Se

CF3F3C

Se

CF3F3C

(77)

Scheme 37

–

benzene reflux

Se

CF3

CF3

"Equation "10## ð72ZN"B#0254Ł[ Similar to the selenal metal complexes\ these complexes behave as ifthe selone moiety retains true selenocarbonyl character ð76CC448Ł[

(21)(CO)5M

R

(78)

+ KSeCN(CO)5MSe

R

(79)

–KCN

M = W, CrR = H, OMe, CF3, Me, Br, NMe2

Ph Ph

A number of stable metal complexes of selenium analogues of b!diketones have been prepared[Complexes such as "79# can be prepared in situ by reactions of b!diketones such as acetylacetonewith hydrogen selenide in the presence of metal ions "Equation "11## ð58AJC780Ł[ Related complexescan be prepared via displacement reactions on activated vinyl halides "Equation "12## ð63ZC177Ł orvia a selenation sequence using selenourea "Scheme 27# ð64ZC55Ł[ An uncomplexed b!diselone "71#has been prepared by ring opening of the selenopyrone "70#\ but exists primarily in its dienediselenolform "72# "Scheme 28# ð51G748Ł[

Se

SeO O

Se

Se

Ni

(80)

+ NiCO3

HCl

H2Se(22)

O

Se

Ph

O

Se

Ph

NiPh Ph

Cl

Ph Ph

CHO + NaHSe + Ni(OAc)2 (23)

O

Se

Ph

O

Se

Ph

M

Ph Ph

O Se

H

Ph Ph

Scheme 38

M2+

Ph

O

PhNH2

Se

H2NO

Ph

Se

Ph

NH2

HN

H2O+

Metal!promoted cleavage of the 0\1!diselenatene derivative "73# also a}ords the metal seleno!carbonyl complex "74# "Equation "13## ð56CC569\ 69IC0719Ł[ Spectroscopic studies indicate that thiscomplex may have signi_cant diselone character[


Se Se O

O

SeSeH SeH O

(83)(82)(81)

+ Na2SeH2O

Scheme 39

Se

Se SeM

Se

Se

Se

F3C

F3C

CF3

CF3F3C

F3C

(84) (85)

+ M(CO)x

M = Mo, Ni, W

(24)

2[98[3[2 Resonance!stabilized Selones

A number of resonance!stabilized selone derivatives\ which are in actuality amide and carbonatederivatives stabilized in a vinylogous manner\ have also been reported[ Selenoacridone "75# can beprepared by treating 8!chloroacridine with sodium hydrogen selenide "Equation "14## ð92JPR61Ł[

N

Cl

N

Se

H

+ NaCl+ NaHSe (25)

(86)

Substituted selenoacridones "76# can be prepared from the corresponding acridones by a similarsequence "Scheme 39# ð28CB0135Ł[ N!Substituted selenopyridones such as "77# can be prepared in asimilar manner "Scheme 30# ð93LA134Ł[

N

Cl

N

O

R R

+ POCl3

+

(87)

N

SeSO3H

R

+

N

Se

R

K2SeSO3, H+

+ [PO2Cl2]–

hydrolysis

Scheme 40

Selena!g!pyrone derivatives such as "78# can be prepared from the corresponding thiones by analkylationÐdisplacement sequence "Equation "15## ð46AC"R#0133\ 66CC066Ł[ Related compounds suchas "89# can also be prepared via halogenationÐselenation\ similar to the method used to prepareselenoacridines "Equation "16## ð60JCS"C#2076Ł[

288Selenoketones

NH

O

N

Cl

N

Cl

R

+ PCl5N

Se

+

RI

RI–

(88)

Scheme 41

X

S

RR X RR

SMe

X

Se

RR

+ I–

(89)X = O, S

MeI NaHSe(26)

S

O

RR S RR

Cl

K2SeO3

+(90)

R RPOCl3

Me2NCHO

R R

S

Se

RR

R R

(27)

The resonance!stabilized selone "80# can also be prepared via a similar displacement "Scheme 31#ð64CC248Ł[ The spectroscopic properties of this molecule\ described as a {{quasi!selenourea\|| indicatea strong p!conjugation interaction between the amino groups and the selenocarbonyl group throughthe cyclopropene ring[

R2N

R2N

Cl

R2N

R2N

NR2

R2N

R2N

Se–

NaHSe, EtOH, H2O

R2N

R2N

Se

+

ClO4–

+

R2N

R2N

Se–

ClO4–

NaHSe, EtOH, H2O

+

+

(91)

R = Pri

Scheme 42

An anionic resonance!stabilized selone "81# can also be prepared via a displacement sequence"Equation "17## ð65AG"E#693Ł[

O O

Ph Br

Ph Se

–O O

Ph Se–

O O

Ph Se–

–O O–

2+H2Se

pyridine

(92)

(28)

Finally\ the preparation of compounds "82# and "83#*formally containing a selone moiety*involvesthe thionation of a diselenacyclopentene "Equation "18##\ readily available via ring opening of theselenopyrone followed by oxidation "cf[ Scheme 28# ð51G748\ 53G37Ł[ These compounds are probablybetter envisioned as containing hypervalent selenium and sulfur\ stabilized by {{no!bond resonance||[


SeSe O

SeSe S SSe S

SSeSe SSSe

+

P2S5

(93) (94)

(29)

2[98[4 TELLUROKETONES "TELLONES#

A single report of telluroketone "tellone# preparation via acid!promoted addition of hydrogentelluride to a ketone has been published ð20CB429Ł[ This report is almost certainly incorrect in thatthe authors had also previously claimed that they had prepared selones via the analogous methodusing hydrogen selenide ð16CB713Ł[ As previously discussed "Section 2[98[3[0#\ this reaction doesnot give selones[ Unfortunately\ the actual products of the hydrogen telluride reaction have not yetbeen characterized[

Tellones can\ however\ be prepared via a telluration sequence using bis"dimethylaluminum# telluride"84#[ As expected\ the tellone "85# is generally unstable and spontaneously dimerizes "Scheme 32#ð78JA7638Ł[ Alternatively\ the intermediate tellone can be trapped by dienes in a DielsÐAldersequence[

O Te

(96)

Te

Te

Te

+ (Me2Al)2Te

(95)

dioxane

100 °C

28%

Scheme 43

The _rst stable tellone\ 0\0\2\2!tetramethylindanetellone "87#\ has been reported in the early 0889s[This compound can be prepared by thermolysis of the corresponding 0\2\3!telluradiazoline "86#"Scheme 33# ð82JA6908Ł[ The telluradiazoline "86# was prepared by a telluration sequence involvingthe N!telluronitrosoimine "88# as an intermediate "Scheme 34# ð82CL0936Ł[ This sequence is similarto that described for the preparation of selones "cf[ Scheme 15#[ The intermediate "88# can losetellurium to a}ord the diazo compound or extrude nitrogen to a}ord the tellone[ The tellone andthe diazo compound undergo a cycloaddition to a}ord the telluradiazoline[

NNH2

NN

TeTe

(97)

TeCl2, Et3N

5 °C, benzene

80 °C

(98)

Scheme 44

A stable metal complex of tellurobenzophenone "099# has been prepared by reaction of thecorresponding metal carbene complex with tellurocyanate "Equation "29## ð72JOM"141#C52Ł[ Similar

390Telluroketones

NN

Te

R

R R

RTe + R

R

N2

R

R

N

R

R NH2

N

R

R N Te

N2

R

R

Te

R

RTe

NN

R

R

TeCl2

–Te

–N2(99)

Scheme 45

to the related selenocarbonyl metal complexes\ these compounds retain tellurocarbonyl characterand react as would be expected for a free tellone ð75JOM"188#C6\ 77JOM"237#C0Ł[

(CO)5W (CO)5WTe+ [Te=C=N]–

(100)

(30)18%

Finally\ a bridged metal complex of telluroacetone "091# has been prepared by insertion ofdimethyldiazomethane into the tellurium complex "090# "Scheme 35# ð73CC575Ł[

•Al2Te3, HCl ••

MnOC O

CO

MnTe

Mn

OC CO OC CO

(101)

N2

–N2

•

Mn Te

COOCMn

COOC

•

(102)

Scheme 46


3.10Imines and Their N-SubstitutedDerivatives: NH, NR andN-HaloiminesGRAEME M. ROBERTSONGlaxo Research and Development, Stevenage, UK

2[09[0 IMINES 3932[09[0[0 General Methods for Imine Synthesis 393

2[09[1 N!H IMINES 3932[09[1[0 N!H Aldimines 3932[09[1[1 N!H Ketimines 394

2[09[2 N!CARBON!SUBSTITUTED IMINES 3942[09[2[0 N!Carbon!substituted Aldimines 3952[09[2[1 N!Carbon!substituted Ketimines 396

2[09[2[1[0 Formation of N!carbon!substituted ketimines via condensation reactions 3962[09[2[1[1 Formation of N!carbon!substituted ketimines via rearran`ement reactions 3962[09[2[1[2 Formation of N!carbon!substituted ketimines via oxidation or reduction reactions 3962[09[2[1[3 Formation of N!carbon!substituted ketimines via miscellaneous methods 397

2[09[2[2 Cyclic Imines 3982[09[2[3 a\b!Unsaturated Imines 300

2[09[2[3[0 Aryl aldimines 3002[09[2[3[1 Aryl ketimines 3012[09[2[3[2 a\b!Unsaturated ketimines 3022[09[2[3[3 Aza!0\2!dienes 302

2[09[2[4 Chiral Imines 3032[09[2[5 a! and b!Haloimines 3042[09[2[6 Acylimines 306

2[09[2[6[0 N!Acylimines 3062[09[2[6[1 a!Acylimines 306

2[09[2[7 Diimines 3062[09[2[8 C!Metal Derivatives of Imines 3072[09[2[09 a!Sulfenylimines 307

2[09[3 N!HALOIMINES 308

2[09[4 IMINIUM ION SALTS 308

2[09[4[0 Iminium Ions 3082[09[4[0[0 Iminium ion cyclizations 319

2[09[4[1 N!Acyliminium Ions 311

392

393 Imines and NH\ NR and N!Haloimines

2[09[0 IMINES

2[09[0[0 General Methods for Imine Synthesis

Imines and their derivatives are important synthetic intermediates[ They perform a signi_cantrole in functional group transformations\ carbonÐcarbon bond formation\ and ring construction[Their early importance as precursors to amines\ including highly substituted examples\ and toazaallyl anions ð62AG473\ 77TL650Ł has latterly been augmented by the developments in chiralinduction and iminium ion chemistry "Scheme 0#[

NR

NHR NR

–

NR

E

HN

( )n

NR

[E+]

[H] base

acidR = (CH2)nCH=CH2R = chiral auxiliary

Scheme 1

H

The literature on the synthesis\ properties\ and chemical reactions of imines "and azaallyl anions#up to 0868 has been reviewed previously ð68COC"1#274Ł[ Several other reviews are available "inaddition to those that cover enamine or imine anion chemistry# ð52CRV378\ B!69MI 209!90\ 71T0864\71T2252\ 72S406\ B!72MI 209!90\ 75T4046Ł[ The traditional method for the formation of ketimines bycondensation of a primary amine with a ketone is generally quite straightforward[ In contrast\ thecorresponding preparation of aldimines can be di.cult\ especially with relatively unhindered andthereby reactive aldehydes\ where further reaction including the formation of aminals can be aproblem[ However\ these aminals often undergo loss of one amine unit thermally "typically duringdistillation# to generate the imine ð47JCS1198Ł[

Iminations of aldehydes\ ketones\ and acid chlorides have been achieved using bis"dichloro!aluminum# phenylimide\ which in turn is prepared from ethylaluminum chloride and anilineð75JOC0737Ł[ This oxophilic iminating reagent is especially useful for the selective conversion of a\b!unsaturated ketones into anils\ with no detectable addition to the C1C linkage[

2[09[1 N!H IMINES

2[09[1[0 N!H Aldimines

The addition of ammonia to aldehydes is not a general procedure for the preparation of N!Haldimines since\ with the exception of diaryl aldimines\ they tend to be unstable and readilypolymerize[ N!H Aldimines may\ however\ be produced via acid! or base!catalyzed decompositionof oxaziridines bearing an a!hydrogen atom on the N!alkyl group ð74JCS"P0#1012Ł[ Unfortunatelythe reaction conditions employed generally prevent isolation of the free aldimine[ This can beovercome by the addition of 0\3!diazabicycloð1[1[1Łoctane "dabco# or 0\4!diazabicycloð3[2[9Łnon!4!ene "dbn# to solutions of the oxaziridine "0# allowing isolation\ or at least detection\ of the N!Haldimine\ depending on the nature of R2 "Equation "0## ð68TL2190Ł[

N

OR1

R2

R3HN R3 (1)

dabco

(1)

394N!Carbon!Substituted Imines

Aldehydes react under mild conditions with lithium aluminum amides "LiAl"NHR#3# to givealdimines in high yields with no polymerization ð82SC0572Ł[ Likewise\ reactions of ketones withlithium aluminum amides give the corresponding ketimines[ The lithium aluminum reagents can bereadily prepared from the desired amine and LiAlH3[

2[09[1[1 N!H Ketimines

N!H Ketimines are also not very common compounds\ and only the bis aryl variants are stable[However\ in contrast to N!H aldimines\ the direct synthesis of N!H ketimines from ketones andammonia can be e}ected\ but requires the use of an ammonium chloride!catalyzed reaction at 49bar pressure at 019>C ð77SC0490Ł[

An important route to N!unsubstituted imines is their preparation from carbonyl compoundsand their derivatives[ Thus\ in situ reduction of oximes to N!H imines is possible\ but the unstableproducts generally need to be trapped out with reagents such as Bu2P0SPh1 ð73CC226Ł or Ru2"CO#01

ð89CL524Ł or intramolecularly\ for example\ to give pyrroles ð73TL2696Ł[ The same reagents alsoreduce nitroalkanes to imines[

Nitriles can also serve as the starting point for the synthesis of N!H ketimines[ Thus\ the additionof Grignard reagents to nitriles can be stopped at the imine stage to give N!unsubstituted\ especiallydiaryl N!H\ ketimines ð50JOC3775Ł[ Yields can be improved by the use of copper"I# salts or by usingbenzene containing one equivalent of ether as the solvent ð79TL044Ł[ Sterically hindered N!Hketimines can also be prepared by copper"I#!catalyzed addition of the appropriate Grignard reagentsto either alkyl or aryl nitriles "Scheme 1# ð76JOC2890Ł[

Scheme 2

R1 CNR2MgCl, THF, CuBr

∆R1 R2

NMgCl

NH3 (dry)

R1 R2

NH

N!H Ketimines have also been prepared by routes not involving carbonyl derivatives[ Forexample\ in a related manner to N!H aldimines\ N!H ketimines "R0 or R1�aryl# can be preparedby the base!catalyzed decomposition of N!alkyloxaziridines "Equation "1## ð75JCS"P0#756Ł[ Alter!natively\ direct lithiation in the presence of phenanthrene as a hydrogen acceptor\ allows thepreparation of lithiated imines[ Alkylation of the resulting anions then leads to the synthesis ofhomologated products ð73S836Ł[

N

O

R1

R2R1 R2

NH(2)

dabco or ButOK

2[09[2 N!CARBON!SUBSTITUTED IMINES

The formation of N!substituted imines from primary amines and aldehydes or ketones is afundamental feature in the synthesis of a wide range of natural products ranging from nitrogenheterocycles to amino acids[

Simple condensation of primary amines to carbonyl compounds is an e}ective route toN!carbon!substituted imines ðB!69MI 209!90\ B!69MI 209!91Ł\ since in contrast to N!H!imines\ N!carbon!substituted imines are generally stable enough for isolation[ With simple R groups\ however\decomposition or polymerization can still be a problem\ especially for imines derived from benzyl!amine\ which decompose with evolution of the amine on standing ð36BSF605Ł[ Stability can beconferred by the presence by the delocalization e}ect provided by at least one aryl group on thenitrogen\ or the carbon[


The preparation of N!substituted imines becomes progressively more di.cult from aldehydes toketones "as the steric demands increase# and with aromatic\ rather than aliphatic amines "as thenucleophilicity of the amine decreases# ð52CRV378Ł[ Ketones react slower than aldehydes\ withhigher temperatures and longer reaction times often required[ Moreover\ the equilibrium must beshifted\ usually by the removal of water\ either azeotropically\ or with molecular sieves ð54JOC3497\60JOC0469Ł\ or with a catalyst prepared from molecular sieves\ silica gel\ and alumina ð61RTC594Ł[Lewis acids\ such as TiCl3 ð56JOC2135\ 69S030Ł\ ZnCl1 ð47JOC424Ł\ or AlCl2 ð74S568Ł\ are also suitablecatalysts for imine formation\ by increasing the polarization of the carbonyl moiety via complexationof the oxygen atom with the Lewis acid[

The conversion of ketones to imines is often used to e}ect ring closure ð76T4060Ł[ The Friedlanderquinoline synthesis ð71OR"17#26Ł is an example[ The use of unreactive carbonyl compounds and:orvolatile imines can also cause problems\ but these can be overcome by utilizing alumina as a basiccatalyst[ Supporting both reagents on alumina\ and reacting them together in the absence of solvent\allows the synthesis of a range of sensitive imines ð74S568Ł[

Alternatively\ a transiminating reagent\ such as benzophenone imine\ can be used to overcomeproblems associated with the instability of the amine component to the reaction conditions or foramines that readily self!condense ð71JOC1552Ł[ This approach allows the synthesis of Schi}|s basederivatives of a variety of amino acid esters in high yield "Equation "2##[ An alternative method forthe synthesis of Schi} bases is the reaction of N\N!bis"silyl#amines with carbonyl compoundscatalyzed by a zincÐcopper couple ð63S701Ł\ or TMS!tri~ate ð74CL0260Ł[ The TMS!tri~ate methodis particularly useful as it is e}ected at modest temperatures and so allows the use of volatile amines[

Ph

NH

Ph+ CO2R3

H2N

R1

R2

Ph

N

Ph

CO2R3

R1

R2

(3)

HCl

2[09[2[0 N!Carbon!substituted Aldimines

A general route to aldimines is provided by the addition of Grignard reagents\ homo! or hetero!cuprates to N!aryl\ N!alkyl\ and especially N!silylated formamidines "Equation "3## ð77S073Ł[

R2N

TMS

O

R1 NR2

(4)R1MgBr, THF, –80 °C to –20 °C

N!Substituted aldimines can be prepared via the hydrogenation of imidoyl chlorides usingdichlorobis"triphenylphosphine#palladium in the presence of triethylamine as acid scavenger"Scheme 2# ð74S856Ł[ This procedure permits the indirect synthesis of N!substituted aldiminesfrom secondary amides[

R1 NH

R2

O

R1 Cl

NR2

R1

N

Scheme 3

R2H2, PdCl2(PPh3)2

Et3N, C6H6, 120 °C

Remotely functionalized aldimines can be obtained from the Michael addition of enamino!stannanes to a\b!unsaturated esters and nitriles "Equation "4## ð79JOM"075#C8Ł[ Iminocyclopropanescan be prepared by the base!induced cyclization of a!bromoketimines via a 0\2!elimination of HBrð79LA0703Ł[

(5)

R2

R1N

SnBu3 R1N

CO2Me

R2

CO2Me+


2[09[2[1 N!Carbon!substituted Ketimines

2[09[2[1[0 Formation of N!carbon!substituted ketimines via condensation reactions

A wide range of methods are available for the formation of ketimines by condensation of anamine with a carbonyl derivative "see section 2[09[1#[ The e.ciency of the process is dependent notonly on the stability of the amine but also on steric crowding in the carbonyl derivative[ Thuscondensation of less hindered ketones can be catalyzed by both acids ð65JA2921Ł and basesð44USP1699570Ł or by the azeotropic removal of water ð66JOC266Ł[ With hindered ketones\ titaniumtetrachloride provides better results ð56JOC2135Ł[ Hindered ketones are also e.ciently convertedinto their imine counterparts under neutral conditions by using dibutyltin dichloride as the catalyst"Equation "5## ð71SC384Ł[

+R2

R1

O

X N

XR2

R1

NH2

(6)Bu2SnCl2, toluene, ∆

Further\ with dibutyltin dichloride as the catalyst\ the extent of racemization in chiral ketonesoccurs is not as marked as with other reagents[

The reaction of ""trimethylsilyl#methyl#iminotrophenylphosphorane\ prepared in situ from "tri!methylsilyl#methyl azide and triphenylphosphine\ with carbonyl compounds or heterocumulenes\provides a one!pot synthesis of the corresponding N!""trimethylsilyl#methyl#imines or ""trimethyl!silyl#methyl#!substituted heterocumulenes respectively\ which are versatile reagents for heterocyclicsynthesis ð73JOC1577Ł[

2[09[2[1[1 Formation of N!carbon!substituted ketimines via rearrangement reactions

Alkyl azides can be pyrolyzed to imines ðB!62MI 209!90Ł in a reaction analogous to the Curtiusrearrangement of acyl azides to isocyanates\ although the rearrangement of tertiary alkyl azidesmay involve free alkyl nitrene intermediates ðB!69MI 209!92Ł[ Cycloalkyl ðB!52MI 209!90Ł and arylð47CB01Ł azides likewise undergo ring expansion to give cyclic imines[ The Stiegliz rearrangementof trityl N!haloamines and hydroxylamines gives the corresponding N!aryl imines\ and similarlylead tetraacetate!induced rearrangement of tritylamines gives N!arylimines ð63JOC2812Ł[

Beckmann!type rearrangements of oxime sulfonates induced by organoaluminum reagents lead tothe formation of imines\ via nucleophilic attack of one of the alkyl groups from the organoaluminumreagent on an intermediate carbonium ion ð74AG"E#557Ł[ Alternatively\ treatment of oxime sulfonateswith Grignard reagents in nonpolar solvents such as benzene or toluene also produces iminesð71TL2284Ł which\ in turn\ can be further converted to a!alkyl! and a\a!dialkylamines[

2[09[2[1[2 Formation of N!carbon!substituted ketimines via oxidation or reduction reactions

"i# Oxidation reactions

Several methods have been reported for the oxidation of amines to imines ðB!69MI 209!90Ł[Direct methods include the treatment of amines with an Na1WO30H1O1 system\ or with t!butylhydroperoxide in the presence of catalytic amounts of dichlorotris"triphenylphosphine#rutheniumand 3A molecular sieves ð74CC502Ł\ or NiSO30K1S1O7 ð81CL712Ł[ The latter two methods have alsobeen applied to the synthesis of dihydroquinolines from tetrahydroquinolines[ Di!t!butyliminoxylin pentane likewise promotes the direct conversion of secondary\ and primary\ amines into thecorresponding imines ð74JOC4271Ł[

Alternatively\ amines can be oxidized indirectly to the corresponding imine via reaction ofpotassium superoxide with primary or secondary N!chloramines ð67JOC0356Ł[


"ii# Reduction reactions

In contrast to the synthesis of imines by oxidative procedures\ the reduction of higher oxidizedspecies to imines has not been as widely studied\ and only a limited number of methods are available[Thus nitrones are reduced to imines by treatment with sodium hydrogen telluride at pH 09Ð00ð74TL3592Ł[ Variation of the reaction pH changes the reducing power of this tellurium reagent^ thus atpH 5 complete reduction to the corresponding secondary amine occurs[ Tributylphosphinediphenyldisul_de reduces ketoximes and secondary aliphatic nitro compounds to the corresponding imines\under anhydrous conditions ð75JCS"P0#1132Ł[ The imine may subsequently be alkynated to give anenamide\ reduced to give an amine\ or captured by hydrogen cyanide to give an a!aminonitrile[

2[09[2[1[3 Formation of N!carbon!substituted ketimines via miscellaneous methods

The addition of N!diphenylmethylenebenzylamine to Schi} bases can be catalyzed by ammoniumsalts and leads to the formation of 0\1!diarylethane!0\1!diamine derivatives "Equation "6## ð73S0927Ł[These compounds can serve as percursors to azaallyl carbanions[

Ph Ph

N

Ph

Ar1 NAr2+ Ph N

NAr2

Ph HPh

Ar1

(7)PhCH2NEt3 Cl–

+

Primary amines add to triple bonds to give enamines that have a hydrogen on the nitrogen andtautomerize to the more stable imines ð54RCR558Ł[

Treatment of enamines with a nitrilium salt\ also gives imines ðB!77MI 209!90Ł[Imines can be prepared from active hydrogen compounds by the treatment with a nitroso

compound ðB!81MI 209!90Ł[Bis"dichloroaluminum# phenylimide\ prepared from ethylaluminum dichloride and aniline\ is

a highly selective reagent for the formation of N!substituted imines from carbonyl compoundsð75JOC0737Ł[ It is of particular use for ketimines bearing two or more aromatic groups and for thetransformation of a\b!unsaturated ketones into anils[ Palladium"9#!catalyzed additions of disilanesto isocyanides provide a convenient method for the preparation of N!substituted bis"silyl#imines"Equation "7## ð76TL0182Ł via a palladium"9#!mediated insertion of isocyanide into the siliconÐtinbond[

R3Si SiR3 R3Si N

SiR3

R1

+ R1 NC (8)Pd(PPh3)4, toluene, ∆

Tertiary alkyl ketimines can be prepared by the reaction between a tertiary alkyl isocyanide andt!butyllithium to give a tertiary lithium aldimine "1#[ This lithium imine acts as an acyl anionequivalent and undergoes alkylation with aryl\ vinyl\ and alkynic halides\ to give the correspondingimines\ which upon hydrolysis yield the parent ketones "Scheme 3# ð71JOC41Ł[

ButNC

But

N But

LiRIButLi, –40 °C

(2)

But

N But

R

R But

O

Scheme 4

H3O+

Imines can be obtained by the palladium!catalyzed reaction of ternary systems comprising bromo!benzene\ t!butyl isocyanide\ and an organotin compound "Equation "8## ð75CL0086Ł[


(9)Ph N

But

RPhBr + ButNC + Bu3SnR

Pd(PPh3)4PhBr + ButNC + Bu3SnR

Pd(PPh3)4

Ketimines can be prepared by the reaction of imidoyl chlorides with a variety of organotincompounds in the presence of a catalytic amount of a palladium complex\ such as dichloro!bis"triphenylphosphine#palladium at 019>C in xylene ð75BCJ566Ł[

An improved synthesis of trialkylketimines by the reaction of a!cyanoenamines with MeLi hasbeen published ð71OPP102Ł[

Cyanimides have been obtained by treatment of cyanamides with lead tetraacetate ð75S0944Ł[Since cyanimides can be hydrolyzed to carbonyl compounds\ the method can also be used to preparealdehydes and ketones from primary amines "Scheme 4#[

N

CN

HN

CN

O NH

O O

Pb(OAc)2N

CN

H

Scheme 5

iii

i or iiiv

i, BrCN, Et2O, –30 °C to 25 °C; ii, EtOH, AcOH, NaOCN, ∆; MsCl, pyridine, 0 °C to 25 °C;iii, c-C6H12, Pb(OAc)4; iv, benzene, Al2O3

Reagents:

A wide range of N!"cyanomethyl#! and N!"a!cyanobenzyl#imines have been prepared ð75BCJ0798Ł^they undergo tautomerism to the N!protonated azomethine ylides which\ in turn\ undergo cyclo!addition reactions with alkenic dipolarophiles[

Van Braun!type dechloroalkylations of heterocyclic phosgeniminium salts\ by thermolysis at039>C\ provide a direct method for the formation of v!chloroalkylisocyanide dichlorides and N!trichloromethyl chloroformamidines from cyclic amines "Equation "09## ð78SC1714Ł[

N

Cl Cl

+

ClN Cl

Cl(10)

140 °C, Kugelrohr apparatus

a\a!Dichloro!b!iminocarbonyl compounds a}ord a\a!dichloroketimines upon treatment withvarious reagents "e[g[ NaOMe\ KOBut\ KCN\ K1CO2# via regiospeci_c fragmentation ð74TL1698Ł[Regiospeci_c alkylations and dialkylations of a!haloketimines have also been demonstratedð74AG"E#770Ł[

2[09[2[2 Cyclic Imines

The methods available for the synthesis of cyclic imines\ which feature as intermediates of nitrogencontaining natural products\ are not as developed as those for their acyclic counterparts\ but haveseen strong development the 0879s and 0889s[

Imines\ and in particular cyclic imines and azadienes\ may be prepared from N\N!disubstitutedhydroxylamines upon treatment with titanium trichloride under anhydrous conditions ð74TL3522Ł[In contrast\ upon treatment with aqueous titanium trichloride further reduction occurs to give thecorresponding amine[

Stereoselective thermally induced cyclizations of N!ðbis"trimethylsilyl#methylŁ!0!aza!0\2!dienes


give 4!trimethylsilyl!D1!pyrrolidines[ Subsequent removal of the TMS!group and concomitant enam!ineÐimine isomerization leads to the corresponding D0!pyrrolidine "Scheme 5# ð80CC413Ł[

Ph

Ph

N

TMS

TMS N

Ph

TMS

Ph

TMSN

Ph Ph

TMS

Scheme 6

240 °C TMS-Cl, MeOH

Acyl nitronates are readily obtained from ketones and nitroalkenes\ and they serve as usefulintermediates for the synthesis of cyclic imines and amines "Scheme 6# ð89CL128Ł[

R1

NOAc

O

R2

O–

+NH

R1 R2

NR1 R2NH

R2R1

HO

H2, 5% Rh on Al2O3, MeOH

H2, PtO2, AcOH

pyridinium p-toluenesulfonate

CHCl3, 60 °C

Scheme 7

Copper"I#!catalyzed formation of nitrogen!centered radicals from oxaziradines bearing an alkenylside chain\ results in stereoselective formation of 4!substituted!D0!pyrrolines "Scheme 7# ð81JA4355Ł[

Scheme 8

Ar N O

Ph

Ar

N•Ph

Cu–O

N

Ar

Ph

[Cu(PPh3)Cl]4, THF, ∆

The intramolecular ð1¦1Ł!cycloaddition of monocyclopentadienyltitanium"IV# metal imidocomplexes with alkynes provides a novel synthesis of D0!pyrrolines and tetrahydropyridine deriva!tives "Scheme 8# ð81JA4348Ł[ Subsequent transformations then allow access to indolizidine alkaloids\in appropriate cases[

CpTiCl3, MeLi, THFNH2

RN

R

Ti Cl

Cp

N Ti

R

Cl

CpN

R

Scheme 9

Similarly\ intramolecular aminopalladations of alkynylamines lead to intermediate alky!enylpalladium complexes\ which upon hydrolysis isomerize to the thermodynamically stable cyclicimines[ Thus\ treatment of 2!alkynylamines with catalytic PdCl1"MeCN#1 gives exclusively D0!pyrrolines\ while 4!alkynylamines a}ord 1\2\3\4!tetrahydropyridines ð80JOC4701Ł[

1!Cyclopropyl substituted piperidine imines can be obtained by 0\2!dipolar cycloaddition reac!


tions involving cyclopropylidine azides "Scheme 09# ð89TL4430Ł[ Acid!catalyzed rearrangement andsubsequent reduction then provides indolizidines[

Scheme 10

N3NCbz

Ph

NCbz

Ph

NN

H

H2N

PPh3, THF

Cyclic imines ranging from D0!pyrrolines to 0!aza!0!cycloheptenes can also be prepared via theboric acid mediated decarboxylation of the corresponding exocyclic b!enaminoester "Equation "00##ð76TL1242Ł[

NH

R

EtO2C

( )n

N

R (11)( )n

H3BO3, 180 °C

Cyclic imines\ like their acyclic counterparts ð67JOC0356Ł\ can be generated from the parent aminevia conversion into an N!chloramine precursor with t!butyl hypochlorite\ followed by treatmentwith potassium superoxide in ether ð79JOC0404Ł[ The imine can then be used in a subsequent reactionwith organolithium reagents to give alkylated amines regioselectively "Scheme 00#[

NH

( )n

N

( )n

N

( )n

Cl

ButOCl KO2-crown ether

Scheme 11

Speci_c baseÐsolvent combinations that promote kinetic deprotonation can control the orien!tation of 0\1!eliminations from cyclic imines to give the thermodynamically disfavored isomerð68TL1098Ł[ Thus N!chloro!1!ethylpyrrolidine gives substantial proportions of 4!ethyl!0!pyrroline"2# "Equation "01##[

N

( )n

N

( )n

N

( )n

Et EtEt

Cl

+base

NaOMe, MeOHButOK, ButOHButOK, hexane

96:473:2758:42

(12)

(3)

Primary aminoalkenes of the type H1C1CH"CH1#nNH1 "n�2 or 3# can be cyclized to pyrrolinesand piperidines under the conditions of the Wacker oxidation ð72JOC5766Ł[ Aminoalkanes withsecondary or tertiary amino groups yield cyclic enamines and aminoalkenes\ respectively\ under thesame conditions[

2[09[2[3 a\b!Unsaturated Imines

2[09[2[3[0 Aryl aldimines

Aryl imines can be prepared by a range of methods\ such as thermal elimination of HNO fromN!nitrosoamines ð79BSB136Ł\ from aldehydes by reaction with iminophosphoranes ð79JPC225Ł\ fromoxaziridines by ring!opening with lithium azide ð79JOC0378Ł\ and from nitrosobenzenes by reactionwith active methyl groups ð79BCJ2585Ł[

Isocyanides can be converted into aromatic aldimines by treatment with an iron complex followedby photolysis in benzene ð76JA4936Ł[ The iodotrichlorosilane!induced reactions of aromatic alde!


hydes with acrylonitrile provide a direct method for the synthesis of unsaturated iminoaldehydes"Equation "02## ð80TL4310Ł[

(13)ArCHO + CN Ar NCHOISiCl3, ClCH2CH2Cl

Two reports of the N!alkylation of Schi} bases by a\b!unsaturated esters and nitriles havebeen published ð68CB0186\ 68TL2342Ł[ a\b!Unsaturated imines are also formed from thiazolidine!3!carboxylic acid esters upon treatment with Ag1CO2 in aprotic solvents "Equation "03## ð68CB096Ł[

(14)NH

S

RO2C

Ar

CO2R

N

Ar

Ag2CO3

a!Aryl!N!phenylnitrones can be reduced to N!benzylideneanilines by treatment withdiiodotriphenylphosphorane\ which is formed in situ from triphenyl phosphine and iodineð78NKK0637Ł[

Primary benzylamines are e.ciently oxidized by excess Fremy|s salt in 4) sodium carbonate atroom temperature to give the imines "3#\ which undergo self!condensation with unreacted amine togive the corresponding N!carbon substituted imines "4# "Scheme 01# ð71T0458Ł[

Ar NH2 Ar NH2

Ar NH2 Ar N Ar+

(4)(5)

Fremy's salt

5% Na2CO3

H2NHN Ar

Ar

Scheme 12

2[09[2[3[1 Aryl ketimines

0\1!Additions of aryl Grignards to aryl thiobenzamides lead to bisarylimines in good yield\ whichcan be isolated as their hydrochloride salts "Equation "04## ð68BCJ2358Ł[

Ar NH2

S+ Ar1MgBr

Ar Ar1

NH•HCl(15)

A methoxy!group at the ortho!position of both benzophenones and anilines is unfavorable forcatalytic condensations leading to imines[ This problem can now be partially overcome by theuse of the aryliminomagnesium reagents "5#\ which react with benzophenones to produce thecorresponding imines in high yields "Scheme 02# ð79BCJ170Ł[

EtMgBr Ph2CO ArN Ph

Ph

Scheme 13

ArNH2 ArN(MgBr)2

(6)

Cobalt Schi} base complexes catalyze the selective oxidations of secondary anilines with t!butylhydroperoxide to give the corresponding imines ð80CL0982Ł via a single electron transfer "SET#dehydrogenation mechanism[

Arylimines can be obtained by the addition of N!silylated amides to the corresponding arylÐ


lithium compound "Scheme 03# ð75TL496Ł[ Imine formation is strongly dependent on the basicityof the lithium reagent\ and fails for alkylÐlithium analogues[

R1 NTMS

O

R2LiO N

TMS

R1

R2

Ar

Ar R1

NR2

Scheme 14

ArLi

In the absence of a base\ N!alkyl!O!"arylsulfonyl#hydroxylamines undergo cationic carbon!to!nitrogen rearrangements to give imines ð74JOC0748Ł[ In the presence of base\ N!alkyl!O!"aryl!sulfonyl#hydroxylamines give imines via a bimolecular elimination process[

2[09[2[3[2 a\b!Unsaturated ketimines

Palladium"9#!catalysts\ in particular\ tetrakis"triphenylphosphine#palladium have been found tocatalyze the 2!aza!Cope rearrangements of N!allylenamines to d\o!unsaturated imines in the presenceof TFA as a cocatalyst ð74TL4452Ł[

Secondary enaminones "6# react with benzoyl or pivaloyl chloride to give iminovinyl carboxylates"7# ð75CB0984Ł[ In contrast they react with acetyl chloride to give the corresponding O\N!diacetylcompounds "8# "Scheme 04#[

NR1

O R2

O

NR1

O

HN

R1

OAc

Ac

Scheme 15

(8) (7) (9)

R2COCl, C5H5N, THF

R2 = Ph, But

AcCl, C5H5N, THF

1!Methyl!0!aza!0!cycloalkenes react with aldehydes and ketones to yield 1!hydroxyamines\ whichare readily dehydrated by dicyclohexylcarbodiimide "dcc#\ in the presence of catalytic CuCl\ toprovide the corresponding alkenylimine ð80SL805Ł[

The synthesis of ynimines\ the imines of a\b!alkynic ketones\ can be achieved by condensationreactions between the aliphatic imines and the desired a\b!alkynic ketone at 14>C and 099 torr for19 h ð72JOC0814Ł[ The syntheses and photochemical reactivities of a\b!unsaturated imines have beenreported ð75JCR"S#35Ł[

2[09[2[3[3 Aza!0\2!dienes

The extensive use of azadienes in DielsÐAlder reactions has been reviewed with particular emphasison mono! and bisaza systems ð72T1758Ł[

"i# 0!Aza!0\2!butadienes

Advances in the 0879s in the chemistry of imines with an emphasis on 0!aza!0\2!butadienes andtheir cycloaddition reactions have been reviewed ð76H"15#666Ł[

The increasing use of azabutadiene systems in synthesis has led to renewed e}orts directed towardstheir preparation[ 0!Aza!0\2!dienes can be prepared by the mercury"II# chloride!mediated additionof amines to 0\2!enynes in basic wet THF "THF ]H1O\ 3 ] 0# ð74CC0264Ł[


"ii# 1!Aza!0\2!butadienes

1!Aza!0\2!butadienes have been widely studied as a result of their importance in DielsÐAlderreactions ð72T1758\ 74TL36Ł[ Several routes are available for their synthesis including caesium ~uoride!induced protiodesilylation of N!"0!trimethylsilylallyl#imines ð74TL36Ł[ Unactivated 1!aza!0\2!buta!dienes\ which can be prepared by an imine dimerization reaction e}ected with TFA in THFð74CB2541Ł\ undergo cycloaddition reactions with dialkyl azodicarboxylates and heterocumulenesð75CC0068Ł[

1!Aza!0\2!butadienes can be prepared by base!catalyzed isomerization of the correspondingunconjugated analogues "09# "Scheme 05#\ and have been used in a three!step N!heterocyclicannulation procedure for the synthesis of 2\3!dihydro!1!quinolines ð72JOC4237Ł based in the thermalelectrocyclization of 0!aryl!1!azabuta!0\2!dienes[

Ar O

R

Ar N

R

Ar N

RN

R

Scheme 16

Ar

(10)

600 °C

0!Aryl!1!aza!0\2!dienes can be prepared by rhodium"0#!catalyzed isomerization of N!allyliminesð72S0998Ł\ and 0!amino!1!azabutadienes are formed by the acid decomposition of 4!amino!0!vinyl!3\4!dihydro!0H!0\1\2!triazoles ð72BCJ530Ł[

b!Hydroxy!g!imino esters are of interest as azadiene precursors and they can be prepared byreaction of a!iminoketones with lithium ester enolates ð74TL3392Ł[

Functionalized 1!aza!0\2!dienes have been prepared ð75JCS"P0#1910Ł via the alkynation of carb!anions derived from N!"diphenylmethyl#arylmethanimines using aroyl chlorides to a}ord a widerange of the 1!azadienes\ in which the imino group is conjugated with an enol ester "Equation "05##[The site selectivity for electrophilic attack on the intermediate azaallyl anion is a function of thesubstituents on the carbanion and on the hardness of the electrophile[

Ar1 N Ph

Ph

N Ph

PhAr1

Ar2CO2

Ar2

(16) i, NaH–HMPA, THF

ii, Ar2COCl, THF, 0 °C

Several substituted 0!thia!2!azabutadienes have been prepared and their reactions with ketenesa}ord 5H!0\2!thiazine!5!ones ð75PS"16#216Ł[

Wittig reactions of N!acrylic phospha!l4!azenes with aldehydes provide a useful entry to 2!ethoxy!carbonyl 1!aza!0\2!dienes "Equation "06## ð77TL3752Ł[

(17)R1

CO2Et

NPPh3

R1CO2Et

N

R2

R2CHO, CHCl3, 60 °C

2[09[2[4 Chiral Imines

The use of chiral imines in asymmetric Michael reactions is an important area\ and has beenreviewed ð81TA348Ł[ The reaction involves an imineÐsecondary enamine tautomerization to generatethe nucleophilic reactant "Scheme 06#[

EWG

N

R*

N

R*

HN

R*

EWG

Scheme 17


The reaction can be highly regio! and stereoselective\ and is a powerful alternative to the Storkenamine reaction[ For example\ Michael!type alkylations of chiral imines have facilitated theenantioselective synthesis of molecules containing quarternary centers ð74JA162Ł[ Although generallyused for the synthesis of functionalized ketones\ the process can be arrested at the imine stage togive similarly functionalized chiral imines[

The other major areas for chiral imines\ is as intermediates for the preparation of chiral aminesand ketones[ For example\ alkylation of the "R#!camphor imine of t!butylglycinate "00# a}ords theimines "01# for which de|s of 64Ð099) were observed when R�allyl "Equation "07## ð75CJC615Ł[The greater diasteroselectivities in the cases of allylic imines "with de of about 49)# probably resultsfrom an interaction between the p!systems of the allylating agent and the imine\ so that alkylationoccurs from the pro!R!face\ for steric reasons[

N

COBut

N

COBut

R(18)

i, lithium diisopropylamide, THF

ii, HMPA, RX

(11) (12)

Chiral camphor derived imines have also been used for the enantioselective synthesis of "R#!a!substituted primary benzyl amines\ via alkylation of the 09!substituted "¦#!camphor derivative "02#ð89SC04Ł[

N

Ph

O

N

H

OH

(13)

Asymmetric syntheses of both "R#! and "S#!a!substituted benzylamines\ are possible via thealkylation of chiral pinanone ketimines "Scheme 07# ð78SC0312Ł[ An important feature of thisprocedure is that the diastereoselectivity of the alkylation is independent of the alkylating agentused[

H2N

R

BuLi, hexane, –78 °C

RX, –78 °C

*

Scheme 18

OH N OH N

R*

H2NOH, AcOH, EtOH

Some examples of work in the preparation of chiral ketones include] "i# the use of chiral iminesprepared from cyclohexane and methoxyamines derived from D!camphor derivatives which readilyundergo metallation and alkylation to give 1!alkylcyclohexanones of high enantiomeric puritiesð75CPB0949Ł\ and "ii# ~uoroacetone imines of cyclohexylamines which undergo regioselective depro!tonation with BunLi\ followed by stereoselective alkylation "Scheme 08# ð77JOC1880Ł and subsequenthydrolysis to give 1!~uoro!1!alkylcyclohexanones[

2[09[2[5 a! and b!Haloimines

The reactivity of a!halogenated imino compounds has been reviewed ð79OPP38Ł[ The synthesis\reactivity\ and properties of a!haloimines and the applications of a!halogenated imino compounds\


O

F N

F

OMe

Ph

NOMe

Ph

R

F

Scheme 19

PhCH2CH(NH2)CH2OMe

CCl4, molecular sieves, 0 °C

BuLi, THF, –90 °C

RI, THF, –90 °C

in particular in the synthesis of cyclopropanimines\ have also been surveyed ðB!77MI 209!91Ł[ Other\more speci_c\ reviews covering their synthesis ð68OPP004Ł and reactivity ð79OPP38Ł are also available[

There are two main strategies for the synthesis of a!haloimines[ The _rst strategy was thecondensation of an a!halogenated carbonyl compound with a primary amine under suitable reactionconditions\ similar to the usual synthesis of imines from carbonyl compounds and primary amines[The second approach involves the halogenation of imines[ The _rst method gives rise to a!haloiminesonly in special cases[ A range of side reactions is commonly encountered\ including] nucleophilica!substitution\ elimination of hydrogen halide\ haloform!type reactions\ Favorskii rearrangementsð75JOC2728Ł\ and rearrangements via intermediate epoxides[ In many cases the initially formeda!haloimino compounds undergo further transformations under the given reaction conditions[ Thuscyclopropylidene amines can be isolated from the treatment of a!haloimines with base underFavorskii!type conditions ð79LA0703\ 75JOC2728Ł[

The second approach to a!haloimines\ via halogenation of imines\ can also be problematical\owing to formation of unstable immonium!type compounds during these reactions prior to aqueousworkup[ Aldimimes are selectively a!monochlorinated by a sequence of reactions involvinga!trimethylsilylation of preformed 0!azaenolates\ a!chlorination using NCS\ and desilylation inMeOH ð80CC637Ł[ a!Chloroketimines can be prepared from ketones via simple chlorination ð71S32Ł\and they undergo facile conversions into cyclopropylimines upon treatment with base "Scheme 19#ð77CC714Ł[

R1

OR1

N

Cl

R2

R1

N

Cl

R2

R3

i, chlorination

ii, R2NH2, TiCl4

LDA, THF, 0 °C

R3X

NaOMe, MeOH

Scheme 20

LiAlH4, Et2O

R1

R3

NR2

R1

R3

OMeR2HN

R1

R3

NH R2

a!Bromoaldimines\ a!chloroaldimines\ and aromatic a!bromoketimines have also been used asprecursors to 0\1!diamines and 1!imidazolidinone derivatives via conversion into the correspondinga!azido imines ð82S0902Ł[ The a!haloaldimines were prepared by reaction of the required aldiminewith the appropriate N!halosuccinimide\ whilst the a!bromoketimines were synthesized via thecondensation of an aromatic a!bromo ketone with the desired amine in the presence of stoichiometricamounts of TiCl3[

b!Chloroimines\ the parent compounds of a comparatively rare class of halogenated iminocompounds\ can be prepared by condensation of b!chloroaldehydes with primary amines in thepresence of MgSO3 or TiCl3 ð75S081Ł\ as for the synthesis of a!haloimines ð71S32Ł[ They are alsoavailable by a sequence involving the condensation of the appropriate b!chloroketone with a primaryamine ð82S78Ł[ b!Chloroimines serve as useful precursors for functionalized azetidines ð82S78Łvia organometallic reagent addition across the imino bond of the b!chloroimine\ followed byintramolecular substitution[


2[09[2[6 Acylimines

2[09[2[6[0 N!Acylimines

N!Acylations of alkylimidate hydrochlorides to a}ord alkyl N!acylimidates\ have beenaccomplished with triethylamine ð74CB2978Ł[ N!Acylimines can be prepared from methyl trichloro!pyruvate\ by reaction with amides\ followed by chlorination and treatment of the resultinga!chloroacylamine with triethylamine ð74S066Ł[ The utilization of N!acylimines and especiallyN!acyl and N!thioacylimines\ as the heterodiene in ð3¦1Łcycloaddition reactions has been reviewedð78CR0414Ł[

2[09[2[6[1 a!Acylimines

a!Bromo esters and ketones can both be converted into their respective a!acylimines[ Thusconversion of a!bromo esters to the corresponding azide\ and treatment with lithium ethoxide inethanol gives a quantitative yield of the target a!imino ester o}ering an improved method for thepreparation of such compounds "Scheme 10# ð79JOC3841Ł[

Scheme 21

ROEt

Br

O

ROEt

N3

O

ROEt

NH

O

NaN3, DMF LiOEt

The preparation of a! or b!ketimines is often problematical[ The conversion of a!bromoketonesinto sulfonamidoketones\ followed by base!induced elimination of tri~uoromethanesul_nic acidresults in the formation of N!phenyl!a!ketimines ð79JOC050Ł[

a!Ketimines were the unexpected products of the reaction between a\a?!dibromoketones andprimary amines ð71TL678Ł[ Enaminosilanes\ the nitrogen analogues of silyl enol ethers\ undergoselective a!alkylation with simple acid chlorides in the presence of potassium ~uoride and a crownether as catalyst to give b!ketimines "Equation "08## ð71TL2962Ł[

R1R3

N

R2

Ph TMS

R1

NPh

R4

O

R4 Cl

O+

KF, crown ether(19)

R2 R3

a!Iminonitriles\ which are useful as intermediates for heterocyclic synthesis\ have classically beenprepared from nitrones and sodium or potassium cyanide ð67S781Ł[ Improved yields of b!ketiminescan be obtained by the alternative reaction of aldonitrones with cyanotrimethylsilane in the presenceof Et2N ð74SC224Ł[

Reactions of phenyl glyoxal with primary amines have allowed the synthesis of some monoiminesð73JCR"S#033Ł[

a!Ketodicarboxylic acid chloride imine chlorides\ which readily undergo cyclization to N!hetero!cycles\ can be prepared by a!addition of dicarboxylic acid chlorides to isocyanides "Equation "19##ð75LA021Ł[

R NC O NR

Cl Cl

O(COCl)2

(20)

2[09[2[7 Diimines

0\1!Diimines "together with a!iminoketones and a!aminopropionamidines# can be prepared byoxidative alkyl and arylaminomercurations of prop!1!ynyl alcohols ð72JCS"P0#0982Ł[

0\1! and 0\2!Diimines can be prepared directly from the corresponding dicarbonyl compounds


via titanium tetrachloride!catalyzed condensation reactions with the appropriate amine "Scheme11# ð76OPP070Ł[

R1R2

O

O

R1R2

N

N

R3

R3

R1 R2

O O

R1 R2

N NR3 R3

R3NH2, C6H6, TiCl4, 25 °C

R3NH2, C6H6, TiCl4, 25 °C

Scheme 22

The preparations and reactions of mono! and diimines of quinones have been reviewed ðB!69MI209!93Ł[

In principle\ the condensation reaction of 0\1!diones with amines should be a straightforwardreaction\ but condensations with branched amines can be problematical[ However\ branched amineswith secondary or tertiary a!carbons can be condensed with glyoxal to give chiral 0\1!diimines"diazadienes# by using formic acid as a catalyst and an excess of a drying agent in a nonpolar solventð73CB583Ł[

Symmetrical 0\3!diimines can be prepared by dehydrodimerization of a!bromoimines using LDAð75TL0696Ł via a single electron transfer reaction[

2[09[2[8 C!Metal Derivatives of Imines

C!Metallated derivatives of imines are the nitrogen analogues of acylmetals and correspondinglythey serve as acyl anion equivalents[ These metallated aldimines are versatile nucleophiles and theyreact with various substrates to give aldehydes\ ketones\ a!keto acids\ or a! or b!hydroxy ketones[Their use has been limited by the sparsity of available methods for their preparation ð58JA6667Ł[Lithium aldimines were the _rst reported variants ð58JA6667Ł[ Isocyanides that lack any a!hydrogensreact with alkyllithium compounds ð89SL134Ł\ as well as with Grignard reagents to give lithium ormagnesium aldimines ð63JOC599\ 67JOC620\ 70JOC4394Ł[

Copper"I# aldimines generated from the corresponding lithio species "prepared by addition of analkyllithium to an isocyanide# undergo conjugative addition to a\b!unsaturated carbonyl compoundsto give 3!iminoketones ð73TL2980Ł[ N!Substituted organo"silyliminomethyl#stannanes "stannyl ald!imines# ð75CC879\ 76JA6777\ 77TL244Ł serve as synthetic equivalents to organosilylcarbonyl anions andcarbonyl dianions[ They can be prepared by the palladium"9#!catalyzed insertion of nitriles into thesiliconÐtin bond of organosilylstannanes ð75CC879Ł[ Zinc aldimines can be prepared similarly viathe a!addition of organozinc reagents to isocyanides ð77JOC3047Ł[

2[09[2[09 a!Sulfenylimines

a!Sulfenylations of simple imines can be achieved via nucleophilic substitution of their a!halocounterparts with the desired sodium thiolate in re~uxing methanol\ or by the condensation ofa!"alkylthio#aldehydes with a primary amine "Scheme 12# ð72S521Ł[

Scheme 23

R2N R1

ClR3

R2O

SR4

R3

R2N R1

SR4

R3NaSR4, MeOH, ∆ R1NH2, Et2O, TiCl4

a!Sulfenylations of more specialized imines\ such as N!activated a\a!dichloroimines ð67ZOR497Ł\0!chloromethyl!2\3!dihydroisoquinoloine ð65JAP6521458Ł\ and 2!halo!0!pyrrolines ð70LA0962Ł\ havealso been reported[

308Iminium Ion Salts

2[09[3 N!HALOIMINES

N!Haloimines are a relatively rare class of compounds\ being both light sensitive and potentiallyunstable ð51JA1226Ł[ They can be prepared via the addition of per~uoroalkyl nitriles and bromineto activated caesium ~uoride "Equation "10## ð73JOC0356Ł[

R CN F N

R

Br

Br2, CsF(21)

2[09[4 IMINIUM ION SALTS

2[09[4[0 Iminium Ions

Iminium ions have long been important functional groups for the synthesis of heterocyclic ringsystems[ Milder methods of iminium preparation\ e.cient modern strategies such as their use intandem reaction procedures "e[g[\ aza!Cope Mannich cyclizations#\ and counter!nucleophile reac!tions demonstrate their increasing value as synthetic tools ð78MI 209!90Ł[

Iminium salts can commonly be prepared from the reaction of amines with aldehydes and ketones[In addition\ iminium ions can be generated from enamines and imines by reaction with electrophilessuch as H¦ ð44CI"L#0928Ł[ Other sp2!nitrogen!containing derivatives\ such as a!amino alcoholsð78JA260Ł\ a!amino ethers ð76S713Ł\ e[g[ oxazolidines ð74HCA634Ł\ a!amino sul_des\ e[g[ thiazolidinesð77IJC"B#021Ł\ and a!amino nitriles ð77TL5430Ł\ are e.cient sources of iminium ions[

Iminium ions can be prepared from noncarbonyl sources via oxidative functionalization of tertiaryamines and subsequent b!elimination ð60JCS"C#2959Ł\ such as in the Polonovski reaction ð65BSF0111Ł\and via decarbonylation of a!amino acids ð70JOC3803\ 75S624Ł[

The chemical\ spectroscopic\ and structural properties of iminium salts have been comprehensivelyreviewed ðB!65MI 209!90Ł[

The syntheses of iminium salts\ including halomethyleneiminium salts\ alkoxymethyleneiniumsalts alkylmercaptomethyleneiminium salts\ amidinium salts\ and related compounds have beenreviewed ð80COS"2#374Ł[ Alkyldiphenylsulfonium salts are useful reagents for the O!alkylation ofamides and ureas\ and in particular for the formation of alkoxymethyleneiminium salts ð72T322Ł[

Arylsilanes are e}ective as an activating group for ipso!attack in the PictetÐSpengler synthesis of7!methoxytetrahydroisoquinolines ð77TL5604Ł^ in the absence of the silyl group only the 5!methoxyisomer is formed[

t!Butoxycarbonyl deprotection of amines using TFA can be coupled with in situ trapping ofcarbonyl groups to provide cyclic iminium ions\ such as "03# "Equation "11## ð78TL3428Ł[

HN

NO

BocHN

Ph

O

Z

HN

N

N

Ph

O

Z

(22)H+

CF3CO2–

TFA, CH2Cl2

(14)

Intramolecular 0\2!dipolar cycloaddition of azides with v!chloroalkenes gives the thermally labiletriazolines "04#[ In situ rearrangement and intramolecular N!alkylation then gives the bicyclic 0!pyrroline iminium ion "05# "Scheme 13# ð89TL6460Ł[

Imination of N!alkyl pyridinium and quinolinium salts can be achieved via oxidation of theappropriate substrates with potassium permanganate in liquid ammonia ð73TL2652Ł[ Quinone imin!ium dyes are of particular use in copying and other printing processes and can be preparedstraightforwardly from aromatic amines using DMSO as the methylating agent\ with a Lewis acidsuch as TiCl3 as a catalyst ð75T3406Ł[

2!"a!Dialkylaminoarylidene#!0!alkylthiotriazenes\ which are readily obtained from thioamidesalts\ a}ord diamidinium iodides when treated with methyl iodide "Equation "12## ð75JCS"P0#508Ł[


Cl

N3

OO

N NN

O

O

Cl

(15)

C6H6, ∆

(16)

N

O

O

Cl– +N

O

O

HOH

Scheme 24

ii, ButNH2, KHMDS

iii, BH3•THF, NaOAc, MeOH, H2O2

R1 NN

NSMe

NR22 R2

2N N NR22

R1 R1

(23)

+MeI, Me2CO

The photochemistry of iminium salts and related heteroaromatic systems has been reviewedð72T2734Ł[ The SET!induced photospirocyclizations of allylsilane!terminated iminium ions\ such as"06#\ have been utilized by Mariano and his co!workers as a versatile route to spirocyclic aminesincluding the harringtonine alkaloids "Scheme 14# ð78TL3074Ł[

N

Ph

TMS

ArButCO2

N

ArButCO2

Ph O

ON

ButCO2

Scheme 25

hν, MeCN, NaHCO3

+

(17)

The possibility of forming C!vinylazomethine ylides via a photoinitiated\ sequential electrontransfer desilylation pathway has been examined ð72JA5059Ł[

Pyrylium ions react with ammonia or primary amines to give pyridinium ions ð71RCR358Ł[

2[09[4[0[0 Iminium ion cyclizations

An excellent review of the use of iminium ions in heterocyclic synthesis has been presented byOverman and Ricca ð80COS"1#0996Ł[

Iminium ion cyclizations have been of importance in two major areas] "i# the iminium ionÐvinylsilane cyclizations\ and "ii# the tandem cationic aza!Cope rearrangementÐMannich cyclizationprotocol[

Iminium ionÐvinylsilane cyclizations are particularly useful for the construction of cyclic aminenatural products\ such as the pumiliotoxins[ For example\ liberation of the incipient iminium ionin the a!aminonitrile "07# followed by reaction with the in situ vinyl silane provides the allo!pumiliotoxin A ring system ð77TL5430\ 80COS"1#0996Ł[

TMS

OH

OBn

N

NC

H

(18)


An elegant and focused method for iminium ion cyclizations of this type is the antarafacialaddition of an internal iminium ion and an external nucleophile to an alkyne\ via an intermediatedelocalized cation "08# "Scheme 15# ð77TL890Ł[ This method of nucleophile promoted iminium ioncyclization allows the facile conversion of amines into cyclic amines with a b!exocyclic double bondof de_ned geometry ð77JA501Ł[ Iminium ion vinyl silane cyclizations can also be induced with Lewisacid catalysts such as TiCl3 as in the synthesis of the piperidine "19# "Scheme 16# ð89JOC0975Ł[Reverse addition of the a!aminonitrile to TiCl3 in CH1Cl1 is critical to achieve a successful cyclization[

OH

NHH

N

+

OHH

(19)

CSA, (HCHO)n, NaI, H2O, 100 °C

N

OHH

N

OHH

I i, BuLi, Et2O, –78 °C; MeOH

ii, Li, NH3, THF, –78 °C

Scheme 26

N

TMS

Ph

R

CN

N

R

Ph

NH

R

Scheme 27

(20)

TiCl4, CH2Cl2 Pd/C, H2, MeOH

Iminium ions can be conveniently generated from a!methoxy amines in a Lewis acid catalyzedprocedure[ The required a!methoxy amines are readily generated electrochemically via the oxidationof the parent amine to provide a chemoselective entry to functionalized substrates for iminium ioncyclization ð82JA0323Ł[ This method has been utilized in a synthesis of the angiotensin!convertingenzyme inhibitors "−#!A47254A and "2#!A47254B "Scheme 17#[

i, Anodic oxidationii, TiCl4N

OOH

O

OH

OH

O

N

OOMe

O

OMe

O

Cl

N

OOMe

O

OMe

O

( )n

Scheme 28

( )n

( )n


The in situ generation of iminium ions for use in tandem reaction sequences\ such as the cationicaza!Cope "1!azonia!ð2\2Ł!sigmatropic# rearrangement of iminium salts "Scheme 18# was _rst reportedin a ring expansionÐpyrrolidine annulation reaction of cyclopentane!derived amino alcoholsð72JOC2282Ł[ This tandem cationic aza!Cope rearrangementÐMannich cyclization procedure hassince been applied to the synthesis of a range of alkaloids\ including Aspidosperma ð72JOC1574Ł\Melodinus ð78JOC0125Ł\ and Amaryllidaceae ð78TL536Ł alkaloids[

HOAr

NH

R1

HOAr

N

R1

R2+

HOAr

N

R1

R2+

N

OAr

R2

R1

Scheme 29

R2CHO, H+

An improved version of Grieco|s method for the formation of 3!hydroxypiperidenes by theiminium ion cyclization of homoallylic amines\ has been used to prepare the N!methyl!D!asparticacid "NMDA# antagonist cis!3!"phosphonoxy#!1!piperidine carboxylic acid ð80JOC3973Ł[

Iminium ion cyclizations have also been used in the _eld of chiral induction through the formationof intermediate chiral oxazolidines[ The required heterocycles can either be formed via in situiminium ion formation from a carbonyl amine condensation ð77T1346Ł\ or via photoinduced oxi!dation of a preprepared amine ð77TL3042Ł[ Chiral oxazolidines have been applied to a number oftargets\ for example\ tetrahydroisoquinoline "10# "Scheme 29# ð77TL5838Ł[

MeO

MeO CHO

BrMeO

MeON Ph

HO

H2NCH(Ph)CH2OH

AcOH, EtOH

Et3N, CH2Cl2, –78 °C

MeO

MeON

O

Ph

MeO

MeO

Scheme 30

Br–

NH

+

i, MeMgI, THF, Et2O, –78 °C

ii, H2, Pd/C, acidic EtOH

(21)

2[09[4[1 N!Acyliminium Ions

The syntheses\ properties\ and utilization of N!acyliminium ions in heterocyclic synthesis havebeen reviewed ð80COS"2#633Ł[ Like their iminium ion counterparts\ N!acyliminium ion cyclizationshave been utilized in a number of areas\ for example\ in the synthesis of alkaloids such as thepentacycle\ gelsemine ð77JOC2771\ 77TL2670Ł\ and the Aspidosperma alkaloids "Scheme 20# ð89T3938Ł[Silicon!assisted N!acyliminium ion cyclizations have also been investigated ð78JA1477Ł[

0!Alkoxy!1!azaallenium salts "11# are prepared by the reaction of N!methyleneamides with tri!alkyloxonium salts "Scheme 21# ð75CB746Ł^ protonation of the amides "12# occurs exclusively atnitrogen to give N!acyliminium salts[

Secondary amine perchlorates react with aldehydes and ketones to give iminium salts ð52JOC2910Ł[


BF3•OEt2, CH2Cl2

LiOBut, ButOH, THF, 5 °C

N OR

NH

O

O N

NH

OR

Ac

O

O

H

N

N

OR

Ac

O

H

TMS

N

N

OR

Ac

O

H

N

NH

Scheme 31

CO2Me

+

N

R1

R2 R3

OR4+ N

R2

R1

O

R3

N

Ph

O

R

H

Scheme 32

+

CF3SO3–

R43O+ SbCl6– TFA

(22) (23)


3.11Imines and their N-SubstitutedDerivatives: Oximes and theirO-R Substituted AnaloguesGRAEME M. ROBERTSONGlaxo Research and Development, Stevenage, UK

2[00[0 OXIMES AND THEIR DERIVATIVES 314

2[00[0[0 Oximes of Aldehydes and Ketones 3142[00[0[0[0 Preparations of oximes from carbonyl compounds 3142[00[0[0[1 Preparations of oximes from noncarbonyl compounds 3152[00[0[0[2 Miscellaneous methods for the preparation of oximes 3162[00[0[0[3 a\b!Unsaturated oximes 3182[00[0[0[4 Cyclic oximes 329

2[00[0[1 O!Carbon!substituted Oximes 3292[00[0[2 Nitrones and Related Derivatives 320

2[00[0[2[0 Acyclic nitrones 3202[00[0[2[1 Cyclic nitrones 3232[00[0[2[2 Miscellaneous nitrone derivatives 324

2[00[0[3 O!Chalcoèn!substituted Oximes 3242[00[0[4 O!Arsenic!substituted Oximes 3242[00[0[5 O!Silicon!substituted Oximes 325

2[00[1 N!HETEROATOM ANALOGUES OF OXIMES 325

2[00[1[0 Sulfur Analoùes 3252[00[1[0[0 Sulfenimines 3252[00[1[0[1 Sul_nimines 3262[00[1[0[2 Sulfonimines 326

2[00[1[1 Phosphorus Analoùes 3282[00[1[2 Nitroèn Analoùes 3282[00[1[3 N!Silicon!substituted Imines 328

2[00[0 OXIMES AND THEIR DERIVATIVES

2[00[0[0 Oximes of Aldehydes and Ketones

Oximes are important functional groups in organic chemistry\ but in particular they feature asprotecting groups for carbonyl groups and as intermediates in the Beckmann rearrangementð77OR"24#0\ B!78MI 200!90Ł[ Unlike imines the geometric isomers of oximes are isolable and themeasurement of syn! and anti!oximes by chemical and especially NMR methods has been reviewedð63MI 200!90Ł[

2[00[0[0[0 Preparations of oximes from carbonyl compounds

Oximes are customarily prepared from the corresponding carbonyl compound\ and the prep!aration of oximes by the addition of hydroxylamine to aldehydes or ketones has been reviewed

314

315 Oximes and their O!R Substituted Analo`ues

ðB!61MI 200!90Ł[ Derivatives of hydroxylamine\ e[g[\ NH1OSO2H and HON"SO2Na#1\ have also beenused[

For hindered ketones\ such as hexamethylacetone\ high pressures ð48JA1040Ł or prolonged reactiontimes may be necessary[ It has also been shown ð48JA362\ 53MI 200!90Ł that the rates of formation ofoximes are at a maximum when the acidity of the mixture is about pH3[

Ketones can also be converted into their oximes by a trans!oximation reaction[ Other oximessuch as ethyl a!"isopropylidene#aminooxylpropionate ð54JOC0296\ 62OSC"4#0920Ł\ and aldehydes orketones can be converted into oximes using acetone oxime in acetic acid ð78JPR769Ł[

2[00[0[0[1 Preparations of oximes from noncarbonyl compounds

Oximes may be prepared from noncarbonyl compounds via redox reactions of other N0Ospecies[ Thus the reduction of nitroalkenes is a useful method for the preparation of oximes\ and awide range of reagents "typically transition metal!based catalysts#\ and conditions have beendeveloped[ Some of the methods are quite general\ whereas others such as reductions with zinc inacetic acid ð33JA241Ł\ or Na1SnO1 ð74TL5902Ł are restricted to the synthesis of ketoximes[

a\b!Unsaturated nitroalkenes are readily reduced to aldoximes in high yield by tin"II# chloride atroom temperature ð77SC582Ł[ Ketoximes can be formed similarly by the reduction of a\b!unsaturatednitroalkenes with Na1SnO1 "produced in situ from aqueous SnCl1 and aqueous NaOH# ð74TL5902Ł[However\ these conditions are not suitable for the preparation of aldoximes[ Corresponding reac!tions carried out under acidic ð59CB21Ł or neutral ð74CL132Ł conditions result in the formation ofa!substituted oxime derivatives[ Thus SnCl1 in the presence of an alcohol or thiol gives high yieldsof the corresponding a!alkoxy! and a!alkylthiooximes\ respectively ð74CL132Ł[ The latter compoundscan also be prepared by metallation of saturated oximes with lithium diisopropylamide\ followedby reactions of the resulting O\C!dianions with diphenyl disul_de ð74OPP072Ł[

a\b!Unsaturated nitroalkenes are also readily converted into ketoximes\ by reduction with chro!mium"II# chloride ð74SC0214Ł[ Unfortunately the corresponding reductions of a!unsubstitutednitroalkenes to aldoximes are accompanied by signi_cant polymerization[ a\b!Unsaturated nitro!alkenes are reduced to the corresponding oximes by sodium hypophosphite in the presence ofpalladium ð75SC80Ł whereas a\b!unsaturated nitroalkanes are readily reduced to the correspondingoximes via palladium!assisted transfer hydrogenation with ammonium formate ð89SC1342Ł[ a\b!Unsaturated nitroalkanes can also be reduced to oximes with leadÐacetic acid in DMF ð89SL366Ł[

Reductions of nitroalkenes with hydride reagents can be capricious\ leading to over!reduction andto mixtures of products ð74JOC022Ł[ However\ zinc borohydride reduces a!substituted conjugatednitroalkenes to the corresponding a\b!unsaturated oximes ð80TL2468Ł\ although nona!substitutedanalogues undergo 0\3!reduction to the corresponding nitroalkanes[

Electroreductions of nitroalkenes are also possible using an aqueous perchloric acidÐdichloro!methaneÐdioxaneÐlead electrode system followed by a hydroxylamine hydrochlorideÐsodium acet!ate workup to yield mixtures of ketoximes and ketones ð72CL596Ł\ or ketoximes and ketalsð72JOC1092Ł depending on the conditions used[

Examples of conjugate additions to a\b!unsaturated nitro compounds are rare[ However\ theconjugate addition of lithium organocuprates has been observed in the reactions of both 0!"3!chlorophenyl#!1!nitropropene ð64TL2480Ł and 2b!acetoxy!5!nitrocholest!4!ene ð72CC49Ł[

Aliphatic nitro compounds that contain an a!hydrogen can be reduced to oximes with a range ofreagents\ such as zinc dust in AcOH ð28JA2083Ł\ Co0CuII salts in alkanediamines ð62JOC2185Ł\CrCl1 ð69JCS"C#0071\ 63S0Ł\ and "for a!nitro sulfones# NaNO1 ð63S38Ł[ Tin"II# complexes preparedby treatment of SnCl1 or Sn"SR#1 with appropriate amounts of RSH and Et2N reduce primary andsecondary aliphatic nitro compounds to oximes ð89CL524Ł[ Secondary nitro compounds are alsoconverted into oximes by reaction with KH and TMS!TMS or MeS!TMS in THF or 0\3!dioxane"Equation "0## ð89T6302Ł[ Primary nitro compounds are converted into the corresponding thio!hydroximates under these conditions[ Secondary nitroalkanes are deoxygenated to the cor!responding ketoximes\ under mild and neutral conditions\ by treatment with iodotrimethylsilaneand hexamethyldisilazane ð72JOC1655Ł[ In contrast\ primary nitroalkanes are converted into nitriles\and tertiary nitroalkanes give the corresponding iodoalkanes via cleavage of the carbonÐnitrogenbond[

R1

R2

NO2

R1

R2

NOH

KH, (TMS)2S, THF, ∆(1)

316Oximes

Methods available for the direct conversion of aliphatic nitro compounds into oximes in thepresence of acid!sensitive groups\ or other reducible functionalities\ are relatively rare[ The bestconditions for such systems is reduction in carbon disul_de\ in the presence of triethylamineð76T440\ 89S222Ł[ Alternatively\ nitro compounds can be converted into oximes photochemically byirradiation in acetone in the presence of Et2N "Equation "1## ð78S195Ł[ a!Nitroketones can also beconverted into the corresponding oxime\ by irradiation in 1!propanol ð62BCJ2087Ł[ Primary aliphaticamines that lack an a!hydrogen can be oxidized to oximes under acidic conditions\ via an inter!mediate nitroso compound ð59CB021Ł[

(2)R1 R2

NO2

R1 R2

NOH

hν, Et3N, acetone

Homologated oximes can be obtained in good yields from nitro compounds after activationwith N\N!dimethylchloromethyleniminium chloride followed by treatment with a Grignard reagent"Scheme 0# ð72CL0426Ł[ Alternatively\ homologated ketoximes can be prepared via carbonÐcarbonbond formation by regioselective attack of Grignard reagents at the a!position of aci!nitro com!pounds activated by Vilsmeier|s salt in the presence of copper"I# iodide as a catalyst ð72CL0426Ł[Since aci!nitro compounds are available by the treatment of nitro compounds with n!butyllithium\this method provides an indirect route for the conversion of nitro compounds into homologatedketoximes[

R1 NO2

BuLi, THF R1 NO–

O– Li+

DMF, (COCl)2, CH2Cl2

R1 NO N

Me

Me

+

Scheme 1

+ Cl– R1 N

R2

CuI, R2MgX, THF

OH

2[00[0[0[2 Miscellaneous methods for the preparation of oximes

Metallations of oximes\ and in particular aldoximes\ have been the subject of several studies\ andthe resulting anions can be alkylated in high yield ð73TL152Ł[ Anions generated from trimethylsilylethers of methyl ketoximes undergo rearrangement with 0\3!migration of the silyl moiety^ thissequence is reversed in a thermal 0\3!migration of silicon from carbon to oxygen ð73TL2382Ł[

Nontertiary carbon atoms that are activated by an electron!withdrawing group can be nitrosatedto provide oximes ðB!77MI 200!90Ł[ The initially formed C!nitroso compound is not stable andisomerizes rapidly to give the more stable imine[

The formation of an oxime is a classical means of derivatizing a carbonyl compound[ Thistransformation can also be applied to a!ketocarboxylate systems\ and an example is found inthe synthesis of a!alkoximinocarboxylic acids from a!keto!thiolic acid esters and alkoxyaminesð73JAN421Ł[ Alkylnitriles can be converted into the corresponding a!"tosyloxyimino#alkylnitriles bynitrosation with freshly distilled nitrosyl chloride in chloroform\ and subsequent O!tosylationð72OPP30Ł[

Quinone monooximes can be prepared from phenols by photolysis of equimolar amounts of thephenol and N!nitrosodimethylamine in dioxane ð74JA2227Ł[ This procedure involves a dual protonand energy transfer process utilizing the enhanced acidity of single!state phenols to cause photo!dissociation of the N!nitrosodimethylamine[

The di}erent methods for the synthesis of a!hydroxylaminooximes\ their properties and their usein heterocyclic synthesis\ have been reviewed ð75S693Ł[ a!Hydroxylaminooximes have a number ofdistinctive properties associated with the vicinal reactive groups[ They have been utilized in thesynthesis of four!\ _ve!\ and six!membered heterocyclic compounds\ with a special emphasis onN!oxide analogues and are also important as metal chelators[ Chiral a!hydroxyoximes are availablein high optical purity via resolution using "0R\ 1R#!"−#!0\1!cyclohexanediamine as the resolving


agent ð80CL652Ł[ a\b!Unsaturated carbonyl compounds are converted directly into the cor!responding a!hydroimino carbonyl compounds upon treatment with butyl nitrite and phenylsilanein the presence of a catalytic amount of N\N?!bis"1!ethoxycarbonyl!2!oxobutylidene#ethylenediaminatocobalt"II# complex "eobe# "Equation "2## ð80BCJ1837Ł[

(3)R

O

R

O NOH

Co(eobe)2, PhSiH3, BuONO, THF

The synthesis of aldohydroximino lactones via oxidations of sugar oximes have been reportedð74HCA1143Ł[ The oxidations were e}ected by manganese dioxide\ or by mercury"II# acetate andoxygen in the presence of cuprous chlorideÐpyridine[

Oximes have been generated by electrocyclic ring!opening reactions involving four!memberedcyclic nitrones "N!hydroxy!0\1!dihydroazetes# following treatment with potassium t!butoxide"Scheme 1# ð75RTC092Ł[

NR1 O–

R2R3

CONEt2

NR1 O–

R2R3

CONEt2

CONEt2

NOHR1

R2

R3

R3

NOHR1

R2

CONEt2

K+

+

KOBut

Scheme 2

NH4Cl (aq.)

+

In the steroid series\ 5!nitro!alkene derivatives have been shown to undergo facile reactions withammonia\ methanol\ and zinc to a}ord exclusively the oximes of the corresponding 5!keto!steroidsð73IJC"B#790Ł[

Cyclic ketones can be cleaved by treatment with NOCl and an alcohol in liquid SO1 to givev!oximinocarboxylic acids "Equation "3## ð48JA4140Ł[

O CO2Et

N

OH

(4)HCl

NOCl, EtOH, SO2

C!Alkylations or arylations of aldoximes have not been widely reported[ The only examples ofboth alkylation ð75S352Ł and arylation ð43JCS0186Ł involve homolytic reaction of free C!radicals[Thus aldoximes are C!arylated e.ciently by decomposition of arenediazonium salts ð75S352Ł\ andaldoximes are converted into ketoximes using a mixture of a peroxy ester and a cycloalkane or etheras the C!alkylating agent ð75S352Ł[ Monosubstituted ketene O!alkyl!O?!silylacetals\ unlike theirdisubstituted analogues\ react with nitric oxide or isoamyl nitrite in the presence of TiCl3\ to givea!ketoxime esters "Equation "4## ð77S794Ł[ This method permits the introduction of a nitrogensubstituent at the a!carbon of the parent carboxylic ester[ a!Ketoxime esters can also be preparedfrom electron!de_cient nitroalkenes via formation of cyclic nitronic esters intermediates followedby their fragmentation by a catalytic amount of base "Equation "5## ð77BCJ350Ł[

C5H11ONO, TiCl4, CH2Cl2R1O

R2

O-TMS R1 CO2R2

NOH

(5)

ON

R1

Ar

R2O O–

CO2Me

+

R1 CO2Me

NOH

Ar

(6)NaOMe, THF

318Oximes

Nitronate salts "RCHNO1Na# act as precursors of hydroxynitrilium ion equivalents\ and reactwith aromatic compounds under acidic conditions to give the corresponding oximes via protonatednitronic acids ð78TL4652Ł[

The a!methyl groups of oximes can be functionalized regiospeci_cally via a cyclopalladationreaction with sodium tetrachloropalladate to form the dimeric organopalladium species "0# ð74CC015\74T588Ł[ A variety of b!functionalized products can then be prepared via subsequent func!tionalization of the C0H bond "Scheme 2#[ For 1!disubstituted cyclohexanone oximes\ A"0\1# straindominates and subsequent reactions lead to the selective functionalization of the smaller 1!substituent[

R1

R2R3

NHO

R1

NHO

Pd

Cl

R2 R3R1

NHO

Pd

Cl

R2 R3

PPh3

R1

NHO

Pd

Cl

R2 R3

py

R1

NHO

OAc

R2 R3R1

NHO

Scheme 3

Cl

R2 R3

Na2PdCl4, NaOAc, EtOH

2

(1)

PPh3

pyridine

i, Ac2O, pyridine ii, Pb(OAc)4iii, NaBH4

i, Pb(OAc)4, AcOH

ii, NaBH4, 1M NaOH

i, Cl2, CCl4

ii, NaCNBH3

The initial product of the addition of NOCl to alkenes is a b!chloro nitroso compound\ and\ ifthe carbon bearing the nitroso group also has a hydrogen atom\ isomerization occurs to give a!halooximes ð57RCR432Ł[

Procedures for the synthesis of 0\2!dioximes have been reviewed ð80OPP482Ł[

2[00[0[0[3 a\b!Unsaturated oximes

Substituted styrenes are converted regiospeci_cally into ketoximes through reaction with ethylnitrite in the presence of a cobalt complex and BH3

− ion "Equation "6## ð77JOC3786Ł[ The reactionproceeds via the formation of an alkylcobalt intermediate and subsequent reaction with ethyl nitrite[Catalytic nitrosations of styrene derivatives could become a useful method for the synthesis ofoximes following the report that the catalyst ðCo"DMGH#1"py#ClŁ promotes the regioselectivehydronitrosation of styrene to give acetophenone oxime ð73CC178Ł[ Nitronate salts\ from nitro!methane or nitroethane\ react with aromatic compounds in acidic media to yield aromatic oximesð80BSF629Ł[ Reductive condensations of trichloromethylarenes with hydroxylamines in pyridine alsoprovide a route to aryl oximes "Equation "7## ð80T336Ł[

RR

NOH

(7)EtONO, ClCo(DH2)py, Et4NBH4, C6H6

CCl3N

OH

(8)NH2OH, py, ∆

1\2!Dioximinopiperazines are formed from the additions of 0\1!diamines to dichloroglyoxime inmethanol ð74H"49#4012Ł[


Allylic nitro compounds are converted into allylic oximes using CS1 under solidÐliquid phase!transfer conditions with K1CO2 as the base "Equation "8## ð89S222Ł[ This method complements therelated procedure of Barton et al[ for the reduction of aliphatic nitro compounds to oximes in CS1

with Et2N as the base ð76T440Ł[

R NO2 R NOH (9)

CS2, K2CO3, PhCH2NEt3Cl

H2O, CH2Cl2

"E#!1!Hydroxyimino!1!arylacetonitriles\ which are useful as synthetic blocks in peptide protectinggroup chemistry\ can be synthesized from styrenes via cycloaddition reactions to 3!azido!2!aryl!furazan!1!oxides\ followed by stereoselective photolysis in EtOH:CH1Cl1 "Scheme 3# ð89BCJ0732Ł[

Ar

NO

N

Ar N3

–O

Ar

NC N

OH

Scheme 4

+NaNO2, NaN3

18-crown-6, AcOH

hν, EtOH, CH2Cl2

2[00[0[0[4 Cyclic oximes

Relatively hindered a!chloronitroso compounds\ such as "1#\ can undergo fragmentation followedby ring closure in an overall sequence which leads to a ring expansion and the formation of cyclicoximes "Scheme 4# ð75RTC11Ł[

ClN

O Cl

NHO

N

OH

Scheme 5

(2)

Me3Al, n-C6H14, –80 °C

H2O

Me3Al, n-C6H14, –80 °C

H2O

2[00[0[1 O!Carbon!substituted Oximes

Oximes can be smoothly alkylated using alkyl halides or sulfates[ N!Alkylation is a possible sidereaction\ leading to a nitrone ðB!77MI 200!90Ł[ The relative yields of oxime ether versus nitronedepend on the nature of the reagent used\ the con_guration of the oxime\ and on the reactionconditions ðB!72MI 200!90Ł[ For example\ anti!benzaldoximes give nitrones\ while the syn!isomerslead to oxime ethers ð56JOC150Ł[ The syntheses of the four isomers of benzylideneacetone oxime O!methyl ether is possible via direct or sensitized irradiation of the "E\E#!isomer or the "Z\E#!isomerand subsequent equilibration ð75JCS"P0#0580Ł[

Alkylations of pyridine aldoximes with alkyl and benzyl halides\ under phase!transfer conditionsin a benzeneÐ09) aqueous NaOH system\ proceed regiospeci_cally to give O!alkylated oxime ethersð78SC2018Ł[ Alternatively\ alkali metal alkoxides in the corresponding alcohols ð65MI 200!90Ł\ orsodium hydride in DMF ð77LA0980Ł\ can be used to generate the necessary anion[

Oximes can be converted into their O!"0!butoxyethyl#oximes analogues by O!alkylation withbutyl vinyl ether catalyzed by either Lewis acids\ such as ZnCl1\ or with mild protic acids such asp!TSA "para!toluene sulfonic acid# ð74ZOR655Ł[ a!Chloro nitroso compounds react with ethercomplexes of trialkylaluminum compounds to give oxime ethers via a radical reaction ð75RTC050Ł[

O!Aryloximes can be prepared from arenetricarbonyl chromium"9# complexes followed by reac!tion under phase!transfer conditions "KOH\ tetraoctylammonium bromide# with oximes and sub!sequent decomplexation with iodine ð74CC306Ł[

O!Methyl aldoximes can be prepared from the corresponding carboxylic acid via hydrogenationof N!methoxyimidoyl halides ð80S649\ 81JOC2134Ł\ or by the one!pot reaction of the carboxylic acidwith methoxyamine and Ph2P0CBr3[ As O!methyl aldoximes can be converted into aldehydes or

320Oximes

ketones by deoximation with paraformaldehyde and Amberlyst!04 in aqueous acetone ð82S452Ł\this procedure not only protects the carbonyl functionality\ but also provides a mild route for theconversion of carboxylic acids into aldehydes[

O!Allyl ethers have been developed as an acid! and base!stable protecting group for oximesð76TL3446Ł[ O!Oxime alkylation is selective in the presence of hydroxyl and amino groups\ whilstpalladium!catalyzed deprotection using triethylammonium formate as the reducing agent is straight!forward even in the presence of acid! or base!sensitive functional groups "Scheme 5#[

allyl bromide, KOH, DMF, 0 °C to 40 °C

Pd(OAc)2, PPh3, HCO2HNEt3, EtOH (aq.), ∆R1 R2

NOH

R1 R2

NO

Scheme 6

Oximes can be prepared directly from carbonyl compounds via a Peterson!type reaction with thebissilyl derivative "2# ð76S720Ł\ proceeding via an intermediate adduct which can be quencheddirectly to the parent oxime\ or trapped with a range of electrophiles to give O!substituted oximederivatives "Scheme 6#[

R1 R2

O

R1 R2

NO– K+

R1 R2

NOE

Scheme 7

TMS-(TMS-O)N– K+ (3), THF, –78 °C to 25 °C ECl, –78 °C

O!Alkyloximes are deprotonated regiospeci_cally by n!butyllithium to give the correspondingsyn!a!lithium species\ which then undergo regiospeci_c carbonÐcarbon and carbonÐhalogen bond!forming reactions leading to syn!functionalized oximes ð78IJ076Ł[

Oxime esters are important as chemoselective acylating reagents\ particularly for bifunctionalsubstrates such as amino alcohols ð80S602Ł[ They can be prepared from the parent oxime eitherchemically ð80S602Ł\ or using lipases biocatalysts ð82S61Ł\ via reaction with vinyl esters or di!t!butylcarbonate to give O!acyloximes and O!"t!butoxycarbonyl#oximes\ respectively[

2[00[0[2 Nitrones and Related Derivatives

2[00[0[2[0 Acyclic nitrones

Nitrones are extremely versatile synthetic intermediates ð74OPP12Ł\ and they are of particularimportance as 0\2!dipoles in cycloaddition reactions with multiple bond systems leading to theproduction of a wide variety of _ve!membered heterocyclic ring systems[ A range of reviews isavailable covering this area ð64S491\ B73!MI 200!90\ 75MI 200!90\ 77OR"24#0\ 78G142\ 80G174Ł[

The traditional method for the preparation of nitrones is by the condensation of carbonylcompounds with hydroxylamines ð68COC"1#499Ł\ or by direct oxidation of hydroxylamines[

For example\ nitrones of the type "3# were prepared by the reaction of the correspondinghydroxymethylene compounds with hydroxylamines "Equation "09## ð75CB1645Ł[ With the exceptionof the N!phenyl nitrone derived from indanone\ the nitrones formed were found to exist in theenolic form[

HO

O

( )n

N

OH

( )n

O–

R(10)

+RNHOH

(4)R = Ph, Me or Bu; n = 1 or 2

The treatment of N\N!disubstituted hydroxylamines with palladium black results in formation ofnitrones ð72TL0938Ł[ Furthermore\ if this reaction is carried out in the presence of an alkene\ a regio!


and stereoselective heterocycle formation is possible "Scheme 7#[ Hydroxylamines are also oxidizedto nitrones by a suspension of Ag1O in ether ð68OPP138Ł[ The oxidations of hydroxylamines withPbO1 in dichloromethane a}ord 0\3!dinitronesdehydrodimers of vinylaminyl oxides ð74CB0094Łpresumably via isomerization of initially formed mononitrones to vinyl!substituted hydroxylamines\followed by abstraction of a hydrogen radical[

N

R1

R2HON

R1

R2–O

+

ON

X R1

R2R3

Pd black, 80–110 °C X

R3

Scheme 8

Both these methods are controlled by the availability of the appropriate hydroxylamine[ Analternative general synthesis of nitrones from aldimines and ketimines is their reaction with thehydroxylamine derivative\ MeNHOSO2H[ This method has been employed in a convenient prep!aration of ~uorenone methylnitrone\ a previously di.cult compound to prepare "Equation "00##ð68OPP84Ł[

NPh NMe O–

(11)

+

MeNHOSO3H, MeOH, 0 °C

Nitrones have been obtained from secondary amines in one step by sodium tungstate catalyzedoxidation with hydrogen peroxide ð73CC763\ 73H"10#372Ł\ or by oxidation with hydrogen peroxide inthe presence of selenium dioxide as catalyst ð76TL1272Ł[ The latter method is also suitable for thepreparation of nitrones in the presence of alkenes[ Imines can be converted into nitrones by treatmentwith potassium permanganate under phase!transfer conditions\ via a ð2¦1Ł cycloaddition typereaction "Equation "01## ð78JOC015Ł[

R1 NR2

R3

R1 NR2

R3

O–

(12)+KMnO4, CH2Cl2, H2O, pH 4.1

Bu4NCl, NaHSO3, H2O

Nitrones are also available via the electrochemical oxidation of N!hydroxy secondary aminesusing a supporting electrolyte such as sodium iodide ð75JOC438Ł[

Ene!type reactions of alkenes ð68T036Ł or allenes ð68RTC07Ł with a!chloronitroso compoundslead to the formation of N!a!chloroalkyl!N!alkenylhydroxylamine intermediates[ Rearrangementthen provides access to aliphatic ketonitrones\ in excellent yields[

An investigation of the reaction of a!chloronitrosoadamantane with Grignard reagents has shownthat adamantylidene nitrones "4# are formed in yields that vary widely with the nature of theGrignard reagent "Equation "02## ð79RTC135Ł[ With MeMgX and PhMgX\ the N!methyl! andN!phenylnitrones can be obtained in 48) and 76) yield\ respectively\ but with all other Grignardreagents nitrone yields are much lower[ Similarly\ methyl and phenyl Grignard reagents react withsimple a!chloronitroso compounds to give the expected nitrones "5# "Equation "03## ð79RTC167Ł[

Cl

NON+

R

O–

(13)RMgX

(5)

R3MgX

R1 R2

NOCl

R2 NO–

R1

R3

(14)+

(6)

322Oximes

The reaction between N!chlorosuccinimide and benzil "E#!monooxime\ in the presence of dimethylsul_de and Et2N\ a}ords a 3 ] 0 mixture of "E#! and "Z#!isomers of C!benzoyl!C!phenyl!N!methyl!thiomethylnitrone ð79JCR"S#255Ł[ These methylthiomethylnitrones undergo cyclization under ther!mal or photochemical stimulation\ leading to oxazoles[

C!t!Butyl!N!phenylnitrone has been prepared\ and its chemistry has been investigated in somedetail ð79JCR"S#011Ł[

Functionally modi_ed cyclic nitrones appear to o}er synthetic potential[ However\ the fact thatsuch nitrones have not been so utilized re~ects the problems associated with their preparation[Nitrones of type "6# have now been prepared in high yield\ and their 0\2!dipolar cycloadditionreactions investigated "Scheme 8# ð79JA262Ł[

Scheme 9

N

O

Et

N

Et

OMeOMe

N

OH

OMeOMe

N

O–

OMeOMe

+

HC(OMe)3, HCl, MeOH HgO

(7)

Treatment of methyl 2\4!dimethoxybenzoate with thallium"III# nitrate in TFA at low temperaturehas been shown to lead to the formation of 3!"1!methoxycarbonyl!3\5!dimethoxyphenyl#imino!2!methoxycarbonyl!4!methoxycyclohexa!1\4!dien!0!one N!oxide "7# ð72SC538Ł[

OMeMeO

N

CO2Me CO2MeO–

OMeO

(8)

+

N!Alkylations of oximes by alkyl halides or sulfonates yield nitrones ðB!77MI 200!90Ł[ Nitroneshave also been obtained by alkylation of O!trimethylsilyloximes with either trialkyloxonium tetra!~uoroborates or alkyl tri~ates in dichloromethane solution ð74TL3220Ł[ The same research groupalso prepared medium!ring cyclic nitrones by heterolytic fragmentation reactions of bicyclicg!N!hydroxylaminosulfonates[ This procedure enabled the conversions of decahydroquinolines toperhydroazulenes to be performed ð74JOC2827Ł[

N!Methylnitrones have been generated in excellent yields by reacting carbonyl compounds withN!methyl!N\O!bis"trimethylsilyl#hydroxylamine ð74JOC4802Ł\ and a!aroyl!N!phenylnitrones havebeen obtained upon oxidation of the adducts derived from silyl enol ethers and nitrosobenzene withsilver oxide ð74S168Ł[

The addition of 1!methyl!1!nitropropane and activated zinc dust to a cold ethanolic solution ofa p!substituted benzaldehyde a}ords derivatives of phenyl!t!butylnitrone in high yields ð74JOC0420Ł[

A nitrone derived from an N!hydroxytryptophan ester and methyl ortho!formate provides a routeto b!carbolines via nitrone cycloadditions ð75JOC298Ł[

Sterically unhindered and certain moderately hindered a!chloronitroso compounds "8# react withtrimethylaluminum to give methyl nitrones "09# "Scheme 09# ð75RTC11Ł[

N

ClRR

ON

ClRR

OAlMe2

MeN

RR

O–Me

Scheme 10

+

(9) (10)

Me3Al, n-C6H14, –80 °C H2O

As part of a mild\ multistep procedure for the oxidative deamination of benzylamines\ 3\5!diphenylpyridinium!1!carboxylates have been converted into nitrones by reaction with p!nitroso!N\N!dimethylaniline in re~uxing dichloromethane "Equation "04## ð72MI 200!90Ł[


N

Ph

Ph CO2–

Ar

+

NMe2

N–O

Ar

(15)+p-Me2NC6H4NO

A selection of methods for the stereocontrolled preparation of "Z#!nitrones is available[ Thus\"Z#!nitrones have been synthesized under mild conditions by addition of alkoxyamines to aldehydesin the presence of sodium bicarbonate and calcium chloride ð73JOC2310Ł\ and the adamantone!derived nitrone "00# reacts with aromatic and aliphatic aldehydes to give the corresponding "Z#!aldonitrone selectively\ via the fragmentation of an initially formed 0\3\1!dioxazolidine to an oxazi!ridine intermediate\ which then rearranges to the "Z#!nitrone "Equation "05## ð89HCA058Ł[

N+

O–

Me

(11)

N

O–

MeR (16)

+RCHO, THF, ∆

C!Aryl!N!"0!carboxyalkyl#!nitrones are prepared by alkylation of aromatic "Z#!aldoximes or bycondensation of a!hydroxyiminocarboxylic acids with aromatic aldehydes ð73LA0434Ł[

N!Carbamoylnitrones were prepared by low!temperature addition of isocyanates to aldoximesð73ZOR877Ł[

The rearrangements of 1!chloro!1!nitrosofenchane and 1!chloro!1!nitrosocamphane to chloro!nitrones have been recorded ð73RTC217Ł[

Acyclic a!heteroatom!substituted nitrones are available via the regioselective alkylation of hy!droxamic acids\ under neutral conditions\ with alkyl tri~ates to give nitrone hydrotri~ates[ Subsequentdisplacement of the a!O!alkyl group from these highly reactive nitrones by heteronucleophiles thenproduces new nitrones with amino\ thio\ and cyano groups in the a!position "Scheme 00# ð78JOC0625Ł[

R1 NOH

O

R2R1 N

R2

O

OH

R3

R3OTf, CH2Cl2 Et3N, MeCN

R1 NR2

O

O–

R3

+ R1 NR2

Nuc

O–

–OTf

Scheme 11

+

+NucH, Et3N, MeCN

1!Butenylmagnesium chloride undergoes 0\1!addition to both aryl and alkyl nitro compounds togive\ after workup\ the corresponding "E#!nitrone "Equation "06## ð89JOC3345Ł[

R NO2 R N

O–

+MgCl, THF, –70 °C(17)

2[00[0[2[1 Cyclic nitrones

The syntheses and reactivity of four!membered cyclic nitrones have been reviewed ð89BSF693Ł[An e.cient synthesis of _ve!ring cyclic nitrones has been achieved by the reduction of g!nitroketones with ammonium formate:Pd!on!carbon "Equation "07## ð77TL0574Ł[

324Oximes

RCO2Me

NO2

NOH

CO2MeN

–O

R(18)

+HCO2NH4, Pd/C, MeOH, 60 °C

The treatment of N!"benzyloxy#amines with concentrated hydrogen peroxide solution in AcOHenables the one!pot preparation of seven!membered cyclic nitrones in respectable yields ð71CB1568Ł\and o}ers some advantages compared with conventional routes[

Four!membered cyclic nitrones are the major products of the reaction between nitroalkenes and0!aminoalkynes[ In all cases only one of the two possible diastereomers is formed "Equation "08##ð72JOC0705Ł[

R1 NO2

R2

NR4R4

R3

N

–O

R1

R3

CONR42

R2

(19)

+

+

2[00[0[2[2 Miscellaneous nitrone derivatives

Acetic nitronic anhydrides are readily prepared via reaction between aliphatic nitroalkenes andlithium enolates in the presence of acetic anhydride "Equation "19## ð89T6458Ł[ Thioimidate N!oxides"nitrones of thio esters# have been prepared by S!alkylations of N!alkylthiohydroxamic acids withalkyl iodides\ followed by treatment of the resulting hydroiodide salts with base "Scheme 01#ð75JOC4087Ł[

NO2

R1

R2

O+ R2

O

R1

N–O

OAc

(20)+LDA, Ac2O, THF, –78 °C

R1NHOH (aq.)

Ph S CO2H

O

Ph NOH

S

R1Ph N

OH

S

R1

R2

NaHCO3

Ph NO–

S

R1

Scheme 12

+

R2

I–

+

R2I, Me2CO

2[00[0[3 O!Chalcogen!substituted Oximes

The Neber rearrangement involves the base!catalyzed conversion of oxime tosylates "or quat!ernary salts of hydrazones or N!chloroimines# into a!amino ketones via isolable azirine intermediatesð53CRV70\ B!69MI 200!90\ 60MI 200!90\ B!62MI 200!90Ł[ For a review of the conversion of ketoximesulphonates into a!amino ketones via the Neber rearrangement the reader is referred to Maruokaand Yamaoto\ {{Functional Group Transformations via Carbonyl Derivatives|| ð80COS"5#675Ł[

2[00[0[4 O!Arsenic!substituted Oximes

The chemistry and physical properties of arsinooximes have been reviewed ð66C125\ 66CZ022Ł[


2[00[0[5 O!Silicon!substituted Oximes

Silylations of a!ketoximes leading to O!silylated ketoximes "i[e[\ no silylation of the ketonefunction# have been achieved using mixtures of zinc chloride and triethylsilane in dioxane at 099>Cð74ZOB1966Ł[ 1!"Trialkylsilyloxy#oxime O!trialkylsilyl ethers can be formed from nitroalkanes byreaction with trialkylsilyl tri~ates\ via a 0\2!trialkylsiloxy migration "Scheme 02# ð75LA317Ł[

R1R3

R2

NO2

R1R3

R2

N(O-TMS)2

R1

R2

N

R3

O-TMS

Scheme 13

TMS-OTf, Et3N

2[00[1 N!HETEROATOM ANALOGUES OF OXIMES

N!Heteroatom substituted aldimines "e[g[\ sulfenimes RCH1NSAr\ silylimines R0CH1NSiR1

2\ sulfonylimines R0CH1NSO1R1\ and the corresponding oximes# are useful synthons forthe unstable N0H aldimine anions\ especially in the synthesis of a!branched primary aminesð80COS"1#883Ł[ Oximes\ oxime ethers\ and sulfenimines have been the most widely studiedcompounds[ Silylimines and sulfonimines have similarly been used to prepare a!aryl!substitutedhomoallylamines[ The corresponding ketimine analogues are also known\ but are much lesscommon[

2[00[1[0 Sulfur Analogues

2[00[1[0[0 Sulfenimines

The preparations of sulfenimines "also known as sulfenylimines and N!alkylidenesulfenamides#\together with their structural characteristics\ their reactions\ and the methods for their conversioninto sul_nimines have been reviewed previously\ and the interested reader is directed to thesecomprehensive articles ð75JOC4913\ 78CR578\ B!89MI 200!90Ł[

Unlike imines and oximes\ sulfenimines undergo relatively facile stereomutation\ but examples ofstereoisomers of sulfenimines are limited to constrained analogues ð78CR578Ł[ Sulfenimines areavailable from sulfenamides by three main routes\ namely] "i# via condensation reactions withcarbonyl compounds^ "ii# from disul_des via reactions with metal salts and carbonyl compounds\and "iii# via the condensation reactions between sulfenyl halides and imines ð78CR578\ B!89MI 200!90Ł[They can also be prepared directly from the corresponding sulfenamide\ by treatment withN!chlorosuccinimide and Et2N ð83SL056Ł[ Application to glycine provides an electrophilic glycineequivalent for amino acid synthesis[

Sulfenimines are versatile synthetic intermediates\ and undergo nucleophilic additions at theiminyl carbon\ electrophilic additions at the nitrogen centre\ and alkylation reactions at sulfurð78CR578\ B!89MI 200!90Ł[ They have also been reduced to N!sulfur!substituted amines by treatmentwith NaBH2CN in TFA ð72JOC2420Ł[ Sulfenimines undergo oxidation to both sul_nimines "sul_nylimines# and sulfonimines "sulfonyl imines# "see Sections 2[00[0[1 and 2[00[1[0[2#[

The focus in the 0889s has been on the preparation of chiral sulfenimines ð83MI 200!90Ł and theirutilization as electrophilic glycine equivalents in the synthesis of amino acids "Scheme 03# ð83SL056Ł[

Scheme 14

R

O

R

O

CO2But

NH S

NO2

R

O

CO2H

NH2

i, LiN(TMS)2, THF, –20 °C

ii, ButO2CCH=NS(o-NO2C6H4), THF, 0 °C

TFA-H2O

326N!Heteroatom Analo`ues

2[00[1[0[1 Sul_nimines

Sul_nimines are more reactive than their sulfenyl analogues\ and they act as ammonia iminesynthons[ Thus\ reduction of the C1N bond with either LAH or NaBH3 a}ords the correspondingsul_namides\ which readily undergo cleavage at the S0N bond with TFA to give the parent aminocompound ð78CR578\ B!89MI 200!90Ł[ Alternatively\ the intermediate sul_namide can be oxidized tothe corresponding sulfonamide ð71JCS"P0#228Ł[ Chiral sul_nimines are therefore valuable as chiralammonia imine synthons in the synthesis of nonracemic amines ð71JCS"P0#228Ł[ They are alsovaluable in the synthesis of a!\ b!\ or g!amino acid derivatives\ via either reaction with diethyl!aluminum cyanide to form a!amino nitriles\ which are readily hydrolyzed to the correspondingamino acids ð80JOC3\ 83TL8240Ł\ or reaction of nitriles with an alkyllithium followed by reactionwith "−#!L!menthyl "S#!p!tolylsul_nate ð80JOC3Ł[ They also undergo Darzen|s!type reactions withlithium enolates to form cis!aziridine!1!carboxylic acids ð83JOC2132Ł[

Sul_nimines are generally accessed by asymmetric oxidations of the corresponding sulfenimineswith reagents such as chiral N!sulfonyloxaziridines ð81JOC5276\ 82PAC522Ł\ or by Andersen!typeprocedures from metalloimines and menthyl p!tolyl sul_nate "Scheme 04# ð82TL5118Ł\ although thisprocedure is limited to the formation of alkyl aryl sul_nimines[

R CN R NAlBui

2R N

AlBui2

OS

p-Tolyl

O

Scheme 15

dibal

RNS

p-Tolyl

MeLi

:

–Li+

O

:

2[00[1[0[2 Sulfonimines

As with most N!heteroatom!substituted oxime derivatives\ sulfonimines are known by a range oftitles such as sulfonyl imines or oxime sulfonates[ They are highly versatile and reactive reagentsand are readily available from oximes by reaction with sulfonyl halides in the presence of baseð64S491Ł[ An alternative and general procedure for the preparation of sulfonimines\ even in systemsprone to tautomerization\ is the treatment of carbonyl compounds with sulfonyl chlorides in thepresence of tertiary amines\ such as Et2N ð81JOC3666Ł[ Sulfonimine formation results from a reactioncascade of amine!catalyzed rearrangement of the initial sulfonyl chloride to a sul_nyl cyanate\followed by oxime O!sul_nylate formation and subsequent homolytic rearrangement to the sul!fonimine[

Sulfonimines have proved to be highly useful precursors ð81BSB270Ł[ In particular\ they readilyundergo Beckmann!type rearrangements under a variety of conditions to give a number ofcompounds\ e[g[\ in the presence of dialkylaluminum thiolates or selenoates to give iminothioethers"valuable as activated amide surrogates# and iminoselenoethers\ respectively ð72JA1720Ł[ A similarreaction with cyanotrimethylsilane and diethylaluminum chloride has a}orded iminonitriles and a!alkylated amines are available via organoaluminum!promoted Beckmann rearrangement of sul!fonimines ð72JA1720Ł[ Rearrangement in the presence of TMS!I or Et1AlI gives imidoyl iodidesð72TL2144Ł[ Regio! and chemospeci_c carbonÐcarbon bond formation results from the Lewis acidpromoted reaction of sulfonimines with silyl enol ethers and provides an e.cient method for thesynthesis of enaminones\ which are useful building blocks for the synthesis of fused carbocycles andpolyheterocycles\ in addition to their reduction to functionalized amino alcohols ð72JA5201Ł[

Alkenic cyclizations promoted by Beckmann rearrangement of sulfonimines provide access to arange of ring systems\ via four distinct cyclization modes "Scheme 05#\ controlled by the Lewis acidemployed as the initiator and the migratory aptitude of the rearranged group ð72JA561\ 72TL832Ł[Natural product applications of these reactions have included syntheses of solenopsin B and


muscopyridine ð72JA561Ł[ Beckmann rearrangement of sulfonimines by reaction with Grignardreagents gives functionalized imines\ which upon reduction give a!alkylamines ð71TL2284Ł[

N

R

OMs

NH

R

R2

N

R1

OMs

R1

NR1R1

R2

Scheme 16

Ph

NMsO

NHPh

exo–exo modeR

NMsO

( )nexo(B)–endo mode( )n

N R

endo(B)–endo mode

endo(B)–exo mode

The C1N bond of sulfonimines is readily reduced under mild conditions with NaBH3

ð70JCS"P0#1332Ł or LAH ð76S608Ł to give the corresponding sulfonamide[ N!Aryl sulfonimines wereused as dienophiles in some of the earliest examples of heterocycle formation via imino DielsÐAlderreactions ðB!56MI 200!90Ł[ Sulfonimines can also be generated in situ for use in both inter! andintramolecular DielsÐAlder reactions by treatment of an aldehyde and 0\2!diene with N!sul_nyl!p!tolylsulfonamide and BF2 =Et1O ð89JOC2926Ł[

Sulfonimines are e.cient acceptors and they readily undergo nucleophilic reactions with organo!metallic reagents ð72S443\ 73TL4840\ 76TL4004Ł to give a!functionalized N!arylsulfonamides[ Hithertothe reaction has been of little use for amine synthesis however\ due to the problems of removal ofthe sulfonyl group[ This problem has now been overcome by the use of diarylsulfamylimines as themasked amine functionality\ as these groups are readily hydrolyzed in re~uxing aqueous pyridine"Scheme 06# ð75TL2846Ł[

Ar NS

N Ar

OO

Ar NH

SNH

Ar

OOR R

Ar NH2

R

Scheme 17

RM i, pyridine, H2O

ii, NaOH

In situ generation of the sulfonimine has also been used for the generation of aldehyde derivedsulfonimine examples\ thus treatment with N!sul_nylsulfonamides a}ords sulfonimines which reactwith Grignard reagents to give N!sulfonylamines ð89JOC282Ł[

N!Tosylimines have been synthesized in variable yields by a diisobutyl telluride:copper powder!induced reaction of aldehydes with tosylazide ð74CL568Ł which does not react even under forcingconditions[ An organotellurilimine has been proposed as an intermediate "Scheme 07#[

328N!Heteroatom Analo`ues

TsN3 + R2Te R2Te NTsR1CHO –R2TeOR2Te+

–O

NTs

R1NTs

R1

Scheme 18

2[00[1[1 Phosphorus Analogues

N!Phosphinoyl imines are highly electrophilic imines[ They are usually prepared by the reactionsof oximes with chlorophosphorus"III# reagents in the presence of Et2N "Scheme 08# ð71S169\ 74CC471Ł[N!Phosphinoyl imines can be reduced by a variety of hydride reagents under mild conditionsð67S410Ł to N!phosphinylamines\ which are then cleaved under mild acidic conditions to the parentamines[ Diastereoselective reductions have also been performed using LiBHBus

2 ð76TL4508Ł\ andenantioselective reductions of N!diphenylphosphinylimines are also possible ð71S169\ 76JOC691Ł[

ArCHOR2PCl [O]

Ar

N

OH

Ar

N

P(O)R2

Ar

N

P(O)R2

O

Scheme 19

N!Phosphinoyl imines serve as precursors to N!phosphinoyloxaziridines\ the phosphorus equiv!alents of the Davis reagents N!sulfonoyloxaziridines "Scheme 08# ð74CC471Ł\ and can also beconverted into primary amines in a stereoselective manner ð76JOC691Ł[

Reactions of phosphinamides or sulfonamides with aryl aldehydes in the presence of TiCl3 andEt2N provide a simple one!step synthesis of N!phosphinoyl! and N!sulfonoyl imines\ respectivelyð77TL2614\ 80T4450Ł[ Extension of this reaction to ketone examples failed owing to competing aldolcondensation reactions\ although nonenolizable ketones or bulky ketones\ such as camphor\ canform both N!phosphinoyl! and N!sulfonoyl imines under more forcing conditions of re~ux intoluene[

2[00[1[2 Nitrogen Analogues

The chemistry ofN!nitrosoimines and N!nitrosamines has been reviewed in depth ðB!71MI 200!90Ł[The chemistry of N!nitrosoimines\ and especially their use in the preparation of heterocycles\ hasalso been reviewed ð66H"6#0020Ł[

The formation of sterically hindered nitroimines is possible via the direct treatment of the parentoxime with NOCl\ although concomitant formation of the parent ketone via intramolecular reactionof the intermediate N!nitrosonitrone can be a problem ð73S368Ł[

The chemistry of N!nitrosoimines as synthetic intermediates\ for example\ in the preparation ofazamonomethinecyanines ð67BCJ424Ł\ or their reduction with LAH ð65BCJ0802Ł\ has been studiedin a series of papers by Akiba et al[ ð65BCJ449Ł[

As for the other N!heteroatom!substituted oximes derivatives\ N!nitroimines "also known asnitrimines# are also reduced by NaBH3 in this case to N!nitroamines "nitramines# ð66JOC2335Ł[However\ in this series\ the reduction must be carried out in AcOH in order to be successful[

2[00[1[3 N!Silicon!substituted Imines

Like their sulfur counterparts\ N!silylimines have been employed as masked N!H imines\ sincethe labile silyl group is readily removed even in situ[ Thus nonenolizable carbonyl compoundscan be converted into primary amines by reaction with lithium hexamethyldisilazide to giveN!trimethylsilylaldimines\ which spontaneously lose trimethyl silyl oxide\ in analogy to thePeterson alkenation\ to give the target amine "Scheme 19# ð72JOC178Ł[ Trimethylsilylimines also


react with organolithium and Grignard reagents to give primary amines\ after hydrolysis ð71S350Ł[Attempts to prepare N!silylimines from enolizable carbonyl compounds have largely been thwartedby the problems of competing enolization and tautomerization to the corresponding enaminesð71S350Ł[ N!Silylimines from enolizable aldehydes have nevertheless been prepared and reacted insitu with ester enolates to provide b!lactams ð76TL4258Ł[ The temperature at which the N!silylimineis generated\ −29>C\ may be the key to success\ since nonenolizable N!silylimines are normallygenerated at −69>C[ Enolizable N!trimethylaldimines can also be prepared by the reaction ofbis"trimethylsilyl#formamide with organolithium reagents ð78TL3164Ł[ Again this method wasdeveloped as a route to b!lactams "Scheme 10#[

LHMDSR N

TMS

O–

TMS

Scheme 20

R NTMS

RCHO

R1 NTMS

TMS

O

R1 NTMS

TMS

OHBuLi, THF, –78 °C

R2CH2CO2Et, LDA

THF, < –70 °CR1 N

TMSNH

O

R2 R1

Scheme 21

A detailed coverage of the methods available for the preparation of N!silylimines\ their mechanismof formation\ and their structure\ is presented in an article by Colvin et al[ on the condensations ofsilyl ketene acetals with N!silylimines ð77T3046Ł[ N!Silylimines are also available via the condensationreactions between N!"trimethylsilyl#phosphimines and carbonyl compounds ð65CB0380Ł and thereaction of nitriles with organometallic reagents when quenched with TMS!Cl ð56JOM"8#120Ł[

As mentioned earlier\ N!silylimines provide a valuable alternative to oxime ethers for the synthesisof N!unsubstituted b!lactams\ as the silyl group is readily removed by protodesilylation duringworkup[ N!Silylimines are similar in reactivity and stereoselectivity to N!arylimines in their reactionswith enolates and silyl ketene acetals[

Like acyclic imines\ they exist in one geometrical form\ presumably the "E#!isomer[Pioneering investigations by Hart et al[ have provided much insight into the scope and stereo!

selectivity of enolate!N!silylimine condensations[ In their original paper\ the viability of thesereactions was demonstrated using mainly a\a!disubstituted esters\ which add via their lithiumenolates to nonenolizable N!silylimines to a}ord mixtures of diastereomeric N!unsubstitutedb!lactams\ following aqueous workup "Equation "10## ð72JOC178Ł[ For a review of this aspect ofN!silylimine chemistry\ see Kleinman and Volkman ð80COS"1#823Ł[

R1 CO2Et

R2

NHO

R2

R1R3

LDA, THF, –78 °C; R3CHN-TMS(21)

A simple route to N!"trimethylsilylmethyl#imines\ which are useful as precursors to {{non!stabilized|| azomethane ylides\ involves the reduction of trimethylsilylmethylazide using LiAlH3\followed by standard imine formation with carbonyl compounds "Scheme 11# ð77SC0864Ł[

330

TMS N3 TMS NH2TMS N R2

R1R1 R2

O

Scheme 22

LiAlH4, Et2O, < 10 °C

Na2SO440nm molecular sieves


3.12Imines and Their N-SubstitutedDerivatives: Hydrazones andOther 1NN DerivativesIncluding Diazo CompoundsJ. STEPHEN CLARKUniversity of Nottingham, UK

2[01[0 HYDRAZONES AND THEIR DERIVATIVES 333

2[01[0[0 Hydrazones and Azines Derived from Hydrazine 3332[01[0[1 N!Substituted and N\N!Disubstituted Hydrazones 3352[01[0[2 Hydrazones from Azo Compounds 3372[01[0[3 Semicarbazones 3382[01[0[4 Osazones 3492[01[0[5 Cyclic Hydrazone and Azine Derivatives 340

2[01[0[5[0 1!Pyrazolines and 1!pyrazolin!4!ones 3402[01[0[5[1 Tetrahydropyridazines 3422[01[0[5[2 Cyclic azines 342

2[01[1 R1C1NX FUNCTIONS "X�P\ As\ Sb\ Bi\ Si\ Ge\ B or METAL# 344

2[01[1[0 Imines Substituted with Phosphorus or Arsenic 3442[01[1[1 Imines Substituted with Silicon\ Germanium\ Tin or Lead 3452[01[1[2 Imines Substituted with Boron or Aluminium 3462[01[1[3 Imines Substituted with Lithium 3482[01[1[4 Imines Substituted with Beryllium or Ma`nesium 3482[01[1[5 Imines Substituted with Titanium\ Zirconium or Hafnium 3592[01[1[6 Imines Substituted with Molybdenum or Tun`sten 3592[01[1[7 Imines Substituted with Manànese 3592[01[1[8 Imines Substituted with Iron 3592[01[1[09 Imines Substituted with Platinum or Rhodium 3502[01[1[00 Imines Substituted with Zinc 350

2[01[2 DIAZO COMPOUNDS 350

2[01[2[0 General Methods for the Preparation of Diazo Compounds 3502[01[2[1 Alkyl and Aryl Diazo Compounds 351

2[01[2[1[0 Diazotization of amines 3512[01[2[1[1 Forster reaction of oximes 3522[01[2[1[2 Dehydroènation of hydrazones 3522[01[2[1[3 BamfordÐStevens reaction of tosyl hydrazones 3532[01[2[1[4 Cleavaè of N!nitrosoamines 3542[01[2[1[5 Diazo `roup transfer 356

2[01[2[2 a!Diazo Carbonyl and b!Dicarbonyl Compounds 3572[01[2[2[0 Diazotization of a!amino carbonyl compounds 3572[01[2[2[1 Forster reaction of a!keto oximes 3582[01[2[2[2 Direct nitrozation of carbonyl compounds 3582[01[2[2[3 Dehydroènation of a!keto hydrazones 3582[01[2[2[4 BamfordÐStevens reaction of a!keto tosyl hydrazones 369

332

333 Hydrazones and Other1NN Derivatives

2[01[2[2[5 Cleavaè of N!nitrosoamides 3602[01[2[2[6 Diazo `roup transfer to carbonyl compounds 3602[01[2[2[7 Substitution at the diazo carbon of a!diazo carbonyl compounds 363

2[01[2[3 a!Diazo Imines\ Amidines\ Imidates and Nitriles 3652[01[2[3[0 a!Diazo imines 3652[01[2[3[1 a!Diazo amidines and imidates 3662[01[2[3[2 a!Diazo nitriles 366

2[01[2[4 Diazo Alkanes Containin` Heteroatoms at the Diazo Carbon 3672[01[2[4[0 Diazo alkanes substituted with haloèns 3672[01[2[4[1 Diazo alkanes substituted with sulfur 3672[01[2[4[2 Diazo alkanes substituted with nitroèn 3682[01[2[4[3 Diazo alkanes substituted with phosphorus 3792[01[2[4[4 Diazo alkanes substituted with arsenic\ antimony or bismuth 3712[01[2[4[5 Diazo alkanes substituted with silicon\ èrmanium\ tin or lead 3712[01[2[4[6 Diazo alkanes substituted with boron or thallium 3742[01[2[4[7 Diazo alkanes substituted with lithium or sodium 3742[01[2[4[8 Diazo alkanes substituted with ma`nesium 3752[01[2[4[09 Diazo alkanes substituted with transition metals 3752[01[2[4[00 Diazo alkanes substituted with silver 3762[01[2[4[01 Diazo alkanes substituted with zinc\ cadmium or mercury 377

2[01[2[5 Unsaturated Diazo Alkanes 3772[01[2[5[0 Diazo alkylidenes 3772[01[2[5[1 a\b!Unsaturated diazo alkanes 3782[01[2[5[2 Diazo alkynes 389

2[01[0 HYDRAZONES AND THEIR DERIVATIVES

2[01[0[0 Hydrazones and Azines Derived from Hydrazine

The most common method for the preparation of N!unsubstituted hydrazones is reaction of analdehyde or ketone with a hydrazine[ During the reaction\ one of the available amino groups of thehydrazine reacts to form a hydrazone\ or both amino groups react to form an azine\ depending onthe stoichiometry and the experimental conditions "Scheme 0#[ Aldehydes and dialkyl ketones reactreadily with hydrazine in aqueous or alcoholic solvents to give the corresponding azines ð32OSC"1#284\47JOC528Ł[ To obtain hydrazones rather than azines\ a large excess of hydrazine is required andtraces of acid must be excluded ð59JOC0664Ł[ In some cases\ hydrazones may be prepared bytreatment of azines with an excess of hydrazine "Scheme 0#ð91CB2123\ 59JOC0664\ 69OS"49#2Ł[ Hydrazonesprepared by reaction of hydrazine with aromatic aldehydes bearing electron!donating substituentsare unstable and form azines in alcoholic solvents[ In contrast\ hydrazones of electron!de_cientaromatic aldehydes are stable even when heated in alcoholic solvents ð0899CB1359\ 59JOC0664Ł[

Scheme 1

R1 R2

O

R1 R2

NN

R2R1

H2NNH2 (<1 equiv.), EtOH, reflux

R1 R2

NNH2H2NNH2 (excess)

EtOH, reflux H2NNH2 (excess)EtOH, reflux

H+, EtOH(R1R2CO)

R1, R2 = H, alkyl, aryl

Arylalkyl ketones can be converted into hydrazones by treatment with hydrazine in an alcoholicsolvent\ but the azine product predominates in the presence of acids ð35JA0872\ 47CB491\ 50JCS4459Ł[The formation of hydrazones of diaryl ketones usually requires prolonged reaction times and hightemperatures ð18CB1022\ 35JA803\ 44OSC"2#240Ł\ and in some cases it is necessary to add a water!absorbing agent to the reaction ð49JA1789Ł[ Azines can be prepared by the addition of a mineralacid to alcoholic solutions of hydrazones at room temperature ð49JA1789Ł\ or by heating hydrazones

334Hydrazones

with ketones in the presence of acids "Scheme 0# ð0899CB1359\ 47JA2937Ł[ The latter method is usefulfor the preparation of unsymmetrical azines[

N!Unsubstituted hydrazones can also be prepared by exchange reactions of N\N!dialkyl hydra!zones with hydrazine ð55JOC566Ł[ This procedure avoids the problem of azine formation frequentlyencountered when aldehydes or ketones are treated directly with hydrazine[ The carbonyl compoundis usually _rst converted into the corresponding N\N!dimethyl hydrazone\ and this compound isthen treated with hydrazine to give the required hydrazone "Scheme 1# ð55JOC566Ł[

Scheme 2

H2NNH2 (excess)

EtOH, refluxR1 R2

NNH2

R1 R2

O

R1 R2

NNMe2Me2NNH2 (anh.)

EtOH, reflux

An unusual example of hydrazone formation is the reaction of the cyclic nitrone "1# with hydrazineto a}ord the ring!contracted hydrazone "0# "Scheme 2# ð56AJC228Ł[ In this case\ hydrazine attacksthe carbon centre adjacent to nitrogen rather than the carbonyl group\ and subsequent ring closurethen gives "0#[ In contrast\ the nitrone "1# reacts with 1\3!dinitrophenylhydrazone to give "2#\ theexpected hydrazone product[

N

N

NH2

O–

N

O

O–

+ +

N

N

O–

+

NH

O2N NO2

Scheme 3

(1) (2) (3)

H2NNH2 (anh.)

C6H6

Brady's reagent

EtOH, H2SO4

There are several routes to azines from compounds other than aldehydes and ketones[ Forexample\ symmetrical azines can be formed by hydrogenation of nitriles with Raney nickel inhydrazine "Scheme 3# ð44G0694\ 51JOC2605Ł[ This sequence proceeds by addition of hydrazine to thenitrile to a}ord an imino hydrazide "3#\ followed by reduction and elimination to give a hydrazone\which reacts with more of the nitrile to give "4#\ and _nally conversion to the symmetrical azine[

R CNN

R NH

H NH2N

R

NH2

Scheme 4

(5)

H2NNH2 Raney Ni, H2

–NH3

(4)

RCN

N

R

NH

R NH

N

R

N

R

Raney Ni, H2

–NH3

Unsymmetrical azines can be prepared by reaction of phosphoranes with diazo compoundsð50TL700\ 51T0912Ł[ Treatment of phenyldiazomethane or an a!diazo carbonyl compound with aphosphonium ylide a}ords the azine product "5# in reasonable yield\ but signi_cant amounts of thephosphazine "6# may be produced by reaction of the diazo compound with the triphenylphosphinegenerated during the reaction "Scheme 4#[


Ph3PR1

N2

R2

+N

Ph3P

N

R1

R2

+

–

R1

NN

R2

+ PPh3N2

R2 Ph3P

NN R2

+

–

Ph3P

NN

R2

Scheme 5

(6)

(7)

2[01[0[1 N!Substituted and N\N!Disubstituted Hydrazones

Reactions of N!alkyl and N\N!dialkyl hydrazines with aldehydes and ketones usually a}ord theexpected substituted hydrazones ð11JCS0537\ 46JOC193\ 48JOC0814\ 59JOC0664Ł[ Although these reactionsare reversible\ the equilibrium usually favours the condensation product "Scheme 5#[ Two isomersof the hydrazone are possible\ and with aryl hydrazones of aliphatic aldehydes and ketones\ theisomer in which the amino group "NHR2 or NR2R3# is trans to the bulkiest group of the carbonylcompound predominates ð51JA642\ 52JA1673\ 52JA2513Ł[

R1 R2

O

R1 R2

NN

R3

H

R1 R2

NN

R3

R4

Scheme 6

H2NNHR3

solvent, heat

H2NNR3R4

solvent, heat

Monoalkyl hydrazones derived from aromatic aldehydes have a labile N!hydrogen\ and additionof the hydrazone to unreacted aldehyde is possible\ especially when the latter is in excess ð11JCS0537Ł[The degree to which this side reaction occurs depends on the experimental conditions employed[

Aryl hydrazines such as phenyl\ p!nitrophenyl\ and o\p!dinitrophenyl hydrazine react with mostaldehydes or ketones to a}ord hydrazones\ and a large number of these compounds have beenprepared ð58QR26Ł[ N!Aryl hydrazones are usually solids\ and their melting points can be used toidentify the parent carbonyl compounds ð38JA2725\ 58QR26Ł[ N!Aryl hydrazones\ and especiallythose substituted with nitro groups\ are stable to acids and are usually prepared under stronglyacidic conditions[

Reactions of aryl hydrazines with formaldehyde do not usually a}ord simple methylene hydra!zones\ but it has been reported that the reaction of p!methylphenylhydrazine with formaldehydein acetic acid a}ords N!methylene!p!methylphenyl hydrazone as well as polymeric by!productsð51CA"45#3534Ł[

Hydrazones can be prepared by exchange reactions of hydrazines with the imines derived fromaniline ð47M607Ł\ or with oximes ð45JOC533Ł "Scheme 6#[ Exchange reactions can also be performedby treatment of the hydrazone of a low boiling ketone\ such as acetone\ with a less volatile aldehydeor ketone "Scheme 6# ð47CA"41#8879Ł[ The reaction is forced to completion by the removal of the lowboiling ketone by distillation[

Tosyl hydrazones are useful precursors for the BamfordÐStevens and Shapiro reactions ð41JCS3624\52JOC769Ł[ These compounds can be prepared by treatment of an aldehyde or ketone with tosylhydrazine under acidic or neutral conditions\ usually with ethanol or acetic acid as solvent[ Mono!tosylhydrazones of a!diketones are important precursors to a!diazoketones "see Section 2[01[2[2[4#\and they can be prepared directly by treatment of a!diketones with tosyl hydrazine ð47JA1146Ł[

Substituted tosyl hydrazines can be converted directly into hydrazones by treatment with baseð50JCS0632\ 53JA1284Ł[ When N!aryl!N!benzyl!N?!tosyl hydrazines are heated with aqueous oralcoholic alkali\ they rearrange to hydrazones with intramolecular migration of the benzyl group"Scheme 7# ð50JCS0632Ł[ The same reaction can be accomplished by heating sodium salts of ben!zenesulfonyl hydrazones in diethylene glycol ð53JA1284Ł[

Oxidation reactions of hydrazines can be useful for the preparation of hydrazones[ Treatment

336Hydrazones

R1 R2

N

R1 R2

NPh

R1 R2

NOH

NN

R3

R4

Scheme 7

N

R3

R4 H2NNR3R4

solvent, heat

H2NNR3R4

solvent, heat

R1R2CO–Me2CO

N N

Ph

Ph

N N

Ts Ph

Ph

N N

H

Ts Ph

Ph

N N

Ts Ph

Ph–

N N

Ph

Ph N

Ph N H

Ph

Scheme 8

+

–

–

base

–Ts–

–Ts–

of hydrazines with oxidising agents\ such as mercury"I# oxide ð00JPR011\ 53CRV038Ł\ or bromineð51JOC2835Ł\ under carefully controlled conditions\ a}ords either hydrazone or azine products[Oxidation of trimethylhydrazine with bromine a}ords the hydrobromide salt of formaldehydedimethylhydrazone "Equation "0## ð51JOC2835Ł[ In certain cases\ rearranged hydrazones may beobtained from oxidation reactions[ For example\ the hydrazone "8# is obtained via the azo compound"7# produced by oxidative rearrangement of N!benzyl!N!phenylhydrazine with mercury"I# oxide"Scheme 8# ð53CRV038Ł[

N N

Me

Me Me

H

N N

Me

Me

(1)HBrHBr, Br2, heat

N NH2

Ph

Ph

N N

Ph

Ph

N N

Ph

PhHHgO

(8) (9)

Scheme 9

Hydrazones can also be prepared by reaction of alkynes or phenyl!substituted alkenes withsodium hydrazide in hydrazine ð53AG195\ 53AG"E#231\ 54CB801Ł[ For example\ diphenylethyne can beconverted into the hydrazone "09# by reaction with sodium hydrazide in ether at 9>C "Scheme 09#ð53AG195\ 53AG"E#231Ł[ This reaction is of limited synthetic use because a mixture of two products is


usually formed with unsymmetrical alkynes\ and the reaction is not applicable to terminal alkynes[Monoalkyl! and N\N?!dialkylhydrazines can be used as substrates for the reaction\ but the reactionis not successful with N\N!dialkylhydrazines and more highly substituted hydrazines[

H2N NH– + Ph Ph

– N

Ph

Ph

NH2N

Ph

Ph

NH2

Scheme 10

H2NNH2 H3O+

(10)

2[01[0[2 Hydrazones from Azo Compounds

Aliphatic azo compounds which contain a hydrogen adjacent to the azo group are unstableand will readily tautomerize to the more stable isomeric hydrazones ð52JA2513\ 54JCS2417Ł[ Thetautomerization between the hydrazone\ azo and ene!hydrazone forms of phenylhydrazones hasbeen the subject of extensive studies ð36BSF327\ 54JCS2417Ł[ In nonpolar solvents or in the pure state\phenylhydrazones exist in the hydrazone form ð52JA2513\ 54JCS1677Ł[ However\ all three tautomersare present in an aqueous methanol solution ð52BAU397Ł[

The conversion of azo compounds into hydrazones can be exploited to prepare hydrazones fromdiazonium salts[ Aliphatic compounds which contain an activated methylene group can be coupledto aryl diazonium salts in the presence of a mild base\ to produce aryl hydrazones "Scheme 00#ð48OR"09#0Ł[ The reaction proceeds by nucleophilic attack of the stabilised carbanion of the methyl!ene compound on to the diazonium ion to form an azo compound which then tautomerizes toa}ord a hydrazone[ The reaction is usually performed in bu}ered aqueous solution\ although it canbe accomplished at lower pH when the activated methylene compound possesses strongly electron!withdrawing substituents[ Coupling is followed by decarboxylation when one of the activatinggroups is a carboxyl group[

–CO2Ar N N

+

Z

Y–

ArN

N Y

Z

ArN

N Y

ZY

NN

Ar

H

Scheme 11

Z = CO2H

Y, Z = electron-withdrawing groups

H

When a compound containing an activated methine group is coupled to an aryl diazonium ion\the intermediate azo compound cannot tautomerize[ If one of the activating groups is an acyl orcarboxyl group\ this is cleaved by hydrolysis on workup "Scheme 01#[ This reaction is known as theJappÐKlingemann reaction\ and there are many examples of its utility ð48OR032Ł[ For those sub!strates in which there is more than one cleavable activating group\ the acyl group corresponding tothe weaker acid is usually lost ð91CB804Ł[ The tendency of various activating groups to undergocleavage is illustrated by the behaviour of various a!substituted cyclohexanones "Scheme 02#[ Theside chain is cleaved when it is either a carboxyl or formyl group\ but when the side chain is an esteror acetyl group\ ring scission is observed ð48OR"09#032Ł[ It is possible to isolate the azo intermediatesformed during the JappÐKlingemann reaction\ by performing addition at low temperature inweakly acidic media ð42LA"468#17\ 46CB0959\ 48OR032\ 51JA2403\ 51JA3776\ 51JA3781\ 54JCS6074Ł[ Hydrolytic

338Hydrazones

cleavage of these azo intermediates is catalysed by acid or base\ and nucleophilic reagents such asethanol\ phenol or aniline also promote this reaction ð51JA2403Ł[

–Ar N N

–OH

Y+

R1

O

R2

Y

NN

Ar

H

R1

ArN

N Y

O R2

HO H

Scheme 12

R1

Y = electron-withdrawing group

O

NN

Ar

H

NHO

O NH Ar

R

O

Scheme 13

O

Y

OO

Y

O

N

NAr

ArN2+X–, base

Y = H, OH

Y = R, OR

Compounds activated by nitro rather than acyl groups react with aryl diazonium salts to a}ordhydrazones ð42LA"468#17Ł[ Primary nitroalkanes react to give the corresponding aryl hydrazones ofa!nitro aldehydes ð48OR"09#0Ł[ For example\ nitromethane reacts with benzenediazonium salts in dilutehydrochloric acid "pH 3[4# to give the phenyl hydrazone of nitroformaldehyde ð37JA0270Ł[ Whenaryl dinitromethanes and diaryl nitromethanes react with benzenediazonium ion\ the nitro groupmigrates to the aromatic ring and p!nitrophenylhydrazones are produced "Scheme 03# ð48OR"09#0Ł[In cases where the para position is blocked\ the nitro group migrates to the ortho position[

Y

Ar

NO2

Ar

NO2

N

Y

NPh

O2N

NN

H

H

Y

Ar

Scheme 14

ArN2+ X–, base

Y = Ar, NO2

Aryl diazonium salts will also couple with a variety of unsaturated compounds to a}ord arylhydrazones ð48OR0Ł[ For example\ enamines couple e.ciently with aryl diazonium salts[ Substrateswith a hydrogen atom on the b!carbon a}ord glyoxal b!arylhydrazones\ and those without ahydrogen atom on the b!carbon are cleaved to furnish ketone hydrazones "Scheme 04# ð45JA4473Ł[

2[01[0[3 Semicarbazones

Semicarbazones and thiosemicarbazones can be prepared by treatment of a ketone or aldehydewith semicarbazide or thiosemicarbazide "Scheme 05#[ The reaction is general acid catalysed\ andthe yield of semicarbazone and the rate of reaction are dependent on the pH of the reaction mediumð21JA1770\ 48JA364\ 55BSB590Ł[ The formation of semicarbazones from ketones can be catalysed bythe addition of anilines ð51JA715Ł[ In this case\ a Schi} base is formed as an intermediate whichthen undergoes exchange with semicarbazide in a subsequent step "Scheme 05#[ The rate of reaction


R1 and R2 = alkyl

R 2= H

N

R2

R1 N R3

R3

Ar N N X– ++

R1 R2

NH N

H

Ar

+ N CHO

R3

R3

N H

R3

R3

R1O

NN

Ar

H

Scheme 15

+C H

of semicarbazide with the intermediate imine is much greater than on the parent carbonyl compoundð47M607\ 51JA715Ł[

X = O, S; R1, R2 = H, alkyl, aryl

R1 R2

NAr

R1 R2

O

R1 R2

NN

NH2X

H

Scheme 16

H2NNHC(X)NH2

ArNH2 H2NNHC(X)NH2

Aliphatic and aromatic nitriles can be converted into semicarbazones of the correspondingaldehydes by reduction with Raney nickel in the presence of semicarbazide ð44CB0845\ 48JA1404Ł[This reaction is analogous to that used to prepare azines from nitriles and hydrazine "see Section2[01[0[0#[

2[01[0[4 Osazones

Osazones are formed by the addition of hydrazines to a!diketones or a!hydroxy ketones[ Thesecompounds have been known since the early days of carbohydrate chemistry\ when Fischer _rstisolated sugar phenylosazones ð0773CB468\ 0776CB710Ł[ Sugar osazones have a {quasi!aromatic| struc!ture "00#\ _rst proposed by Fieser and Fieser "Equation "1## ð52ACS448\ 54AG479\ 54AG"E#463\ 54JA485Ł[This structure accounts for the di}erences in spectral and chemical properties in comparison tononsugar osazones ð54AG479\ 54AG"E#463Ł[ In aqueous or alcoholic solutions\ reactions of arylhydrazines bearing electron!withdrawing substituents\ with aldoses or ketoses a}ord the cor!responding hydrazones ð47CB1534Ł[

CHO

CHOH

CHOH

CHOH

CHOH

CH2OH

CHOH

CHOH

CHOH

CH2OH

N

NH

NN

H

Ph

Ph

(2)PhNHNH2

(11)

340Hydrazones

During osazonization of sugars by phenylhydrazine\ hydrazone formation occurs with oxidationof the hydroxyl group adjacent to the carbonyl group\ but the other hydroxyl groups are una}ected[However\ reactions of sugars with N!methyl!N!phenylhydrazine give osazones in which the quasi!aromatic structure cannot be formed\ and all primary and secondary hydroxyl groups are convertedinto hydrazones ð53JA621Ł[

Osazones may be prepared from a!diketones by treatment with an excess of a substituted hydra!zine\ or from a!hydroxy\ a!halo\ a!methoxy\ a!acetoxy and a!dialkylamino ketones "Scheme 06#[The reaction of aryl hydrazines with a!hydroxy ketones or aldehydes leads to formation of arylhydrazones\ osazones\ or both[ The ratio of products is dependent on the stoichiometry of reactants\the experimental conditions employed\ and the structure of the reactants[ Several alternative mech!anisms have been proposed to account for the formation of osazones from a!hydroxy ketonesð25CB230\ 41JA3220\ 55JA2754Ł[ Hydrazones are produced in the presence of strong acids ð46CB241\47CB1534\ 52CB540\ 52CB547Ł\ but in mildly acidic media both the hydrazone and osazone productsmay be obtained[ In aqueous acetic acid\ the proportion of osazone to hydrazone rises withincreasing acid concentration ð52CB547Ł[ Hydrazones rather than osazones are favoured in neutralaqueous or alcoholic solutions ð46CB241\ 52CB540Ł[

R1R2

O

O R1R2

N

O

N

R4

R3

R1R2

N

N

N

R4

R3

NR3

R4

R1R2

O

X

Scheme 17

+R3R4NHNH2 R3R4NHNH2

X = OH, Cl, Br, OMe, OAc, NR2

a!Halo carbonyl compounds react with hydrazines to give hydrazones or osazones depending onthe structure of the reactants\ stoichiometry and the experimental conditions used ð41JA3220Ł[ Forexample\ Brady|s reagent reacts with a variety of a!halocycloalkanones at room temperature tofurnish the corresponding a!halo hydrazones\ and osazones can be prepared from these a!halohydrazones by heating them with an excess of the reagent ð41JA3220\ 44JA0992Ł[ In contrast\ treatmentof dichloroacetaldehyde with either phenyl hydrazine or o\p!dinitrophenyl hydrazine a}ords onlythe corresponding glyoxal osazones ð29JCS85\ 50JOC468Ł[ In general\ if the hydrazone of an a!haloaldehyde is required\ the reaction should be performed in a concentrated mineral acid ð50JOC468Ł[

The a!halo hydrazones are very reactive and will react with methanol to a}ord a!methoxyhydrazones ð41JA3220\ 44JA0992Ł\ and with acetic acid to give a!acetoxy hydrazones ð42JA5915Ł[ a\b!Unsaturated hydrazones can be formed by elimination reactions of these compounds ð41JA3220Ł[

Aryl hydrazines oxidise benzylic or allylic primary and secondary alcohols to give ketones whichthen react further to a}ord hydrazones ð40JCS0651\ 47JOC1903Ł[ The reaction is acid catalysed andosazone formation is favoured when aryl hydrazines with electron!withdrawing substituents areused ð25CB230\ 49JCS0217Ł[ The mechanism of this reaction is similar to that proposed for theformation of sugar osazones ð41JCS550Ł[

2[01[0[5 Cyclic Hydrazone and Azine Derivatives

There are many synthetic methods for the preparation of cyclic hydrazones and azines ð73CHEC"2#0\73CHEC"4#056\ 73CHEC"4#294Ł[ The following brief survey focuses on those methods of general pre!parative use or of special interest\ in which ring construction occurs concurrently with hydrazoneor azine formation[

2[01[0[5[0 1!Pyrazolines and 1!pyrazolin!4!ones

One of the simplest methods of preparing 1!pyrazolines is by reaction of a\b!unsaturated ketoneswith hydrazines[ Aryl hydrazines react with a\b!unsaturated ketones under acidic or basic conditionsðB!73MI 201!92Ł[ Terminal enones are the best substrates for the reaction\ and catalysts are not


usually required with these substrates[ For example\ reaction of phenylhydrazine with the ketone"01# occurs at re~ux in ethanol\ in the absence of catalysts\ to give the 1!pyrazoline "02# "Equation"2## ð44JA873Ł[ In contrast\ a\b!unsaturated aldehydes tend to be reluctant to undergo cyclization\and usually a}ord hydrazones when treated with aryl hydrazines ð14CB0863Ł[

(3)Ph

O

Ph

N N

Ph

Ph

Ph(12) (13)

PhNHNH2

EtOH, reflux

Many b!substituted ketones will react with hydrazine or aryl hydrazines to give 1!pyrazolines[The reaction can be performed using b!chloro ð25JA1949\ 42JCS1723\ 50CA"44#06415Ł\ b!bromoð42JCS1723Ł\ b!seleno ð40JA0963Ł\ b!hydroxy ð12CB0025Ł and b!amino ketones ð13CB0097\ 34JCS015\41JCS0210Ł "Equation "3##[

R1 R4

R2 R3

O XNN

R5

R1 R4

R2 R3

(4)R5NHNH2

EtOH, reflux

1!Pyrazolines can also be prepared by 0\2!dipolar cycloaddition reactions with alkenes[ Forexample\ nitrilimine "05# can be generated from either the tetrazole "03# or the a!chloro imine "04#\and reacts readily with the alkene "06# to a}ord the 1!pyrazoline "07# in good yield "Scheme 07#ð51T2Ł[ Many other alkenes can participate in this reaction ð51T2Ł[

(17)N

N

H

H

Ph

Ph

Ph N N Ph+ –

(18)

N

NN

NPh

Ph

Ph Cl

NN

H

Ph

Scheme 18

(14)

(15)

heat, 15 0–160 °C–N2

Et3N, C6H6, 20 °C(16)

N!Formyl!1!pyrazolines can be prepared by the acid!catalysed cyclization of azines "Equation"4## ð69BSF3008Ł[ The reaction occurs readily with aldazines and with ketazines which have small alkylgroups\ but hydrazone or ketone products are obtained with more hindered ketazines ð69BSF3008Ł[

NN

R1 R2

R2

R1

CHO

NN

R2 R1

R2

R1

CHO

+HCO2HN

N

R1R2

R1 R2

(5)

Acetone azine can be converted to a 1!pyrazoline hydrochloride salt by reaction with methyl!magnesium bromide followed by treatment with dilute hydrochloric acid "Equation "5## ð51JOC1654Ł[The reaction is presumed to occur by a!deprotonation by the Grignard reagent followed by cycli!zation\ but the same reaction has been reported to yield t!butylhydrazine as the major productð30LA"436#0Ł[

342Hydrazones

(6)NN

H

HClN

N i, MeMgBr

ii, HCl (aq.)

There are many methods for the preparation of 1!pyrazolin!4!ones\ the most general being thereaction of hydrazines with b!aldehydo or b!keto esters "Equation "6##[ A variety of substituentscan be present in the dicarbonyl compound\ and b!thiono esters\ b!oximino esters and b!keto amidescan be used[ In general\ substrates with small substituents give the highest yields\ and reactions failwhen R0 and R1 are both very large[ The reaction is usually performed by heating the dicarbonylcompound with the hydrazine at 099Ð199>C\ without the addition of a catalyst[ Formation of thehydrazone occurs at lower temperatures than those required to accomplish cyclization\ and hydra!zone formation and cyclization can be performed in separate reactions if required ð42CJC0914Ł[Acids and bases can be used to promote the cyclization reaction ð37JA0879Ł[

R1 OR4

O O

R2 R3

NN

R1 O

R5

R2 R3

H2N NHR5 (7)+

R1–R3 = H, alkyl, aryl; R4, R5 = alkyl, aryl

1!Pyrazol!4!ones can be prepared by treatment of alkynyl acids\ esters or amides with phenylhydrazine "Equation "7## ð30JA0040Ł[ b!Alkoxy!\ b!alkylthio! and b!acylthio!a\b!unsaturated estersreact with hydrazine in a similar manner[ 1!Pyrazol!4!ones can also be prepared by reaction ofmany other heterocyclic compounds with hydrazine\ as summarized in Scheme 08[

(8)NN

R1 O

Ph

H2N NHPh+R1

X

O

R1 = alkyl, aryl; X = OR2, NR22

2[01[0[5[1 Tetrahydropyridazines

0\3\4\5!Tetrahydropyridazin!5!one "10# can be prepared from the hydrazone "19# formed bytreatment of the g!keto nitrile "08# with a diazo compound[ Treatment of hydrazone "19# with HBrin acetic acid leads to the formation of "10# in good yield "Scheme 19# ð58LA"615#70Ł[

0\3\4\5!Tetrahydropyridazin!3!ones "12# can be prepared by JappÐKlingemann reaction of g\d!unsaturated b!keto esters and b!diketones "Scheme 10# ð79S512Ł[ The reaction proceeds via theintermediate hydrazone "11#[

0\3\4\5!Tetrahydropyridazines can be prepared by ð3¦1Ł!cycloaddition reactions[ For example\the diazadiene "13# generated from an a!chloro hydrazone\ undergoes an inverse!electron!demandDielsÐAlder reaction with cyclopentene to give the cycloaddition product "14# in good yield "Scheme11# ð66TL006Ł[

An unusual example of the preparation of 0\3\4\5!tetrahydropyridazine involving ring expansionof pyrrolidine has been reported ð54JA282Ł[ Treatment of pyrrolidine with Angeli|s salt a}ords0\3\4\5!tetrahydropyridazine\ presumably by formation and rearrangement of the diazene "15#"Scheme 12#[ This reaction is of limited synthetic value\ and is not successful when piperidine ormorpholine are used as substrates ð54JA282Ł[

2[01[0[5[2 Cyclic azines

Cyclic azines such as 3\4!dihydropyridazines can be prepared by reaction of 0\3!diketones withhydrazine "Equation "8## ð59JOC845Ł[ This is usually the simplest way of making these compounds[Other 0\3!dicarbonyl compounds can be used as substrates for this reaction[ For example\ reactionsof g!keto esters with hydrazine a}ord dihydropyridazinones[ The reaction can also be applied to


NN

H

O

R2

R1

N

NHO OHON

Ph O

ON

NH2

O O

EtO2C

O

O O

O

O OHO2C

Scheme 19

⟨54CA3342⟩

⟨24CR(178)811⟩

⟨54JA4931⟩

⟨1894CB970⟩

⟨1894CB970, 05CB2023⟩

⟨1893CB2053⟩H2NNH2

H2NNH2

H2NNH2

H2NNH2

H2NNH2

H2NNH2

Cl

O

Cl N2 CO2Et

OCN

N

CO2Et

CN

N

H

Cl

HO

Cl

i, HBr, HOAc

ii, H2O

(19) (20)

+

Scheme 20

N

Cl

HO

ClN

O

CO2Et

(21)

R1 Y

R2 O O

R3

R1 Y

R2 O O

NN

Ar

H

Y

O O

NN

Ar

Scheme 21

R1

R2

(22) (23)

ArN2+ X–

R1, R2 = H, alkyl, aryl; Y = R3, OR3

344R1C1NX Functions

NN

H

Cl

CO2Me

CONH2

NN

CO2Me

CONH2

NN

CO2Me

CONH2

H

H

Scheme 22

(17)

(24) (25)

NaHCO3 (aq.), Et2O

NH N

H

NN

N–

Scheme 23

+Na2ONNO2

(26)

the preparation of larger cyclic azines[ For example\ the diazepine "17# can be synthesized in goodyield by reaction of 0\4!diketones such as "16# with hydrazine "Equation "09## ð45JA3369Ł[

(9)

OO

R1

R2

NN

R1

R2H2NNH2

(10)H2NNH2

O

O

R1

R2

N

N

R2

(27) (28)

R1

An interesting reaction occurs when cyclopropane!0\1!dicarboxaldehyde is treated with hydrazineð57CB0243Ł[ The unusual polycyclic compound "29# is obtained as a mixture of three isomers\ insteadof dihydropyridazine "18# "Scheme 13#[

CHO

CHON

N N

N

NN

N

N

Scheme 24

(29) (30)

H2NNH2

2[01[1 R1C1NX FUNCTIONS "X�P\ As\ Sb\ Bi\ Si\ Ge\ B or METAL#

2[01[1[0 Imines Substituted with Phosphorus or Arsenic

Phosphorus!substituted ketimines can be prepared straightforwardly from N!unsubstituted keti!mines or from N!metallo imines[ The reaction of phosphines of the type PX1Cl with imines in thepresence of triethylamine a}ords the corresponding N!phosphinyl ketimines X1PNCR1 in good yield[The N!phosphinyl ketimines from this reaction can be converted to N!thiophosphinyl ketimines


PPh1"S#NCR1 "R�Ph\ OMe\ OEt# by treatment with sulfur\ or converted to phosphonium salts"MeX1PNCR1#¦ I− "X�Cl\ Me\ Ph and R�Ph\ OMe\ OEt# by treatment with iodomethaneð60CB0088Ł[

Reactions of phosphorus chlorides such as PCl2\ Ph1PCl and P"O#Cl2 with one\ two orthree equivalents of LiNCR1 at low temperature a}ord compounds of the type Cl1P"NCR1#\P"NCR1#2\ Ph1P"NCR1#\ Cl1P"O#"NCR1#\ ClP"O#"NCR1#1\ P"O#"NCR1#2 "R�But\ Ph\ p!MeC5H3#ð67JCS"D#875Ł[ Similarly\ treatment of PCl2\ PF2 or PF1Cl with three equivalents of LiNC"CF2#1 atroom temperature results in formation of PðNC"CF2#1Ł2 ð60MI 201!91\ 61IC131Ł[ Compounds of thetype ClP"NCR1#1 cannot be prepared by this procedure because of disproportionation of thesecompounds to mixtures of Cl1P"NCR1# and P"NCR1#2[

Arsenic!substituted imines can be prepared by reactions that are analogous to those used toprepare the phosphorus compounds above[ Thus\ treatment of AsCl2 with three equivalents ofLiNC"CF2#1 at low temperature a}ords As"NCR1#2 in modest yield ð60MI 201!91\ 61IC131Ł[

2[01[1[1 Imines Substituted with Silicon\ Germanium\ Tin or Lead

There are many ways of preparing N!silyl aldimines and ketimines\ and these compounds havebeen used extensively as intermediates for the synthesis of b!lactams[ The simplest route to N!silyl imines involves treatment of an appropriate carbonyl compound with a sodium or lithiumbis"trialkylsilyl#amide "Scheme 14# ð52CB1021Ł[ This method has the disadvantage that it is onlygenerally suitable for the preparation of N!silyl imines from nonenolizable aldehydes and ketonesð72JOC178\ 74CC428\ 78JCS"P0#168Ł\ although some enolizable aldehydes can be converted into N!silylaldimines when the reaction is performed at low temperature ð76TL4258\ 80TL1856Ł[

R1 R2

O+ M N

SiR33

SiR33

N

SiR33

SiR33MO

R1

R2

R1 R2

NSiR3

3

Scheme 25

–78 °C to RT –MOSiR33

M = Li, Na

Because of the problems associated with the preparation of N!silyl imines from enolizable carbonylcompounds\ several alternative methods of preparing these compounds have been developed[ Enol!izable N!trimethylsilyl aldimines can be prepared in good yield by treatment of "TMS#1NCHO withorganolithium reagents at low temperature "Scheme 15# ð78TL3164Ł[ N!Silyl imines can also beprepared by the reaction of silyl chlorides with N!lithio imines ð56JOM"8#120\ 61IC131\ 62JCS"D#046\65JCS"D#0Ł\ iminoborates ð65JOM"007#C0Ł\ iminoaluminates ð75TL0584Ł\ or N!trialkylstannyl imines"Scheme 16# ð89PAC594Ł[

N CHO + RLi

TMS

TMS–78 °C, THF –LiO-TMS

N

TMS

TMS OLi

R R

NTMS

Scheme 26

R1 R2

NLi

R1 R2

NSnR3

R1 R2

NSiR3

R1

NAl(OR)3Li

R3SiCl, (R3Sn)2O

–[(R3Sn)3O]+ Cl–

R3SiCl, –LiCl

Scheme 27

R3SiCl–LiCl, –Al(OR)3

(R2 = H)

346R1C1NX Functions

Enolizable N!trimethylsilyl aldimines can be synthesized in good yield by vacuum gasÐsolidreactions "VGSR# in which a!"N!silylamino#nitriles are dehydrocyanated on solid potassium hydr!oxide "Scheme 17# ð77TL0176Ł[

NH2

CNR1

N

CNR1

R2Me2Si HN

R1

Scheme 28

SiMe2R2R2Me2SiCl, Et3N, CH2Cl2, –60 °C

MeCN, 50 °C

KOH, 60 °C (VGSR)

–HCN

R1 = H, Me, Et, Pr; R2 = Me, But

The reaction of N!trialkylsilyl iminophosphoranes with ketones provides an interesting route toN!trimethylsilyl imines[ For example\ reaction of the iminophosphorane "20# with the ketone "21#in dichloromethane or diethyl ether a}ords the N!trimethylsilyl imine "22# in good yield "Equation"00## ð65CB0380Ł[

N

PPh Ph

Ph

TMSN

F3C CN

TMSO

F3C CN(11)

(31) (32) (33)

+CH2Cl2, Et2O

–Ph3PO

N!Germyl imines can be prepared by reaction of alkyl germanium chlorides or GeX3 "X�Cl\Br# with N!lithio imines ð56JOM"8#120\ 60JA5692\ 62JCS"D#046\ 65JCS"D#0Ł\ and mixed imino germyleneÐchromium complexes such as "CO#4CrGe"Cl#NCPh1 and "CO#4CrGe"NCPh1#1 can be synthesized byreaction of one or two equivalents of Et2GeNCPh1 with Cl1GeCr"CO#4 =THF at room temperatureð76JOM"220#00Ł[

N!Stannyl imines are easily synthesized by reaction of alkyl tin halides or SnX3 "X�Cl\ Br# withN!lithio imines ð56JOM"8#120\ 62JCS"D#040\ 62JCS"D#046\ 65JCS"D#0Ł[ These compounds can also beprepared directly from the corresponding aldehyde or ketone by treatment with N"SnMe2#2 "Scheme18# ð89PAC594\ 80SL132Ł[ Because of the low basicity of N"SnMe2#2\ enolizable carbonyl compoundsare not deprotonated\ and N!stannyl imines are obtained in good yield ð89PAC594Ł[

N

R1 R2

SnMe3O

R1 R2N SnMe3

Me3Sn

Me3Sn

Me3SnN OSnMe3

R1R2

Me3Sn

+

Scheme 29

–(Me3Sn)2O

Rearrangement reactions of a!azidostannanes provide a rather unusual but mild method ofpreparing N!trimethylstannyl imines "Equation "01## ð81JA0218Ł[ Although there are very few exam!ples of this reaction\ it may prove to be useful for the preparation of N!stannyl aldimines that aredi.cult to prepare by conventional methods[

(12)N3

SnMe3

NSnMe3

21 °C, –N2

It has been reported that the N!plumbyl imine Ph2PbNCPh1 can be prepared by reaction ofLiNCPh1 with Me2PbCl ð56JOM"8#120Ł[ However\ only impure material was obtained\ and thecompound was not fully characterized[

2[01[1[2 Imines Substituted with Boron or Aluminium

Alkyl and aryl nitriles can be converted into N!boryl imines by partial reduction with dialkyl!boranes "Equation "02## ð53JCS0538\ 81TL516Ł[ Monoalkylboranes can also be used\ and reaction


times are usually shorter than with dialkylboranes ð81TL516Ł[ The N!boryl imines produced byreaction of nitriles with monoalkylboranes contain a hydrogen which exhibits low reactivity withimines\ and so overreduction does not occur ð81TL516Ł[ N!Boryl imines can also be preparedby partial reduction of nitriles using diborane or boraneÐtetrahydrofuran complex ð59JCS1503\80JCS"P0#0656Ł\ and these compounds have been used as intermediates in the synthesis of secondaryamines from nitriles ð80JCS"P0#0656Ł[ A related reaction has been used to prepare iminoboratecompounds[ For example\ treatment of RCN "R�But\ c!C5H00\ Ph# with one equivalent ofM¦"HBEt2#− "M�Na\ Li# a}ords the corresponding iminoborate M¦"Et2BNCHR#− in goodyield ð65JOM"007#C2Ł[ Trialkyl boranes can also be used to prepare N!boryl imines from nitrilesð58JCS"A#322Ł[ For example\ reaction of Bun

2B with ButCN at 049Ð059>C gives Bun1BNCHBut

ð57CC149A\ 58JCS"A#322Ł[

(13)R1 CN + H B

R2

R3

THF, RT

R1

NB

R2

R3

R1 = alkyl, aryl; R2, R3 = H, alkyl

Many N!boryl imines have been prepared by the reaction of haloboranes with N!trialkylsilyl orN!lithio imines\ or from free imines "Scheme 29# ð57CC149B\ 69JCS"A#1909\ 61JCS"D#269Ł[ Good yieldsof N!boryl imines can be obtained using this method ð61IC131Ł[

N

R1 R2

LiN

R1 R2

BRnX2–nN

R1 R2

H

Scheme 30

BRnX3–n, –196 °C to RT BRnX3–n, toluene, reflux, –HX

X = F, Cl, Br, I; R1, R2 = alkyl, aryl

N!Alumino imines are useful precursors for the synthesis of other substituted imines and can beprepared by a variety of routes ð89PAC594Ł[ The simplest method of preparing aluminum aldiminesis by treatment of nitriles with diisobutylaluminum hydride "Equation "03## ð89JOC3088Ł[ A largenumber of aluminum imines have been prepared from nitriles ð56AG"E#792\ 56AG707\ 82JOM"345#050Ł\or cyanohydrins in this manner ð89TL2370\ 82T2798Ł[

(14)R CN + Al H

Bui

Bui

R

NAl

Bui

BuiC5H12, –78 °C

R = alkyl, aryl

Aldimino aluminates can be prepared in good yield by partial reduction of aromatic and aliphaticnitriles with lithium triethoxyaluminum hydride ð53JA0974\ 75TL0584Ł[ Lithium aluminum hydridecan be used to perform the same reaction\ but overreduction can be a problem with certain substratesð53JA0974Ł[ Sodium or lithium trialkylaluminum hydrides of the type M¦"R0

2AlH#− "M�Li\ Na\R0�Et\ Bui# react with nitriles of the type R1CN "R1�Et\ Pr\ Ph\ p!MeC5H3\ p!MeOC5H3\ c!C5H00\PhCHCH\ 1!furyl\ 1!thienyl# to give the imino aluminates M¦"R0

2AlNCHR1#− ð65JOM"007#C2\77JCS"P0#834Ł[ The aluminate Li¦ðAl"NCBut

1#3Ł− can be prepared by reaction of aluminium chloridewith four equivalents of LiNCBut

1 ð60CC0164Ł[N!Alumino ketimines can be prepared by the addition of trialkylaluminum reagents to nitriles[

Addition of a trialkylaluminum to an alkyl or aryl nitrile furnishes complex "23# which rearrangesto the corresponding dimeric N!alumino ketimine "24# in good yield when heated to 099Ð199>C"Scheme 20# ð53CB1550\ 54JCS1551\ 54JCS4972Ł[

The gallium!substituted imines "Et1GaNCHPh#1 and "Et1GaNCHBut#1 can be synthesized bythermal rearrangement of the complexes produced by reaction of GaEt2 with PhCN or ButCNð56JCS"A#0111Ł[ These reactions are analogous to those of trialkylaluminum reagents with nitriles[

348R1C1NX Functions

2R1 C N 2R1 C N AlR23

Al

N

Al

N

R2R2

R2 R2

R2

R1 R2

R1

Scheme 31

+ AlR23

(34) (35)

100–200 °C

2[01[1[3 Imines Substituted with Lithium

N!Lithio ketimines are usually prepared by reaction of alkyl lithiums with nitriles or by depro!tonation of N!unsubstituted ketimines[ Both methods are of limited synthetic use because competingdeprotonation can occur with substrates containing labile hydrogen atoms adjacent to the nitrile orimine ð63BSF0609Ł[ N!Lithio ketimines such as LiNCBut

1\ LiNCPh1\ and LiNCPhBut have beenprepared by addition of ButLi or PhLi to t!butylnitrile or benzonitrile ð61JCS"D#0490\ 76JCS"D#0960\76JCS"D#1030Ł\ and LiNCBut

1\ LiNCPhBut and LiNC"CF2#1 have been prepared by deprotonationof the corresponding N!unsubstituted ketimines ð61IC131\ 82CB846Ł[ The ketimine precursors areeasily obtained by Grignard additions to the corresponding nitriles and subsequent hydrolysis[ Theimine HNC"CF2#1 can be prepared from hex~uoroacetone ð54JOC0287Ł\ and then deprotonated withan alkyl lithium reagent to give the potentially explosive compound LiN1C"CF2#1 ð54JOC0287\61IC131Ł[

2[01[1[4 Imines Substituted with Beryllium or Magnesium

Beryllium!substituted imines can be prepared by reaction of N!lithio ketimines with berylliumchloride ð69JCS"A#1905Ł[ Reactions of beryllium chloride with LiNC"p!MeC5H3#1 or LiNC"p!MeC5

H3#"But# a}ord "BeClðNC"p!MeC5H3#1Ł#1 and "BeðNC"p!MeC5H3#1Ł1#2\ or "BeClðNC"p!MeC5H3#"But#Ł#1 and "BeðNC"p!MeC5H3#"But#Ł1#1\ depending on the reaction stoichiometry ð69JCS"A#1905Ł[The oligomeric complex ðBe"NCPh1#1Łn can be obtained by treatment of beryllium chloride withLiNCPh1\ and the dimeric complex ðBeCl"NCPh1#Ł1 can be prepared by reaction of berylliumchloride with TMS!NCPh1 in diethyl ether ð69JCS"A#1905Ł[ The compound ðBe"NCBut

1#1Ł1 can beprepared by reaction of two equivalents of HNCBut

1 with BePri1 in diethyl ether ð65CC059Ł[

Addition of Grignard reagents to nitriles is the most direct method of preparing N!magnesioketimines[ Many examples of the reaction are known ð37JA1901\ 49JA765\ 40JA31\ 44OSC"2#15\44OSC"2#451Ł\ and the reaction mechanism has been studied in detail ð36JA1295Ł[ Rates of additionare markedly altered by the amount of magnesium bromide added to the reaction ð55JOC2264Ł\ andproduct yields can be improved by using benzene containing one equivalent of diethyl ether assolvent\ rather than diethyl ether alone ð79TL044Ł[ Competing deprotonation can be a problemwhen acetonitrile is reacted with Grignard reagents\ but nitriles without a!hydrogens\ or those withlonger alkyl chains\ react to form N!magnesio ketimines in good yield ð61JOC2258Ł[ Even sensitivea\b!epoxy nitriles can be converted into the corresponding N!magnesio imines by reactions withGrignard reagents ð81JOC4945Ł[

N!Magnesio imines can be prepared by treatment of d! or o!iodonitriles with magnesium in ether"Scheme 21# ð64JOM"76#14Ł[ Intramolecular reactions between the nitrile group and the Grignardreagent formed from the iodide a}ord the corresponding metallated cyclopentyl or cyclohexylimine[

IMgCN

R2

R1

( )nI

CN

R2

R1

( )n

R1

R2

NMgI

Scheme 32

( )n

Mg, Et2O, reflux

n = 1, 2; R1 = H, alkyl; R2 = alkyl


2[01[1[5 Imines Substituted with Titanium\ Zirconium or Hafnium

Several titanium and zirconium N!metallo ketimines are known[ The complexes Cp1MCl"NCR1#and Cp1M"NCR1#1 "M�Ti\ Zr and R�Ph\ p!MeC5H3\ But# can be prepared by treatment oftitanocene or zironocene dichloride with either one or two equivalents of an appropriate N!lithioketimine in diethyl ether ð60MI 201!90Ł[ Forcing conditions are usually necessary for successfuladdition of a second equivalent of the N!lithio ketimine\ and with bulky substrates\ such as LiNCPh1

and LiNCBut1\ the second chlorine on titanium is not replaced[ The complexes Cp1TiClðNC"CF2#1Ł

and Cp1TiðNC"CF2#1Ł1 have been prepared in an analogous fashion by treatment of titanocenedichloride with one or two equivalents of LiNC"CF2#1 ð60CC104\ 60MI 201!90Ł[

The compound Cp1TiCl"NCPh1# can be prepared by reaction of titanocene dichloride withMe2SiNCPh1 in xylene at re~ux\ with removal of the trimethylsilyl chloride produced during thereaction ð60MI 201!90Ł\ and Cp1TiClðNC"CF2#1Ł can be obtained by treatment of titanocene dichloridewith Me2SnNC"CF2#1 in benzene at re~ux ð62JCS"D#040Ł[

The complexes Cp1Zr"NCPh1#1\ Cp1Hf"NCPh1#1 and Ti"NCPh1#3 can be synthesized by treatmentof Cp1Zr"NMe1#1\ Cp1Hf"NEt1#1 and Ti"NMe1#3 with either two or four equivalents of HNCPh1 indiethyl ether at re~ux ð60MI 201!90Ł[

2[01[1[6 Imines Substituted with Molybdenum or Tungsten

Molybdenum and tungsten N!metallo ketimines can be prepared in good yield from N!trialkylsilylimines[ For example\ heating TMS!NCPh1 with CpM"CO#2X "M�Mo\ W and X�Cl\ Br\ I#a}ords the complexes ðCpM"CO#"NCPh1#Ł1 and CpM"CO#1"NCPh1# in good yield ð69JCS"A#1168Ł[When CpMo"CO#2X is used\ the reaction proceeds via a dinuclear complex\ and careful control ofthe reaction conditions is required if the mononuclear complex is to be isolated[

The corresponding reactions of LiNCPh1 with CpM"CO#2X "M�Mo\ W and X�Cl\ Br\ I# arenot successful\ and a}ord complexes of the type CpM"CO#1"Ph1CNCPh1# "M�Mo\ W# rather thanN!metallo ketimine complexes ð69JCS"A#1168Ł[ Other N!lithio imines such as LiNCPhBut and LiNCBut

1 do react to give the desired N!metallo imines ð69CC441\ 60JCS"A#181Ł[ When LiNC"p!MeC5H3#1is used\ mixtures of the N!metallo imine complex and CpM"CO#1"Ar1CNCAr1# "M�Mo\ W# areproduced[ The relative amount of each product depends on the reaction conditions employed andthe metal ð61JCS"D#042Ł[

2[01[1[7 Imines Substituted with Manganese

N!Metallo imines of manganese can be prepared from either N!lithio or N!stannyl imines ð79MI201!90Ł[ Reaction of either LiNC"CF2#1 or Me2SnNC"CF2#1 with Mn"CO#4Br at room temperature inan appropriate solvent a}ords the dimeric complex Mn1ðNC"CF2#1Ł1"CO#6 in good yield ð64IC0564Ł[Addition of a phosphine "Ph2P\ Ph1MeP\ or PhMe1P# to this dimeric complex gives the monomericcomplex Mn"CO#1"PR2#1ðNC"CF2#1Ł in good yield[

2[01[1[8 Imines Substituted with Iron

The dimeric complex di!m!"3\3?!dimethylbenzophenoniminato#bis"tricarbonyliron# "25# has beenprepared by the reaction of Fe"CO#4 with the azine "Ph1CN#1 "Equation "04## ð56CC134Ł[

Ph NN Ph

Ph

Ph

2Fe(CO)5 +Fe

N

Fe

N

COOC CO

COOC CO

Ph

PhPh

Ph

(15)–4CO

(36)

A more general approach to the synthesis of iron!substituted imines involves reaction of ironcomplexes of the type CpFe"CO#1X "X�Cl\ Br\ I#\ or Fe"CO#3X1 "X�Br\ I#\ with N!lithio ketiminesat low temperature ð63JCS"D#0519Ł[ The complexes CpFe"CO#"NCBut

1#\ ðFe"CO#2"NCPh1#Ł1\

350Diazo Compounds

"Fe"CO#2ðNC"3!MeC5H3#1Ł#1\ ðFe"CO#2"NCPhBut#Ł1\ Fe1"CO#5I"NCPh1#\ Fe"CO#5I"NCPh1#\ Fe"CO#5IðNC"3!MeC5H3#1Ł\ and Fe"CO#5I"NCPhBut# have been prepared in low yield by this routeð63JCS"D#0519Ł[

2[01[1[09 Imines Substituted with Platinum or Rhodium

Several platinum!substituted ketimines are known\ and they can be prepared from N!lithioketimines ð60CC104Ł[ For example\ reaction of LiNC"CF2#1 with cis!"Ph2P#1PtCl1 a}ords cis!"Ph2P#1PtClðNC"CF2#1Ł in good yield\ even when an excess of LiNC"CF2#1 is used[ In contrast cis!"Me1PhP#1PtCl1 reacts with LiNC"CF2#1 to give cis!"Me1PhP#1PtðNC"CF2#1Ł1 as the major product\even when the reactants are present in equimolar amounts[ Platinum complexes such as trans!"Ph2P#1PtHðNC"CF2#1Ł and trans!"Me1PhP#1PtHðNC"CF2#1Ł can be prepared by similar reactions\and the rhodium complex "Ph2P#2RhðNC"CF2#1Ł has been prepared by reaction of "Ph2P#2RhClwith LiNC"CF2#1 ð60CC104Ł[ Treatment of cis!"Ph2P#1PtCl1 with HNC"CF2#1 in the presence oftriethylamine provides a low yielding alternative route to "Ph2P#1PtClðNC"CF2#1Ł ð60CC104Ł[

The preparation of platinum!substituted ketimines can also be accomplished from the cor!responding N!stannyl ketimines[ For example\ treatment of cis!"Ph2P#1PtCl1 with eitherMe2SnNC"CF2#1 or Me2SnNCPh1 in benzene at re~ux a}ords cis!"Ph2P#1PtClðNC"CF2#1Ł or cis!"Ph2P#1PtClðNCPh1Ł in excellent yield ð62JCS"D#040Ł[ The more bulkly imine Me2SnNCBut

1 fails toreact with cis!"Ph2P#1PtCl1 under these conditions[ Reaction of trans!"Ph2P#1Pt"Cl#H withMe2SnNC"CF2#1 in xylene at re~ux gives a low yield of trans!"Ph2P#1Pt"SnMe2#ðNC"CF2#1Ł\ themajor product being "Ph2P#1PtðHN1C"CF2#1Ł ð62JCS"D#040Ł[

2[01[1[00 Imines Substituted with Zinc

The formation of zinc ketimines by addition of zinc ester enolates to nitriles has been known formany years ð90CR"021#367Ł\ and provides a useful route to b!keto esters "Scheme 22# ð72JOC2722Ł[The Blaise reaction is analogous to the Reformatsky reaction and works best with bromoesterswhich contain at least one alkyl group in the a!position ð42JOC0483\ 55BSF0708Ł[ Acetonitrile is apoor substrate for the reaction when the original procedure is used "reaction in benzene at re~ux#ð42JOC0483Ł\ but later reports suggest that acetonitrile and nitriles with labile a!hydrogen atomsreact in a satisfactory manner under modi_ed conditions ð55BSF0708\ 63JOM"70#028Ł[ High yields ofaddition products are obtained when the Reformatsky reagent is prepared using activated zinc dust\and the reaction is performed by slow addition of the a!bromo ester to the metal in tetrahydrofuranat re~ux in order to minimize self!condensation ð72JOC2722Ł[ Even a!unsubstituted bromoacetatesreact e.ciently with nitriles when these conditions are used[

R1OBr

O

R2

R1OZnBr

O

R2R1O

O

R2

R3

NZnBr

Scheme 33

Zn, THF, reflux R3CN, THF, reflux

Dialkyl zinc reagents add to benzonitrile to give zinc!substituted imines ð57JCS"A#46Ł[ Additionof R1Zn "R�Me\ Et\ Ph# to benzonitrile at low temperature\ followed by warming to roomtemperature\ a}ords zinc complexes of the type "RZnNCPh1#1 "R�Me\ Et\ Ph# ð57JCS"A#46Ł[ Whenthese complexes are heated to 79>C they disproportionate to give Zn"NCPh1#1 and R1Zn[

2[01[2 DIAZO COMPOUNDS

2[01[2[0 General Methods for the Preparation of Diazo Compounds

There is a wide array of methods available for the preparation of diazo compounds\ and choiceof method is largely dictated by the nature of the functional groups required in the diazo compound[The most commonly used and widely applicable methods for the synthesis of diazo compounds fall


into three general categories] "i# reaction of two nitrogen!containing compounds to form a diazocompound\ "ii# conversion of a group which contains two nitrogen atoms into a diazo group\ and"iii# diazo group transfer to a substrate from a suitable donor compound[

Diazo compounds can be modi_ed\ usually by electrophilic substitution at the diazo carbon orby functionalization at remote sites\ but the reactive nature of the diazo group limits the choiceof reagent in subsequent functionalization reactions and precludes the use of many standardtransformations[

A comprehensive account of the synthesis and properties of diazo compounds\ in which thepreparation of diazo compounds is listed according to reaction type\ is given in an excellent bookby Regitz and Maas ðB!75MI 201!90Ł[

2[01[2[1 Alkyl and Aryl Diazo Compounds

2[01[2[1[0 Diazotization of amines

Diazotization of amines with nitrous acid is one of the oldest methods of preparing aliphaticdiazo compounds "Scheme 23# ð0772CB1129Ł[ The success of this reaction is dependent on the natureof the substituents that are adjacent to the amino group in the precursor[ It is usually necessary tohave one or more electron!withdrawing substituents "R0 or R1# at the a!position in order to facilitatedeprotonation of the intermediate diazonium species "26#\ otherwise loss of nitrogen a}ords acarbocation which then reacts further[

N2

R2

R1

R2

R1

Scheme 34

+

NH2

R2

R1

N2+

R2

R1H+, HNO2

–2H2O

–H+

–N2

R1 or R2 = electron-withdrawing group

(37)

Methylamine can be converted into diazomethane using nitrosyl chloride under basic conditions"Scheme 24# ð59CB0430Ł[ In this case\ an intermediate nitrosoamine "27# is formed and activatinggroups are not required[ Other diazo alkanes can be prepared by this reaction\ but careful controlof the stoichiometry is necessary in order to obtain good yields ð57ACS0722Ł[ The same trans!formation can be accomplished by reacting an amine with nitrosyl chloride and then treatment ofthe resulting diazohydroxide "28# with acetic acid and ammonia "Scheme 25#[ Partial decompositionof the diazo compound by acetic acid may occur during the reaction\ and in many cases poor yieldsof the diazo compound are obtained ð70ACS"B#068\ 71ACS"B#016Ł[

N NO

Me

H

(38)

KOH (aq.)Me NH2

Me

N N

O– K+

H2C N2+

Scheme 35

EtOK, –EtOH

KOH (aq.)

NOCl, Et2O, –80 °C

352Diazo Compounds

NH2

R2

R1

N

R2

N

OH

N2+

R2

R1

N2

R2

R1

Scheme 36

(39)

NOCl, Et2O, –78 °C MeCO2H

–H2O+ MeCO2H

R1

MeCO2–

2[01[2[1[1 Forster reaction of oximes

The Forster reaction is useful for the synthesis of diazomethane and aryldiazoalkanes "Scheme26# ð48JA3640Ł[ In this reaction\ an oxime is treated with chloramine to give the intermediate "39#which decomposes to a}ord the diazo compound ð04JCS159Ł[ Diazomethane can be prepared fromthe sodium salt of formaldehyde oxime using this reaction\ but application of the method to thesynthesis of diazo compounds possessing alkyl substituents has not been successful ð51AG358\51AG"E#392Ł[ Aryl!substituted diazo compounds can be synthesized in modest yield using this reactionð48JA3640Ł[

N

OH

R2

R1

N

OH

R2

R1

NH2

+ N2

R2

R1

+ H2N Cl

Scheme 37

–Cl– –H+, –H2O

(40)

2[01[2[1[2 Dehydrogenation of hydrazones

A variety of oxidizing agents can be used to dehydrogenate hydrazones\ and this reaction isespecially useful in cases where the hydrazone precursor can be prepared directly from the cor!responding carbonyl compound "Equation "05##[

(16)N

NH2

R2

R1

N2

R2

R1

oxidant = HgO, AgO, MnO2, Pb(OAc)4, I2, NBS, Ph3Bi(CO)3

–'H2'

oxidant

Mercury"II# oxide is often used to dehydrogenate hydrazones "Scheme 27#[ The reaction can beperformed in a variety of solvents\ and sodium sulfate can be used to trap the water liberated duringthe reaction[ Addition of trace amounts of alcoholic KOH promotes the deprotonation step andaccelerates the reaction ð48JOC459Ł[ Mercury"II# acetamide and mercury"II# tri~uoroaetamide canbe used as dehydrogenating agents in some cases ð09JCS1045\ 48JOC274Ł[

N

NH2

R2

R1

N2

R2

R1

N

N

R2

R1 Hg–OH

H

N

N

R2

R1 Hg–OH

Scheme 38

–

HgO KOH, –H+ –Hg, –HO–

(41) (42)

In certain circumstances\ the dehydrogenation of a hydrazone with mercury"II# oxide results inthe formation of products other than the desired diazo compounds[ When the reaction is performedwith secondary hydrazones\ azine formation is sometimes observed "see Section 2[01[0[0# ð00CB1086\05CB0786\ 05CB0812\ 46LA"593#022\ 55JCS"C#356Ł[ If the initial product is a reactive diazo methyl com!pound then further reaction to give the metallated diazo compound is also possible "see Section2[01[2[4[5#[

Another reagent that is frequently used to dehydrogenate hydrazones is silver"II# oxideð46LA"593#022Ł[ The reaction is promoted by the use of water absorbing agents and catalytic amounts


of base[ Reactions of hydrazones with silver"II# oxide are generally faster than those with mercury"II#oxide\ and they can be performed at lower temperatures[ Consequently\ it is usually better to usesilver"II# oxide rather than mercury"II# oxide when preparing sensitive diazo compounds fromhydrazones[

Activated manganese"IV# oxide has also been used to prepare alkyl and aryl diazoketones fromhydrazones ð50JOC1506\ 58JPR"200#593Ł[ It is essential to use freshly prepared manganese"IV# oxideotherwise a large excess of the reagent is required and yields may be reduced ð43JOC607Ł[

There are many cases in which hydrazones have been dehydrogenated using lead"IV# acetate[However\ signi_cant amounts of acetic acid are produced during the reaction\ so the method is onlysuitable for the preparation of moderately acid stable diazo compounds such as those which possessone or more electron!withdrawing groups at the diazo carbon[ The stoichiometry of the reaction isalso important and use of excess lead"IV# acetate can lead to secondary reactions[ For example\benzophenone hydrazone is converted into diphenyldiazomethane in quantitative yield when oneequivalent of lead"IV# acetate is used under optimum conditions ð63JCS"P0#0683Ł[ When two equi!valents of lead"IV# acetate are used\ side reactions occur and the yield is signi_cantly reducedð44CB416\ 69T0090Ł[

Hydrazones can be dehydrogenated to the corresponding diazo compounds using iodine in thepresence of a tertiary amine base "Scheme 28# ð51JCS369Ł[ However\ further reactions can occur insome cases leading to the formation of vinyl iodides\ and azine formation is observed in the absenceof base ð00LA"270#118\ 51JCS369Ł[

N

R2

R1

NH2 N

R2

R1

N

I

H

N2

R2

R1

Scheme 39

I2, R3N –R3NH+ I–

Several other reagents can be used for the dehydrogenation of hydrazones to diazo compounds[Reactions of metallated hydrazones with molecular oxygen have been used to prepare some simplediazo compounds ð56JA4201Ł[ Nickel peroxide has found occasional use\ and good yields of thediazo products have been obtained ð55CC629\ 70TL3826Ł[ N!Bromosuccinimide has been used toaccomplish dehydrogenation\ but signi_cant amounts of azines are formed which detract from thesynthetic utility of this reagent ð44JA0569Ł[ Triphenylbismuth carbonate has been used to preparediphenyldiazomethane from benzophenone hydrazone in excellent yield\ but the generality of thisreaction has not been explored ð68CC694Ł[

2[01[2[1[3 BamfordÐStevens reaction of tosyl hydrazones

The BamfordÐStevens reaction provides a versatile method for converting carbonyl compoundsinto diazo compounds ð41JCS3624Ł[ During the reaction\ an aryl sulfonyl hydrazone of an aldehydeor ketone is cleaved to give a diazo compound and an aryl sul_nate "Scheme 39#[ The success of thereaction is dependent on the nature of the substrate and the reaction conditions employed[ For!mation of carbenes\ cationic intermediates or vinyl anions can be problematic\ and azine formationis sometimes observed ðB!75MI 201!90Ł[

N2 + –SO2Ar

R2

R1

N

R2

R1 N SO2Ar

H

N

R2

R1 N SO2Ar

Scheme 40

–

base, –H+

The BamfordÐStevens reaction of tosyl hydrazones derived from alkyl or aryl ketones is usuallyachieved by heating the substrate with a base[ A variety of solvent and base combinations havebeen used to e}ect the reaction ðB!75MI 201!90Ł[ Unfortunately\ the rather harsh conditions requiredto promote the reaction often lead to low yields of sensitive diazo compounds[

The BamfordÐStevens reaction can also be accomplished by alkaline cleavage of methylsul_nylor 1!nitrophenylsulfenyl hydrazones ð64CC003\ 64TL0454Ł[ In the _rst case\ the diazo compound isusually isolated after treatment of the unsubstituted hydrazone with methanesul_nyl chloride in the

354Diazo Compounds

presence of two equivalents of triethylamine\ without isolation of the intermediate methylsul_nylhydrazone[

It is possible to transform aldehyde and ketone tosyl hydrazones to diazo compounds underbiphasic conditions ð66BSB628\ 67SC458Ł[ Triisopropyl benzenesulfonyl hydrazones may be used assubstrates in this reaction\ and they are cleaved more rapidly than the corresponding tosyl hydra!zones ð71S308Ł[

Dialkyl diazo compounds are often unstable under the conditions of the BamfordÐStevensreaction\ even when the reaction is performed in an aprotic solvent[ Vacuum pyrolysis of salts oftosyl hydrazones is an alternative method for the preparation of these compounds ð54JA824Ł[ Thepyrolysis reaction is useful for the synthesis of aryl diazoalkanes\ but gives only low yields whenheat!sensitive diazoalkanes are produced[ Phenyldiazomethane can be prepared in good yield fromthe sodium salt of benzaldehyde tosylhydrazone using this method ð75OS"53#196Ł[ The reaction canalso be performed by photochemical methods ð70JOC3574Ł[

2[01[2[1[4 Cleavage of N!nitrosoamines

Cleavage of b!"N!alkyl!N!nitrosoamino#ketones or !sulfones under alkali conditions results information of diazo alkanes[ For example\ cleavage of b!"N!alkyl!N!nitrosoamino#methylpentan!3!ones has been used to prepare many diazo alkanes "Scheme 30# ð24JCS175Ł[ The reaction precursorsare readily prepared by addition of the appropriate primary amine to mesityl oxide and subsequentnitrosation ð22JCS252\ 44OSC"2#133Ł\ and sodium alkoxides are usually the bases of choice for thecleavage reaction ð26JCS0440\ 38JA0518Ł[ The yield of diazoalkane may be reduced as a result ofð2¦1Ł!cycloaddition of the product with the enone liberated during the reaction[ The main use ofthis procedure is for the synthesis of diazomethane and homologous diazo alkanes ð24JCS175\55JA3624Ł[

N O

R

N

O

RO H

N O

R

N

O

O

HON

N R

Scheme 41

N2

R

–

+RO– –H2O

Diazo alkanes can be prepared by cleavage of "N!alkyl!N!nitrosoaminomethyl#carboxamides\ byanalogy to the reaction discussed above "Scheme 31#[ The reaction precursors are prepared by thecondensation of carboxamides with formaldehyde and an appropriate alkylamine hydrochloride\followed by nitrozation of the resulting amine hydrochlorides[ Both amides and urethanes havebeen used as precursors in this reaction ð65CPB258\ 68CPB571Ł[

R1 NH2

O

R1 NH

O

N

R2

+

H H

R1 NH

O

N

R2

NO

NaNO2 KOH (aq.)HCHO

R2CH2NH4Cl

–H2O

N2

R2

+R1 N

H

O OH

Scheme 42

Cl–

Diazomethane and other diazo alkanes can be prepared by the cleavage of N!acyl!N!nitroso!amines "Scheme 32#[ Urethanes\ ureas\ carboxamides\ arylsulfonamides and guanidines can be usedas precursors[ With urethanes and carboxamides\ nucleophilic attack of the base at the carbonylgroup leads to the formation of a diazotateð51OS"30#05Ł[ The diazotate intermediates have been isolatedð91CB786\ 59ZN"B#640\ 50AG110\ 52CB0601\ 54JOC3146\ 55JOC0971\ 57T1770Ł\ but are usually protonated insitu to form diazohydroxides which are then converted diazonium ions[ The diazonium ion is eitherdeprotonated to a}ord the diazo compound or loses nitrogen and forms a carbonium ion[ The


course of the reaction is in~uenced by the nature of the substituents present in the precursorð63ACR310Ł\ with branched alkyl groups favouring the formation of carbonium ions ð55JOC0971Ł[When both substituents are primary alkyl groups\ the diazo alkane is produced along with productsarising from cationic species ð40LA"462#052\ 55JOC0971Ł\ but with methyl\ benzyl and allyl substituents\diazo alkane formation is favoured ð91CB786\ 61TL4036\ 62JOC0710Ł[

XN R2

R1

NO

HON

N R2

R1 R1 R2

N2+

R1 R2

N2

Scheme 43

ROH, RO– –HO– –H+

X = RO2C, R2NCO, RCO, ArSO2, (O2NNH)C=NH

Decomposition of N!methyl!N!nitrosourethanes is accomplished by treatment with catalyticamounts of a base\ such as potassium carbonate\ in an alcoholic solvent ð41LA"464#063Ł[ Base!promoted cleavage of N!alkyl!N!nitrosoureas can also be used to prepare diazo alkanes[ In thisreaction\ deprotonation is followed by fragmentation to isocyanic acid and an alkyl diazotate[Proton transfer then a}ords the diazohydroxide which loses water to form the diazo alkane"Scheme 33# ð56LA"696#33\ 61TL4036\ 62JOC0710Ł[ N!Methyl!N!nitrosourea has been widely used forthe generation of diazomethane by this process\ in spite of the fact that it is thermally unstable[ Thereaction is usually performed in a two!phase system of aqueous potassium hydroxide and eitherbenzene or diethyl ether ð08JCS0982\ 32OSC"1#350Ł[ Removal of diazomethane by distillation allowsorganic solvents to be omitted from the reaction ð52BSF30\ 53JA0704Ł[ Other diazoalkanes have beensynthesised in good yield from their respective N!nitrosoureas under these conditions\ althoughdiazocycloalkanes are usually generated at lower temperatures because of their instability[

N

O

H2N NO

R2

R1

N

O

K+ HN N

R2

R1

OKOH, –H+

–

+ KOCNR1 R2

N2

N

R2

R1 N OH

Scheme 44

–H2O

Diazo alkanes can be prepared by treatment of N!alkyl!N?!nitro!N!nitrosoguanidines with a base"Scheme 34# ð36JA2917\ 37JA0863Ł[ The reaction proceeds by deprotonation of the amino group andsubsequent decomposition to a diazotate and nitrocyanamide\ followed by proton transfer to givea nitrocyanamide salt and the diazo hydroxide which then decomposes to the diazo compound[ Thesynthesis of diazo alkanes by this method can be hampered by di.culties associated with thepreparation of the nitrosoguanidine precursors[

N

HN

N NO

R2

R1

KOH, –H+

H

O2NN

K+ – N

N N

R2

R1

OH

O2N

–H2O

Scheme 45

–O2NNCN–K+

R1 R2

N2

N

R2

R1 N OH

356Diazo Compounds

Diazo alkanes have been prepared by base!promoted fragmentation reactions of N!alkyl!N!nitrosocarboxamides[ For example\ treatment of N!methyl!N!nitrosoacetamide with potassiumhydroxide in methanol a}ords a solution of diazomethane ð42CB65\ 42CB167Ł[ The same trans!formation can be e}ected using alkyllithium reagents ð50AG110Ł[ Diazomethane can also be preparedby cleavage of N\N!dimethyl!N\N!dinitrosooxalamide with methylamine "Equation "06##[ Diazo!methane may be distilled from the reaction mixture when a high boiling alcohol solvent is used\ orcan be generated and reacted in situ using methanolic potassium carbonate in the presence of anappropriate substrate ð50CB1436Ł[

NMe

MeNO

O

NO

NO

NHMe

NHMeO

O

(17)+ 2H2C=N2

MeNH2 or K2CO3, MeOH

a\v!Bis"diazo# alkanes can be synthesized from the corresponding dinitroso compounds "Equation"07##[ Although 0\1!bis"diazo#ethane has not been observed directly\ the existence of this compoundhas been shown by trapping experiments ð43JA330Ł[ 0\2!Bis"diazo#propane has marginal stability insolution and can be prepared by treatment of N\N?!dibenzoyl!N\N?!dinitroso!0\2!propanediaminewith sodium hydroxide in methanol ð58JA695Ł[

(18)RO2C

N NCO2R

NO NO

( )nN2 N2( )n

base

Longer chain a\v!bis"diazo# alkanes have been prepared and fully characterized ð49CB026\43JA330Ł[ A useful and high yielding route to 0\5!bis"diazo#hexane has been developed in which thenitrosamide polymer formed by nitrozation of Nylon 55\ is treated with potassium hydroxide inaqueous methanol "Equation "08## ðB!75MI 201!90Ł[

(19)NN

O

O

NO

ON

nN2

N2

KOH, MeOH, H2O, Et2O

Diazo alkanes can be prepared in good yield by reaction of N!alkyl!N!nitroso!p!toluene!sulfonamides with base[ The stable commercially available compound N!methyl!N!nitroso!p!tolu!enesulfonamide "Diazald# has a good shelf!life and has become the reagent of choice for thegeneration of diazomethane "Equation "19##[ Reaction temperatures of 49Ð69>C are required toaccomplish cleavage of this compound with base\ and gaseous diazomethane or alcohol free solutionsof diazomethane can be obtained when a high boiling solvent is used ð43RTC118\ 52OSC"3#149\79JOC4266Ł[

S

O

O

N

N

Me

O

S

O

O

ORH2C N2 + (20)KOH, ROH

2[01[2[1[5 Diazo group transfer

Enamines readily undergo regioselective cycloaddition with azides\ and during the reaction theelectrophilic azide nitrogen becomes bonded to the electron!rich carbon atom "Scheme 35# ð52CB791\54CB0027Ł[ The triazoline intermediates are isolable\ but usually decompose to the diazo alkane andan amidine during the reaction ð54CB0027\ 54CB1604\ 69LA"623#69Ł[ The reaction pathway is determinedby the nature of the substituents present in the precursor\ and the method has been used mainly forthe synthesis of diazomethane ð52CB791\ 54CB1604\ 66T754Ł[


R1 R2

N2

R1 R2

NR42R3 N

NN

R2

R1

R3

R42N R5

N–

N2+

R2

R1

R3

R42N R5

R3

N

NR42

R5

Scheme 46

+R5N3

2[01[2[2 a!Diazo Carbonyl and b!Dicarbonyl Compounds

2[01[2[2[0 Diazotization of a!amino carbonyl compounds

Diazotization of a!amino carbonyl compounds is an important reaction for the synthesis of a!diazo carbonyl compounds "Equation "10##[ This reaction was _rst used to synthesize ethyl diazo!acetate from glycine ethyl ester hydrochloride ð0772CB1129Ł\ and has been studied extensively sincethen ð0773CB842\ 91JCS487\ 13JA620\ 52OSC"3#313Ł[ The reaction is especially useful for the preparationof a!diazo esters\ a!diazo acetamides ð64JHC0080Ł\ and peptidic diazoesters ð93CB0173\ 95CB0262\95CB0268Ł[ 5!Diazopenicillinic acid derivatives have also been prepared using this reactionð56HCA0216\ 63JOC0333\ 67JOC1192Ł[

(21)R1

Y

O

NH2

R1

Y

O

N2

NaNO2, H+

Y = R2, OR2, NR22

It is possible to accomplish selective monodiazotization of substrates which contain more thanone amino group by controlling the pH of the reaction[ The reaction has been used to good e}ectin order to synthesize a!diazo esters of serine ð43JA1773\ 43JA1776\ 67JOC3555Ł[ A variety of diazoacetates ð93CB0150Ł\ diazo succinates ð29CB691\ 21CB154Ł and diesters of diazo glutaric acid ð21CB154Łhave also been synthesized in this manner\ although yields are generally low[ a!Diazo esters can beprepared by treatment of a!amino acid esters with isoamyl nitrite and acetic acid rather than sodiumnitrite ð60TL3384\ 64T116\ 71TL0764Ł[

Diazotization of a!amino ketones is not usually a good method for the preparation of a!diazoketones[ Rearrangement with loss of the amino group usually occurs during the reaction ð48JOC1960\50JA288Ł[ There are some exceptions however\ and compounds such as 2!diazocamphor ð0770CB0264Łcan be prepared using this reaction[

Diazotization of reactions of certain aromatic amines a}ord the corresponding a!diazocompounds[ For example\ 8!amino!09!nitrophenanthrene reacts with nitrous acid under acidicconditions to form 8!diazo!09!phenanthrenone "Scheme 36# ð60JCS"C#0273Ł[ In a similar fashion\diazotization of 0!aminophenazine a}ords the corresponding a!diazo ketone "Scheme 37#ð66JHC0144Ł[

NH2

NO2

N2

O

N2+

NO2

Scheme 47

H2ONaNO2, H2SO4, AcOH

a!Diazo b!dicarbonyl compounds are readily accessible by diazotization of amines\ and there aremany examples which testify to the success of the reaction ðB!75MI 201!90Ł[ The side reactionsencountered during diazotization of a!amino ketones do not usually occur with a!amino!b!dicar!bonyl compounds because proton loss from the diazonium intermediate is facilitated by the presenceof two electron!withdrawing groups[

358Diazo Compounds

N

N

NH2

N

N

N2+

N

N

N2

O

Scheme 48

Cl–

NaNO2, HCl H2O

2[01[2[2[1 Forster reaction of a!keto oximes

The Forster reaction "see Section 2[01[2[1[1[# can be used to convert a!keto oximes into a!diazoketones "Scheme 38#[ The reaction has been used extensively for the preparation of cyclic a!diazoketones and can also be applied to the synthesis of a\a?!bis"diazo#ketones[ In special cases\ thetransformation may be accomplished by condensation of an oxime with phenylhydrazine[ Thisreaction has been used to prepare 2!diazo!1\3!chromanedione "32# "Scheme 49# ð54G872Ł[

R1R2

O

R1R2

O

N2

Scheme 49

R1R2

O

NHO

oxime formation H2NCl

O

O

NOH

O O

O

N2

OO

O

NNH

O

NPh

H

Scheme 50

(43)

H2NNHPh

–H2O

–PhNH2

2[01[2[2[2 Direct nitrozation of carbonyl compounds

The synthesis of a!diazo carbonyl compounds can be accomplished by direct nitrozation of certainsubstrates[ For example\ nitrozation of the lactone "33# leads to a complex mixture which contains"34a# and "34b# "Scheme 40# ð57BCJ1696Ł[ This method has also been used to convert 0\5!diarylhexane!0\2\3\5!tetraones into bis"diazo#compounds ð79JCS"P0#1569Ł[

O

O

CO2H

CO2Et

O

O

N2

CO2EtOR

O

O

N

CO2Et

H

OH

Scheme 51

NaNO2, AcOH (aq.)

5 to 10 °C

(44) (45) a; R = Hb; R = OAc

2[01[2[2[3 Dehydrogenation of a!keto hydrazones

Many a!diazo carbonyl and b!dicarbonyl compounds have been prepared by dehydrogenation ofhydrazones "see Section 2[01[2[1[2#[ Mercury"II# oxide\ silver"II# oxide and manganese"IV# oxideare the oxidizing agents most commonly used[

When mercury"II# oxide is employed in this reaction\ a metallated a!diazo ketone may be producedif the _rst formed product is a diazomethyl ketone "see Section 2[01[2[4[01#[ The success of the


dehydrogenation reaction with mercury"II# oxide depends on the quality of the reagent[ For example\reaction of the hydrazone "35# with active mercury"II# oxide a}ords the a!diazo ketone "36#\ whereastreatment of "35# with a reagent of lower activity results in Wol}ÐKishner reduction and subsequentoxidation to the a!diketone "37# "Scheme 41# ð57HCA532Ł[

ArAr

O

N2

(46) (48)

ArAr

O

O

ArAr

O

N

(47)

Scheme 52

NH2

HgO, THF, –20 °CNa2SO4, KOH

ArAr

Odeactivated HgO oxidation

Ar = p-MeC6H4

Some less widely used dehydrogenation reagents can be used to dehydrogenate monohydrazonesof a!diketones[ For example\ 1!diazo!0\1!diphenyl!0!ethanone has been prepared in very highyield by treatment of benzil monohydrazone with copper"II# chloride and pyridine ð62TL3462Ł[Dehydrogenation of monohydrazones of a!diketones has also been accomplished using calciumhypochlorite in methanol ð50JOC1506Ł[

Oxidation of monosemicarbazones of a!dicarbonyl compounds with lead"IV# acetate is also auseful method of preparing a!diazo carbonyl compounds\ and proceeds in a similar fashion to theoxidation reactions discussed above ð67S424Ł[

2[01[2[2[4 BamfordÐStevens reaction of a!keto tosyl hydrazones

BamfordÐStevens reactions of monotosylhydrazones of a!diketones are performed by reactionwith base at room temperature\ and are especially useful for the preparation of cyclic a!diazoketones[ The harsh conditions necessary for the formation of alkyl or aryl diazo alkanes are notusually required[ Treatment with basic alumina in a suitable solvent is often su.cient to promotereaction ð47JA1146Ł\ and reactive substrates such as phenanthraquinone\ can be transformed intothe a!diazo carbonyl compound directly without base ð47JA1146\ 47LA"506#19\ 69JA1480Ł[

In some cases iminocarbonyl compounds can be used as substrates in the BamfordÐStevensreaction ð55LA"580#49\ 58TL2392Ł[ For example\ the a!diazo ketone "49# is produced by reaction of"38# with tosyl hydrazine\ and subsequent hydrolysis of this compound then a}ords the diazo dione"40# "Scheme 42# ð58TL2392Ł[

(49) (50) (51)

Ph Ph

O N

N

Ar

Ar

Ph Ph

O N

N2

Ar

Ph Ph

O O

N2

Scheme 53

TsNHNH2, C6H6 H3O+

The BamfordÐStevens reaction is also useful for the preparation of a!diazoacetates of unsaturatedalcohols[ For example\ acylation of "E#!but!1!en!0!ol with tosyl hydrazonoacetyl chloride gives theester "41#\ which upon treatment with triethylamine in dichloromethane a}ords the a!diazoacetate

360Diazo Compounds

"42# "Scheme 43# ð57JOC42Ł[ The transformation may also be achieved in a one!pot fashion byperforming the acylation reaction in the presence of two equivalents of base[

OH N O

Cl

N

Ts

HN

O

O N

Ts

H

N2

O

O

Scheme 54

(52) (53)

+NaHCO3

CH2Cl2

Et3N

CH2Cl2

The a!diazo succinate diester "44# can be prepared in good yield from methyl alkynedicarboxylate"Scheme 44# ð64BSF136Ł[ Nucleophilic addition of tosylhydrazine to the alkyne and subsequentisomerization a}ords the tosyl hydrazone "43#\ and the a!diazo ester "44# is then obtained bytreatment of "43# with potassium carbonate[

MeO2C CO2Me

MeO2CCO2Me

NN

Ts

H MeO2CCO2Me

N2

(55)(54)

Scheme 55

TsNHNH2

MONOGLYME

K2CO3 (aq.), 80 °C

2[01[2[2[5 Cleavage of N!nitrosoamides

There are a few examples of the preparation of a!diazo carbonyl compounds from N!alkyl!N!nitrosocarboxamides[ For example\ the a!diazo penicillin derivatives "46a# and "46b# have beenprepared from the acetamides "45a# and "45b# "Equation "11## ð56HCA0216\ 63JOC033Ł[ Ethyl diazo!acetate can be prepared in high yield by treatment of the nitrosoacetamide "47# with a mixture ofbarium oxide and barium hydroxide in methanol "Equation "12## ð59AG22\ 59CB1051\ 53JOC1969Ł\ andt!butyl diazo acetate can be obtained in a similar manner ð59CB1051Ł[

NO

S

HCO2R2

NR1

N

O

O

H H

NO

S

HCO2R2

H

(22)

N2

C5H5N, CHCl3, silica gel

(56) a; R1 = Ph, R2 = CH2CCl3b; R1 = PhO, R2 = CH2Ph

(57) a; R2 = CH2CCl3b; R2 = CH2Ph

(23)EtO

O

NON

O

EtO

O

N2

(58)

BaO, Ba(OH)2, MeOH

2[01[2[2[6 Diazo group transfer to carbonyl compounds

Diazo group transfer reactions are transformations in which an intact diazo unit is transferredfrom a donor to an acceptor molecule ð56AG675\ 56AG"E#622\ 61S240Ł[ This is undoubtedly the mostversatile class of reactions for the synthesis of a!diazo carbonyl and a!diazo b!dicarbonylcompounds[


The most useful substrates for diazo group transfer are those possessing active methylene groups[For example\ diazo transfer to b!dicarbonyl compounds from sulfonyl azides is performed in thepresence of tertiary amine bases "Scheme 45#[ Because of the mildness\ simplicity and reliability ofthis reaction\ it has replaced amine diazotization as the method of choice for the preparation of a!diazo b!dicarbonyl compounds[ In most cases\ diazo group transfer to an active methylene com!pound proceeds via an intermediate triazine which is formed by attack on the azide by the anion ofthe active methylene compound[ Spontaneous decomposition of this intermediate\ accompanied bya proton shift\ then leads to the product diazo compound[ A wide variety of azides\ including tosylazide ð56AG675\ 56AG"E#622\ 89CC541Ł\ methanesulfonyl azide ð75JOC3966Ł\ p!carboxybenzenesulfonylazide ð57JOC2509Ł and azidotris"diethylamino#phosphonium bromide ð89TL3876Ł\ have been used asdiazo transfer reagents in this reaction[

R1 R2 R1 R2

–

N

NN–

R1

R2

Ts

R1 R2

N2

Scheme 56

base, –H+ TsN3 H+, –TsNH2

A limitation of diazo transfer reactions of this type is the requirement of two electron!withdrawingsubstituents to activate the methylene group[ This problem can be circumvented by temporaryactivation with a formyl group\ which can be introduced by Claisen condensation and is lost duringdiazo group transfer[ The reaction can be performed in a one!pot sequence by using the alkalisalt formed during Claisen condensation directly in the diazo group transfer reaction ð56TL628\57CB1511Ł[

Deformylative diazo group transfer is very useful for the synthesis of a!diazo ketones\ a!diazoaldehydes\ a!diazo esters and a\b!unsaturated diazo ketones ð57CB1511\ 69LA"628#063Ł\ and can pro!ceed by two possible pathways "Scheme 46#[ In the _rst pathway "a#\ a triazoline intermediate isformed which decomposes to give the sulfonylformamide and the a!diazo ketone product[ In thealternative mechanism "b#\ an intermediate triazine is formed\ and loss of the formyl group occursby alcoholysis[ When the diazo transfer reaction of a formyl ketone is performed in dichloromethanein the presence of triethylamine\ there is evidence that the reaction proceeds by way of a triazolineintermediate ð56TL628\ 57CB1511Ł[ The formation of a triazoline intermediate can be a problemduring diazo group transfer to some types of a!formyl cycloalkanones\ and may lead to formationof a b!keto amide rather than the a!diazo cycloalkanone ð56TL628\ 57CB0152Ł[

NN

N

O

O–

Ts

R

O

N2

R

OO

N2

N

NN–

Ts

COR

CHO

Scheme 57

–R

OO

R

OObase, –H+

TsN3, ROH

–Ts(CHO)N–

TsN3, ROH

–TsNH–

ROH, –HCO2R

(a)

(b)

Other proton!activating groups can be employed to achieve temporary activation of the methylenegroup during the formation of a!diazo ketones[ For example\ the benzoyl group has been used asan activator in the synthesis of steroidal a!diazo ketones ð79TL04Ł\ and the alkoxyoxalyl group hasbeen used as an activator during the synthesis of a\b!unsaturated diazo ketones ð57CB1511\ 63S466Ł[A useful new diazo group transfer method for the synthesis of a!diazo ketones has been developed[In this procedure\ tri~uoroacetylation of a ketone enolate\ followed by treatment of the resulting

362Diazo Compounds

b!diketone with methanesulfonyl azide in the presence of triethylamine a}ords the a!diazo ketone"Scheme 47# ð89JOC0848Ł[ This protocol is especially useful for diazo group transfer to a\b!unsatu!rated ketones which are poor substrates for deformylative diazo group transfer[ Yields are superiorto those obtained by deformylative diazo group transfer in many other cases[

R1

O

R2

R1

O

R2

CF3

O

R1

O

N2

R2

Scheme 58

LiN(TMS)2, CF3CO2CH2CF3

THF, –78 °C

MsN3, Et3N, MeCN (aq.), RT

R1 = aryl, α,β-unsaturated, heteroaromatic; R2 = H, Me, cycloalkane

Phase transfer conditions can be employed in cases where deformylative diazo group transfercannot be used[ Tosyl azide is usually utilized as the diazo group transfer reagent\ but azidiniumsalts have also been used[ When p!carboxybenzenesulfonyl azide is used as the diazo transfer reagent\excess azide and the product sulfonamide can be removed from the product by treatment withaqueous base[ This can be advantageous in cases where incomplete reaction complicates puri_cationof the a!diazo carbonyl product ð57JOC2509Ł[

In some cases it is possible to accomplish diazo group transfer from diazo compounds ratherthan sulfonyl azides[ For example\ reaction of 0\0!dimethylcyclohexane!2\4!dione with ethyl diazo!nitroacetate a}ords the product of diazo group exchange "Scheme 48# ð54LA"576#103\ 58LA"611#34Ł[

O

O

NO2

CO2Et

N2

O

O

N N

CO2Et

O2N

Scheme 59

+

O

O

N2 + O2N CO2Et

H+Et3N, EtOH, –H+–

a!Diazo ketones can be prepared by diazo group transfer from azidinium compounds to activatedsubstrates under acidic or neutral conditions rather than basic conditions ð50LA"536#00Ł[ This reactioncan also be accomplished under acidic or neutral conditions using azidochloromethylene!dimethylammonium chloride ð79AG643\ 79AG"E#605Ł[

Although diazo group transfer to enamines is usually employed to prepare diazo alkanes whichdo not possess adjacent carbonyl groups\ the reaction can also be used to synthesize a!diazo carbonylcompounds\ and is especially useful for the preparation of a!diazo aldehydes[ Treatment of a formylenamine with tosyl azide gives the corresponding a!diazo aldehyde in good yield "Scheme 59#ð55TL0098\ 56CC188\ 69CCC2507Ł[ Ethyl diazoacetate and various diacyldiazomethanes have beenprepared from their respective enamines in this fashion ð69LA"623#69Ł[

R1N

CHO

R2 R3

NN

N

NCHO

R3

Ts

R2

R1 R3 CHO

N2

+R1

N

R2

NTs

Scheme 60

TsN3

a\b!Unsaturated diazo ketones can be prepared by cycloaddition of diazo alkanes to strainedcycloalkenones followed by ring opening of the resulting bicyclic pyrazoline[ For example\ additionof a diazo alkane to the cyclopropenone "48# results in formation of an a\b!unsaturated diazo ketone"59# "Scheme 50# ð58TL1548\ 61JA3676Ł[


R1 R1

OR2 R2

N2

+

NN

O

R1R1

R2

R2

R1

R2

O

N2 R1

R2

Scheme 61

(59) (60)

2[01[2[2[7 Substitution at the diazo carbon of a!diazo carbonyl compounds

Many carbon electrophiles can be used for the alkylation or acylation of diazomethyl compounds[Metallated diazo compounds "see Section 2[01[2[4# can be alkylated with reactive electrophiles[ Forexample\ lithium "ethyl diazoacetate# reacts smoothly with allyl iodide or methyl iodide ð69AG180\69AG"E#290Ł\ and silver "ethyl diazoacetate# reacts with allyl bromide\ crotyl bromide and benzylbromide ð56AG127\ 56AG"E#150\ 58CB377Ł[ Many similar alkylation reactions of metallated diazocarbonyl compounds are known[

Diazomethyl compounds possessing electron!withdrawing groups will undergo nucleophilicaddition to reactive aldehydes[ The method is a general one\ and there are many examples ofadditions of ethyl diazoacetate to aldehydes promoted by potassium hydroxide[ Additions of a!diazomethyl ketones and ethyl diazoacetate to aldehydes can be performed at low temperature usingstrong bases such as lithium diisopropylamide "LDA# or n!butyl lithium "Equation "13## ð63LA0656Ł[Aldehydes react with ethyl diazotrimethylsilylacetate in the presence of 07!crown!5 and potassiumcyanide to a}ord the silylated product "50# "Equation "14## ð65JOC2224Ł[

X

O

N2

+O

RX

O

N2

R

OH

(24) i, base

ii, H3O+

X = R, OR

(25)EtO2C

N2

+O

R

EtO2C

N2

R

O-TMSTMS

(61)

18-crown-6-KCN

The acylation of diazo alkanes is probably the most important and widely used method for thesynthesis of a!diazo ketones and there are many examples "Scheme 51# ð05CB0867Ł[ This method ofpreparing a!diazo ketones has become popular with the advent of protocols which minimize a!haloketone formation during the reaction ð04JCS0380\ 05CB0867\ 13JA1440\ 13JA1445\ 14JA0617Ł[ The reactionis a general one\ and has been applied to the synthesis of many a!diazo carbonyl compoundsð31OR"0#27\ B!75MI 201!90Ł[ Acyl halides and anhydrides are particularly good substrates for thereaction\ and cyclic imide chlorides also react readily ð46JA833\ 47JCS0023Ł[ Diazomethane can alsobe acylated with various vinylogous acid chlorides ð70TL330Ł[

R1 X

O

R1 O

O

R1

O

Scheme 62

R1

O

R2

N2

excess R2CHN2 or

R2CHN2, R3N

R2CHN2 (2 equiv.)

–R1CO2CH2R2

X = Cl, Br

During the formation of a!diazo ketones by reaction of diazomethane with acid chlorides\ a largeexcess of diazomethane is used to scavenge the acid evolved during the reaction and preventdecomposition of the diazo ketone ð17JCS0209Ł[ Bases such as triethylamine can be used as acidscavengers\ and only one equivalent of the diazomethane is required in these cases ð38JA0495\38JA0518\ 46LA"591#088\ 66JOC2646Ł[ a!Diazo ketones can be prepared by reaction of acid chlorides

364Diazo Compounds

with diazomethane generated in situ from an N!nitrosourethane or N!nitrosourea\ however\ thisprocedure can a}ord unwanted by!products ð31OR"0#27Ł[ In certain circumstances it may be advan!tageous to acylate trimethylsilyl diazomethane rather than diazomethane because of the relativethermal stability and reduced toxicity of this compound ð79TL3350Ł[

Carboxylic acid anhydrides are good acylating agents for diazomethane\ and two moles ofdiazomethane are consumed during the reaction "Scheme 51# ð46JOC134Ł[ Attack occurs at the moreelectrophilic carbonyl group of mixed anhydrides ð69HCA0946Ł[ Symmetical anhydrides formed bytreatment of carboxylic acids with dicyclohexylcarbodiimide can be used directly in the reactionwithout further puri_cation ð69HCA0946\ 60LA"636#10Ł[ The disadvantage of this technique is that halfof the original acid is converted to the methyl ester rather than the diazo ketone[

a!Diazo b!dicarbonyl compounds can be prepared by acylation of a!diazo carbonyl compounds\usually a!diazo esters\ with acid chlorides "Scheme 52#[ Another method of acylation which has abroad scope is the reaction of diazomethyl carbonyl compounds with acyl isocyanates to give thecorresponding a!diazo b!dicarbonyl compounds "Scheme 52# ð62CB0385\ 62T0872Ł[ Some acyl keteneswill react with diazo ketones in an analogous fashion ð67ZOR1123Ł[

ArCOCHCO

R1

O

R2

O

N2

R1

O

N2

R1

O

NH

O

N2

R2

O

R2COCl R2CONCO

R1

O

N2

Ar

O

Scheme 63

O

Diazo acetates are less prone to undergo cycloaddition to electron!de_cient alkenes than diazo!methane\ and react with a\b!unsaturated acyl chlorides to give the corresponding unsaturated a!diazo b!dicarbonyl compounds ð05CB0867Ł[ However cycloaddition is problematic when additionalelectron!withdrawing groups are present in the a\b!unsaturated acyl chloride ð53LA"564#36Ł[ Theratio of reactants may in~uence the outcome of this reaction\ and an excess of diazo substrate canlead to acylation and cycloaddition ð56CJC0616Ł[

a!Diazo b!dicarbonyl compounds can be converted into a!diazo carbonyl compounds by alkalinecleavage "Scheme 53# ð01LA"283#12\ 05CB0867Ł[ For example\ t!butyl diazoacetate can be prepared ingood yield by treatment of t!butyl diazoacetoacetate with sodium methoxide in methanolð57OS"37#25Ł[ The same compound is formed when t!butyl acetoacetate is reacted with tosylazide inaqueous acetonitrile in the presence of potassium hydroxide ð58OPP88Ł[ In this case\ isolation of t!butyl diazoacetoacetate is not required\ and high yields are obtained if this reaction is performed ina two!phase system in the presence of a phase transfer catalyst ð63S236Ł[ Diazophenylmethane canbe prepared from azibenzil by a reaction which is analogous to those described above ð47JOC648Ł[

R

O

R

O

N2

X

O

R

N2

O

X

O

N2

Scheme 64

i, NaOH (aq.)ii, H3O+

–RCO2HX = R

NaOMe, MeOH

–RCO2MeX = OR

a!Diazo carbonyl compounds can sometimes be prepared from other a!diazo carbonyl compoundsby substitution reactions[ For example\ diazoacetic acid can be converted to diazoacetyl chlorideby treatment with the a!chloroenamine "51# "Scheme 54# ð68CC0079Ł[ Diazoacetyl chloride can thenbe converted to a variety of a!diazo esters and amides with preservation of the diazo group ð68AG0901\68AG"E#836Ł[

a!Diazo esters can be converted into the corresponding a!diazo amides by substitution withammonia or amines\ and this reaction can be used to prepare a!diazo acetamide from methyl


N2

CO2H Cl NMe2

N2

O NMe2

O

Scheme 65

+ Me2CHCONMe2Cl

O

N2Cl–

+

+

(62)

diazoacetate ð93CB0173\ 95CB0272\ 97CB233Ł[ p!Nitrophenyl diazoacetate is an especially good substratefor this reaction "Equation "15## ð57JA3977\ 69JA5695\ 61JA0518Ł[

O

N2

ONO2

HO

NO2

+ H N

R1

R2N2

O

NR1

R2

(26)+ROH or H2O

2[01[2[3 a!Diazo Imines\ Amidines\ Imidates and Nitriles

2[01[2[3[0 a!Diazo imines

a!Diazo N!cyano imines can be prepared directly from the reaction of alkynes with cyanogenazide[ Cycloaddition a}ords the 0\1\2!triazole "52# which then undergoes ring opening to the a!diazo imine "53# "Scheme 55# ð56JA3659Ł[ Unsymmetrical alkynes give mixtures of isomeric products\which obviously limits the utility of this method ð70BSB504Ł[

R R + N3 CNN

NN

R R

CN N2 N

R R

CN

Scheme 66

MeCN, 45 °C

(64)(63)

Alkynes possessing electron!withdrawing groups do not react with cyanogen azide\ but react withtrimethylsilyl azide to a}ord triazoles which can be converted into a!diazo N!cyano imines bydeprotonation and subsequent reaction with cyanogen bromide "Scheme 56# ð70BSB504Ł[

Y RN

NN

Y R

CN N2 N

Y R

CNNN

N

Y R

Scheme 67

–

Na+

i, TMS-N3 ii, H2O

iii, NaH, THF

BrCN

–NaBr

Y = electron-withdrawing group

a!Diazo imines can be synthesized by the reaction of acyl phosphoranes with azides "Scheme 57#[Treatment of cyanogen azide with an acyl phosphorane results in formation of the triazoline whicheliminates a phosphine oxide to form the triazole "54# ð55JOC0476\ 69TL4114Ł\ which then undergoesring opening to a}ord the a!diazo imine ð79TL898\ 70AG007\ 70AG"E#002\ 70BSB504Ł[

NN

N

R1 R2

CN N2 N

R1 R

CN

–Ph3PO

NN

N CN

Ph3PR1 R2

O–+

R1R2

O

PPh3

Scheme 68

NCN3

(65)

366Diazo Compounds

2[01[2[3[1 a!Diazo amidines and imidates

The most general method of preparing a!diazo amidines is by diazo group transfer to ynamines[Ynamines function as acceptors in diazo group transfer reactions and undergo sequential ð1¦2Ł!addition and ring opening with various azides "Scheme 58# ð70ZN"B#107Ł[ In principle\ diazo amidinescan be in equilibrium with the corresponding triazoles[ However\ in cases where the imine substituentis a good electron!acceptor group\ the open chain compound predominates ð61CB1852\ 68LA0717Ł[ Incases where the azide substituent is a weak electron!acceptor or an electron!donor\ the triazole isfavoured ð55JOC0476\ 62LA0494Ł[ The presence of bulky N!substituents or electron!acceptor groupson the ynamine tends to favour formation of the open chain products ð61S460\ 63CB1402Ł[

NN

N

R1 NR22

Y N2 N

R1 NR22

Y

Scheme 69

R1 NR22 + N3 Y

(65)Y = electron-withdrawing group

a!Diazo imidates\ such as "55#\ can be prepared by reaction of alkynyl ethers with azides "Scheme69# ð52TL0728\ 54CB512\ 61CB1864\ 70BSB504\ 71S038Ł[ In contrast to the alkynyl amines\ the reactionbetween alkynyl ethers and 3!dimethylaminobenzene sulfonyl azide occurs without isolation of thepresumed intermediate triazoles[ However\ addition of sulfonyl azides to substituted alkynyl ethersresults in an equilibrium between the triazoles and their corresponding a!diazo imidates ð61CB1864\62LA0494Ł[

NN

N

R1 OR2

R3 N2 N

R1 OR2

R3

Scheme 70

R1 OR2 + N3 R3

(66)

2[01[2[3[2 a!Diazo nitriles

a!Amino nitriles readily undergo diazotization to a!diazo nitriles due to the large activatinge}ect of the electron!withdrawing cyano group[ The explosive compounds diazoacetonitrile anddiazophenylacetonitrile have been prepared using this method ð0783CB48\ 0787CB1378\ 45JA4341\47JA4880Ł[

a!Diazo nitriles bearing aryl\ carbonyl\ sulfonyl\ phosphoryl and aryl substituents can be preparedby diazo group transfer from 1!azido!2!ethylbenzthiazolium tetra~uoroborate "Equation "16##ð67HCA86Ł[ Tosyl azide is not a suitable diazo transfer reagent in these reactions because theproducts undergo further reactions with the base required to facilitate deprotonation ð57CB1240Ł[

Y CNY CN

N2N

SN3

Et

+ BF4– N

SNH2

Et

(27)+ BF4–+ +

ROH (aq.)

Y = COR, CO2R, CONH2, SO2R, Ar

There are several methods for the preparation of a!diazo nitriles which do not rely on diazo grouptransfer reactions[ For example\ the explosive compound dicyano diazomethane can be obtainedby oxidation of the corresponding hydrazone with lead tetraacetate ð54JOC3087Ł\ and ethyl cyano!diazoacetate has been prepared in quantitative yield by thermal fragmentation of the a!diazothiatriazole "56# "Equation "17## ð71TL0092Ł[


(28)EtO2C CN

N2

EtO2C

N2

SN

NN

(67)

CHCl3, 60 °C

The cycloaddition reaction of acrylonitrile with phenylazide produces the triazoline "57#\ whichcan be converted into the a!diazo nitrile "58# by treatment with triethylamine in benzene "Scheme60# ð55CB364Ł[ However\ only an equilibrium mixture of "57# and "58# is obtained by this method[

NCN

NN

NC

Ph N2 NHPh

NC

Scheme 71

(68) (69)

PhN3

a!Diazo nitriles such as diazophenylacetonitrile can be prepared by decomposition of hydrazonesbearing an aziridine ð64T0706Ł[ For example\ reaction of the iminophosphorane "69# with theacylnitrile "60# a}ords the hydrazone "61#\ which undergoes decomposition to diazophenyl!acetonitrile upon heating at re~ux in benzene "Scheme 61#[

N N PPh3

R

PhPh CN

ON N

R

PhCN

Ph

Scheme 72

Ph CN

N2

+

(71)(70)

+ PhR

(72)

C6H6

reflux

2[01[2[4 Diazo Alkanes Containing Heteroatoms at the Diazo Carbon

2[01[2[4[0 Diazo alkanes substituted with halogens

Direct halogenation reactions of diazo compounds are of little general preparative use\ althoughdiazomethane can be chlorinated with t!butyl hypochlorite to a}ord chlorodiazomethane\ andbromodiazomethane has been prepared in an analogous fashion ð54JA3169Ł[

Diazohalogenmethyl carbonyl and phosphoryl compounds can be prepared by metalÐhalogenexchange[ Thus\ treatment of the corresponding silver or mercury derivatives with the free halogenor halogenating reagents such as sulfuryl chloride or cyanogen bromide a}ords the correspondinghalogenated compound in good yield[ For example\ ethyl chlorodiazoacetate can be prepared bytreatment of mercury bis"ethyl diazoacetate# with sulfuryl chloride at −29>C ð57LA"605#193Ł\ andethyl bromodiazoacetate and ethyl iododiazoacetate can be prepared from reaction of mercury orsilver ethyl diazoacetate with bromine or iodine ð56AG49\ 56AG"E#63\ 57LA"605#193\ 58CB377Ł[Halodiazomethyl phosphoryl compounds have been prepared by treatment of silver diazomethylphosphoryl compounds with either cyanogen bromide or iodine ð68LA0991Ł[

2[01[2[4[1 Diazo alkanes substituted with sulfur

Many a!diazo sulfoxides and sulfones are known\ and there are many possible syntheticapproaches to these compounds[

Dehydrogenation of hydrazones is a useful method for the preparation of a!diazo sulfones[ Forexample\ bis"arylsulfonyl#formaldehyde hydrazones can be dehydrogenated to the correspondingbis"arylsulfonyl#diazomethanes using manganese dioxide ð52JOC1822\ 54JOC1161Ł[

a!Methylenesulphones are not su.ciently acidic to participate in diazo group transfer reactions[In contrast\ b!oxosulfonyl and bis"sulfonylmethanes# are good substrates for diazo group transfer\

368Diazo Compounds

and many a!diazo b!oxosulphonyl and bis"alkylsulfonyl# diazomethanes or bis"arylsulfonyl# diazo!methanes have been prepared using this reaction[ Sulfonyl diazomethanes can be prepared byreaction of arylsulfonylmethylenetriphenylphosphorane with p!carboxybenzenesulfonyl azide"Scheme 62# ð64T486\ 70JOC0780Ł[

RSO2 PPh3

NN

N

RSO2

SO2Ar

+

CO2H

SO2N3

RSO2

N2

CO2H

SO2NPPh3

Scheme 73

+PPh3

Diazo group transfer reactions can also be used to prepare a!diazo sul_nyl compounds[ Anadditional electron!withdrawing group is required in the sulfoxide precursor to facilitate the reaction[For example\ the diazo cephem "62# can be prepared directly by diazo group transfer becausea vinylogous carbonyl group is present in the precursor "Equation "18## ð65CC427\ 66JCS"P0#1187\68JOC3586Ł[

N

S

O

CO2R2

R3O

H

R1

H

N

S

O

CO2R2

R3O

H

R1

HN2

(29)R4

3N, MeCN or CH2Cl2

(73)

Deformylative diazo group transfer provides an indirect route to a!diazo sulfonyl compoundswhich do not possess additional electron!withdrawing groups\ and compounds such as a!phenyl"p!toluenesulfonyl#diazomethane and t!butylsulfonyldiazomethane have been prepared using thisapproach ð62TL4196\ 64T486Ł[

Diazo vinyl sulfones can be synthesized by reaction of diazo alkanes with thiiriene!0\0!dioxides"Scheme 63#[ However\ formation of the diazo compound "63# is always accompanied by a signi_cantamount of pyrazole formation ð60JA365\ 79CB0521Ł\ and when the reaction is performed with diazo!methane\ the product reacts further to give a pyrazoline ð79CB0521Ł[

S

R1 R1

O O SO O

NN

R1 R1

R2

N2

SR1 R1

R2

OO

NNH

R1 R1

+ R2 CHN2 +

Scheme 74(74)

R2

Diazo substitution provides an alternative to diazo group transfer for the preparation of sulfur!substituted diazo compounds[ Although sulfonyl chlorides are generally not electrophilic enoughto react with diazo alkanes ð22CB0901Ł\ there are some exceptions[ For example\ diazophenylmethanewill react with tosyl chloride to give diazophenyltosylmethane ð62C219Ł\ and phenylsul_nyl diazo!methane can be prepared by treatment of diazomethane with phenylsul_nyl chloride[

2[01[2[4[2 Diazo alkanes substituted with nitrogen

Diazo group transfer to alkyl nitro compounds using sulfonyl azides is not usually possibleð76JOC2355Ł[ Although azidinium salts have been used to accomplish diazo group transfer to methylnitroacetate and nitroacetophenone\ this method is not successful for nitromethane and other alkylnitro compounds ð55TL4710\ 67HCA86Ł[

Direct nitration of diazo compounds bearing electron!withdrawing groups at the a!position ispossible using dinitrogen pentoxide in an inert solvent[ For example\ ethyl diazoacetate can benitrated with dinitrogen pentoxide "Scheme 64# ð54AG268\ 54AG"E#247\ 58LA"611#34\ 78TL3086Ł[ The


maximum possible yield is only 49) because half of the diazoacetate is converted into the cor!responding nitrate ester "65# by proton transfer from the diazonium intermediate "64# to ethyldiazoacetate and reaction of nitrate with the resulting diazonium compound[ Attempts to preventthis side reaction by deprotonation of "64# with tertiary amine bases have not been successfulð58LA"611#34Ł[

N2

CO2EtO2NCCl4, –30 °C N2CHCO2Et

(76)

+

(75)

N2 NO3–

CO2EtO2N

N2

CO2Et

ONO2

CO2Et

Scheme 75

++ N2O5

t!Butyl diazonitroacetate can be prepared by reaction of mercury bis"t!butyl diazoacetate# withdinitrogen pentoxide "Equation "29## ð55TL5088\ 58LA"611#34Ł[ Nitrodiazomethane is an extremelyexplosive compound\ but can be prepared in high yield by deacylation of t!butyl diazonitroacetatewith tri~uoroacetic acid "Equation "29## ð55TL5088\ 60LA"637#196\ 77TL5920\ 89T6230Ł[ Dinitro!diazomethane can be prepared directly by treatment of nitrodiazomethane with dinitrogenpentoxide\ but the maximum yield for this reaction is only 49) ð58AG466\ 58AG"E#501Ł[

(30)N2

CO2ButO2N+ N2O5

N2

O2N

N2

CO2ButHgButO2C

N2

CF3CO2H, Et2O

–CH2CMe2, –CO2

2[01[2[4[3 Diazo alkanes substituted with phosphorus

Many a!diazo phosphine oxides\ phosphinates and phosphonates are known and can be preparedby many of the methods used for preparation of other diazo compounds[

Diazomethyl phosphonates\ methyl "diazobenzyl#phosphinate\ and diazomethyldiphenyl!phosphine oxide are available from the corresponding amines by diazotization "Equation "20##ð54AG0027\ 54AG"E#0967\ 69TL1382\ 60JOC0268\ 60LA"637#196\ 64CB1939Ł[ Phosphoryl diazomethanes aremore acid sensitive than the corresponding carbonyl compounds\ and consequently diazotizationreactions are often performed in acetic acid rather than in mineral acids ð50TL8\ 79CB2292Ł[

(31)R1

P NH2

O

R2R1

P N2

O

R2

NaNO2, AcOH

R1, R2 = OMe, Ph

The BamfordÐStevens reaction provides an important route to a!diazo phosphoryl compoundssuch as a!diazo phosphonates\ and is usually the reaction of choice for the synthesis of a!diazophos!phinates[ The starting a!ketophosphoryl compounds are readily available\ and the reaction isgenerally performed using sodium or potassium hydroxide or carbonate to deprotonate the inter!mediate hydrazone "Scheme 65#[ Sodium borohydride in methanol can also be used to cleavedimethyl a!tosylhydrazono phosphonates ð64S33Ł[

R1OP R3

O

OR2

R1OP R3

O

NR2 R1O

P R3

O

N2R2

NTos

H

Scheme 76

TosNHNH2, EtOH, heat KOH

Diazo transfer is an important method for the synthesis of a!diazo phosphoryl compoundswhich possess electron!withdrawing groups "Equation "21##[ Several a!diazo phosphine oxides\phosphonates and phosphinates have been prepared by this method ð64AG148\ 64AG"E#111Ł[Thiophosphoryl diazo alkanes have also been synthesized by diazo group transfer ð68T070\ 68TL1304Ł[

370Diazo Compounds

In some cases\ azide transfer competes with diazo group transfer and thiophosphoryl azides maybe isolated instead of the required diazo compounds ð68T070Ł[

(32)R1

P X

O

R2

R1P X

O

R2N2

base, TosN3, solvent

R1, R2 = Ar, RO; X = COR, CO2R, CONR2, Ar, P(O)Ar2, P(O)(OR)2

Deformylative diazo group transfer is of limited use for the synthesis of diazo phosphorylcompounds[ For example\ deprotonation of diethyl "1!oxoethyl# phosphonate followed by reactionwith tosyl azide a}ords only a low yield of diethyl "diazomethyl#phosphonate ð48CB0234\58LA"629#083Ł[ The major products of these reactions are triazoles such as "66# "Scheme 66#[

R1P R2

O

N2R1

R1P

O–

O

R1

+N

NNH

R2

+ OHC NTs–

(77)

R1P

O

R1

CHO

R2

R1P

O

R1N N

N

R2 O–

Tos

Scheme 77

R1 = OEt, Ph; R2 = H, OEt, Ph

g\d!Unsaturated a!diazophosphoryl compounds are readily prepared by photochemical or thermalisomerization of bicycloð2[0[9Łdiazahexenes produced by addition of diazoalkanes to 0!cyclo!propenylphosphonates or 0!cyclopropenylphosphine oxides "Scheme 67# ð63TL0714\ 68CB1498\79LA489Ł[

R1 POR42

R2 R3

R5 R6

N2N

N

R3R2

R1 POR42

R5

R6

R6POR4

2

R5

R1 N2

R3R2

+

Scheme 78

Et2O, 0 °C heat or hν

b!Imino!phosphoryldiazoalkanes can be prepared by diazo group transfer from methyl or phenylazide to 0!cyclopropenylphosphonates ð68CB1498Ł[ The b!imino!phosphoryldiazoalkane productsare moisture sensitive and are hydrolysed to the corresponding b!oxo!phosphoryldiazoalkanesduring chromatography on silica gel "Scheme 68#[

PO(OR3)2

R1 R2

PO(OR3)2

O N2

R2R1

PO(OR3)2

N N2

R2R1

R4

Scheme 79

R4N3 silica gel, H2O

A diazomethyl phosphonium salt is produced by diazo group transfer to a phosphacumulenylide\presumably via formation and subsequent ring opening of the triazole intermediate "67# "Scheme79# ð66AG250\ 66AG"E#238Ł[ Other a!diazo phosphonium salts are produced in high yield by reactionof "acylmethyl#triphenylphosphonium salts with azidinium salts in ethanol or benzene ð68S794\


70LA0754Ł[ This method can also be used to prepare diazo bis"phosphonium# salts and bis"diazo#bis"phosphonium# disalts ð70LA0754Ł[

Ph3P • • O Ph3PNTs

O

N2

–

NN

N

Ph3P O–

Ts

+

Scheme 80

+

TsN3

(78)

A variety of phosphoryl diazo alkanes can be prepared by alkylation of metallated a!diazomethylphosphonates\ phosphinates or phosphine oxides[ The silver!substituted compounds react with alkylhalides by SN0 addition to give alkylated products ð69TL1382\ 60JOC0268Ł[ Mercury derivatives havealso been used for this reaction ð68LA0991Ł[

a!Diazomethyl phosphoryl compounds can be acylated directly with acid chlorides in the presenceof tertiary amine bases ð65CB1928\ 68LA0991Ł\ and many acyl diazo phosphine oxides and phos!phonates have been prepared in this way[ Bis"a!diazo b!oxophosphonates# can be prepared byacylation with bis!acid chlorides such as oxalyl chloride ð68LA0991Ł[ The carbamoylation of phos!phorylated a!diazomethyl compounds can be performed with acyl isocyanates and isothiocyanatesð79LA294Ł[

a!Diazo phosphonates and phosphinates can be cleaved to give their respective a!diazomethylphosphonic and phosphinic acids[ Cleavage is usually accomplished by reaction with trimethylsilylbromide\ but sodium iodide in acetone or aqueous sodium hydroxide can be used ð65JA6216\ 66JA0156\71JOC0173Ł[ Many dimethyl a!diazo phosphonates\ a!diazophosphonic acid methyl ester amides andmethyl a!diazo phosphinates react with trimethylsilyl bromide to give trimethylsilyl esters in highyield[ The trimethylsilyl groups can be cleaved with t!butylamine under mild conditions to give t!butylammonium a!diazo phosphonates or phosphinates ð74T708Ł[

2[01[2[4[4 Diazo alkanes substituted with arsenic\ antimony or bismuth

Ethyl diazodimethylarsylacetate can be prepared by treatment of ethyl diazoacetate with dimethyl!aminodimethylarsane\ and an analogous reaction occurs with tris"dimethylamino#arsaneð64JOM"86#48Ł[ Diazomethane does not react under these conditions\ but bis"dimethyl!arsano#diazomethane is formed if trimethylstannyl chloride is added to the reaction "Scheme 70#ð64JOM"82#228Ł[ Trimethylstannyl chloride increases the electrophilicity of the arsenic centre andthus promotes nucleophilic attack of diazomethane[ Although the arsyl!substituted diazomethaneis more nucleophilic than diazomethane and the diarsylated product is usually obtained\diazomethyldimethylarsane can be isolated when diazomethane is used in large excessð65JOM"009#084Ł[ Mixed substituted diazomethylarsanes containing silyl and germyl groups havebeen prepared using this method ð66JOM"021#248\ 79JOM"080#260Ł[

Me2As NMe2 + H2C N2

Me2As

N2

Me2As

N2

AsMe2

Scheme 81

Me3SnCl, Et2O

–HNMe2

Me2AsNMe2

–HNMe2

Bis"dimethylantimony#diazomethane and ethyl "dimethylantimony#diazoacetate have been pre!pared by the reaction above\ but without trimethylstannyl chloride as an activator[ Bis"dimethyl!bismuth#diazomethane and ethyl "dimethylbismuth#diazoacetate have been synthesized byanalogous reactions ð64JOM"82#228Ł[

2[01[2[4[5 Diazo alkanes substituted with silicon\ germanium\ tin or lead

Trimethylsilyldiazomethane can be prepared by silylation of diazomethyllithium with tri!methylsilyl chloride ð56CC725Ł\ and this compound can then be converted to bis"trimethylsilyl#

372Diazo Compounds

diazomethane by deprotonation at low temperature and subsequent reaction with trimethylsilylchloride "Scheme 71# ð79JOM"080#260Ł[

LiHC N2

TMS

N2

TMS

N2

TMSTMS

N2

Li

Scheme 82

TMS-Cl BunLi, pet. ether

–110 °C to 80 °C

TMS-Cl

a!Diazo!a!"trialkylsilyl#alkanones can be prepared by acylation of trimethylsilyldiazomethanewith acid chlorides ð79TL3350Ł\ or by treatment of diazomethyl ketones with trialkylsilyl tri~ates inthe presence of Hu�nig|s base ð76CB524Ł[ Reaction of mercury bis"diazocarbonyl# compounds withdisilylmercury compounds provides an alternative route to trialkylsilyl substituted a!diazo carbonylcompounds "Scheme 72# ð66JOM"031#044Ł[ Silyl!substituted ethyl diazoacetates can be obtained inexcellent yield by reaction of mercury bis"ethyl diazoacetate# with appropriate iodo trialkylsilanesð57ZC151Ł\ and the unusual compound ethyl diazopentamethyldisilanylacetate "79# has been pre!pared by reaction of mercury!bis"ethyl diazoacetate# with the disul_de "68# "Equation "22##ð70JA4462Ł[

(Et3Si)2Hg + RHg

R

O O

N2N2

Et3SiHgR

O

N2

Et3SiR

O

N2

Scheme 83

THF, 20 °C –Hg

R = Me, OMe

EtO2C Hg CO2Et

N2N2TMS

SiS

SSi

TMS

MeMe

MeMe

Si CO2Et

N2

TMS

MeMe

(33)+

(79) (80)

There are many methods other than substitution of diazo alkanes which can be used to preparesilicon!substituted diazo alkanes[ For example\ triphenylsilylphenyldiazomethane has been preparedby the oxidation of the corresponding hydrazone with manganese"IV# oxide ð57TL3862Ł[ The Bam!fordÐStevens reaction of trialkylsilyl!substituted hydrazones has also been used to prepare silicon!substituted diazo alkanes ð58CJC3242\ 67JA883Ł[

Trimethylsilyldiazomethane can be synthesized in reasonable yield by treatment of N!"trimethyl!silyl#methyl!N!nitrosourea with potassium hydroxide "Scheme 73# ð57JA0979\ 61JOM"33#168\62JCS"D#372Ł[ Treatment of lithiated trimethylsilylmethane with tosyl azide at 9>C a}ords the samecompound in modest yield\ and this method can be employed to prepare bis"trimethyl!silyl#diazomethane ð79JA0473Ł[ Bis"trimethylsilyl#diazomethane can be prepared by diazo grouptransfer of trimethylsilyl azide to the silaethene "70# via the triazasilacyclopentene "71# "Scheme 74#ð70CB2407Ł[

H2N

N

TMSO

NOLi TMS

Scheme 84

TsN3 +20% KOH, C5H12, pentane 0 °C

N2

TMS

There are many examples of the synthesis of germyl!substituted diazo compounds[ Diazomethaneand diazoacetates can be metallated directly using dimethylaminotrimethylgermane "Scheme 75#ð69JCS"A#1843\ 60JOM"16#292\ 66JOM"016#08Ł\ and bis"trimethylgermyl#diazomethane can be preparedanalogously[ Trimethylgermyltrimethylsilyl diazomethane has been prepared from trimethyl!silyldiazomethyl lithium ð79JOM"080#260Ł\ and this compound and bis"trimethylgermyl# diazo!methane have been synthesized by diazo group transfer "Equation "23## ð79JA0473Ł[


Me2Si

TMS

TMS

TMS N3+ Si

NN

N

Me

Me TMSTMS

TMS

TMS TMS

N2

Scheme 85

Et2O, –10 °C

(81) (82)

Scheme 86

N2CHCO2Et, 80 °C CH2N2, Et2OMe3GeNMe2

Me3Ge CO2Et

N2

Me3Ge

N2

(34)Me3N

Me3N

Me3N

Me3N

N2

i, ButLi, C5H12, THF, HMPA, –78 °C

ii, TsN3, –78 °C to 20 °C

M = Si, Ge

Diazomethyl compounds can be stannylated directly with either dimethylaminotrimethylstannaneor dimethylaminotriphenylstannane "Scheme 76# ð69JCS"A#1843Ł[ Diazomethane can be di!stannylated using these reagents\ and both diazoacetates and a!diazomethyl ketones can be metallateddirectly ð57JOM"04#140Ł[ Diazoacetates can also be stannylated by reaction with triethyl!methoxystannane ð64ZOB708Ł[ Bifunctional stannylating agents\ such as bis"dimethylamino#dimethylstannane\ react with ethyl diazoacetate to form dimethyltin bis"ethyl diazoacetate#ð57JOM"04#140Ł[

N2CHCOR2, Et2O CH2N2, Et2O R13Sn

N2

R13SnNMe2

R13Sn

N2

R2

OSnR3

3

Scheme 87

R1 = Me, Ph; R2 = Me, Ph, OEt

Treatment of lithium diazoacetate with an appropriate trialkylsilyl trialkylstannyl or tri!alkylplumbyl halide can be used as a general method for the preparation of diazoacetates substitutedwith silicon\ tin or lead at the diazo carbon ð61LA"650#026\ 63LA0656Ł[ Silyl\ stannyl and germyl groupscan also be introduced by reaction of mercury bis"ethyl diazoacetate# with the respective metalsul_des ð56AG895\ 58AG"E#773\ 58LA"629#0\ 61LA"650#026Ł[

Lead!substituted diazomethyl compounds can be prepared by reactions that are analogous tothose described for tin!substituted diazo compounds[ For example\ bis"trimethylplumbyl#diazomethane is produced upon treatment of diazomethane with dimethylaminotrimethylplumbane"Equation "24## ð69JCS"A#1843\ 63JOM"67#110Ł\ and trimethylplumbyltrimethylsilyldiazomethane canbe prepared by reaction of trimethylðbis"trimethylsilyl#aminoŁplumbane with trimethylsilyl diazo!methane ð60JOM"16#292\ 79JOM"080#260Ł[ Direct metallation of ethyl diazoacetate can be accomplishedby treatment with dimethylaminotrimethylplumbane ð60JOM"16#292\ 61LA"650#026\ 63JOM"67#110Ł\ anda variety of other trimethylplumbyl a!diazo ketones have been prepared using this method "Equation"25## ð63JOM"67#110Ł[

(35)Me3PbNR2 + H2C N2

Me3Pb PbMe3

N2

R = Me, SiMe3

(36)Me3PbN(TMS)2 +

O

R

N2

O

R

N2

Me3PbEt2O, –30 °C to 20 °C

R = Me, Ph, OEt

374Diazo Compounds

2[01[2[4[6 Diazo alkanes substituted with boron or thallium

The _rst boron!substituted diazo alkane to be prepared was ethyl "0\1\2!benzodioxaborol!1!yl#diazoacetate "72#\ which was prepared by reaction of 1!chloro!0\1\2!benzodioxaborole andlithium or mercury "ethyl diazoacetate# "Scheme 77# ð63LA0656Ł[ Two other examples of diazoalkylboranes are known ð78CB484\ 80JA4745Ł[ For example\ ðbis"diisopropylamino#boranylŁdiazomethanewas isolated after treatment of an ethereal solution of lithiated diazomethane with bis"diiso!propylamino#chloroborane at low temperature "Equation "26##[

OB

OCl

OB

OCl

Scheme 88

EtO2C Hg CO2Et

N2 N2 OB

O CO 2Et

N2

Li CO2Et

N2

(83)

CH2Cl2, –10 °C to 0 °C C5H12, THF, Et2O, –100 °C

(37)N2

LiB Cl

Pri2N

Pri2N

B

Pri2N

Pri2N

N2

+Et2O, –78 °C

a!Diazoalkyl borates can be synthesized by treatment of bis"diisopropylamino#!chloro!diazomethylene phosphorane with either boron tri~uorideÐetherate or boraneÐtetrahydrofurancomplex "Equation "27## ð80AG0063\ 80AG"E#0043Ł[

P •

Pri2N

Pri2N

P

Pri2N

Pri2N

+Cl BY3N2 (38)Cl

N2

BY3–

PhMe, RT

BY3 = BF3•OEt2, BH3•THF

+

There are few examples of thallium!substituted diazo compounds\ but diazo bis"dimethyl!thallium#methane can be prepared by treatment of diazomethane with either the metallated amine"73# or trimethylthallium "Scheme 78# ð65JOM"019#020Ł[

Me2Tl TlMe2

N2

H2C N2 + Me3TlH2C N2 + Me2TlNMe2

Scheme 89

(84)

Et2O

–190 °C to 0 °C

Et2O

–190 °C to 0 °C

2[01[2[4[7 Diazo alkanes substituted with lithium or sodium

Diazomethyl lithium can be prepared directly by treatment of diazomethane with an alkyl lithiumor lithium N!methyl!N!trimethylsilylamide in ether ð43CB0776\ 54ZN"B#0998Ł\ or by reaction of methyllithium with dinitrogen monoxide "Scheme 89# ð46CB0291Ł[ The related sodium derivative can beprepared by treatment of diazomethane with tritylsodium ð23LA"401#149Ł[ Both compounds arehighly explosive[

H2C N2 N2ORLi or

TMS(Me)NLi

MeLiN2

Li

Scheme 90


Metallation of ethyl diazoacetate can be accomplished by reaction with butyl lithium at lowtemperature in an ethereal solvent "Scheme 80# ð69AG180\ 69AG"E#290Ł[ The reagent can be preparedby transmetallation from mercury bis"ethyl diazoacetate# "see Section 2[01[2[4[01# using phenyl orbutyl lithium\ or lithium thiolates[

OEt

O

N2

OEt

O

N2

Hg

N2

Scheme 91

EtO

OBuLi, –100 °C RLi or RSLi

–70 °COEt

O

N2

Li

2[01[2[4[8 Diazo alkanes substituted with magnesium

Ethyl diazoacetate reacts with Grignard reagents at low temperature to form the correspondingmagnesiated species "Scheme 81#[ For example\ iodomagnesium ethyl diazoacetate can be preparedby treatment of ethyl diazoacetate with methyl magnesium bromide\ but the diazo magnesiumspecies is stable only in solution ð63LA0656Ł[ It is likely that Schlenk equilibrium gives rise to themagnesium bis"diazoester# "74# in this case[

EtO

O

N2

OEt

O

N2

Mg

N2

Scheme 92

EtOEtO

O

N2

MgI2 + MgI2

MeMgI, Et2O, –65 °C

(85)

2

O

2[01[2[4[09 Diazo alkanes substituted with transition metals

Although diazo compounds can react with many late transition metal complexes to form highlyreactive carbenoid species\ it is possible to synthesize diazo compounds that are substituted with atransition metal at the diazo carbon\ usually by transmetallation from the corresponding lithium ormercury diazo compound[

The synthesis of the a!diazomethyl osmium complex "75# by reaction of OsCl"NO#"PPh2#2 withHgðC"N1#CO1EtŁ1 has been reported "Scheme 82# ð73CC0991Ł[ Treatment of the complex "75# withexcess iodine results in loss of mercury and a}ords the new complex "76#[

PPh3

Os

Ph3P

NO

Hg

Cl

CO2Et

N2CO2Et

N2

I2

(87)

I2

PPh3

Os

Ph3P

NO

I

Cl

CO2Et

N2

OsCl(NO)(PPh3)3 + Hg(CN2CO2Et)2

Scheme 93

(86)

PPh3

Os

Ph3P

NO

Hg

Cl

CO2Et

N2I

The unstable diazomethyl rhodium complex RhðC"N1#TMSŁIMe"PMe2#2 has been prepared byreaction of LiC"N1#TMS with Rh"PMe2#3Cl at low temperature ð76OM0711Ł[ The complex was notisolated in pure form and decomposed after several days in the solid state or in solution[ Treatment

376Diazo Compounds

of this complex with iodomethane a}orded a new air!stable complex "77# which was isolated andcharacterized by x!ray crystallography[

Rh

PMe3

PMe3

Me

I

Me3P

TMS N2

(88)

The diazomethyl nickel complex NiðC"N1#TMSŁCl"PMe2#1 has been prepared by reaction ofLiC"N1#TMS with "PMe2#1NiCl1 in tetrahydrofuran at −14>C[ The air!sensitive complex wascharacterized spectroscopically but decomposed at temperatures above −14>C ð89JA4240Ł[

Several a!diazo palladium complexes have been synthesized[ Palladium complexes such as "78#can be prepared in moderate yield by reaction of diazo mercury compounds with bis"trialkyl!phosphine#! or bis"triarylphosphine#palladium"II# halides "Equation "28## ð68CC349\ 75OM245Ł[Complexes such as "89# have been synthesized by treatment of the appropriate palladium"II#complex with two equivalents of an a!lithiodiazo compound at low temperature\ or by addition ofa bis"a!diazomethyl# mercury compound to Pd"Ph2P#3 at room temperature "Scheme 83#[ Bothtypes of complex are relatively stable and several have been characterized by x!ray crystallographyð68CC349\ 75MI 201!90Ł[

(39)(PR13)PdX2 + Hg[C(N2)R2]2

C6H6Pd X

PR13

PR13N2

R2

(89)

(PR13)PdX2 + LiC(N2)R2 (PR1

3)4Pd + Hg[C(N2)R2]2THF C6H6

Pd

PR13

PR13N2

R2 N2

R2

Scheme 94

(90)

R1 = Et, Bu, Ph; R2 = CO2Et, C(O)Me, Ph, p-MeC6H4, Pri, But; X = Cl, Br, I

Lanthanide!substituted diazo alkanes can be prepared by transmetallation[ Reaction of lithiumtrimethylsilyldiazomethane with the lanthanide complexes YClCp�1\ LuClCp�1\ or YbClCp�1

"Cp��pentamethylcyclopentadienyl# in tetrahydrofuran at low temperature a}ords the air! andheat!sensitive complexes MðC"N1#TMSŁCp�1 =THF "M�Y\ Lu\ Yb#\ in which the diazo carbon iss!bonded to the metal ð81JOM"327#72Ł[

2[01[2[4[00 Diazo alkanes substituted with silver

The hydrogen of a diazomethyl compound is rather acidic when there is an adjacent electron!withdrawing group\ and direct metallation of the diazo carbon with silver"I# oxide is possible[ Silver"ethyl diazoacetate# and a variety of other silver "a!diazocarbonyl# compounds have been prepareddirectly by this reaction "Equation "39## ð56AG127\ 56AG"E#150\ 58CB377Ł[ These compounds are ofsynthetic importance because the silver is easily replaced with other metals and with carbon elec!trophiles[ Silver "a!diazocarbonyl# compounds are rather unstable and must be prepared and usedat temperatures below 9>C[ Diazomethane can be metallated directly using silver acetate in a mixtureof diethyl ether and pyridine to give disilver!diazomethane\ which crystallizes with an equivalent ofpyridine "Equation "30## ð63CC355Ł[


(40)R

N2

R

N2

AgAg2O, –H2O

R = CO2Et, COMe, COPh, PO(OEt)2, PO(OMe)(Ph), PO(Ph)2

(41)2MeCO2Ag + 3 H2C N2

Ag Ag

N2

•

N

+ 2MeCO2Me + 2N2

Et2O

pyridine

2[01[2[4[01 Diazo alkanes substituted with zinc\ cadmium or mercury

Zinc and cadmium bis"ethyl diazoacetate# can be prepared by treatment of ethyl diazoacetate withzinc or cadmium bisðbis"trimethylsilyl#amideŁ\ and are unstable but isolable compounds "Scheme 84#ð60JOM"16#292Ł[ The polymeric compounds diazomethyl zinc and diazomethyl cadmium can beprepared from diazomethane in an analogous fashion "Scheme 84# ð60JOM"16#292Ł\ andbis"diazomethyl# cadmium has been prepared from diazomethyl lithium by transmetallation withcadmium"II# chloride at low temperature ð57TL4126Ł[

EtO2C M CO2Et

N2 N2

(MC=N2)n M[N(TMS)2]2

Scheme 95

N2CH2, Et2O, –40 °C N2CHCO2Et, Et2O, –35 °C

M = Zn, Cd

Mercury may be introduced directly into diazomethyl compounds which possess an electron!withdrawing group on the diazo carbon ð0784CB104Ł[ This transformation is usually accomplishedby treatment of the diazo compound with mercury"I# oxide in the presence of a water!absorbingagent[

Mercury bis"ethyl diazoacetate# can be prepared in high yield by treatment of ethyl diazoacetatewith mercury bisðbis"trimethylsilyl#amideŁ at −19>C in diethyl ether ð60JOM"16#292Ł[Bis"diazomethyl# mercury is a highly explosive compound\ and has been prepared by reaction ofmercury"II# acetate with diazomethane "Scheme 85# ð52NAT892Ł[ This compound has also beenprepared by lithiumÐmercury exchange from diazomethyl lithium with mercury"II# chlorideð57TL4126Ł[ Alkyl! and arylmercury diazo alkanes can be prepared in good yield by metallationof diazo alkanes with alkylmercury bis"trimethylsilyl#amides or by reaction of diazo alkanes withalkyl! or arylmercury ethoxides "Scheme 86# ð60JOM"16#292\ 62JOM"43#12Ł[

H2C N2 + Hg[N(TMS)2]2 Hg(H2C N2)2 H2C N2 + Hg(OAc)2

Scheme 96

R1HC N2 + R1HC N2 + R2HgOEtR2Hg N

TMS

TMS

R1 HgR2

N2

Scheme 97

R1 = CO2Me, CO2Et, COMe, COPh, CN; R2 = Me, Et, Ph

2[01[2[5 Unsaturated Diazo Alkanes

2[01[2[5[0 Diazo alkylidenes

Diazo alkylidenes have not been isolated\ but they have been identi_ed as transient intermediatesin a number of reactions[ For example\ cleavage of the N!nitroso!oxazolidone "80# with lithiumethoxide results in formation of 0!diazo!1!methylpropene which decomposes "Scheme 87#

378Diazo Compounds

ð58JA5350Ł[ The resulting vinylcarbene can be trapped with alkenes in situ to give cyclopropanes[ Asimilar sequence of reactions occurs when the spiro!fused system "81# is treated with base in thepresence of an alkene "Scheme 88# ð57JA3078\ 58JOC0119Ł[

R

R R

RO

N

NO

ON

O

CO2Et

NO– Li+

N2+

•

N2

R

R R

R

Scheme 98(91)

EtOLi

R

R R

R

(92)

O

N

NO

OR

R R

R

Scheme 99

•

N2

base

The diazoallene "83# has been implicated as an intermediate during the base!catalysed decompo!sition of the bis"N!nitrosourethane#cyclopropane "82# "Scheme 099# ð60TL206\ 61JOC582Ł[ The prod!uct isolated from this reaction was that produced by trapping of the carbene derived from "83# with1\2!dimethylbut!1!ene[

NCO2Et

CO2EtNPh

Ph

NO

NO

• •

Ph

Ph

N2

Scheme 100

(93) (94)

MeONa

•

Ph

Ph

N CO2Et

ONMeONa

Diazoketene "84# has been prepared by treatment of diazoacetyl chloride with 0\3!diazabicyclo!ð1[1[1Łoctane "dabco# "Equation "31## ð68AG0901\ 68AG"E#836Ł[

(42)Cl

O

N2

O • • N2

dabco, Et2O, heat

(95)

2[01[2[5[1 a\b!Unsaturated diazo alkanes

The preparation of a\b!unsaturated diazo alkanes via the BamfordÐStevens reaction is of limiteduse because of secondary reactions ð52JA2685\ 64CC348Ł[ Vinyl diazo alkanes produced by this reactioncan form cyclopropenes by way of a carbene intermediate\ or may cyclize to form a 2H!pyrazolewhich can then undergo a ð0\4Ł!sigmatropic shift[ Although BamfordÐStevens reactions of tos!ylhydrazones derived from a\b!unsaturated cycloalkanones usually result in formation of pyrazolesand allyl ethers ð66JOC0241Ł\ a\b!unsaturated diazo cycloalkanes have been prepared by vacuumpyrolysis of tosylhydrazone salts ðB!75MI 201!90Ł[

"0!Diazo!1!alken!0!yl# phosphonates can be prepared by the BamfordÐStevens reaction of thetosylhydrazones ð60JOC017\ 63TL0714\ 67CB2957Ł[ The nature of the substituents determines whetherthese compounds are isolable or isomerize to the corresponding pyrazoles ð60JOC017\ 67CB2957Ł[

Many a\b!unsaturated diazo alkanes have been prepared from N!nitrosourethanes and N!nitroso!ureas[ Cleavage of N!allyl!N!nitrosourethane "85# by potassium hydroxide or sodium methoxide


a}ords 2!diazopropene\ which slowly cyclizes to give pyrazole "Scheme 090# ð24JA1545\ 24JCS175\64JOC645Ł[ The same compound can be prepared from an N!nitrosourea in an analogous fashionð43CB0388\ 60OPP36Ł[

NCO2Et

NO

NH

N

Scheme 101

base

N2

(96)

A variety of diazo cycloalkenes can be prepared by diazo transfer[ For example\ 4!diazo!0\1\2\3!tetraphenylcyclopentadiene can be synthesized in high yield by treatment of the 0\1\2\3!tetra!phenylcyclopentadiene with p!toluenesulfonyl azide and triethylamine in dichloromethaneð79TL898Ł[

o! and p!Quinone diazides are synthesized in good yield by diazotization of amino phenols[Although the intermediate diazonium salts may be isolated in some cases\ they are readily depro!tonated in acidic media[ Deprotonation can also be accomplished with a mild base ð34JA844\54LA"570#34\ 60S370Ł[

The conjugated diazo allene "87# has been implicated as an intermediate during the ~ash vacuumpyrolysis of the heterocyclic compound "86# "Scheme 091# ð79JOC3954Ł[ The compound actuallyisolated from the reaction was the enyne "099#\ produced by ring opening of the carbene!derivedmethylenecyclopropene "88#[

NN

OPh OPh

N2

• PhPh

Scheme 102

(97) (98) (99) (100)

2[01[2[5[2 Diazo alkynes

Diazopropyne can be prepared from an N!methyl!N!nitrosurea or the N!nitrosoacetamide "090#ð59JA136\ 51AG141\ 51AG"E#105\ 57LA"602#002Ł[ This compound can also be prepared from "091# viatris"diazo#propane "Scheme 092# ð57LA"602#002Ł[

(101) (102)

N

O NO

N2

N2 N2

N2

N N

N

COMeMeOC

ON COMe

NO ON

Scheme 103

NaOMe, MeOH

Et2O, –15 °C

–2N2


3.13Synthesis of P, As, Sb and BiYlides (R 3P1CR2, etc.)EAMONN J. COYNE and DECLAN G. GILHEANYUniversity College Dublin, Republic of Ireland

2[02[0 PHOSPHONIUM YLIDES FROM PHOSPHONIUM SALTS 381

2[02[0[0 Preparations of Phosphonium Salts 3812[02[0[1 Deprotonations of Phosphonium Salts 3822[02[0[2 Dehalo`enations of Phosphonium Salts 3842[02[0[3 Desilylations of Phosphonium Salts 3852[02[0[4 Ylides from Vinylphosphonium Salts 3852[02[0[5 Ylides from Cyclopropylphosphonium Salts 3852[02[0[6 Ylides by the Electrolysis of Phosphonium Salts 386

2[02[1 PHOSPHONIUM YLIDES FROM PHOSPHINES 386

2[02[1[0 Reactions with Carbenes 3862[02[1[1 Via Azines 3862[02[1[2 Reactions with Activated Multiple Bonds 3872[02[1[3 Reactions with Aziridines 3872[02[1[4 Reactions with Arynes 387

2[02[2 PHOSPHONIUM YLIDES FROM PHOSPHORANES 388

2[02[3 PHOSPHONIUM YLIDES FROM OTHER PHOSPHONIUM YLIDES 388

2[02[3[0 By Halo`enations 3882[02[3[1 By Alkylations and Acylations 388

2[02[4 PREPARATION OF As\ Sb AND Bi YLIDES 499

2[02[4[0 From the Precursor Onium Salts 4992[02[4[1 From Arsines\ Stibines and Bismuthines 4992[02[4[2 From the Dihalo Pentacoordinate Derivatives 4992[02[4[3 From the Tertiary Oxides 499

There are a great many more preparations of the phosphonium ylides than of their group 04analogues and this is re~ected in this review[ Thus 2[02[0Ð2[02[3 are concerned with the preparationof phosphorus ylides and 2[02[4 deals with the other ylides\ classi_ed in a similar manner[

There is a good variety of methods available for the construction of the P1C bond[ However\by far the most commonly used method for the synthesis of phosphonium ylides is by deprotonationof an appropriate precursor phosphonium salt*the {salt method|[ Therefore this method is discussed_rst\ including reference to methods for obtaining the requisite phosphonium salts\ followed by therelated dehalogenation and desilylation of phosphonium salts[ Thereafter\ all the other preparativelyuseful methods are discussed\ grouped according to the source of the phosphorus atom viz[ phos!phonium salts\ phosphines and phosphoranes[ Finally\ although they are not strictly methods forconstruction of the P1C bond\ the most common interconversions of ylides are brie~y described[

Phosphorus ylides have been comprehensively reviewed by Johnson ðB!82MI 202!90Ł\ and the oldercompilation of methods for the Wittig reaction by Gosney and Rowley is still very useful ðB!68MI

380

381 P\ As\ Sb and Bi Ylides

202!90Ł[ Sections on ylides can also be found in other series ðB!68MI 202!91\ 80COSŁ although mentionof arsenic\ antimony and bismuth ylides is brief at most[ However\ these ylides have been reviewed"with particular attention to arsenic# by Lloyd\ Gosney and Ormiston ð76CSR34Ł[

2[02[0 PHOSPHONIUM YLIDES FROM PHOSPHONIUM SALTS

Scheme 0 shows the {salt method| for the formation of ylides which involves two distinct steps]"i# the formation of the phosphonium salt^ and "ii# the deprotonation of that salt to produce theylide[ These separate steps are discussed in the following two subsections[ Further subsections dealwith the related dehalogenation and desilylation of appropriate precursor phosphonium salts andwith nucleophilic attack on vinyl phosphonium salts[ Finally\ the electrolysis of phosphonium saltsis brie~y mentioned[

PR13 + R1

3P

R2

R3

R13P

R2

R3

+X– –H+

R2

R3

X

Scheme 1

2[02[0[0 Preparations of Phosphonium Salts

Tertiary phosphines are good nucleophiles\ so simple SN1 quaternisation of trialkyl or triarylphosphines with alkyl halides forms the phosphonium halides[ As with many other substitutionreactions\ halide reactivity is typically I×Br×Cl with other leaving groups being employed morerarely\ for example\ the trimethylammonium group ð50LA"539#68\ 52JCS1889Ł[ Usually only mildreaction conditions are required for salt synthesis "heat is sometimes required for some higherhalides# and a wide range of solvents have been used to that end "e[g[\ benzene\ ether\ chloroform\acetone\ acetonitrile\ dimethylformamide\ nitromethane#[ Choice of solvent is often determined bythe ease of isolation of the produced salt\ most commonly by its direct precipitation from solution[Solvent electrophilicity\ polarity and polarisability\ in that order were also found to be importantð71G14Ł[

Since most ylide chemistry is designed to produce a phosphorus!free _nal product\ the choice ofphosphine to be employed is virtually unlimited[ Despite this\ however\ the phosphine of choice formost ylides has been triphenylphosphine for a number of reasons] it is crystalline\ safe\ easy tohandle and air stable^ it is relatively cheap and readily available^ it is of the correct nucleophilicityfor quaternisation and it has no hydrogen adjacent to the phosphorus that would compete inthe ylide!forming deprotonation step[ Trialkylphosphines are also e}ective and may have certainadvantages over their aryl analogues[ In particular they are more nucleophilic than the tri!arylphosphines producing ylides of increased nucleophilicity ð55JA0842Ł and further manipulationof the produced ylide "e[g[\ hydrolysis# may require alkyl substituents rather than aryl ones[ However\these trialkylphosphines have also associated problems] they are easily oxidised and are thereforedi.cult and hazardous to handle and may pose the risk of competitive deprotonation at thea!position[ The use of phosphines other than the commercially available triphenylphosphine and tri!n!butylphosphine has been limited to specialised studies[ For example\ substituted triarylphosphinessuch as "XC5H3#2P ð55JA0842Ł\ and mixed alkyl!arylphosphines such as MenPh2−nP ð59CI822Ł\ havereadily produced useful phosphonium salts[ Similarly optically active phosphines have been used toproduce optically active phosphonium salts and consequently ylides ð51JA565\ 54LA"574#0Ł[

A wide variety of alkyl halides have been used to quaternise triphenylphosphine[ Thus in thephosphonium salts R0CH10PPh2

¦X−\ R may be alkyl\ aryl\ alkoxy\ thioalkyl\ carboalkoxy\carbamido\ keto\ formyl\ cyano\ halo\ alkenyl\ alkynyl or silyl[ Dihalides may form mono! or bis!phosphonium salts\ and allylic halides can give rearranged products[ Table 0 gives some speci_chalides with appropriate references for quaternisation to the phosphonium salt[

This process is very reliable and would rarely be the step which causes di.culty in synthesisof ylides[ However some problems can occur\ including the possibility of HX elimination fromthe alkyl halide\ as has happened in the reaction shown in Equation "0# ð78S574Ł[ More seriously\the reaction with a!bromoketones is less reliable with the competing Perkov:Arbusov process

382From Phosphonium Salts

Table 0 Halides used for the preparation of phosphonium salts[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐHalide Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐMethyl iodide 42LA"479#33n!Butyl bromide 47JA3275Chloromethyl ether 47JA5049Chloromethylthioethers 56AG"E#138Phenacyl bromide 0788CB0455\ 46JOC30Chloroacetimides 89JA6990Imidoyl chlorides 66S515Cyclopropyl bromide 55CC555Cyclohexyl bromide 50AG16Benzylic bromides 48CB16458!Bromo~uorene 36JA6120\1!Dibromoethane 47LA"508#09\ 48CB1645\ 55JA3989Dibromides "0\2! and 0\3!# 46LA"592#004\ 48CB1645\ 52NAT0025\ 54JCS60390\1!Dibromobenzocyclobutene 56JA3885Di"bromomethyl#benzenes 48CB1645Allyl chloride 60HCA06560\3!Dibromo!1!butene 50MI 202!90Farnesyl bromide 69JA1028*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

ðB!89MI 202!90Ł[ The preparation of phosphonium salts has been comprehensively reviewed byCristau and Ple�nat ðB!83MI 202!90Ł[

F3C

Br

F3CPPh3 Br–+Ph3P

(1)

2[02[0[1 Deprotonations of Phosphonium Salts

This process is commonly done by addition of base to a slurry of the phosphonium salt in anappropriate solvent at\ or below\ room temperature[ The ylide obtained will be coloured and soluble\enabling visual monitoring and leaving the product ready for further reaction[ A range of solventsis possible with the restriction that it must be inert to reaction with base and ylide[ Common solventsare hexane\ benzene\ ether\ THF\ DMF and DMSO[ If the salt is of high enough acidity then water\alcohols and chlorinated solvents may be present[ For example\ benzylides are commonly generatedfor Wittig reaction using a two!phase CH1Cl1*H1O system with the salt and acceptor dissolved inthe organic layer and NaOH as a base[

The base used in ylide!forming reactions has been the subject of much research\ with attentionbeing paid particularly to the acidity of the phosphonium salt and the nature of the by!products[Salt acidity depends on the phosphonium moiety and especially on the substituents "R# of carbon[Ylides are often loosely classi_ed as being nonstabilised "R�alkyl\ halo#\ semistabilised "R�aryl\alkenyl# or stabilised "R�carbonyl\ cyano etc[# and this is the order of increasing acidity of theparent phosphonium salt[ Thus the base required varies from organolithium for preparation ofalkylides\ to methoxide for carbomethoxymethylides\ and ammonia for ~uorenylides[ This isre~ected in the ordering in Table 1 which lists typical baseÐsolvent combinations for ylide generationfrom phosphonium salts[ Interestingly\ the base used can be another "more basic# ylide\ in whichcase the process is called transylidation ðB!82MI 202!91Ł[ Other bases which have been used includesodium metal\ acetylide\ trityl and tetraalkylammonium ~uoride ðB!68MI 202!90\ B!82MI 202!91Ł[

Obviously the choice of base is limited by the other functional groups present "especially carbonyl#in the phosphonium salt[ However\ more important is the counterion which will be present in theylidic solution\ especially if that ylide is to be used in situ[ Because of the popularity of organolithiumreagents as bases\ many ylides are produced with lithium salts as by!products[ However\ these saltsare not innocuous because the lithium may complex to the ylide[ In particular they cause variationof the E:Z ratios of alkene products in Wittig reactions ðB!68MI 202!90Ł and seriously complicate theinterpretation of the mechanistic studies of that reaction ð78CRV752Ł[ For this reason\ much workhas gone into producing {salt!free| ylides\ which in this context means free of lithium cations andmost of the inorganic salts[ The di}erence that this makes is highlighted by the striking di}erencesin 20P NMR between these {salt!free| ylides "20P ¼ 1[9 ppm^ JP!C ¼ 89Ð099 Hz# and lithium!


Table 1 Base and solvent combinations used for the deprotonation of phosphonium salts[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐBase Solvent Ylide type Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐNa1CO2 Water Ester\ phenyl 49CB180\ 51JCS1226\ 53CB2108

Aqueous methanol Acyl 52JOC1335NH3OH EtOH Fluorenylide 58JA612NEt2 CH1Cl1\ EtOH Acyl\ ester 50JCS0155\ 51CB2992\ 51JOC887\ 79HCA327Pyridine CH1Cl1 Acyl\ ester 50JCS0155\ 51JOC887NaOH Water Ester 51JOC887\ 78JCS"P1#0394

Aqueous CH1Cl1 Phenyl 62S184\ 63TL1476NaOCH2 Methanol Phenyl 55JCS56\ 60CR"161#617NaOEt Ethanol Phenyl\ benzoyl 44CB0543\ 59JA2808\ 71S486KO!But ButOH Phenyl 54JOC0362

THF Alkyl\ vinyl 64JA3216DMF Phenyl\ vinyl 62AG"E#126DMSO Alkyl 54CB593

MeSOCH1−Na¦ DMSO Alkyl\ phenyl\ vinyl 58CC622\ 69JA286\ 69JA2318\ 69T0180\

"Dimsyl# 64JOC2345\ 65JCS"P0#0355\ 66JOC1672\66HCA0050

NaH THF Alkyl 57JCS"C#1337\ 57JOC2971NaNH1 Liquid NH2\ C5H5 Alkyl\ phenyl 59JA2808\ 54JCS6039\ 56LA"697#0LiNEt1 Toluene Phenyl 51CB1452LiN!Pri

1 THF Alkyl\ phenyl\ vinyl 64TL0248NaHMDS THF Alkyl\ phenyl 67CB137\ 75CB0249\ 89JGU502Li piperidide Ether Alkyl 51AG22\ 54JCS6039BunLi Et1O Alkyl\ vinyl 59JOC82\ 52JOC261\ 62OSC"4#640\ 64HCA0905\

66T0734THF Alkyl 58CC292\ 60CJC1032\ 60T4868\ 62JA4667\

71SC358Toluene Alkyl 66JOC1251DMSO Alkyl 69SCI76DMF Alkyl\ phenyl 56T1698\ 69BRP0191242

PhLi Et1O Alkyl\ vinyl 43CB0207\ 62TL3314THF Alkyl\ vinyl 58S27\ 60JA4200

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

complexed ylides "20P ¼ 11 ppm^ JP!C ¼ 49Ð54 Hz# ð65JOC0057Ł[ The earliest procedure for salt!freeylide solutions\ due toBestmann andArnason ð51CB0402Ł used sodium amide in liquid ammonia todeprotonate the salt\ followed by addition of benzene\ ammonia evaporation and airless _ltrationof the insoluble Na¦ salts[ Later THF replaced benzene but more recently the need for liquid ammoniahas been circumvented by use of NaH in THF ð69LA"628#100Ł or sodium hexamethyldisilazide "Na!HMDS# in a variety of solvents ð65CB0583\ 75CB0249Ł\ again with _ltration of the insoluble sodium salts[

Other complications which attend the deprotonation of phosphonium salts include ligand ex!change and elimination[ It is known ð53JOM"1#090\ 54JA2356\ 55AG"E#857Ł that treatment of phos!phonium salts with carbanionic reagents can result in a ligand exchange process via a pentavalentintermediate "Scheme 1#[ This process is favoured where R�Ph and has in fact been used as a routeto ylides\ for example the cyclopropylide in Scheme 2 ð56CC299Ł[ b!Elimination must be taken intoaccount when there is a potential leaving group at the b!position or another acidic hydrogen[ Thusb!bromoethyltriphenylphosphonium bromide and b!triphenylphosphonioethyltriphenylphos!phonium bromide undergo initial elimination of hydrogen bromide and triphenylphosphine\ respec!tively\ when treated with phenyllithium ð55JOM"5#194Ł[

R1

PR2

R1

R1

R1R1

4PX–+

R13PR2 Br– + R1Li

+R2Li

Scheme 2

Li PPh3PPh3 Br–+

+PhLi

Ph4PBr–+

–C6H6

–LiBr

Scheme 3

384From Phosphonium Salts

2[02[0[2 Dehalogenations of Phosphonium Salts

Ylides may be derived from phosphonium salts by abstraction of an a!halogen rather than ana!H[ This can be a problem when both are present\ but it can be controlled by variation of thehalide and the base[ This is shown in Table 2 where it can be seen that a!halogen attack increasesCl×Br×I and BunLi×PhLi×Li piperidide×HMDS[ Abstraction of halogen is also a usefulroute to otherwise inaccessible ylides and thence to alkenes[ Thus Smithers ð67JOC1722Ł was able toprepare terminal vinyl bromides by the route shown in Scheme 3[

Table 2 a!Halogen vs[ a!H abstraction in halogenomethylphosphonium salts[

Ph2¦PCH1X

−004

Base Ph2P1CH1¦Ph2P1CHX*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

Methylide HalomethylideX Base ")# ")# Ref[*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐCl PhLi ³0 ×88 55JOM"4#156Br PhLi 49 49 55JOM"4#156I PhLi 64 14 55JOM"4#156Br BuLi ×88 ³0 51AG22\ 55CB578Br Lipip ³0 ×88 51AG22\ 55CB578I NaHMDS minor product major product 78TL1062*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

Scheme 4

Ph3P

R1

Br

+Br–

BuLi

R2CHO

Br

R1

BrR2

R1BrPh3P

Br

Br

The system resulting from the addition of triphenylphosphine to tetrahalomethanes is also quiteuseful for the production of haloylides[ This complex reaction system is summarised in Scheme 4[With careful control of conditions it is possible to select each of the di}erent possible pathways[Thus the addition of controlled amounts of water gives the dichloro and monochloro saltsð64AG"E#790\ 66S568\ B!68MI 202!92Ł\ and the system is a well!known reagent for the conversion ofalcohols to halides ðB!68MI 202!92Ł[ Also the dichloro ylide "0# has been used for the preparation ofa wide variety of dichlorovinyl systems ð60JOC2275\ 65BSF1957\ 77TL2992\ 80SL472Ł[ Vorbruggen et al[ð89T2378Ł cleverly combined these aspects of the system\ _rst converting a carboxylic acid into thechloride which subsequently acylated the ylide "0#[ The dibromo derivative is easier to generateand use ð51JA0634\ 61TL2658\ 67JOC1722\ 89S774Ł\ but the di~uoro case ð62JA7356\ 89T4102Ł is morecomplicated[ This is because\ on generation\ in the absence of other reactants\ it dissociates givingdi~uorocarbene which in turn can be trapped by more nucleophilic phosphines ð72JOC2505Ł "see2[02[1#[ The monochloro! and mono~uoromethylides can also be prepared using this sort of systemwith iodochloromethane ð68BCJ0086Ł and iodo~uoromethane ð64JOC1685Ł respectively\ as the elec!trophiles[ Fluorine!containing ylides have also been reviewed ð70RCR179\ 71RCR0Ł[

Ph3P

Cl

Cl

Ph3P PPh3

Cl Cl

Ph3P + CCl4 Ph3PCCl3 Cl–+ PPh3

+ Ph3PCl2 +

Ph3P

Cl

Cl

(1)

Cl–

+

Ph3P Cl+

Cl–

(1)

++

Ph3P H2O

Scheme 5


2[02[0[3 Desilylations of Phosphonium Salts

This is another alternative to deprotonation and is the best way of making truly salt!free non!stabilised ylides[ Usually it is the trimethylsilyl group which is removed\ for example\ meth!ylenetrimethyphosphorane was _rst made by the route shown in Scheme 5 ð57CB484Ł[ A shortermodern version of this route uses the nonnucleophilic tri~ate anion as shown in Scheme 6\ but isonly applicable to methylides ð68JA5341\ 75CRV830Ł[

CH2Me3PPMe3 –ORTMS–RO-TMS

+PMe3TMSPMe3 Cl–TMSClTMS

+

Me3P –HCl ROH

Scheme 6

Scheme 7

CH2Ph3P+PPh3TMSOTfTMS

Ph3P CsF

–TMS-F

2[02[0[4 Ylides from Vinylphosphonium Salts

In principle\ nucleophilic attack at the b!position of a vinylphosphonium salt can lead to an ylide"Equation "1##[ Obviously there are a number of possible complicating side reactions\ such as attackat phosphorus[ However\ it has been found that dialkyllithium cuprates are especially e}ectiveð74TL0688\ 80CB0760Ł\ and the process is often used where the resulting ylide is already set up forfurther reaction*especially intramolecular[ For example\ Schweizer et al[ ð53JA1633\ 55JOC356Łhave used the salicylaldehyde anion as a nucleophile on vinyltriphenylphosphonium bromide in asynthesis of chromene "Scheme 7#[ The necessary precursor salts can be made in a number of ways]from vinyltri~ates ð78JOC1672\ 89JOC4922Ł^ from alkenes by electrolysis ð74TL1088\ 76CPB3859Ł and byrearrangement of allylic salts ð78IZV0071\ 89S290\ B!83MI 202!90Ł[ There is a fairly wide variety of othernucleophiles which can also be used in this process\ including amines ð67JA0437\ 70JOC2008\ 72TL2932Ł\enolates ð63TL3944\ 63TL3112\ 64JOC099\ 72JCS"P0#1868\ 81TL466Ł and alkoxides ð72JOC1458\ 78JOC863Ł[The formation of heterocycles in this way has been reviewed ðB!68MI 202!93Ł\ as has the participationof 0!cycloalkenylphosphonium salts ð80RHA169Ł[

NUCPPh3PPh3NUC –

+ (2)

O

CHO

OPPh3

CHO

O–

PPh3+

+–Ph3PO

62%

Scheme 8

2[02[0[5 Ylides from Cyclopropylphosphonium Salts

In a manner analogous to that in the previous section\ nucleophilic ring opening of a cyclo!propylphosphonium salt can also lead to an ylide "Equation "2##[ Ring opening can be in bothdirections which was observed in the case of salicylate ring opening of the unsubstituted cyclo!propylphosphonium bromide ð57JOC225Ł[ However\ if the phosphonium salt bears an ylide sta!bilising group at the a!position only one product is obtained ð63JA0596\ 64TL3242\ 74TL4340Ł as shown\for example ð64TL3242Ł\ in Equation "3#[ Other nucleophiles used have included enolates ð63JA0596Łand thiolates ð74TL4340Ł[

386From Phosphines

NUCNUC –

+

(3)PPh3PPh3

PPh3

CO2EtCO2EtRCO2

–

+(4)RCO2

Ph3P

2[02[0[6 Ylides by the Electrolysis of Phosphonium Salts

Phosphonium salts usually undergo electrolytic reductive cleavage to a hydrocarbon and aphosphine ðB!82MI 202!92Ł[ However\ under certain conditions a two!electron transfer process canresult in the formation of ylides as shown in Scheme 8 ð57JA1617\ 61BSF2438\ 66JOC0131\ 70JCS"P0#0419Ł[

R PPh3 R PPh3 R PPh3+ • RCH2

– + RMeR PPh3+ e + e

+

RCH2 + Ph3P•

Scheme 9

2[02[1 PHOSPHONIUM YLIDES FROM PHOSPHINES

2[02[1[0 Reactions with Carbenes

In principle\ the direct interaction of a phosphine and a carbene could lead to an ylide[ Such areaction is known and has been studied theoretically in some detail ð68JA6058\ 75CB0220Ł[ However\at least for phosphonium ylides\ it is not very useful preparatively[ The early experiments involvedtreating polyhalomethanes with a base such as t!butoxide or an organolithium reagent\ trappingthe resulting carbenes with triphenylphosphine and detecting the resulting ylide by Wittig reactionð50JA0506\ 50CB0262\ 51JA743Ł[ Yields were at most modest[ With the advent of smoother routes tothe carbenes\ yields have been improved somewhat[ Thus\ decarboxylation of sodium di~uoroacetatein the presence of triphenylphosphine and a carbonyl compound gives the phosphine oxide and thedi~uorovinyl compound ð54JOC0916\ 54JOC1432\ 57TL60Ł[ The smoothest reaction of this type isfrom the phenyldihalomethylmercuric bromides shown in Scheme 09 "X�H\ Cl\ Br^ Y�Cl\ Br#ð55JOM"4#156Ł[ This route to halomethylides is better than that described in 2[02[0[2 because thereare no by!products such as Ph2PCl1[ Dithio! and diselenomethylides can be made by carbeneroutes\ either by tosylhydrazone reduction ð53TL134Ł "Equation "4##\ or from tri"phenylseleno#! ortri"phenylthio#methanes ð56AG"E#332\ 61CB376\ 61CB400Ł "Equation "5#^ E�S\ Se#[

X

Y

Ph3P

X

Y + Ph3P

C6H6

∆

O

–Ph3PO

X

Br

PhHg Y

Scheme 10

Ph3P

SEt

SEt

TsNHN

SEt

SEt

NaH

Ph3P(5)

Ph3P

EPh

EPh

PhE

EPh

EPh

PhLi

Ph3P(6)

2[02[1[1 Via Azines

In a method related to that in the previous section\ ylides can result from the thermal decompo!sition of phosphine azines[ In fact the _rst phosphonium ylide was produced in this way "Scheme


00# ð08HCA508Ł[ However\ the method is not generally applicable to the synthesis of phosphoniumylides\ the only useful cases being cyclopentadienylides ð47JOC1925\ 56CI213\ 56T1690\ 61T242Ł whichalso require the presence of a copper"I# catalyst[

PPh3

Ph

PhPh2CN2 + Ph3P

∆

Ph

Ph

N

N PPh3

–N2, 195 °C

Scheme 11

2[02[1[2 Reactions with Activated Multiple Bonds

Activated alkenes undergo nucleophilic attack by tertiary phosphines to yield ylides after pro!totropy in the initially formed carbanionic intermediate ð39JCS0263\ 50ACS581\ 50CB0220\ 52HCA1067\53JOC2610\ 54TL190\ 55T456\ 57T1130Ł[ The process is straightforward if the alkene is doubly activatedas this provides an adjacent ylide stabilising group\ e[g[\ Equation "6# ð39JCS0263\ 50ACS581\ 52HCA1067\57T1130Ł[ However\ even if there is no second ylide stabilising group\ the intermediate adduct canbe trapped as the silylenol ether ð75JOC2391\ 77TL4302Ł and the ylide can then be generated bydeprotonation of the resulting phosphonium salt "Scheme 01#[

O

O

O

O

O

O

Ph3P

PPh3 + (7)

(CH2)n

O

(CH2)n

O

Ph3P/THF

TfOSiMe2But

i, BuLi

ii, RCHOiii, HF

R(CH2)n

OSiMe2But

PPh3

+

Scheme 12

These reactions have the drawback that they may turn out to be rather complex when examinedin detail[ An example of this would be the addition of phosphines to acrylonitrile where very carefulcontrol of conditions and addition of an agent to promote proton transfer are necessary ð51JA378\53TL0542\ 54JOC0246\ 56TL1390\ 57BCJ1704\ 69JOC2934\ 73SC0156\ 77T3542\ 78TL1620Ł[

The reactions of phosphines with activated alkynes are not as useful because the reactions tendto be very complicated[ A case in point is the reaction with dimethyl acetylenedicarboxylate "DMAD#which with careful control yields a bis!ylide "Equation "7## ð56JCS"C#1331Ł but which can also yieldseveral other products ð50JCS1015\ 54CB252\ 56JCS"C#1331\ 58JCS"C#0099\ 78JCS"P0#1314Ł[ Dibenzoyl!acetylene reacts similarly ð69JCS"C#4Ł[

PPh3

CO2MeMeO2C

Ph3P

CO2MeMeO2CPPh3

(8)

2[02[1[3 Reactions with Aziridines

Again in a manner analogous to that in the previous section\ ring opening of aziridines withphosphines leads to b!amino ylides\ e[g[\ Equation "8# ð89TL1550Ł[

N BOCtNH

Ph3P BOCtPh3P + (9)

2[02[1[4 Reactions with Arynes

Tertiary phosphines bearing an a!H add to arynes to produce ylides ð52JOC1352Ł[ It is assumedthat the initial adduct undergoes proton transfer as shown in Scheme 02[

388From Other Phosphonium Ylides

PPh2

Me

PPh2

CH2

+

–

Ph2PMe

Scheme 13

2[02[2 PHOSPHONIUM YLIDES FROM PHOSPHORANES

Highly stabilised ylides can be made by the reaction of dichlorotriphenylphosphorane with activemethylenes in the presence of triethylamine "Equation "09##^ X\ Y�CO1R\ CN\ SO1Ph\ COR#ð47CB326\ 56JPS"B#0928Ł[

Ph3P

X

YPh3PCl2 + X Y

Et3N(10)

2[02[3 PHOSPHONIUM YLIDES FROM OTHER PHOSPHONIUM YLIDES

Although not strictly involving construction of the P1C bond\ the following reactions arepowerful methods for changing the substituents at the ylidic carbon atom[

2[02[3[0 By Halogenations

A variety of halogenating agents will convert an ylide bearing an a!H to the halo!substitutedderivative ðB!82MI 202!93Ł[ This is the preferred route to a!halo ylides because the alternative saltmethod is complicated by the possibility of base attack at the halogen "see 2[02[0[2#[ In the absenceof any other reagent the maximum yield of ylide is 49) with the other 49) being the conjugateacid of the original ylide\ because the initial product is the a!halophosphonium salt which undergoestransylidation ð50CB1885Ł "Scheme 03#[ However\ there are several ways to raise the theoretical yieldto 099)] use of excess halogen ð51JOC887\ 52JOC354Ł^ use of added base\ e[g[\ pyridine or triethylamineð51JOC887Ł^ use of t!butylhypohalite as halogenating agent*the t!butoxide generated acts as thebase ð51JOC887Ł[

Scheme 14

Ph3P

X

R

+Ph3P

R +X2

Ph3P

X

R

+X–

Ph3P R Ph3P R

2[02[3[1 By Alkylations and Acylations

Most alkylating agents will react with the nucleophilic ylidic carbon to give the correspondingphosphonium salts "Equation "00##[ This is a powerful way to elaborate the carbon skeleton of theoriginal ylide and there has been a great deal of work done to explore all the possibilities of thereaction\ including transylidation e}ects ðB!82MI 202!93Ł[

Ph3P CH2 + RX Ph3P R X–+ (11)

Acylation of ylides is similar and has been studied in as great detail ðB!82MI202!93Ł[ The acylatingagent of choice is the acyl halide or acyclic acid anhydride[ Acylation is particularly useful for thepreparation of b!keto ylides which are not reliably available by quaternisation of a!bromoketones"see 2[02[0[0#[ Once again the reaction is invariably complicated by transylidation e}ects because ofthe extra carbanion stabilising e}ect of the added acyl group\ and again various strategies have beendevised to overcome the resulting loss of yield ðB!82MI 202!93Ł[


2[02[4 PREPARATION OF As\ Sb AND Bi YLIDES

Methods used for the preparation of As\ Sb and Bi ylides are in general similar to those used forphosphorus ylide generation[ Perhaps a di}erence could be noted in the shift of emphasis awayfrom the salt method towards the carbene method[

2[02[4[0 From the Precursor Onium Salts

This is a comparable method to that described in 2[02[0 and subsequent subsections[ Salts aremade and converted into ylides as usual\ the only real di}erence being that the pKa of these tendto be higher than that of their phosphorus analogues and therefore a stronger base may be necessary[Ylides which have been prepared using the salt method include] various types of methylides ð54IC0347\57JOM152\ 69ACS2661\ 60JCS"C#0003\ 67CB1691\ 68IJC"B#526Ł^ propynylides ð77S210Ł^ cyclopenta!dienylides ð60JCS"C#1830Ł and ~uorenylides ð42LA"479#46\ 59JOC072\ 67IJC"B#512Ł[

2[02[4[1 From Arsines\ Stibines and Bismuthines

This method is directly related to 2[02[1 in that the ylide is prepared by the direct interaction ofan arsine\ stibine or bismuthine and a carbene[ This method has been used extensively in thesynthesis of As\ Sb and Bi ylides where thermal decomposition of diazo compounds or iodoniumylides\ usually in the presence of copper\ provides the source of the carbene[ This carbene methodhas again a}orded various types of ylides including\ from diazo compounds] methylides ð75T2776\77S208\ 77JCS"P1#0718Ł^ cyclohexylides ð77CL736\ 77JCS"P1#0718\ 77S208Ł and cyclopentadienylidesð61CC805\ 61T232\ 71T2244\ 72T186\ 75T2776\ 77JCS"P1#0718\ 77S208Ł^ and from iodonium ylides] methylidesð71T2244\ 76JCR"S#263\ 77S802Ł^ cyclohexylides ð71T2244\ 78TL5562Ł and cyclopentadienylides ð71T2244Ł[

2[02[4[2 From the Dihalo Pentacoordinate Derivatives

As in 2[02[3\ numerous methylides have been prepared by the reaction of triphenylarsine dichloridewith various substituted active methylene compounds in the presence of triethylamine ð47CB326\48LA031Ł[ Schmidbaur and Hasslberger described the preparation of pentakisð"trimethylsilyl#methylŁantimony by the trimethylsilylmethylation of trisð"trimethylsilyl#methylŁantimony dibromideð67CB1691Ł[ More recently\ bismuthonium ylides have been prepared by the reaction of the sodiumsalts of some active methylene compounds with triphenylbismuth in THF ð89BCJ849Ł[

2[02[4[3 From the Tertiary Oxides

This is the only preparative method for As\ Sb and Bi ylides which has no counterpart in thephosphorus analogues[ It is analogous to that described above "2[02[4[2#\ the only di}erence beingthat H1O is produced as the by!product rather than a hydrogen halide[ Thus an active methylenecompound reacts with Ph2MO "M�As\ Sb and Bi# in acetic anhydride or in triethylamine "withphosphorus pentoxide also present# to give an ylide and H1O[ This method has been used to prepare\among others\ methylides ð72T186\ 89BCJ849Ł and cyclopentadienylides ð60JCS"C#1830\ 62T0586\ 63T1146\72T186Ł[


3.14Doubly Bonded MetalloidFunctions (Si, Ge, B)TAO YE and M. ANTHONY McKERVEYThe Queen’s University of Belfast, UK

2[03[0 GENERAL METHODS FOR THE PREPARATION OF C1METALLOIDFUNCTIONS "Si\ Ge\ B# 490

2[03[0[0 Doubly!bonded Silicon Functions 4902[03[0[1 Doubly!bonded Germanium Functions 4922[03[0[2 Doubly!bonded Boron Functions 493

2[03[0 GENERAL METHODS FOR THE PREPARATION OF C1METALLOIDFUNCTIONS "Si\ Ge\ B#

Those compounds with general structures "0#Ð"2# are named\ in general\ as silenes\ germenesand methyleneboranes\ respectively[ Reviews containing information on the synthesis of thesecompounds have appeared "silenes] ð68CRV418\ 73JOM"162#030\ 74CRV308\ 75AOC"14#0\ B!78MI 203!90Ł^germenes] ð71AOC"10#130\ 73JOM"162#030\ 89CRV172\ 83CCR316Ł^ methyleneboranes] ð82AG"E#874Ł[ Onlythe formation of these silenes\ germenes and methyleneboranes in which the two sigma bonds ofthe carbenic atom are not directly attached to a heteroatom will be surveyed in this Chapter[ Manysilenes and germenes have been recognised or identi_ed as transient intermediates\ very few of whichare stable enough to be isolated[ In addition\ nonheteroatom!containing methyleneboranes are rare[

Si

R2

R1 R3

R4

Ge

R2

R1 R3

R4

B

R2

R3

R1

(1) (2) (3)

Several routes leading to the formation of C1metalloid functions "Si\ Ge\ B# have been exploited[The principal methods may be assigned to one of three general categories] "i# photochemicalgeneration\ "ii# generation by pyrolysis and "iii# processes involving 0\1!elimination reactions[

2[03[0[0 Doubly!bonded Silicon Functions

A large number of silenes can be generated from the photoinduced or thermal decomposition ofsuitable precursors[ Silenes of the general type "4# can be synthesised via ð1¦1Ł cycloreversionprocesses from the thermolysis of silacyclobutanes "3# at high temperature "Equation "0## ð63JA6094\68CRV418\ 79JOM"077#040\ 79JOM"086#02Ł[ The larger the substitutent at the silicon atom in "3# thepoorer the yield of "4#[ More substituted silacyclobutane precursors are also suitable for the

490

491 Doubly Bonded Metalloids "Si\ Ge\ B#

generation of silenes ð76OM0395Ł[ In addition\ photochemical methods for the generation of silenes"4# from the silacyclobutanes "3# are also possible ð68JA1380\ 70T1764Ł[ The silene ""4#\ R0�R1�Me#has been detected by IR spectroscopy of products trapped by the matrix!isolation techniqueð74CRV308Ł[ Silenes "6# and "8# can be prepared via ð1¦3Ł cycloreversion processes from pyrolysisof silabicycloð1[1[1Łoctadiene derivatives "5# and "7# "Scheme 0# ð71OM109\ 71JA5039\ 79JA3869\72JA5614Ł[ Two indirect routes to silenes\ one derived from silylenes and the other from silylcarbenes\are of some generality and importance ð75AOC"14#0Ł[ Photolytic decomposition of trimethyl!silydiazomethane "09# yields a!silylcarbenes which then smoothly rearrange to give 0\0\1!trimethyl!silaethylene "00# "Equation "1## ð65JA6733\ 65JA6735Ł[ 0!Methylsilene "03# can be produced fromphotoconversion of dimethylsilylene "02# and is stable for many hours in argon at 24 K[ Dimethyl!silylene "02# can be obtained\ in turn\ by irradiation of dodecamethylcyclohexasilane "01# "Scheme1# ð70JA0734\ 72JA5065\ 73JA414Ł[ Similarly\ irradiation of the cyclic divinyldisilane "04# yields thecyclic silene "05# "Equation "2## ð80JA2875Ł[ Alternative routes to the formation of silenes involve0\1!elimination reactions[ Thus addition of t!butyllithium to vinyl chlorosilanes "06# produces silenes"07# by 0\1!elimination of lithium chloride "Equation "3## ð79JA3869\ 80AG"E#333\ 80OM1418Ł[ In 0881Apeloig and co!workers reported a new route for silene formation which involves a Peterson!typeelimination process[ One example is shown in Equation "4# ð81OM1215Ł[

(4) (5)

Si

R2

R1 Si

R2

R1400–700 °C

5–100%(1)

R1 = R2 = Me, vinyl, Ph; R1 = Me, R2 = Ph; R1 = Ph, R2 = vinyl

SiRMe

CF3

CF3

Si

R

Me

(8) (9)

Si

Me R

But

(7)(6)R = H or TMS

∆Si

R

Me

∆

But

R = Me or Ph

Scheme 1

TMS

N2Si

Me

Mehν

(10) (11)

(2)

(12) (14)(13)

SiMe

H(Me2Si)6 (Me2Si)5 + Me2Si

hν

254 nm

hν

450 nm

Scheme 2

492C1Metalloids "Si\ Ge\ B#

SiMe

TMSSi Me

TMS

hν

(15) (16)

(3)

(4)

(17) (18)

R1

SiCl

R2

R1

SiBut

R2

LiBut

R1 = R2 = Me, Cl; R1 = Ph, R2 = vinyl

(5)

OSi

TMS

TMS

(TMS)3SiLi•3THF

2[03[0[1 Doubly!bonded Germanium Functions

Transient germene "19# can be prepared via ð1¦3Ł cycloreversion processes involving pyrolysisof the bicyclic compound "08# "Equation "5## ð62JA2967Ł[ Transient germenes can also be generatedfrom a!germylcarbenes[ Pyrolysis of phenyltrimethylgermyldiazomethane "10# has yielded transientgermene "11# "Equation "6## ð79JA0473Ł[ Alternative routes to the formation of germenes involveinteraction between germylenes and carbenes[ Examples are shown in Equation "7# ð79JA4302Ł[Other important routes to the formation of germene involve 0\1!elimination reactions[ A fewthermally stable but highly air! and moisture!sensitive germenes "13# have been obtained as orangecrystals by dehydrohalogenation reactions involving the corresponding chloro! or ~uorogermanesat low temperature[ Thus\ addition of t!butyllithium to the halogermanes "12# at −67>C a}ordedthe corresponding germenes "13# in good yields "Equation "8## ð76JA3300\ 80JOM"392#82\ 80POL0042Ł[Similarly\ addition of t!butyllithium to ~uorovinylgermane "14# followed by elimination of LiF hasa}orded the stable dimesitylneopentylgermene "15# in 89) yield "Scheme 2# ð81OM2065Ł[

(6)

Ge

CF3

CF3Cl

EtEt

Ge

Et

Et

(19) (20)

450 °C

(7)Ph

Me3Ge

N2

Ph

GeMe2

(21) (22)

450 °C

(8)Ph2Ge + N2

RGe

Ph

Ph

R

Cu, 60 °C

R = Ph, CO2Et

493 Doubly Bonded Metalloids "Si\ Ge\ B#

(9)Ge

X

R2

R1 Ge

R1

R2

(23) (24)

ButLi, –78 °C

–ButH, –LiX

R1 = R2 = ; X = F ; X = FR1 = R2 = ; X = ClR1 =But, R2 =

R1 = (TMS)2CH, R2 = ; X = FR1 = R2 = (TMS)2CH; X = F

GeF

FGe

FGe

F

Li

But G eBut

(25)

MgBr

(26)

ButLi

–78 °C

–50 °C

–LiF

Scheme 3

2[03[0[2 Doubly!bonded Boron Functions

Simple substituted boraethenes "17# can be prepared via ð1¦3Ł cycloreversion processes frompyrolysis of corresponding bicyclic compounds such as "16# "Equation "09## ð74AG"E#0954Ł[ Alter!native routes to the formation of methyleneborane involve a dehalogenation process[ Thus\ treat!ment of 8!~uorenyltetramethylpiperidinoboron halides "18# with lithium or sodium amide at roomtemperature has been shown to lead to the amino"methylene#borane "29# in 59Ð69) yield "Equation"00## ð74AG"E#305Ł[

B

X

CF3

CF3

∆

(27) (28)

X B

X = OMe or NMe2

(10)

494C1Metalloids "Si\ Ge\ B#

(11)

(29) (30)

N B

X

N BMNR2

–MX, –HNR2

X = F, Cl; M = Li, Na; NR2 = N(TMS)2, N(TMS)But


3.15Doubly Bonded Metal FunctionsTAO YE and M. ANTHONY McKERVEYThe Queen’s University of Belfast, UK

2[04[0 INTRODUCTION 496

2[04[1 GENERAL METHODS FOR THE PREPARATION OF THE C1METAL FUNCTION 497

2[04[2 THE C1Ti FUNCTION 497

2[04[3 THE C1Zr FUNCTION 498

2[04[4 THE C1V FUNCTION 409

2[04[5 THE C1Nb FUNCTION 409

2[04[6 THE C1Ta FUNCTION 400

2[04[7 THE C1Cr FUNCTION 402

2[04[8 THE C1Mo FUNCTION 402

2[04[09 THE C1W FUNCTION 403

2[04[00 THE C1Mn FUNCTION 407

2[04[01 THE C1Fe FUNCTION 408

2[04[02 THE C1Ru FUNCTION 419

2[04[03 THE C1Rh FUNCTION 419

2[04[04 THE C1Re FUNCTION 410

2[04[05 THE C1Os FUNCTION 411

2[04[0 INTRODUCTION

These compounds\ LnM1CR0R1\ are generally named as metal carbene "alkylidene# complexesand are often subdivided into two broad groups[ In the _rst group the ligated carbene carbontypically possesses heteroatom substituents or aryl groups[ These carbene complexes act as carbonelectrophiles toward other chemical species and are referred to as Fischer!type carbenes[ The secondgroup of metal complexes are called Schrock!type carbenes or alkylidene complexes[ The ligatedcarbon of this type of carbene species is attached directly to a metal by a double bond while theother two bonds are not attached directly to any heteroatom[ In contrast to the Fischer!typecarbenes\ the Schrock!type carbene "alkylidene# complexes behave chemically as carbon nucleo!philes[

This chapter will concentrate on the methods for the synthesis of the nonheteroatom!stabilisedcarbene "alkylidene# complexes[ Methods for the preparation of heteroatom!stabilised carbenecomplexes are summarised in Chapter 4[13[1[ Although some workers have preferred to use theterms {carbene| and {alkylidene| to distinguish complexes having di}erent types of reactivity\ in thischapter no distinction will be made between the two terms and all the nonheteroatom!stabilisedmetal complexes which will be discussed are simply referred to as carbenes[

496

497 Doubly Bonded Metal Functions

2[04[1 GENERAL METHODS FOR THE PREPARATION OF THE C1METAL FUNCTION

Reviews containing information on the synthesis of nonheteroatom!stabilised carbenes haveappeared ð79MI 204!90\ B!72MI 204!90\ B!75MI 204!90\ B!77MI 204!90\ 80MI 204!90Ł[ Several routes leadingto the formation of carbene complexes have been exploited[ The principal methods may be dividedinto three broad categories] "i# carbonÐmetal double bond formation via an intermolecular reactionof a metal complex with a carbene or carbene precursor "Equation "0##^ "ii# transformation of amolecule containing a carbonÐmetal single bond or triple bond into a metal carbene "Scheme 0#^and "iii# modi_cation of a preformed metal carbene molecule\ that is exchange or modi_cation ofthe carbene ligand\ exchange or modi_cation of the ligand"s# on the metal\ or by changing theoxidation state of the metal "Scheme 1#[

MLn1 +R1

R2

Ln2M

R1

R2(1)

Ln2M

R1

R2

Ln1M R1Ln1M

R1

R2

Scheme 1

LnM

R1

R2

Changing the oxidation state

Exchange or modification

Exchange or modification

Scheme 2

A wide range of synthetic procedures can be used for the preparation of nonheteroatom!stabilisedcarbenes and some of these have proved very successful[ However\ no general methods exist whichare suitable for preparing all types of nonheteroatom!stabilised carbenes[ In this chapter\ the generalsurvey of the synthetic routes leading to metal carbenes has been organized according to the natureof the metal involved[ Representative examples have been chosen to demonstrate the syntheticstrategies[ Metal carbenes which are incapable of isolation\ but can be generated mainly by metal!catalysed decomposition of diazo compounds\ are not included in this chapter ð83CR0980Ł[

2[04[2 THE C1Ti FUNCTION

The titanium methylene complex\ Cp1TiCH1\ can be generated from a number of precursorsð73PAC48Ł[ These include titanacyclobutane complexes ð72PAC0622Ł as well as titanium adducts withLewis acids ð67JA2500\ 72TL1932\ 72TL2824Ł[ A variety of titanacyclobutanes can be prepared in turnfrom the Tebbe reagent ð67JA2500Ł\ and these titanacyclobutanes can be handled in air for reasonableperiods of time ð70JA6247\ 72PAC0622Ł[ Titanium methylene complexes derived from the thermolysisof the titanacyclobutanes\ or from base removal of the Lewis acid of the {Lewis acid adducts|such as the Tebbe reagent Cp1Ti"m!CH1#"m!Cl#AlMe1 ð67JA2500Ł\ are usually observed as reactiveintermediates "Scheme 2#[ However\ reaction of the bicyclic titanacyclobutane "0# at room tem!perature with an appropriate alkylphosphine a}ords the monophosphine!containing carbene com!plex "1# which can be cleanly isolated ð75OM610Ł[ The titanacyclobutane "0# was obtained from areaction of the Tebbe reagent with 2\2!dimethylcyclopropene in the presence of "dimethyl!amino#pyridine "Scheme 3#[ Similarly\ treatment of a solution of b\b!dialkyltitanacyclobutane "2#with excess trialkylphosphine at room temperature yields the corresponding titanocene methylidenephosphine complex "3# "Equation "1##[ The carbene complex "3# can be isolated as an extremely air!and moisture!sensitive\ thermally unstable\ yellow!brown powder ð78OM472Ł[ In the late 0879s\Binger et al[ reported that the titanocene"vinylcarbene# complex "6# can be prepared via a new

498C1Zr Function

route as shown in Equation "2#[ Thus\ treatment of the readily accessible cyclopropene "5# withtitanocenebis"trimethylphosphine# "4# a}ords "6# in good isolated yield ð78AG"E#509Ł[ The vinylcarbene complexes "6# seem to be more stable than the methylene or substituted carbene complexesshown in Schemes 2 and 3 and Equation "1#[

Cp2TiR2

R1

Cp2Ti Cp2TiCl

AlMe

Me

Scheme 3

5–60 °C base, –40 °C

R1 = R2 = Me; R1 = Me, R2 = Prn; R1 = H, R2 = But

Cp2TiCl

AlMe

Me+

dmap Cp2Ti PMeR2

50–55% Cp2(PMeR2)Ti

Scheme 4

R = Me, Ph (1) (2)

(3) (4)

Cp2Ti + phosphinevacuum

49–77% Phosphine

Cp2Ti

phosphine = PMe3, PMe2Ph, PEt3

(2)

(3)Cp2Ti(PMe3)2 +RR

0–20 °C

PMe3

Cp2Ti

R

R(5) (6) (7) a; R = Me, 81%

b; R = Ph, 72%

2[04[3 THE C1Zr FUNCTION

The thermally labile zirconium carbene complex "8#\ formed via reaction of H1C1PPh2 with thezirconocene phosphine complex "7#\ has only been detected in situ and not isolated "Equation "3##ð79JOM"073#C0Ł[ However\ Cp1Zr1CHCH1R"L# complexes of type "00# can be isolated as thermallylabile oils by hexamethylphosphoramide "HMPA#!induced bridge cleavage of the zirconoceneÐaluminum precursors "09# ð72JA539Ł[ Yields for the formation of the carbene complex "00# vary asa function of the trapping phosphine ligand used "see Equation "4##[ The zirconocene"vinylcarbene#complex "02# can be prepared in an analogous manner[ Thus\ reaction of the cyclopropene "5^R�Ph# with the zirconoceneÐalkene complex "01# a}orded equal amounts of the zircono!cene"vinylcarbene# complex "02# and the "h1!diphenylcyclopropene# complex "03# "Equation "5##ð78AG"E#509Ł[ The stable zirconium carbene complex "05# has been prepared via the a!hydrogenabstraction process shown in Equation "6#[ Thus\ reaction of the zirconium complex "04# with oneequivalent of MgBn1 =THF generated a mixture of the corresponding monobenzyl derivative whichwas then photolysed or thermolysed to provide the stable zirconium carbene complex "05# in 74)yield ð82JA4225Ł[

(4)Cp2Zr(PPh2Me)2 +(8) (9)

Ph3P Cp2(PPh2Me)Zr


(10)

Cp2ZrCl

Al

R

Bui

BuiCp2LZr

R i, L

ii, HMPA(5)

(11)

R = But, L = PPh3, 54%; R = But, L = PMe2Ph, 70%R = c-C6H11, L = PPh3, 69%; R = c-C6H11, L = PMe2Ph, 59%R = CMeEt, L = PPh3, 33%; R = CMeEt, L = PMe2Ph, 52%

Cp2Zr

PMe3

+PhPh

PMe3

Cp2Zr

Ph

Ph

+Cp2Zr

PMe3

PhPh

(6)20 °C

(12) (6b) (13) (14)

(15) (16)

ZrCl3

SiSi

PPPri

Pri Pri Pri

Me

MeMe

Me

Zr

SiSi

PPPri

Pri Pri Pri

Me

MeMe

Me

Ph

(7)Cl i, MgBn2•2THF

ii, hν or ∆ (–Bn)

2[04[4 THE C1V FUNCTION

Nonheteroatom!stabilised vanadium carbene complexes are rare[ Teuben and co!workers havereported the preparation of the _rst vanadium carbene complex "19#\ which probably involved thea!hydrogen abstraction process shown in Scheme 4[ Thus\ the vanadium complex "06# was treatedwith two equivalents of the Grignard reagent "07# to give the extremely air!sensitive carbeneprecursor "08#[ When "08# was decomposed thermally in the presence of the chelating phosphinedmpe "dmpe�0\1!bis"dimethylphosphino#ethane#\ the greenish!brown vanadium carbene complex"19# was isolated ð78JA4866Ł[

CpVCl2(PMe3)2 2ButCH2MgClV

CpV(CH2But)2PMe3

But

P

P

Me

MeMe

(17)

+

(20)(19)

Scheme 5

(18)

Me+ (Me2PCH2)2

–C(Me3)4, –PMe3

2[04[5 THE C1Nb FUNCTION

Niobium carbene complexes can be prepared from the corresponding complexes containing acarbonÐniobium single bond[ Reaction of the niobium complex "10# with two equivalents of LiCH1!But in pentane at −67>C provided the thermolabile niobium carbene "11# in 72) yield ð67JA2248Ł[When the niobium carbene "11# was treated subsequently with two equivalents of the chelatingphosphine PMe2 or PMe1Ph\ a new niobium carbene "12# was isolated in 64) yield "Scheme 5#ð67JA4853Ł[ The thermally stable niobium carbene "14# can be obtained as golden orange crystals in31) yield via reaction of the niobium complex "13# with two equivalents of TiCp as shown inEquation "7# ð67JA2682Ł[ The simplest type of niobium carbene complex is the THF ligated niobiumcarbene complex "16#\ which can be prepared in good yield simply by adding THF to the niobiumcomplex "15# "Equation "8## ð79JA5125Ł[ The THF ligands of the niobium carbene complex "16# are

400C1Ta Function

labile and can be readily displaced thereby allowing other types of niobium carbene complexes tobe prepared[

Scheme 6

Cl2Nb(CH2But)3

(21) (22) (23)

(ButCH2)3NbBut

Nb

But

But

But

L L

2 LiCH2But, –78 °C

83%

2 L

75%

L = PMe3, PMe2Ph

Nb(CH2But)2Cl3(24) (25)

Cp2ClNbBut

+ TiCptoluene, 6 h

42%(8)

(9)Nb(CH2But)2Cl3(26) (27)

Cl3(THF)2NbBut

+ THF–30 °C to 25 °C

2[04[6 THE C1Ta FUNCTION

The _rst example of an isolable tantalum carbene was accidentally obtained by Schrock via anintramolecular a!hydrogen abstraction process "Equation "09## ð63JA5685Ł[ More thermally stabletantalum carbenes\ such as "17#\ can be obtained by introducing a cyclopentadienyl ligand "Equation"00## ð67JA2248\ 68JA2109Ł[ The a!hydrogen abstraction process has proved to be a very e}ectivestrategy for the preparation of tantalum carbene complexes[ Structural and steric crowding aboutthe tantalum are both believed to be important factors in determining where a!hydrogen atomabstraction occurs to give carbene complexes ð67JA2248Ł[ A number of tantalum carbene complexeshave been prepared through the use of an a!hydrogen abstraction protocol\ and some representativeexamples are shown in Equations "01#Ð"03# and Schemes 6 and 7 ð64JA5466\ 67JA1278\ 79JA5125\79JA5633\ 75JA4236Ł[ As shown in Equation "01# ð79JA5125Ł the donor ligands\ such as tertiaryphosphine\ readily promote the a!hydrogen abstraction process[ Furthermore\ the terminal tantalumcarbene "29# can be obtained by using a similar technique "Scheme 7# ð64JA5466\ 67JA1278Ł[ Inaddition\ the tantalum carbene "18# can also be prepared by a dehydrohalogenation protocol\ asshown in Equation "04# ð79JA5633Ł[

(10)(ButCH2)3TaBut

+MeCMe3

2LiCH2But

Cl2Ta(CH2But)3

(11)Cp(ButCH2)nCl2–nTaBut

Ta(CH2But)2+nCl3–nTiCp

(28)n = 2 or n = 0

(12)X3L2TaBut

Ta(CH2But)2X32L

X = Cl, Br; L = PMe3, PPhMe2, PPh2Me, THF

(13)

X = Cl, Br

X3(PMe3)2TaPh

TaBn2X3

2PMe3

70–79%

(14)Cp*(Bn)(Cl)TaPh

TaBn3Cl2 + LiCp*12 h

70%

(29)


Cp*2(H)Ta Cp*2MeTaCp*2TaCl22MeLi, Et2O

80%

CH2PMe3

~100%

Scheme 7

Scheme 8

Cp2MeTaTaCp2Me3

Ph3C+ BF4–

–Ph3CMe

base

82%(30)

(TaCp2Me2)+BF4–

base = Me3P(CH2), LiN(TMS)2 or NaOMe

(15)Cp*(Bn)(Cl)TaPh

(29)

toluene, –Ph3P+Me Cl–

~100%Ph3PTaCp*Bn2Cl2 +

Formation of a carbene hydride complex from a tantalum alkyl complex is also possible[ Thecarbene hydride complex "21# can be obtained in moderate yield as beige crystals by reducingTa"CH1But#Cl3 "20# with two equivalents of sodium amalgam "Equation "05## ð79JA5597Ł[ Analternative route to the tantalum carbene complex "21# is via transformation of a carbene moietyfrom a main group ylide to tantalum"III# under the appropriate conditions[ Two examples are shownin Equation "06#\ and both the tantalum carbene complexes are thermally stable ð68JOM"060#32Ł[ Onphotolysis in hydrocarbon solution with an ultraviolet light source\ the methyl complexes "22#containing very bulky aryloxide ligands lose one equivalent of methane to form tantalum carbenecomplexes "23# in essentially quantitative yields "Equation "07## ð75JA0491Ł[

(16)(H)(PMe3)3Cl2TaBut

(32)

Ta(CH2But)Cl4

(31)

+ 2Na/Hg + 5PMe3

Et2O/THF

(17)Cp2MeTa

Cp2Ta(PMe2R)Me +R

Et3PR

PhH, 60 °C

40–50%

R = Me, Ph

MeTaMeMe

OAr

OAr

Ta

OAr

OAr

(18)Me

(33) (34)

hν

~100%

ArO = 2,6-di-t-butylphenoxide2,6-di-t-butyl-4-methoxyphenoxide

A number of new tantalum carbene complexes can be prepared from preexisting tantalum carbenecomplexes via modi_cation of the carbene ligand or the tantalum ligand[ The tantalum carbenecomplex "24# reacts with two equivalents of LiOCMe2 to give "25# as light yellow crystals in 54)yield "Equation "08## ð70JA0339Ł[ Similarly\ bulky tantalum carbene complexes containing phenoxideor benzenethiolate ligands of type "27# can be prepared from the readily accessible tantalum carbene"26# ð79JA5125Ł in good yield by analogous methods ð75OM1051\ 77JA3853\ 89IC0093Ł[ The relatedpyridine and diethyl sul_de adducts "28# can be easily obtained from "27# in high yields "Equation"19##[ Another interesting tantalum carbene complex "39# with the terdentate monoanionic 1\5!bis"dimethylamino#methyl#phenyl ligand has been prepared in 89) yield starting from "26# "Equa!tion "10##\ and it is thermally stable at room temperature ð89RTC335Ł[

(19)+ 2LiOButCl3(PMe3)2Ta

But

(ButO)2Cl(PMe3)TaBut

(35) (36)

–PMe3

402C1Mo Function

+ 3LiXCl3(THF)2TaBut

X3(THF)TaBut

(37) (38)

–3LiCl

61–85%X3YTa

But

(20)

(39)

Y

61–75%

X =2,6-diisopropylphenoxide;2,6-dimethylphenoxide;2,4,6-triisopropylbenzenethiolate

Y = pyridine;SEt2

Cl3(THF)2TaBut

(37)

TaNMe2Me2N

But

Cl Cl

(21)

(40)

+

Li NMe2Me2N

–78 °C, Et2O

90%

2[04[7 THE C1Cr FUNCTION

Syntheses of nonheteroatom!stabilised chromium carbene complexes are rare\ although the syn!thesis of their heteroatom!stabilised counterparts has been thoroughly investigated[ The geminaldichlorocyclopropene "30# reacts with the pentacarbonylchromium complex "31# to give a novelcyclopropenylcarbene complex "32# "Equation "11## ð57AG"E#849Ł[ However\ this technique is oflimited applicability[ Nonheteroatom!stabilised chromium carbene complexes can be obtained fromthe corresponding heteroatom!stabilised chromium carbenes by reaction with an aryl lithium reagent"Scheme 8#[ The methoxy group of the anionic aryl chromium complex of type "33# can be eliminatedby silica as shown in Scheme 8 ð66CB545Ł[

(42)(41) (43)

Ph

Ph

Cl

Cl+ (CO)5CrNa2

Ph

Ph

(CO)5Cr–20 °C

–NaCl(22)

(44)

(CO)5Cr

OMe

Ph

(CO)5Cr

OMe

Ph

Ar–

(CO)5Cr

Ar

Ph

ArLi

–78 °C

SiO2

–30 °C~80%

Ar = Ph, p-MeC6H4, p-CF3C6H4

Scheme 9

2[04[8 THE C1Mo FUNCTION

Nonheteroatom!stabilised molybdenum carbene complexes can be prepared from correspondingcomplexes containing the carbonÐmolybdenum triple bond[ Thus\ reaction of the molybdenumcarbyne complex "34# with excess t!butylalkyne yields the molybdenum carbene complex "35# inhigh yield "Scheme 09# ð74JA4888Ł[ Analogous molybdenum carbene complexes of type "36# can beobtained by treatment of "35# with two equivalents of a carboxylic acid "Scheme 09#[ Molybdenumcarbene complexes of the type Mo"CHR0#"NAr#"OR1#1 "49# can be obtained from MoO1Cl1"THF#1by the routes shown in Scheme 00 ð76OM0262\ 89JA2764Ł[ Key intermediates "37# are readily preparedquantitatively in dimethoxyethane at 14>C[ Reaction of "37# with Grignard reagents and tri~ic acidresulted in the formation of the carbene complexes "38#[ More thermally stable carbene complexes"49# have been prepared straightforwardly from "38# in good yield "Scheme 00# ð89JA2764Ł[


Furthermore\ reaction of "49# with 6!isopropylidene!1\2!dicarbomethoxynornadiene has providedthe molybdenum carbene complex "40# in high isolated yield "Equation "12## ð89JA7267Ł[

Mo

OCH(CF3)2

OCH(CF3)2(F3C)2HCO

O

O

Me

MeBut

But

But

But

But

Mo

(F3C)2HCO

(F3C)2HCO

But

But

But

But

Mo

RCO2

RCO2

(46)(45) (47)

But

Scheme 10

(excess), Et2O

91%

RCO2HCH2Cl2

78–83%

R = Me, Pri, CF3

NAr

MoNAr

Cl

Cl

O

OMe

Me

Scheme 11

NAr

MoOTf

TfO

O

OMe

Me

R1 2LiOR2

50–95%R2O Mo

NAr

OR2 R1

i, R1CH2MgClii, 3TfOH

i, DME ii, 2.6-lutidineiii, TMS-Cl

95% R1 = But, 65%R1 = PhMe2C, 76%

MoO2Cl2(THF) + 2ArNH(TMS)

(48)

(49) (50)

Ar = 2,6-diisopropylphenylR 2 = But, 2,6-diisopropylphenyl, 2-t-butylphenyl

ButO Mo

NAr

ButO But

(50)

+

(51)

CO2Me

CO2MeBut

CO2MeMeO2C

Mo

NAr

ButO

ButO45–55 °C

90–95%(23)

Ar = 2,6-diisopropylphenyl

Four!coordinate molybdenum carbene complexes that contain the t!butylimido ligand have beenprepared by the routes shown in Schemes 01 and 02[ Reaction of the molybdenum complex "41#with ButNCO\ followed by alkylation with "ButCH1#1Mg resulted in the formation of the imido!alkyl compound "42#[ Treatment of "42# with ButCH1Li then yielded the molybdenum carbenecomplex "43# in 64) yield[ The new carbene complex "44# can be obtained by reaction of "43# withPh2SiOH "Scheme 01# ð76CC018Ł[ The molybdenum carbene complex "48#\ which is analogous to"49#\ has been prepared by treatment of "45# with hexa~uoroisopropanol "Scheme 02#[ When "48# wastreated with a terminal alkene such as styrene\ its carbene ligand was exchanged stoichiometrically toform the phenyl carbene complex "59#[ Five!coordinate molybdenum carbene complexes such as"47# can be prepared from the key complex "46# by replacement of the t!butylamine ligand withstronger Lewis bases "Scheme 02# ð78CC0951Ł[

2[04[09 THE C1W FUNCTION

Nonheteroatom!stabilised tungsten carbene complexes can be prepared via an a!hydrogenabstraction process[ Thus\ reaction of the tungsten complex "50# with trimethylphosphine in a sealedtube at 099>C provided the carbene complex "51# as yellow crystals "Equation "13## ð67JA5663Ł[Similarly\ both of the phenylimino tungsten carbene complexes "53# and "54# can be obtained fromthe tungsten complex "52# in good yield "Scheme 03# ð71JA6372Ł[ Osborn and co!workers have

404C1W Function

MoO2Cl2(MeCN)2

(52)

Mo(NBut)(CH2But)3Cl

(53)

i, ButNCOii, (ButCH2)2Mg•dioxane

35%

ButCH2Li

75%

NBut

MoPh3SiO

But

ButCH2NBut

Mo

But

ButCH2

ButCH2

(55)(54)

Ph3SiOH

Scheme 12

NBut

Mo

Ph

(CF3)2HCO

(CF3)2HCO

Scheme 13

(59)(60)

Mo(NBut)2(CH2But)2

(56)

MoO2Cl2

i, ButNCOii, 2LiCH2But

81%

Mo

NBut

But

(CF3)2HCO

(CF3)2HCO

2HOCH(CF3)2

80%ButNH2

NBut

Mo

But

(CF3)2HCO

(CF3)2HCO

Mo

NBut

LBut

(CF3)2HCO

(CF3)2HCO

(58)

LMeCN, vacuum

Ph

90%

(57)

L = PMe3, pyridine

reported a general protocol for the synthesis of tungsten carbene complexes of the type "56#\ whichsimply involves reaction of the oxo ligand!containing tungsten complexes "55# with aluminumhalides "Equation "14## ð71CC403\ 74CC682Ł[ In addition\ other types of tungsten carbene complexesare readily prepared from "56# by a metathesis reaction ð76JA2842Ł[ The phenylimino tungstencarbene complex "58# can also be synthesised from the readily available precursor "57# by using asimilar technique\ as shown in Scheme 04 ð89OM1151Ł[ In 0882\ oxygen! and moisture!stable tungstencarbene complexes "69# containing a bulky hydridotris"pyrazolyl#borate ligand were prepared inmodest yields by an a!hydrogen abstraction reaction "Scheme 05# ð82OM1703Ł[

+ 2PMe3

100 °C, –CMe4

~100% W

PMe3

But

But

ButCH2

Me3PW CH2ButButCH2

CH2But

But

(24)

(61) (62)

W

Cl

Me3P NPh

ButBut

W

Cl

NPh

But

Me3P

ClMe3P

PMe3

Me3P•HCl

60%

(65)

W

Cl

NPh

ButBut

But

W

CpBut But

NPh

NaCp, THF, 36 h–NaCl, –CMe4

80%

(63) (64)

Scheme 14


O

W

ButCH2O

ButCH2O

CH2But

CH2But

ButCH2O W

ButCH2O X

XBut

(66) (67)

+ AlX3

–CMe4

(25)

X = Cl, Br, I

W

ButCH2

ButCH2

NAr

OButButOW

Cl But

NArClO

O

Me

Me

(68) (69)

WOCl4PCl5, DME

90%

i, ArNCO ii, 2 LiOBut

iii, 2 (ButCH2)MgCl 62%

Ar = N-2,6-C6H3-Pri2

Scheme 15

NN

KHB

3

22–38%

NAr

W

OEt2Cl Cl

ClClNAr

WCl CH2R

CH2RRCH2

NN

N N

N NHB W

CH 2R

NAr

CHR3ClMgR

(70)

R = Me, Ar = Ph; R = Ar = Ph; R = Me, Ar = 2,6-Pri2C6H3

Scheme 16

Tungsten carbene complexes can be prepared from the corresponding complexes containing thecarbonÐtungsten triple bond[ Thus\ reaction of the carbyne complexes "60# with two equivalents ofHX "X�Cl\ Br\ MeCO1\ OPh\ OC5F4\ O!p!C5H3Cl# gave the carbene complexes "61# "Equation"15## ð74OM0826Ł[ The halide complexes are the least thermally stable members of this class\ whilethe carboxylate derivatives appear to be quite stable[ Protonation of the carbonyl!containing carbynecomplexes "62# in dichloromethane with excess concentrated HCl at room temperature gave thetungsten carbene complexes "63# "Equation "16## ð76OM322Ł[ Lewis acid!free\ four!coordinate tung!sten carbene complexes "67# have been prepared from the tungsten carbyne complex "64#\ as shownin Scheme 06 ð75JA1660Ł[ Catalytic proton transfer in the carbyne complex "65# to give the tungstencarbene complex "66# is the key step in the synthesis[ All these reactions proceed in high yield[ Theasymmetric tungsten carbene complexes "70# and "71# have been prepared via reactions analogousto those shown in Equation "15#[ The carbyne complex "68# reacts with one or two equivalents ofthe ligand "79# to give "70# and "71#\ respectively "Scheme 07# ð82OM1454Ł[

ButO W

ButO

ButO

But WButO

ButO

X

X But

(26)

(71) (72)

+ 2HX

–ButOH

X = Cl, Br, MeCO2, OPh, OC6F5, O-p-C6H4Cl

Me3P W R

(73)

Me3P

Me3P

Cl

CO

Me3P W

(74)

Me3P

Cl

Cl

CO

(27)

R

HCl

CH2Cl2

R = Ph, p-Me-C6H4

406C1W Function

W

ClCl

Cl

O

O

Me

Me

ButW

NHArCl

Cl

O

O

Me

Me

ButW

NArCl

Cl

O

O

Me

MeBut

NAr

WRO

RO But

(75) (76) (77) (78)

+ArNH(TMS)

–TMS-Cl

NEt3(0.2 equiv.)

–40 °C

+2 LiOR

–DME,–2 LiCl

R = OBut, OCMe2(CF3), OCMe(CF3)2, OAr; Ar = 2,6-diisopropylphenyl

Scheme 17

W

ButO

ButO

ButO

Ph

OHOH

OHOH

O

OO

O

W OBut

OBut

Ph

(79)

Scheme 18

W O

O

2

(80)

Ph

(80)

(81) (82)

–ButOH –3ButOH

A number of nonheteroatom!stabilised tungsten carbene complexes can be prepared via inter!molecular reactions of a tungsten complex with a carbene or carbene precursor[ Casey et al[ havesuccessfully synthesised the diphenylcarbene adduct "73# from the heteroatom!stabilised tungstencarbene "72#\ as shown in Scheme 08 ð66JA1016Ł[ Tungsten oxocarbene complexes "76# can beprepared in high yield by carbene transfer from the tantalum carbene complex "74# to the tungstencomplex "75# "Equation "17## ð79JMOC62Ł[ Bryan and Mayer have reported the remarkable reactionbetween the tungsten complex "77# with the C1O double bond of a cyclic ketone\ forming a six!coordinate tungsten oxocarbene complex[ Thus\ treatment of the tungsten"II# complex "77# withtwo equivalents of cyclopentanone in benzene at room temperature a}orded the tungsten carbenecomplexes "78# "Equation "18## ð76JA6102Ł[ In addition\ six!coordinate tungsten carbene complexes"81# can also be prepared by transformation of a carbene moiety from variously substituted arylylides "80# to the tungsten complex "89#[ A few examples are shown in Equation "29# ð82JA7056Ł[Furthermore\ the vinyl tungsten carbene complex "83# can be prepared in good isolated yield fromreaction of the tungsten complex "82# with diphenylcyclopropene\ as shown in Scheme 19 ð82JA7029Ł[Reaction of "83# with two equivalents of LiOR "R�CMe"CF2#1\ or 1\5!C5H2Pri

1# yielded thecorresponding tungsten alkoxide complexes "84#[

(CO)5W

OMe

Ph

(CO)5W

Ph

Ph

(CO)5W

OMe

Ph

Ph–PhLi

–78 °C

HCl/–78 °C

50%

(83) (84)

Scheme 19

(28)

(85) (86) (87)

Ta(CHBut)X3L2 + W(O)(OBut)4 Ta(OBut)X + W(O)(CHBut)X2L2

pentane

L = PMe3 or PEt3; X = Cl or Br


(29)

(88)(89)

WCl2(PMePh2)4 + 2 O–2PMePh2

–cyclopentanone

W

Cl

PMePh2OCl

Ph2MeP

+–PPh3

–PMePh2

NPh

W

Cl

PMePh2

Ph2MeP

Cl

PMePh2

Ph3PR

(90)

NPh

W

Cl

PMePh2

Ph2MeP

Cl

CHR(30)

(91) (92)

R = Ph, C6H4-p-Me, C6H4-m-Me, C6H4-o-Me, C6H4-p-OEt, C6H4-o-OMe, C6H4-p-CF3, C6F5, CH=CMe2

NAr

W

Cl

P(OMe)3

(MeO)3P

Cl

P(OMe)3

NAr

W

Cl

P(OMe)3

(MeO)3P

Cl

Ph

Ph

Ph

Ph

(94)

NAr

W

RO

P(OMe)3

(MeO)3P

RO

+

(95)

2LiOR–78 °C

64%

Ph

Ph

(93)

80 °C, 2 h–P(OMe)3

72%

Ar = 2,6-C6H3Pri2; OR = OCMe(CF3)2 or O-2,6-C6H3Pri

2

Scheme 20

Finally\ a variety of new tungsten carbene complexes can be prepared from preexisting tungstencarbene complexes[ Thus\ the carbene complexes "85# were readily obtained from "56# by metathesisreactions involving a terminal alkene\ as shown in Scheme 10 ð76JA2842Ł[ Further reaction of "85#with one equivalent of Li"OCH1But# then yielded trineopentoxo complexes "86#[ In addition\ the_ve!coordinate tungsten carbene complex "88# can be prepared from the corresponding six!coor!dinate carbene complex "87# by scavenging one phosphine ligand with PdCl1"PhCN#1 "Equation"20## ð71OM037Ł[

W

Br

Br But

ButCH2O

ButCH2OW

Br

Br R2

ButCH2O

ButCH2OW

ButCH2O

Br R2

ButCH2O

ButCH2O

R1 R1

(67) (96) (97)

+ H2C=CR1R2

– H2C=CHBut

69–98%

H2C=CR1R2 = H2C

Li(OCH2But) (1 equiv.)

pentane

R1 = H, R2 = Bun; R1 = H, R2 = Bus; R 1= H, R2 = Ph;

Scheme 21

W(O)(CHBut)Cl2(PEt3)2 W(O)(CHBut)Cl2(PEt3)

(98) (99)

Pd(PhCN)2Cl2

80%(31)

2[04[00 THE C1Mn FUNCTION

The dimethylcarbene complex "090# has been prepared by treating the corresponding cationiccarbyne complex "099# with MeLi at low temperature\ as shown in Equation "21# ð65AG"E#432Ł[Alternatively\ nonheteroatom!stabilised manganese carbene complexes can be obtained via an

408C1Fe Function

intermolecular reaction of a manganese complex with a diazo compound[ Some examples areshown in Equation "22# ð63AG"E#488Ł and Equation "23# ð73JOM"153#216Ł[ These manganese carbenecomplexes\ in general\ can be isolated in high yield[

(32)

(100) (101)

[Cp(CO)2Mn≡CMe]+BCl4–MeLi, –50 °C

15%Cp(CO)2Mn

MnOC THF

CO

+ PhPh

O

N2

–N2, –THF

37%

MnOC

CO

Ph

O Ph

(33)

N2

R1

R2

Cp(CO)2Mn

R1

R2

R2 R1

(34)

Ph Ph

MnCp(CO)2(THF) +–N2, –THF

72–82%

=

2[04[01 THE C1Fe FUNCTION

Almost all the types of nonheteroatom!stabilised iron carbene complexes are obtained fromthe corresponding carbonÐiron single bonded complexes[ Brookhart and Studabaker\ in 0876\summarised some general techniques for generating iron carbene complexes ð76CR300Ł[ The mostwidely used approach to the preparation of these compounds is by ionisation of a leaving groupattached directly to the potential carbene carbon of a carbonÐiron single bond containing complex[Removal of the leaving group\ in general\ can then be accomplished by using Bro�nsted or Lewisacids[ Some representative examples concerning the preparation of ironÐcarbene complexes by thisionisation protocol are shown in Scheme 11 ð55JA4933\ 72JA147\ 72JOM"143#222\ 74JA1813\ B!78MI 204!91Ł[The a!ether precursors "092# are readily accessible from the corresponding heteroatom!stabilisediron carbene complexes "091#[ In general\ the a!ether precursors "092# exhibit varying degrees ofsensitivity to air and temperature[ Additionally\ the carbene complexes "091# can be obtained fromthe readily available ferrate Cp"CO#1Fe−Na¦[ Iron carbene complexes "093# can also be easilygenerated from the a!thioether complexes "094#[ Thus\ methylation of "094# with FSO2Me orMe2O¦BF3

− gives the corresponding sulfonium salts "095# which can be decomposed to give "093#"Scheme 12# ð68JA5362\ 70JA0751\ 74JOC4787Ł[ In contrast with the a!ether carbene precursors "092#\the sulfonium salts "095# are quite stable^ in selected cases\ these sulfonium salts can be stored in airat room temperature for long periods[

Cp(CO)LFe

R1

OMe

Cp(CO)LFe

R1

OMe

R2

+

Cp(CO)LFe

R1

R2

+

(102) (103) (104)

[R2]– H+ or CF3SO2-TMS

L = CO, PMe3, PPh3; R1 = Me, Et, Pri, Bun, Ph, C6H4-p-Me, c-C3H5; R2 = H, Me

Scheme 22


Scheme 23

Cp(CO)2Fe

R1

SR3

Cp(CO)2Fe

R1

SMeR3

R2Cp(CO)2Fe

R1

R2

+

(105) (106) (104)

R2FSO3Me

or Me3O+BF4–

25–100 °C

+

R1 = H, Me, Et; R2 = H, Me; R3 = Me, Ph

An alternative approach to the preparation of iron carbene complexes "009# is through pro!tonation of h0!vinyl iron complexes "098#[ The h0!vinyl iron complexes "098# can be prepared fromeither the sodium ferrate "096# or the iron iodide "097#\ as shown in Scheme 13 ð71JA2650\ 71JA5008Ł[

+ Cp(CO)2Fe

R1

Cp(CO)2Fe

R1

R2 R2

M

R1

R2

Cp(CO)2FeI25–40%

Cp(CO)2Fe

O

+

(108)

R1

(109)

R2

(110)

HBF4

R1Cl

O R2

hν

Scheme 24

–CO60–90%

Cp(CO)2Fe–Na+ +

R1 = H, Me, Ph; R2 = H, Me, C(CH2)Me

(107)

M = Li or MgBr

2[04[02 THE C1Ru FUNCTION

The stable ruthenium carbene complex "001# can be prepared from the reaction of the rutheniumcomplex "000# with diazomethane "Equation "24## ð75JOM"299#056\ B!78MI 204!90Ł[ In the early 0889s\Grubbs and co!workers reported the reaction of an Ru"II# complex with 2\2!diphenylcyclopropeneto produce the stable ruthenium carbene complex "002# in essentially quantitative yield "Equation"25## ð81JA2863Ł[

RuCl(NO)(PPh3)2 Cl(NO)(PPh3)Ru

(111) (112)

CH2N2(35)

(36)

(113)

Cl2(PPh3)2Ru

Ph

Ph

CH2Cl2/PhH, 53 °C, 11 h

~100%Ph

Ph+RuCl2(PPh3)n

n = 3 or 4

2[04[03 THE C1Rh FUNCTION

In general\ rhodium carbene complexes generated from reactions between rhodium"II# complexesand diazo compounds are incapable of isolation[ However\ reaction of the rhodium complex "003#

410C1Re Function

ð81CB1530Ł with diphenyl diazomethane has led to the stable rhodium carbene complex "004# in85) isolated yield[ Stable rhodium carbene complexes "005#\ "006# and "007# can be obtained bymodi_cation of the rhodium ligands of "004#\ as shown in Scheme 14 ð82AG"E#0379Ł[

Cl Rh

Pri3Sb

Pri3Sb

N2

Ph

PhCl Rh

Pri3Sb

Pri3Sb

Ph

Ph

Rh

Ph

PhPri3Sb

Rh

Ph

PhL

Cl Rh

Pri3P

Pri3P

Ph

Ph

[RhCl(C2H4)2]2

(114) (115) (116)

(118)(117)

96%

NaCp

78%

PPri3

98%

L87–89%4SbPri

3

82%

L = CO or CNBut

Scheme 25

2[04[04 THE C1Re FUNCTION

The stable rhenium carbene complex "019# can be isolated from the reaction of the rheniumcomplex "008# with three equiv[ of a Grignard reagent\ as shown in Scheme 15 ð72OM0494Ł[ Caseyand Nagashima have reported that reaction of h1!acylzirconium compounds "010# with the rheniumcomplex "011# leads to the formation of rhenium carbene complexes "012# as orange solids "Equation"26## ð78JA1241Ł[ A few rhenium carbene complexes can also be obtained from the correspondingcarbonÐrhenium single bond containing complexes[ Dehydrohalogenation of the rhenium complex"013# using 0[94 equivalents of 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# in ether at −29>C proceededsmoothly to give rhenium carbene complexes "014# in 69) isolated yield[ The chloride ligand in"014# can be replaced by alkoxide ligands to give the new carbene complexes "015# "Scheme 16#ð76OM782\ 77POL0730Ł[

4HCl

–TMS-OH

3ButCH2MgCl

–CMe4

Re(NBut)3(O-TMS) Re(NBut)2Cl3 ButN Re

ButN But

(119) (120)

Scheme 26

But

Cp2Zr(η2-COR)Cl + K+Cp(CO)2ReH–THF, RT

52–58%

Cp(CO)2ReR

(121) (122) (123)

(37)

R = Me, CH2CH2But

(RO)(ArN)2ReBut

(124) (125) (126)

LiOR

45–65%

Cl(ArN)2ReButRe(NAr)2(CH2But)Cl2

dbu

70%

Scheme 27

Ar = 2,6-C6H3Pri2; R = CH(CF3)2, 2,6-OC6H3Pri

2

Oxocarbene complexes "017# have been prepared in 65) isolated yield by photolysis ofthe rhenium cis!dioxo complex "016# in pyridine\ as shown in Equation "27# ð77CC0378Ł[


Nonheteroatom!stabilised rhenium carbene complexes have been synthesised from the reaction ofcationic rheniumÐcarbyne complexes[ Thus\ addition of diethylaluminum hydride or methyllithiumto the phenylcarbyne complex "029# has a}orded the rhenium carbene complexes "018# and "020#\in 63) and 35) yields\ respectively "Scheme 17# ð65JOM"019#C5\ 67CB2639Ł[ Furthermore\ a series ofnew rhenium carbene complexes can be prepared from preexisting rhenium carbene complexes[Addition of excess gaseous hydrogen chloride to rhenium carbene complexes "021# in di!methoxyethane yielded the rhenium complexes "022# in 74) yield[ Addition of excess t!butylamineto "022# then a}orded the new carbene complex "023# in 84) yield\ as bright yellow _bres "Scheme18# ð81JA2256Ł[ Similarly\ four!coordinate rhenium carbene complexes "026# can be prepared in amanner analogous to that described for "023#[ Thus\ addition of two equivalents of gaseous hydrogenchloride to the carbene complex "024# a}orded the rhenium complex "025# in high yield[ The complex"025# reacts with two equivalents of lithium or potassium alkoxide to give "026# quantitatively"Scheme 29# ð81JA2256Ł[

hν, pyridine

76%ReO2(CH2But)3

(127) (128)

ReButO

O (38)

But

(130) (131)(129)

Cp(CO)2Re

Ph

Cp(CO)2RePh

[Cp(CO)2Re≡CPh][BCl4]

Et2AlH–78 °C, 15 min

74%

LiMe–40 °C, 8 h

46%

Scheme 28

(132) (133)

Scheme 29

2Re(NAr)2(CHBut)(CH2But) [Re(CBut)(CHBut)(ArNH2)Cl2]2

ButH2N

Re

ButH2NCl

Cl

But

But

(134)

6HCl, DME

–ArNH3Cl

ButNH2 (excess)

95%

Ar = 2,6-C6H3Pri2, But

2

Scheme 30

(136) (137)(135)

Re(O)2(CHBut)(CH2But) 1/x [Re(CBut)(CHBut)Cl2]xRO

ReRO

But

But

+2HCl–2H2O

85%

+2MOR

~100%

M = K, Li; R = But, CMe2(CF3), CMe(CF3)2, 2,6-C6H3Pri2, SiBut

3

2[04[05 THE C1Os FUNCTION

The osmium carbene complex "028# can be prepared in 71) isolated yield from the reaction ofthe osmium complex "027# with diazomethane "Equation "28## ð72JA4828Ł[ Osmium carbene com!plexes "039Ð031# can be obtained in a similar manner\ as shown in Equation "28# ð75JOM"299#056Ł[Grubbs and co!workers have demonstrated that the osmium carbene complex "033# can be preparedfrom "032# via a reaction analogous to that described for the preparation of "002#\ as shown inEquation "39# ð81JA2863Ł[

412C1Os Function

OsCl(NO)(PPh3)2 + CHRN2 Cl(NO)(PPh3)OsRPhH

R = H, 82%

(138) (139) R = H(140) R = Me(141) R = Ph(142) R = CO2Et

(39)

(40)OsCl2(PPh3)4 +Cl2(PPh3)2Os

CH2Cl2/PhH

∆

(143) (144)

Ph

Ph Ph

Ph


3-16Ketenes, their CumuleneAnalogues and their S, Seand Te AnaloguesDAVID C. HARROWVEN and SHELAGH T. DENNISONUniversity of Southampton, UK

3.16.1 KETENES 525

3.16.1.1 From Acid Halides 5263.16.1.2 From 2-Haloacyl Halides 5303.16.1.3 From a-Diazocarbonyl Compounds 5303.16.1.4 From Carboxylic Acid Anhydrides 5343.16.1.5 From Other Acyclic Ketones, Carboxylic Acids and their Derivatives 5353.16.1.6 From Carbocyclic Ketones and Related Compounds 5373.16.1.7 From Alkoxyalkynes 5403.16.1.8 From Heterocyclic Materials 5413.16.1.9 From Transition Metal Complexes 5443.16.1.10 Miscellaneous Methods 545

3.16.2 THIOKETENES 546

3.16.2.1 From Ketenes and Thioketenes 5463.16.2.2 From Acid Chlorides and Thioacyl Chlorides 5473.16.2.3 From the Sulfur Analogues of Carboxylic Acids and Esters 5473.16.2.4 Via Alkynyl Sulfides and Alkynyl Thiolates 5483.16.2.5 From Sulfides of Carbon 5493.16.2.6 From Ketene-S,X-Acetals 5503.16.2.7 From Heterocyclic Materials 5503.16.2.8 From Vinylidene Transition Metal Complexes 552

3.16.3 SELENOKETENES 553

3.16.1 KETENES

Ketenes are inherently reactive species that show a strong tendency to dimerise, suffer nucleophilicattack or undergo aerial oxidation. As a result, they are often difficult to isolate and relatively fewhave been properly characterised. The stability of a ketene is, however, greatly influenced byits substituents. Dialkylketenes are considerably more stable than the corresponding monoalkylderivatives; for example, dimethylketene dimerises at room temperature in about an hour whilstmethylketene suffers this fate in just a few minutes. Electronic factors also play an important role,with phenyl, silicon, germanium and tin substituents imparting a stabilising effect on the system.Halogen and chalcogen substituents, by contrast, tend to accelerate the polymerisation process.

For synthetic purposes the instability of a ketene is often of little consequence, especially whenan in situ preparation is available. In this chapter, therefore, those processes that have resultedunambiguously in the formation of ketenes are presented alongside those for which it is reasonable

525

526 Ketenes, Cumulenes and S, Se and Te Analogues

to assume their intermediacy. Limitations on space prohibit a truly comprehensive overview. Theinterested reader is therefore directed to the excellent monologues by Ward <B-8OMI 316-01 >, Buehlerand Pearson <B-70MI 316-01), Luknitskii and Vovsi <69RCR487>, Borrmann <68HOU(7/4)65>, Lacey<B-64MI 316-01 >, Wagner and Zook <B-53MI 316-01 >, Hanford and Sauer <46OR(3)l08>, and the remark-able pioneer of ketene research Staudinger <B-12MI 316-01 >, for additional examples of ketenesyntheses.

The mechanism through which this conversion occurs has been subject to much speculation. It isnow generally accepted that ketene formation arises through the collapse of an intermediate acylammonium salt (49JA2242, 52JA4962, 62CJC2362). Some confusion arose when a series of experimentsrevealed that the dehydrohalogenation of a-haloacyl halides by tertiary amines first led to theformation of enolate salts <68HCA1466, 68TL1977, 70HCA120, 70JOC1515>. These studies appeared tosuggest that a second mechanistic route to ketenes might be operative <73JA7447>. This idea wasdispelled by Brady and Scherubel when they showed that the two salts could be interconverted, bythe series of equilibrations outlined in Scheme 1, and that the reactions each exhibited were distinct<74JOC3790>. The observation that sodamide may be used in the analogous preparation of di-r-butylketene from the corresponding acid chloride would appear to be exceptional (60JA2498,81T4189).

Scheme 1

The fact that this protocol has found most favour for the in situ generation of ketenes may alsobe due to the presence of residual trialkylammonium hydrohalides. These have been shown tocatalyse the addition of nucleophiles to ketenes and many of the cycloaddition reactions theyundergo. Unfortunately, the rate of polymerisation of ketenes is also dramatically increased and sotheir isolation is rendered more difficult.

As a preparative route for the in situ generation of ketenes, this is of little consequence and

(2)

Nevertheless, the propensity for the deprotonation of acid halides by amine bases introducessome additional complications to this protocol as exemplified by the formation of the vinyl ester (2)when the dichloride (1) was treated with triethylamine (Equation (2)) <68TL6003>. This difficulty canbe circumvented by the slow addition of the acyl halide to a solution of the amine <74JOC3790>.

3.16.1.1 From Acid Halides

The most widely encountered method for the preparation of ketenes involves the dehydro-halogenation of acid halides by treatment with tertiary amines (Equation (1)). There are severalreasons for this popularity. First, the reaction is easy to perform and is readily adapted to enableaccess to unstable ketenes through in situ generation. Moreover, it is extremely broad in scope withalmost all acyl halides that possess an a-hydrogen undergoing the reaction.

(i)

Ketenes 527

countless references to its use could be cited. There would appear to be few limitations and the listof ketenes that have been accessed in this fashion is impressive. These include simple di- andmonoalkylated ketenes, aryl-, vinyl-, acyl- and allylketene together with an array of ketenes bearingheteroatom substituents. The examples in Table 1 serve to illustrate the diversity in application ofthis synthetic entry.

Table 1 Ketenes prepared by dehydrohalogenation of acid halides.

Interestingly, when a,j9-unsaturated acid halides are exposed to tertiary amines, the productsusually appear to implicate the intermediacy of the corresponding methyleneketenes <66JOC718>. Inall the examples investigated to date, this assumption has been shown to be erroneous <B-80MI 316-03)and the reaction actually proceeds via 1,4-dehydrohalogenation. Trapping of the resulting vinyl-ketene then leads to a /?,y-unsaturated ketone, which suffers alkene migration under the conditionsemployed, as, for example, in Scheme 2 <7OHCA2159>.

Scheme 2

The use of pyrolysis or photolysis to initiate elimination of HCl from acid chlorides has, bycomparison, received scant attention. The thermal decomposition of acetyl chloride to ketene hasbeen established for many years <77AG(E)1O5>, but extensions are few and have tended to be confinedto 0^/z0-substituted aroyl halides. The pyrolysis of salicyloyl chloride, for example, provides readyaccess to the highly reactive ketoketene (3; X = O) <68M1958>, whereas ortho-toloy\ chloride and

1 Bu' L^~~~J CF3 Ph

67JCS(B)360 60JA2498 70RTC23 67FCR107 72OS3676JCS(P1)2O79

/O ^0 o

v * ci^-* Br- -* Y T YF Br 1

70TL2963 69JA5679 74JOC763 67DOK1117 66JOC2676 77JOC4157O O ^ 0 Ô

Ô Ô PhCV ^ - * P h S ^ ^ » * E t S \ ^ * " ™ S - ^ ^ ' "MeO^.* EtO^-* Y Y Y Y1 1 SEt Br

79JOC1208 70JA1766 71JOC1486 79JOC2067 77JHC249 76TL155370HCA417 70JA1768

o * °67T4769 68CB1120 70TL3657 77JOC2111 57JA6261

76JOC3303


related homologues yield products derived from the corresponding vinylketenes (Scheme 3)<77AG(E)469>.

Scheme 3

In the 1980s and 1990s, considerable attention has focused on the synthesis of ketenes that barechiral substituents as they offer a convenient and enantioselective entry towards /Mactams bymeans of a ketene-imine cycloaddition <81CC344>. Several encouraging developments of this generalstratagem have been reported, of which two examples are highlighted (Schemes 4 and 5) <91TL1O39,92TL4823).

Scheme 5

Synthetic entries towards several other naturally occurring ring systems have incorporated thismethodology as a key feature. Oppolzer and Nakao, for example, explored an ingenious entrytowards 6-protoilludene (6) in which the conversion of the acid chloride (4) to the ketene (5) withPr'2EtN played a pivotal role (Scheme 6) <86TL547l>. A strategically similar approach to isocomene(11) by Snider and Beal proved equally rewarding. Thus, when the mixture of acid chlorides (7)was treated with triethylamine, the tricyclo[5.3.0.0]decane (9) was provided via an intramolecular[2 + 2] cycloaddition of the transient ketene (8). Isomerisation of the exo-cyclic alkene in (9) to (10)using HI then completed a formal total synthesis (Scheme 7) <88JOC4508>.

Scheme 6

Syntheses of a diverse array of terpenes have utilised this strategy <82JA747, 87CC1728, 88CC1421,91JOC321). Few have been as efficient as that described by Corey et al. in their total synthesis ofretigeranic acid (12) (Scheme 8) <85JA4339>. An interesting extension was described by Brady et al.who found that treatment of the acid chloride (13) with triethylamine initiated sequential ketene

Scheme 4

Ketenes 529

Scheme 7

formation, cycloaddition and decarboxylation giving the benzofuran (14) in high yield (Scheme 9)<86JOC2145>. The in situ generation and intermolecular trapping of ketenes by alkenes has found moregeneral application. For example, in the early stages of Ghosez's approach to the prostaglandins,dehydrohalogenation of the acid chloride (15) first produced the ketene (16) which was then trappedwith cyclopentadiene to give the bicycle (17). A short sequence of standard transformations was thenestablished to convert this material (17) into the Corey intermediate (18) (Scheme 10) <8UA4616>.

Scheme 8

Scheme 9

Scheme 10

3.16.1.3 From a-Diazocarbonyl Compounds

The turn of the century was undoubtedly the most important era in the history of ketene chemistry.Most of the common entries to ketenes that are in use today were first formulated during thisperiod. Indeed, in 1902 Wolff inadvertently stumbled upon a route to ketenes that, although notrecognised at the time, remains important to the present day <02LA(325)129>.

Wolff showed that treatment of diazoacetophenone with water and silver oxide gave phenyl aceticacid rather than the anticipated hydroxyketone. Furthermore, when aqueous ammonia was presentin the reaction medium, the corresponding amide was formed in good yield (Equation (4))<04LA(333)l, 12LA(394)23>. The intermediacy of ketenes in this type of rearrangement was first recog-nised by Schroeter who found that thermolysis of PhCOC(N2)Ph led smoothly to the production ofdiphenylketene <09CB2336,09CB3356,16CB2697).

The precise manner in which the ketene is formed has been the subject of considerable debate,and there would appear to be no single mechanistic description for the reaction. In fact, there iscompelling evidence for both concerted <85JA7597> and nonconcerted rearrangement, the latterinvolving the intermediacy of a-ketocarbenes <88JA1O25> and oxirenes (Scheme 11) <72JCS(P2)2623,80PAC1623, 83CRV519, 85JOC135>. An overview containing numerous pertinent references has beenpresented by Gill, and the interested reader is referred to this text for further details <91COS(3)887>.

While the production of a ketene intermediate is a pivotal feature of the Wolff rearrangement,these species are seldom isolated. The reaction is most widely used for the preparation of carboxylic


3.16.1.2 From 2-Haloacyl Halides

The preparation of ketenes by dehalogenation of 2-haloacyl halides was first described by Stau-dinger in 1905 and remains to this day a popular and convenient route to these materials (Equation(3)) <05CB1735>. The most common method used to accomplish this conversion involves the treat-ment of an ethereal solution of the dihalide with zinc <82JOC387l, 93S606). In later years this hasoften been used in the form of a zinc-copper couple <9UOC7048> where the presence of phosphorylchloride may be beneficial (78JOC2879, 87JOC4885). Other reagents such as magnesium <O9CB4213>,silver <08LA(356)51>, mercury <46OR132>, triphenylphosphine <68JOC3974> and pentacarbonyl-manganate salts <86JOC3558> have also been successfully employed, and would appear to be advan-tageous in some cases.

(3)

Various methods have been described for the isolation of ketenes prepared in this manner. Whensufficiently inert, residual salts may be removed by aqueous workup, though this is more commonlyachieved by distillation under reduced pressure <63OSC(4)348, 86S43>. In the cases of methyl- anddimethylketene, higher yields have been observed when the reaction is conducted under reducedpressure with the ketene removed, in solvent, as it is formed <63OSC(4)348,75JCS(P1)16OO>.

The reaction has also been widely used as a convenient method for the in situ generation of ketenes<62AG32>. Their intermediacy is usually inferred but may often be established more rigorously byspectroscopic means (e.g., by a strong infrared active band at ca. 2130 cm"1) <B-80MI 316-02). Thishas greatly increased the scope of this methodology, and numerous examples have now beendocumented (Table 2).

The fact that this method has not found as much favour as the dehydrohalogenation of acidhalides may reflect the greater synthetic challenge involved in the preparation of the requisite startingmaterials, though the presence of residual zinc bromide may also be deleterious.

Ketenes 531

Table 2 Various routes to ketenes involving dehalogenation of a-halo acylhalides.

Scheme 11

acids, esters and amides and is therefore well represented in other chapters. The limited discussionpresented here reflects this fact.

Several methods to initiate the Wolff rearrangement have been described. Typically, the decompo-sition of a-diazoketones is achieved by exposure to light <59CB528>, heat <82CPB526> or transitionmetals <4UOC669>. Each of these methods has limitations. Thermolysis of these materials oftenrequires temperatures in the region of 200 °C, where other electrocyclic processes may also be facile<91COS(3)887>. The addition of transition metal catalysts lowers the decomposition temperatureappreciably but these may alter the reactivity profile of the carbene intermediate. Rhodium, pal-ladium and copper catalysts, for example, readily form complexes with these carbenes and arenormally avoided when ketene formation is desirable <B-71MI 316-01, B-78MI 316-0l>. Most commonly,WolfFs original catalyst, freshly prepared silver oxide, is employed together with either sodiumcarbonate or a tertiary amine <35CB85O, 71T1317). Silver salts such as the benzoate <70OS(50)77> or

Br X z« \ ^ * * 0 II Zn *°

>^*< —- Y Br-^Br ^63OSC(4)348 PPh3,68JOC3974

ZnorMg,09CB4213

0 O °

87JOC4885 05CB173578JOC2879 93CB297

F 3 C ^ a - F3C . - ° But H ^ zn Bu. .^°

F 3 C l r Cp3 BU" Cl BuI

68T1341 86S43

,— ph ci / — \ Ph fl ^ n ^%

73AG(E)25 ^ ^ ^ ^ ^ ^06CB3062

II Mn(CO)5- ^ O ||

86JOC3558 Ph88JOC4877


nitrate <58JOC1166> have also found common usage. A selection of illustrative examples are collectedin Table 3.

Table 3 Ketene intermediates derived by Wolff rearrangement.

The greatest drawback of this method is the number of competing side reactions that may occur.Diazoketones are themselves very reactive species which can participate in 1,3-dipolar cycloadditions<(38CB1179>, suffer attack by soft nucleophiles <63CB1948), undergo other rearrangements<85JOC280l), and react in aldol-type condensations <72S35l>. The ketocarbene intermediate adds tothese difficulties; being prone to collapse by 1,2-hydrogen shift <72JCS(Pl)2623>, inter- and intra-molecular hydrogen abstraction <B-71MI 316-01, B-78MI316-01), insertion into vicinal carbon to carbonand other sigma bonds <70JA6706> or through cycloaddition to an appropriately situated Tt-system<68BSF4913>. Perseverance often holds the key to success. For example, when the diazoketone (19)was exposed to copper salts, the product of carbene insertion (21) predominates. By contrast,photolytic rearrangement of (19) leads to the bicycle (23) via the intermediate ketene (22) (Scheme12) <65CI(L)424, 65CI(L)425>.

Increasingly, the photolytically induced Wolff rearrangement has found favour <84SC163,85JOC4404). On many occasions, a greater selectivity towards ketene formation is observed whenthis method, rather than the thermolytic and transition metal-catalysed variants, are employed<51LA(573)17,52CB225,55CB934). This has been attributed to a lesser tendency to exhibit carbenoidinsertion reactions. Most commonly, irradiation is conducted at 0°C using a medium pressuremercury arc. The use of higher energy photons and elevated temperatures has, on occasions, beenprofitable though complications associated with the photolabile nature of the products may arise(66T209, 69T2121).

While carbene insertion usually prevents ketene formation, in the vinylogous Wolff rearrangementit is a prerequisite for their formation <74JOC3355>. Thus, when /?,y-unsaturated diazoketones areexposed to copper(II) salts, the intermediate carbene is intercepted by the vicinal alkene with thegeneration of a bicyclo[2.1.0]pentanone. Rupture of this highly strained intermediate then providesthe ketene which is usually trapped in situ by a suitable nucleophile (Scheme 13).

0 r -,

JL hv ^ 0 HSEt II

|1 ' ^ ' ' \ A S E t 59CB528

N 2

o r 1 i 1 o. 11 , A 1 - * ° PhCH2OH 1 UYY ^^^f~ " ^ Y ^ O Ph 82CPB526

' N2 SO2Bn S02Bn

/ V n [ 0

i^Xx r y : f X ^ 41JOC669

N 2 L J

O r -iN\ — \ /= ' = O \ /~C02H

° [ *°1 if^ ^ ^ ^ Y ^ ^ r n T Ph y NH2 48JCS1674

N2 L / J ^ /

O ^ ^ ^ . ° * . CO2Et

r ^ Y i " S0B^ I ^ V ^ J^^ f \ * \ 70OS?7

533

Scheme 12

Scheme 14

Scheme 15

Scheme 16

Scheme 13

The yields and degree of selectivity observed in this process are moderate to high, and it hasfound many applications <84JA3995, 84JA4001, 86TL3913). A few illustrative examples are given inSchemes 14^16. Interestingly, /?,>>-unsaturated diazoketones can also be encouraged to undergonormal Wolff rearrangement through exposure to silver ions or by conducting the reaction underthermolytic or photolytic conditions. These processes are however, prone to give complex mixturesarising from the competitive vinylogous rearrangement <74CC695, 76JA7456, 77JOC3165,84JOC2052).

Finally, it has been shown that a-silyl- and a-germyl-a-diazocarbonyls may be converted intobismetalloketenes by treatment with bis(triethylsilyl)mercury (75IZV199, 76ZOB930).

Ketenes


3.16.1.4 From Carboxylic Acid Anhydrides

In 1907 Wilsmore and Stewart disclosed their finding that the immersion of a hot platinum wireinto acetic anhydride could be used to generate ketene, H ;C==G=O <O7JCS1938). While this processwas of little preparative use, subsequent modifications to the procedure have established this sourceof the parent compound invaluable for the preparation of ketene in the laboratory <53JOCI055>.The method has also found application in the synthesis of other ketenes in moderate to high yield<61CP6!8722.68MI 316-03). For example, pyrolysis of isobutyric anhydride to dimethyl ketene (68M1316-01), and the preparation of silyl- and germylketenes from the requisite met a Elated acetic anhydridesproduced these materials in good yield and a high state of purity (Equation (5)) <69ZOB467,70ZOB707).

Another convenient route to ketenes involves the pyrolysis of malonic acid anhydrides <08CB2208.13CB3539). These materials, on gentle warming (100"C) under reduced pressure, readily extrudecarbon dioxide with the liberation of a ketene (Equation (6)). The synthetic value of this entry liesin the preparation of dialkylketenes where yields in excess of 50% are usually achievable <23HCA29i,63AG(E)608>. The reaction is capricious, especially when the anhydride is prepared HI situ by dehy-dration of the malonic acid derivative with acetic anhydride. Extreme care has to be exercised toremove all traces of residua! acetic anhydride from the vessel prior to thermolysis if side reactionsare to be avoided. An alternative, more forgiving protocol has been developed in which isobutyricanhydride is used to accomplish dehydration of the malonic acids <63AG{E)608).

A variety of mixed anhydrides of malonic acids have also been employed in the synthesis ofketenes. Commonly, these are either the diphenylacetic anhydride (Scheme 17), interestingly pre-pared by the action of diphenylketene on the malonic acid derivative <I3CB3539>, or the bis(tri-fluoroacetic) anhydride, formed by reaction with trifluoroacetic anhydride (TFAA) <62JOC3146>.Again, decomposition of these materials is usually effected by the action of heat, but in the latterinstance may also be accomplished using triethylamine (Scheme 18) <90CPB]60!>.

Scheme 18

(6)

(5)

Scheme 17

Ketenes 535

The synthesis of vinylketenes can be achieved by flash vacuum pyrolysis of crotonic anhydrides.This method has been exploited in a synthesis of sibirinone (23), a metabolite of Hypomycessemitranslucens G. Arnold (Scheme 19) <82JA6779>.

Scheme 19

3.16.1.5 From Other Acyclic Ketones, Carboxylic Acids and their Derivatives

The preparation of ketene by pyrolysis of either acetone or ethyl acetate was among the first routestowards this compound (07JCS1938,07NAT510,07PCS229). In the following years it was established thatalmost any molecule containing a methyl group directly bound to a carbonyl will liberate ketene onthermolysis. Thus, syntheses of ketene through the action of heat on acetic acid <29JA3614>, biacetyl<25JA1779>, acetaldehyde <25BRP273622>, together with numerous methylalkyl ketones <23JA3095>,acetic esters <23JA2167> and amides <32JA2432> have been established (Scheme 20).

The preferred method to accomplish these conversions consists of passing a vaporised sampleover a heated metallic surface. A detailed overview of the experimental procedures that have beenestablished was presented by Hanford and Sauer <46OR132>, and the interested reader is directed tothis account for further information. For most laboratory-scale uses, the generation of ketene bypyrolysis of acetone has found most favour <40JOC122,46OR132).

One drawback of the protocol is that it fails to provide a general synthetic entry towardshomologous ketenes owing to the difficulties associated with the control of cracking processes. Theelevated temperatures necessary to induce fragmentation of ketones, for example (typically > 600 °C)also induce rupture in pendant side chains; as exemplified by the thermolytic conversion of diethyl-ketone to ketene rather than the anticipated methylketene <23JA3095>. In spite of these difficulties,these reactions are not without synthetic value. For example, Streith and Tschamber found that,although pyrolysis of butanone provided a 7:3 mixture of ketene and methylketene, the rate ofreaction of the latter with imines was several powers often greater than that observed with ketene.

Scheme 20


Consequently, good yields of 8-methyl-5-azanonamdienes could be obtained by exposure of thecorresponding diazepines to the pyrolysis gas of butanone (Scheme 21) <83LA1393>.

Scheme 21

There are, however, a growing number of exceptions to this rule. The pyrolysis of higher homo-logues of aliphatic carboxylic acids have been used successfully in the generation of a variety ofmono- and dialkylketenes <63CI(M)1216>, and high yields of these materials have been reportedwhen the reaction is conducted in the presence of catalytic quantities of triethylthiophosphate<60GEP1081455>. In exceptional cases, dehydration has even been achieved using phosphorus pent-oxide <72ZOR654>. More recently, other dehydrating agents have been developed that achieve thisconversion under considerably milder conditions<87JOC3457,91S1027,92CB571 > as exemplified by Funket al. in their total synthesis of clovene (24) (Scheme 22) <88TL1493>.

Scheme 22

The thermally induced degradation of alkylphthalimides (Equation (7)) and also dehydration ofmalonic acid monoesters, have found general application, since both of these processes may beaccomplished at greatly reduced temperatures <35JA774>. In addition, there exist a plethora ofsynthetic entries to specific classes of ketenes. For example, phenylketene may be prepared byirradiation of benzoyldimethylsulfonium methylide (64JA4866, 66JA1587) while the generation of theacylketene (26) may be accomplished by dehydrohalogenation of 2-bromocyclohexane-l,3-dione(25) (Scheme 23).

(7)

Scheme 23

Similarly noteworthy is the preparation of cyclopentadienylketenes by flash vacuum pyrolysis(FVP) of ortho-hy&roxy aromatic esters (Scheme 24) which is strikingly contrasted by the analogouspyrolysis of or?/!o-mercaptobenzoic acid (Scheme 25). The thermolysis of isopropenyl esters also

Ketenes 537

provides a smooth entry towards ketenes (Equation (8)) <68MI 316-02), a process that has foundconsiderable use in the synthesis of vinyl acetates <60JA320l, 65JOC2502).

Scheme 24

Scheme 25

(8)

Finally, it should be mentioned that some useful entries to metalloketenes have been reported.Rathke et al. have uncovered two unusual routes to bis(trimethylsilyl)ketene. First, they showedthat this material could be prepared from /-butyl bis(trimethylsilyl) acetate simply by generation ofits lithium enolate (Scheme 26) <77JOC2038>, and second through sequential treatment of tri-methylsilylketene with butyllithium (— 100°C) and trimethylsilyl chloride (Scheme 27) <78JOC376>.The former has now been extended towards a variety of dialkylketenes <85JA5396>.

Bryce-Smith and co-workers have also prepared copper(I), silver(I) and gold(I) ketenides<70JCS(D)699, 73CC921, 74CC513). In a typical procedure, silver ketenide is formed by the action ofacetic anhydride on silver acetate in the presence of pyridine (Equation (9)) <7lGP2047373>.

(9)

3.16.1.6 From Carbocyclic Ketones and Related Compounds

The photochemically induced cleavage of cyclic ketones has often been shown to produce ketenesas either transient species or isolable products. Thus, when the bicyclo[5,2,l]decanone (27) wasirradiated using a medium pressure arc, the initial Norrish type 1 cleavage was accompanied by aradical abstraction to afford cycloundecanylketene (28) (Scheme 28). A similar rearrangement has

Scheme 27

Scheme 26


been implicated in many other cases including the photochemical interconversion of the bicycles(29), (30) and (31) (Scheme 29) (62JA4148, 62TL221, 62TL1297, 64CB1799, 68JA2449).

Scheme 28

The diradical intermediate produced by a Norrish cleavage of this type may also yield ketenes byother means. Thus, when 5,5-dimethylcyclopentenone was subjected to photolysis, the cyclo-propylketene (32) was generated by recombination of the radical species through the allylic carboncentre (Scheme 30) <69TL4517>. A similar rearrangement occurs when ethano-bridged anthracenesare subject to irradiation, as exemplified by the conversion of (33) into ketene (34). These systemsare also prone to undergo cycloreversion, with the release of anthracene and the generation ofhighly reactive cumulated ketene (Scheme 31) (68TL4995,73JA6294,77JA4554). Indeed, it is this processthat prevails when the related saturated analogues are photolysed <77T389>.

Scheme 30

Scheme 31

The cycloreversion of cyclobutane-l,3-diones is also best achieved by pyrolysis. The process iswell documented as a method for regeneration of ketene monomers from ketene dimers, and israrely used as a truly independent method of synthesis. The reaction is none the less valuable as itprovides a convenient source of these materials in a high state of purity (Scheme 32) <46OR(3)l08>.

Scheme 32

In fact, ketenes may be accessed from almost all cyclobutanone derivatives. The photochemicallyinduced fragmentation of the parent system has been established for many years (67TL545, 72JA663,

Scheme 29

Ketenes 539

73CC795, 83T1567), and has featured in a rearrangement of hydroxybicyclo[3.2.0]heptanones to lac-tones (Scheme 33) <89CC303>.

Scheme 34

The cycloreversion of benzocyclobutenediones <73JA6134> provides a valuable entry to bisketenedienophiles. The utility of these intermediates has been highlighted in a short synthetic entry to theanthracyclinones (Scheme 35) <88LA943>. Methylenecyclobutenones <76BSJ2645> and cyclobutene-1,2-diones <69TL1179> may also undergo scission to transient ketene intermediates. The latterprovides a particularly valuable route to cyanoketenes, as exemplified by the high yields of chloro-cyanoketene that were obtained from 3,4-dichlorocyclobutenedione by treatment with sodium azide(Scheme 36) <84JOC2190>. In this example the reaction was spontaneous at ambient temperature. Avariety of cyanoketenes have also been prepared by the thermolysis of 2,5-diazidoquinones (Equa-tion (10)) <76OS(55)32, 81CSR289, 88RRC83), while vinylogous cyanoketenes are available by similartreatment of azidotropones <68CC764> or 3-azido-l,2-benzoquinones <86JOC2814>.

(10)

Scheme 33

The thermally induced, electrocyclic ring opening of cyclobutenones (68JA2449,85JA3392) had, formany years, received scant attention. However, the use of this protocol in a highly imaginativesynthesis of A-6-tetrahydrocannabinol by Kowalski and Lai (Scheme 34) <88JA3693> and relatedentries towards benzoquinones <85JA3392, 86JOC3067> and bicyclo[3.2.0]heptenones <9UOC6094>described by Moore et al. will undoubtedly inspire further exploration of this chemistry.

Scheme 35


Finally, mention should be made of the conversion of cyclohexa-2,4-dienones to vinylketenes bypyrolytic or photolytic cleavage (Equation (11)) <60JCSl, 65AG(E)2ll, 67JCS(C)ll97,68JA5296,77CB3582),and of the surprising observation that diphenylcyclopropenone may be converted into ketenephosphorenes with triphenylphosphine (Equation (12)) <72TL1849,75CPB2933).

(11)

(12)

3.16.1.7 From Alkoxyalkynes

Another important route to ketenes involves the thermolysis of alkoxyalkynes. Provided there isa hydrogen atom situated on the j3-carbon of the ether, these materials readily suffer elimination ofan alkene to provide the corresponding 'aldoketene', often in almost quantitative yield (Equation(13)) (61RTC810, 73ZOB2088, 77TL4437, 89SL36>.

(13)

The resulting ketenes usually react with the parent alkyne to afford a cyclobutanone (Scheme 37)<85S1118>, or they suffer attack by a suitable nucleophile (Scheme 38) <93TL207l>. However, whensilyl- <65DOK(164)357,68DOK(164)892> and germyl alkoxyalkynes are thermolysed, the increased stab-ility of the resulting ketene allows these materials to be isolated by simple distillation <65DOK(179)357,90JOC395). By contrast, when ethoxy(trimethylstannyl) acetylene was thermolysed, only bis(tri-methylstannyl) ketene was obtained <73AG(E)675>. More conveniently, dimetalloketenes (Si, Ge, Sn,B and combinations thereof) may be prepared from the requisite metallated alkoxyacetylene inmoderate to high yield by the action of R3MBr (M = Si, Ge or Sn) in the presence of magnesiumbromide <71ZOB240, 73AG(E)675> or exposure to boron trihalide (Scheme 39) <84ZOB1817>.

Scheme 37

Alkyl (trimethylsilyl)ketenes may also be accessed from alkyl alkoxyacetylenes by treatment withtrimethylsilyl iodide (Equation (14)) <79S740>. A substantial improvement to this procedure has

Scheme 36

Ketenes 541

(14)

been developed by Kocienski and Pons during their syntheses of tetrahydrolipstatin <89TL1833> and(-)-lipstatin (Scheme 40) <93JCS(P1)1549>.

3.16.1.8 From Heterocyclic Materials

Numerous heterocyclic materials have been converted into ketenes, the advent of flash vacuumpyrolysis and low temperature photolytic techniques undoubtedly being responsible for the renewedinterest in this field of chemistry. Dialkyl ketenes, for example, have been accessed from an arrayof sources, and some representative examples are highlighted in Scheme 41 (08CB2208, 13CB3539,32JA2432, 35JA774, 48JA3426, 63AG(E)608, 64JA4871, 64JOC2200, 64JOC2242, 66JA1242, 70CC206, 70JCS(B)830,74AJC2373, 75CB844).

Of these methods, the pyrolytic fragmentation of disubstituted malonic anhydride and Meldrum'sacid derivatives are most commonly exploited <54JA5563, 77AJC179, 85TL833, 86CC369,88TL5919). Thelatter of these is particularly valued since numerous derivatives can be easily prepared, allowingaccess to a broad spectrum of ketenes. These include dialkyl- and heterosubstituted ketenes, togetherwith the highly reactive methyleneketenes that are difficult to access by other means (Scheme 42)(74AJC2385, 76JA7421, 77AJC459, B-80MI 316-03, 87TL885>.

Other heterocyclic materials have been used to access these cumulated systems, but none hasassumed such universal application. Dimethylmethyleneketene, for example, has been postulatedas an intermediate in the photolytic cleavage of the a-methylene-/Mactam (35), though this is subjectto some speculation (Scheme 43) (77JCC53, B-80MI316-03). By contrast, spectroscopic evidence hasbeen obtained to verify that the parent methyleneketene (38) is produced when an argon matrix

Scheme 39

Scheme 40

Scheme 38


Scheme 42

containing the a-diazo-y-lactone (36) is subject to photolysis (Scheme 44) <J5JA6586>. Interestingly,this reaction proceeds via the ketene (37) and has been extended towards o-quinonoid methyl-eneketenes, for example, (39) (Scheme 45) (75JA6586,80TL343).

Scheme 43

A number of routes to o-quinonoid ketenes from condensed heteroaromatics have also beendisclosed, a selection of which are highlighted in Scheme 46 (62JOC3365,64M1053,66TL3465,68JCS(C)2730,70JA7001, 7UCS(C)3328, 72CC451, 72TL3443, 73JA406l>. In each case acyl-, thioacyl- or iminoketenes are

Scheme 44

Scheme 41

Ketenes 543

Scheme 45

provided, and some parallels can be drawn between these entries and the more generally applicableroutes to such materials outlined in Scheme 47 <72TL1849, 73JA244, 73CC247, 73JA247, 73JA248,73JA5412,73TL2875, 74HCA2583, 75AG(E)636, 75CPB2933, 76TL2961, 79TL59, 84H(22)2563, 85S224, 90CPB94, 90TL3677,91T5689, 92S977).

Scheme 46

Phosphorylketenes have also been reported. Indeed, treatment of diphenylcyclopropenone withtriphenylphosphine provides a stable example of such a compound (72TL1849). In the reaction ofdiphenylcyclopropenone with triethylphosphite, however, a ketene could only be implicated as atransient intermediate (Scheme 47) <75CPB2933>. Vinylketenes have also been accessed by cyclo-reversion of condensed heteroaromatic materials. Of those entries highlighted in Scheme 47 thephoto-induced Wolff rearrangement of 5-acyl-3/f-pyrazoles has found most widespread application.

Several other examples of ketene syntheses from heterocyclic materials are worthy of note. Forexample, pyrolysis of the o-phenylene carbonate (40) has been shown to produce the Wolff-typeintermediate (41) on route to cyclopentadienylketene (42) (Scheme 48) <70JOC4204,71CC77O>. Similartreatment of 4-azido-3-halo-5-methoxy-5(//)furan-2-ones, on the other hand, facilitates rearrange-ment with extrusion of nitrogen to provide halocyanoketenes (Equation (15)) <76JA3728, 78TL929,84JOC2190). Nitrogen extrusion from the cycloadducts of 6-oxo-l,3,4-oxadiazines also leads to theproduction of ketenes (Scheme 49) <90CB2031 > as does the photolysis of dihydrocoumarin <69JA4309>.Finally, mention should be given to the BuLi-initiated fragmentation of 3,4-diphenylisoxazole whichgives rise to phenyltrimethylsilylketene upon quenching with chlorotrimethylsilane (Scheme 50)<75AG(E)765>.


Scheme 47

Scheme 48

(15)

Scheme 49

Scheme 50

3.16.1.9 From Transition Metal Complexes

Reports concerning the formation of transition metal 71-complexes of ketenes and vinylogousketenes abound in the contemporary literature. These include a variety of cobalt <85JA6715>, chro-mium <92JA299l,93JOC538>, manganese <79JA3133>, niobium <89JA8738>, osmium <88JA7868>, rhenium

(18)

Ketenes 545

<85JA3172>, titanium <86JA3318>, tungsten <86AG(E)643> and zirconium (84JA5178, 84CC220) species.Since these are beyond the scope of this chapter, only a few leading references are presented here.One reason for their inclusion is that, on occasions, the presence of additional 7t-donors may causethese materials to rearrange to the corresponding metalloketene (Equation (16)) <86AG(E)643>. Thischemistry has yet to be studied in detail. Similarly, there are reported examples of ketenes bound totransition metals through donor substituents, for example, (43), that are worthy of note<88JOM(355)267>.

(16)

Several routes to c-bound metalloketenes have been described. Thus, exposure of a THF solutionof Cp2Sm(THF)2 to an atmosphere of carbon monoxide resulted in the smooth formation of theketene carboxylate (44) <85JA3728>. Treatment of ((Bu'3Si)3TaCO)n in a similar manner facilitatedthe formation of the moderately stable ketene (45) <89JA9057>, while the reaction betweenCl2W(PPh2Me)4 and carbon suboxide leads to the ketene (46) baring both tungsten and phosphorussubstituents <88JA4855>.

(17)

Perhaps more useful is the observation that, when the tungsten, molybdenum or chromiumcomplexes (47) were exposed to an atmosphere of carbon monoxide, the stable silyl ketene (48) wasfurnished in reasonable yield (Equation (17)) <89JOM(373)203>. Similarly, treatment of chromiumcarbene complexes, for example, (49) with bistrimethylsilylacetylene, provided the vinylogous silyl-ketenes (50) and (51), in useful quantity (Equation (18)) <79AG(E)954>.

3.16.1.10 Miscellaneous Methods

Some very unusual, highly fluorinated ketenes have been described by England, using chemistrythat would appear to be unique. For example, the polyfluorinated ether (52) could be transformedinto the acyl ketene (53) by treatment with sulfur trioxide (Equation (19)) <8UOC147,8UOC153).

(19)


3.16.2 THIOKETENES

Thioketenes are considerably less stable than ketenes, due in part to less efficient Tt-orbital overlapbetween the carbon and the sulfur atom. This is compounded further by a tendency for thesematerials to form dimers and higher oligomers (Equations (20) and (21)). An unfortunate conse-quence of this is that many early reports detailing the preparation of thioketenes, including the firstclaimed synthesis <1877CB70l, 88T1827), were in error <189OCB1571,88T1827>.

(20)

(21)

As with ketenes, the stability of this functional group is greatly influenced by the nature of anysubstituents. Highly congested thioketenes such as di-/-butylthioketene are stable indefinitely atambient temperature, whereas the parent compound H 2 C = C = S dimerises when warmed above— 200°C! <(88T1827>. Electronic factors also play an important role with silicon, phosphorus andtrifiuoromethyl substituents imparting a clear stabilising influence on the system. In general,however, the synthesis of thioketene monomers is difficult, and requires the use of techniquessuch as flash vacuum pyrolysis, matrix isolation or careful generation and characterisation at lowtemperature. It is therefore wise to treat thioketenes as transient species, to be prepared in situ formost synthetic purposes. For that reason the authors again highlight those processes which haveresulted in the isolation and characterisation of thioketenes, alongside those for which it is reasonableto assume their intermediacy.

The interested reader is directed to a series of invaluable overviews. Of particular note are twoearly articles by Borrmann <68HOU(7/4)312> and Mayer and Krober <75ZC91>, respectively, whichcritically evaluate many of the pioneering studies. Two later articles by Schaumann <85HOU(El 1)233,88T1827) are especially noteworthy since they provide a detailed and learned account on all aspectsof thioketene chemistry, and give a most valuable insight into this curious functional group.

3.16.2.1 From Ketenes and Thioketenes

The observation by Newman et al. <60JA2498> that di-?-butylketene was extremely unreactive, ledworkers in the Kodak laboratories to rationalise, correctly, that the corresponding thioketenemight be similarly inert <68JOC2738>. Indeed, they found that simply reacting dw-butylketene withphosphorus pentasulfide in refluxing pyridine for 15 hours gave the corresponding thioketene in anisolated yield of 41%. It was, however, observed that under these conditions, most thioketenesoligomerised (Equation (22)) <79CB2698, 82CB2755>.

(22)

Interestingly, when r-butylcyanoketene was treated with triphenylphosphine sulfide, the reactionprofile indicated the presence of a thioketene intermediate. This has yet to be rigorously established,with spectroscopic analysis failing to detect the presence of a thioketene <7OJA4132, 71JA2812).Triphenylphosphoranylidenethioketene, on the other hand, has been prepared from the cor-

3.16.2.3 From the Sulfur Analogues of Carboxylic Acids and Esters

One of the earliest routes to thioketene involved the pyrolysis of thioacetic acid <77CPH(22)453,77JA1663). This method of synthesis has been used widely, particularly as a means to study thespectroscopic characteristics of this material, but has few useful extensions <33CB237>. An alternativeroute to thioketenes from dithiocarboxylic acids first involves the generation of the correspondingdianion. On occasions these intermediates may even collapse to the thioketene spontaneously,although it is more usual to promote this degradation by the addition of electrophiles such asacid chlorides (62CB2861, 74ZC92, 79LA1715), alkoxycarbonyl chlorides or tx-chloroenamines (75ZC19,81 LAI361 >. In all cases the reaction conditions employed render the thioketene a transient species.<62CB287i, 71CJC1456). One potentially useful modification of these methods, that has led to thio-ketene monomers, first involves monoacylation of the dithiocarboxylic acid dianion. The resultingdithioanhydrides may then be transformed into the corresponding thioketene through the action ofheat (Scheme 53) <88T1827>. This method, while showing much initial promise, has yet to be fullyevaluated and may prove to be less versatile than the analogous procedure using phosgene (detailsin Section 3.16.2.4).

The sulfur analogues of carboxylic esters have also, on occasions, been used to access thioketenes.For example, pyrolysis of phenyl diphenyldithiocarboxylate has been shown to yield the dimerof diphenylthioketene <31CB237>, while treatment of methyl triphenylphosphoranylidene dithio-acetate with sodium hexamethyldisilylamide provides a useful synthesis of triphenylphos-phoranylidenethioketene <75AG(E)634>. The use of alkynyl thiocarboxylates represents a special casewhich is considered in more detail in the following section.

Thioketenes 547

responding ketene through the action of carbon disulfide <(68JA3842>; and when this material isadded to electron-deficient alkynes a (2 + 2)-cycloaddition, electrocyclic ring opening sequence isinitiated that provides access to cumulated thioketenes (Scheme 51) <75AG(E)53>.

Scheme 51

3.16.2.2 From Acid Chlorides and Thioacyl Chlorides

Di-?-butylthioketene can also be prepared from di-?-butylacetyl chloride through the action ofP2S5 in refluxing pyridine (Scheme 52) (68JOC2738). This method has been used in the synthesis ofseveral thioketenes, and yields tend to be superior to corresponding reactions with ketenes<82CB2755>. Conceptually, the elimination of HX from thioacyl chlorides should offer a concise andversatile entry to thioketenes. Unfortunately, the use of this tactic is limited by the scant methodsavailable to access the highly reactive thioacyl chlorides. Consequently, the use of this protocol hasbeen limited (Scheme 52) <81BCJ2845,83AG(E)32i>.

Scheme 52


Scheme 53

3.16.2.4 Via Alkynyl Sulfides and Alkynyl Thiolates

Alkynyl thiolates are a convenient source of thioketenes since they are tautomerically equivalentto the aldothioketene anion. Indeed, protonolysis of these species first provides the alkynyl thiolwhich may then undergo a 1,3-hydrogen shift to the thioketene <68RTC38>. These species are mostconveniently generated and used in situ, and a variety of preparations have been disclosed. Forexample, treatment of alkynyl thiocarboxylates with nucleophiles <67RTC907>; protonolysis of alky-nyl thiocyanates <82RTC31O>; addition of sulfur to the alkynyl anion or pyrolysis of alkynylalkylsulfides (62USP3O35O3O, 62ZOR1759, 66RTC889) have variously been explored (Scheme 54), althoughonly the latter procedure has allowed the isolation of monomeric thioketene <60RTC866,71ZOR1120>.

Scheme 54

One important extension to these studies has shown that trimethylsilylalkynyl sulfides readilyrearrange to the corresponding trimethylsilylthioketenes under thermolysis or by the action of aLewis base (Scheme 55). Moreover, silylalkynyl sulfides display considerable 'thioketenoid' characterin their reactions. For example, the addition of methanol to trimethylsilylethynyltriethylsilyl sulfidefirst provides trimethylsilylthioketene <77JOM(127)Cl>, which may then be quenched by a furtherequivalent of methanol <76CC1008, 77RTC179, 78ZOB2137, 80CB3024, 83CB66, 83CB509, 84AG(E)439>.

Scheme 55

With alkynylallyl sulfides the thia-Cope rearrangement is also facile, providing a ready access toallylthioketenes (Equation (23)) <68RTC1236, 74CB3562, 77TL4307, 79LA1746>. Similarly, thermolysis ofalkynylpropargyl sulfides <74RTC26,79RTC55) and alkynylallenyl sulfides <72RTC578> can be readilyaccomplished thereby providing access to allenic and propargylic thioketenes respectively (Equa-tions (24) and (25)).

Thioketenes 549

(23)

(24)

(25)

3.16.2.5 From Sulfides of Carbon

The use of carbon disulfide in Wittig, and related, alkeneation sequences has resulted in theformation of products which can be considered to have arisen through the intermediacy of thio-ketenes (Scheme 56) <20HCA853, 62CB3077, 76JCS(P1)692, 82CB3653, 84JCR(S)370>. This has only beenestablished formally in the case of triphenylphosphoranylidenethioketene <66TL5707>. An interestingextension to this protocol has been described by Kolodyazhnyi who found that treatment of tertiaryphosphines with carbon disulfide in carbon tetrachloride smoothly led to the production of stablephosphorylated thioketenes (Equation (26)) <87TL88l>.

(26)

Several other alkeneation procedures have been extended towards reaction with carbon disulfide,albeit in less detail. The use of the Peterson protocol (Scheme 57) <88TL1827> and of sulfur ylides(Scheme 58) <71T1781> to effect construction of the carbon to carbon double bond have also beenreported, but the true effectiveness of these methods has yet to be fully determined. For completion,the conversion of P h 3 P = C = C = O to P h 3 P = C = C = S by the action of carbon disulfide should alsobe mentioned <68JA3842>.

Scheme 58

Scheme 57

Scheme 56


Another conceptionally simple approach to thioketenes is through the union of a carbenoidspecies and carbon monosulfide. Unfortunately, this process has proven to be of limited use<9UOC1317> owing to the readiness with which most thioketenes undergo [3 + 2] cycloadditionreactions with diazo complexes (see Scheme 61) <70JOC3470>.

3.16.2.6 From Ketene-S,X-Acetals

Ketene-S,X-acetals provide an excellent route to thioketenes through ^-elimination (70CB949,9UA5120). Ketene-N,S-acetals <79JOC4877> and ketene-O,S-acetals <76TL3093> have each beenemployed in this way, but as yet these have only provided trapped and oligomeric products (Scheme59). Ketene-5'-methyl-5'-(trimethylsilyl)acetals, by contrast, readily undergo flash vacuum pyrolysisto the corresponding thioketene. In the case of the anthracene derivative (54) a [4 + 2]-cycloreversionwas used in conjunction with the /^-elimination sequence to access methylenethioketene (Equation(27)) <86TL4313>. In fact, a plethora of cycloreversion strategies have been used to access thioketenesfrom cyclic ketene-S,X-acetals, and these are presented in the following section.

Scheme 59

(27)

3.16.2.7 From Heterocyclic Materials

The deprotonations of 2-alkylidene-l,3-dithiolanes 1,1-dioxides, which are easily derived from thecorresponding ketenthioacetals by oxidation, offer a convenient in situ method for the preparation ofseveral thioketenes <83AG(E)55, 88TL1827). A similar fragmentation sequence can also beaccomplished through alkylation or arylation of 2-alkylidene-l,3-dithiolanes. The resulting dithio-lonium salts readily extrude alkyl- or arylvinyl sulfide on treatment with base (Scheme 60) (85TL5269,88TL1827).

[2 + 2] Cycloreversions offer many routes to thioketenes. For example, dithietanones, which arereadily formed by the addition of phosgene to the dianions of dithiocarboxylic acids, may be cleavedto thioketenes by pyrolysis, photolysis or by the action of a Lewis base <82AG(E)225>. Flash vacuumpyrolysis of 2,2,4,4-tetramethylcyclobuta-l,3-dithione may be used in the preparation of di-methylthioketene <74TL555>. Cyclobutanethiones too, when exposed to similar conditions, readilycleave to give an alkene and a thioketene <87CC573). More importantly, the [2 + 2] cycloreversionof 2,4-bis(alkylidene)-l,3-dithietanones, that is cracking of the dimer, can often provide an effectiveroute to the monomeric species (66CC577, 70JOC3470, 91CB1485). For completion the addition ofcarbon monosulfide to diazo compounds and the addition of carbon disulfide to phosphorus ylides

Thioketenes 551

Scheme 60

are also noted here, as the intermediacy of diazetinethiones and thiaphosphetanes, respectively,have been implicated in these processes <91JOC1317> (Scheme 61).

Scheme 61

Interestingly, cracking of the thioacetone trimer, 2,2,4,4,6,6-hexamethyl-l,3,5-trithiane, at900 °C produces thioketene. The reaction proceeds first to give thioacetone, which then suffers lossof methane on extended thermolysis (Scheme 62) <74CC739>. The photochemical degradation of2-alkylidene-l,3,4-thiadiazolines <90TL357l> and the chemically induced reteroreversion of 2-alkyl-idene-l,3-oxathioles <89TL1249> have also provided access to thioketenes, albeit in low yield. Thesynthetic utility of each is of limited interest as these materials are accessed from the thioketeneseach provides!

Scheme 62

One of the most important routes to thioketenes involves the extrusion of nitrogen from 1,2,3-thiadiazoles <77AG(E)835> which leads to the generation of a Wolff-type intermediate that mayundergo rearrangement to a thioketene <58LA(614)4, 71T5953). Several methods have been described


to accomplish this transformation, including the use of thermolysis (20HCA833, 77T449, 87CC573),photolysis <85LA(614)4> and, needless to say, flash vacuum pyrolysis <75AG(E)248,77CB1225,79LA1734).Of these techniques, the former and the latter have found most favour since they are less prone toside reactions (Scheme 63).

Nitrogen extrusion from 1,2,3-thiadiazoles can also be brought about by treatment with alkyllithium reagents (66RTC889, 68RTC38, 77S888, 79CL535). This procedure is believed to proceed via thelithium alkynyl thiolate (Scheme 64), the chemistry of which has been discussed in Section 3.16.2.4.

Scheme 64

The intermediacy of carbenoid species has been implicated in several other thioketene syntheses.For example, flash vacuum pyrolysis of 2-mercaptoaryloic acid derivatives is believed to giverise to thioketenes via sequential dehydration to the jS-thiolactone, loss of carbon monoxide andrearrangement of the carbenoid precursor (Scheme 65) <83AG(E)543>. l,3-Dithiolen-2-thiolones<79NJC149> and isothiazoles <77JA4842> also suffer elimination, of carbon disulfide and hydrogencyanide, respectively, to give first carbenoid intermediates which rearrange to thioketenes. Thephotochemically induced extrusion of carbon monoxide from l,3-dithiolen-2-ones, on the otherhand, leads to an unstable a-dithione which then equilibrates to the corresponding mer-captothioketenes (Scheme 66) <82NJC40l>. 1,2-Dithiolene-3-thiones <74CB502> and isothiazol-5-thiones <85CB85l> have also been transformed into thioketenes through phosphine-induced desul-furisations, while l,2-dithiolen-3-ones <75LA1513> and 3-isothiazolthiones <70T1493>, each sufferdecomposition in the presence of base with the formation of thioketene dimers.

Scheme 65

Scheme 66

3.16.2.8 From Vinylidene Transition Metal Complexes

A plethora of accounts have recently appeared concerning the chemistry of transition metalbound thioketenes. Indeed, r\ 1 (S), r]2 (CS) and even rjl> (CCS), complexes of thioketenes to all mannerof transition metal centres have been described (e.g., Ir and Pt <70JCS(A)944>, Cr <76JOM(118)C4l>, Co

Scheme 63

Selenoketenes 553

and Rh <81AG(E)593>, Mn and W <82CB1332>, V <84JOM(272)C40>, Co <84JOM(270)93, 85CB873), Ti<85JOM(288)C47». The most commonly employed route for the synthesis of such materials involvessimple ligand displacement, and is not considered in detail here.

An alternative entry to the r\l (CS bound) complexes, through the addition of elemental sulfur tovinylidene rhodium and osmium carbene complexes, is perhaps more noteworthy since it formallyconstitutes a new synthetic entry to thioketenes (Equation (28)) <83AG(E)981, 85CC1145). Moreover,these complexes have been shown to possess significantly improved thermal stability compared tothe free ligand <91OM3967>. However, this chemistry is still in its infancy, and as yet no method forthe liberation of these ligands from a metal centre has been disclosed.

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3.16.3 SELENOKETENES

Very few selenoketenes have been reported, and access to this curious functional group hasgenerally followed analogous procedures towards thioketenes. Thus, a variety of 1,2,3-selenodiazoleshave been converted into the corresponding selenoketene by thermolysis <79CC99> or photolysis(Equation (29)) <72TL445, 76JA7872, 77JA4842). Similarly, the thermally induced rearrangement ofbenzo-l,2,3-selenodiazole (Equation (30)) <80AG(E)69> and the seleno-Cope rearrangement of vari-ous allyl butynyl selenides have provided routes to selenoketenes, albeit transiently (Equation (31))<79RTC55, 80TL4251). In addition, a [3 + 2]-cycloaddition reaction between a transient selenoketeneand its anion has been postulated in the base-catalysed conversion of 4-aryl-1,2,3-selenodiazolesinto diselenofulvenes (Scheme 67) <73JOC338, 74JOC3906). Phenylselenoketene has also been invokedas an intermediate in the reaction between bis(dimethylaluminium)selenide and the ketene silylacetal (55), on the basis that the adduct (56) was obtained (28%) when the reaction was performedin the presence of cyclopentadiene (Scheme 68) <92TL7865>.

(29)

(30)

(31)

Scheme 67


Scheme 68

Transition metal complexes of selenoketenes are usually considerably more stable than the parentcompound. Indeed, by analogy with thioketenes these may be synthesised by the addition of seleniumto vinylidene transition metal complexes <91OM3967>. Again, a method of liberating the monomerfrom the metal centre has yet to be described. Finally, it is necessary to note that a ChemicalAbstracts Service on-line search failed to reference any example of a telluroketene (R 2C=C=Te).Whether such compounds can be prepared is a matter for speculation; however, their use in synthesiswould surely be limited.


3.17Ketenimines and Their P, As, Sb,and Bi AnaloguesJOSEPH P. MICHAEL and CHARLES B. DE KONINGUniversity of the Witwatersrand, South Africa

2[06[0 KETENIMINES AND THEIR DERIVATIVES "R1C1C1NH"R#\ ETC[# 444

2[06[0[0 Introduction 4442[06[0[1 Ketenimines from Precursors Containin` the CCN Triad 445

2[06[0[1[0 By elimination reactions 4452[06[0[1[1 By elimination reactions accompanied by skeletal rearran`ement 4522[06[0[1[2 From alkanenitriles\ their a!anions or their a!radicals 4542[06[0[1[3 By cleava`e of heterocyclic compounds 4632[06[0[1[4 From other ketenimines 4792[06[0[1[5 By miscellaneous pericyclic processes 471

2[06[0[2 Ketenimines from "CC¦N# Precursors 4732[06[0[2[0 From ketenes "or related precursors# and iminophosphoranes "or related precursors# 4732[06[0[2[1 From haloalkenes or haloalkynes and amines or amine derivatives 477

2[06[0[3 Ketenimines from "C¦CN# Precursors 4802[06[0[3[0 From phosphorus ylides and isocyanates or related compounds 4802[06[0[3[1 By alkylation of isocyanides 4822[06[0[3[2 Formal cycloaddition processes 599

2[06[0[4 Keteniminium Salts 590

2[06[1 P\ As\ Sb\ AND Bi ANALOGUES OF KETENES AND THEIR DERIVATIVES"R1C1C1P0R\ ETC[# 591

2[06[1[0 0l4!Phosphaallenes and 0l4!Phosphacumulenes 5922[06[1[0[0 From precursors containin` the CCP triad 5922[06[1[0[1 From "C¦CP# precursors 593

2[06[1[1 0l2!Phosphaallenes and 0l2!Phosphacumulenes 5942[06[1[1[0 By the Peterson reaction and related ole_nations 5942[06[1[1[1 By other routes 5962[06[1[1[2 Transition metal complexes of 0l2!phosphaallenes and 0l2!phosphacumulenes 598

2[06[1[2 0!Arsacumulenes 598

2[06[0 KETENIMINES AND THEIR DERIVATIVES "R1C1C1NH"R#\ ETC[#


Ketenimines "IUPAC name] 0!alkenylideneamines# are comparative latecomers to organic chem!istry\ the _rst stable member of the group having been reported by Staudinger in 0808 ð08HCA524Ł[Their relatively recent discovery and continuing rarity re~ect the susceptibility of the C1C1N unitto decomposition by hydrolysis\ dimerization\ and polymerization\ amongst other reactions[ Ingeneral\ hydrogen!substituted ketenimines and those with small unbranched alkyl substituents areelusive substances[ For example\ the simplest ketenimine\ H1C1C1NH\ was _rst isolated in anargon matrix at 3 K ð52JA167Ł[ Although longevity\ and hence synthetic signi_cance\ is conferred

445 Ketenimines and P\ As\ Sb\ and Bi Analo`ues

by substituents that stabilize the 0!azaallene core either electronically or sterically\ many keteniminesthat do not survive puri_cation are stable for limited periods at low temperature or in solution[Ketenimines also play a role as discrete but transient intermediates in many interconversions\especially in eliminationÐaddition processes and in the formation of heterocyclic systems[ Theselection of material for this chapter has thus been complicated by the hazy distinction that existsbetween unstable but spectroscopically characterizable ketenimines\ and ephemeral species producedby methods that nonetheless have synthetic value[

The inherent axial dissymmetry of the formal C1C1N unit means that appropriately substitutedketenimines should\ in principle\ be obtained in two enantiomeric forms[ However\ such enantiomershave never been isolated\ though ketenimine diastereomers have been detected in one highly spe!cialized case ð70CL416Ł[ Inversion at nitrogen appears to constitute the principal mechanism forracemization\ and spectroscopically determined barriers to racemization for a substantial numberof ketenimines are in the range 29Ð52 kcal mol−0 "015Ð153 kJ mol−0# ð70CB2640\ 73T782Ł[ In fact\ thedescription of ketenimines as 0!azaallenes "0a# may well be an oversimpli_cation[ Other feasiblecanonical forms include a zwitterionic form "0b# highlighting the nucleophilicity of the b!carbonatom\ and an alternative zwitterion "0c# in which the electrophilicity of the central carbon atom isemphasized "Scheme 0#[ Single!crystal x!ray di}raction studies have con_rmed the approximatelylinear "069Ð065># nature of the CCN triad\ but several examples "e[g[\ with R0�R1�MeSO1# inwhich a linear C1N0R2 angle is apparent point to a large contribution from the canonical form"0b# ðB!79MI 206!90\ 78AX"C#371Ł[ The pronounced shielding of the terminal allenic carbon "dC 26Ð67ppm for various methyl! and phenyl!substituted ketenimines# also suggests the conjugative inter!action between the C1C bond and the nitrogen lone pair implicit in the canonical form "0b#ð64CL40Ł^ and a similar conclusion can be drawn from up_eld 04N chemical shifts ð70OMR"06#079Ł[

•

R2

R1

N

R3

(1a)

:

R2

R1

N

(1b)

R3+–

R2

R1

(1c)

N R3–

+

Scheme 1

The _rst review dealing with the synthesis and reactions of ketenimines was published in 0857\and contained experimental procedures for preparing representative compounds ð57HOU"6:3#212Ł[Subsequent reviews by Krow ð60AG"E#324Ł and by Barker and McHenry ðB!79MI 206!91Ł alsoincluded structural and spectroscopic properties of ketenimines[ Specialized reviews by Gambaryanð65RCR529Ł and Aumann ð77AG"E#0345Ł cover the topics of ~uorinated ketenimines and metalcomplexes of ketenimines respectively[ A very thorough review of post!0857 ketenimine chemistryhas appeared in the Houben!Weyl series ð82HOU"E04:2#1420Ł[

2[06[0[1 Ketenimines from Precursors Containing the CCN Triad


Elimination reactions from substrates incorporating the intact CCN triad have proved to bereasonably versatile and general reactions for preparing ketenimines bearing a variety of substitu!ents[ In virtually all of the examples that _t this category\ the substrates undergoing elimination areamides or compounds readily prepared from amides[

"i# Dehydration of secondary amides with phosphorus pentoxide

A much!cited method for accomplishing this reaction\ introduced in 0853 by Stevens and Singhal\involves heating secondary amides with phosphorus pentoxide in re~uxing pyridine ð53JOC23Ł[Florisil\ sand\ or alumina\ added to the reaction mixture to facilitate stirring\ were found to increasethe rate of reaction[ Some representative examples are shown in Table 0[ Most of the compoundsoriginally prepared weretriaryl ketenimines derived from anilides of diphenylacetic acid "entries 0Ð4#\but strongly electron!withdrawing substituents on the N!aryl group inhibited the reaction "entry 1#[The high boiling point of pyridine makes the reaction unsuitable for preparing thermally labile

446Ketenimines

ketenimines such as those bearing N!alkyl and C!alkyl substituents "entries 4 and 5#[ However\ bychanging to the lower!boiling solvent triethylamine\ Singer and Davis succeeded in preparing mixedalkylÐaryl ketenimines and even a trialkyl ketenimine "entries 6 and 7#\ although in general theiryields were low "½19)# ð56JA487Ł[ Other workers have been more successful with this variation"entry 00# ð73T782Ł[

Table 0 Representative ketenimines\ R0R1C1C1NR2\ prepared by dehydration of secondary amides\R0R1CHCONHR2\ with phosphorus pentoxide[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Ketenimine Methoda Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 Ph1C1C1N"C5H3R# "R�o!Me\ o!OMe\ p!Me\ p!OMe\ i 56Ð76 53JOC23

p!Br\ p!SMe#1 Ph1C1C1N"p!C5H3R# "R�SO1Me\ NO1# i 29\ 9 53JOC232 ðPh1C1C1N"p!C5H3#Ł1X "X�CH1\ S1# i 73\ 16 53JOC233 Ph1C1C1NBun ii 49 53JOC234 Ph1C1C1NBut i 9b 53JOC235 Et"Bun#C1C1NR "R�p!Tol\ Bun# i 08\ 9 53JOC236 Me1C1C1NR "R�c!C5H00\ Ph# ii ½19 56JA4877 Et"Ph#C1C1NR "R�Ph\ Bus# ii ½19 56JA4878 0\n!"Ph1C1C1N#1C5H3 "n�2\ 3# i 55\ 60 66MI 206!90

09 Me"R#C1C1N"p!C5H3NMe1# "R�Pri\ BnMe1C# ii 21\ low 70CB264000 Me"Pri#C1C1N"1!Cl\5!R0C5H2# "R�Cl\ Me# ii 34\ 61 73T782*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa i\ P1O4:pyridine\ re~ux^ ii\ P1O4:NEt2\ re~ux[ b Diphenylacetonitrile "58)# was formed[

"ii# Dehydration of secondary amides with dihalotriphenylphosphoranes

A milder procedure for dehydrating secondary amides to ketenimines uses reagents of the formPh2PX1 "Scheme 1#[ Bestmann and co!workers originally employed dibromotriphenylphosphorane"prepared in situ from triphenylphosphine and bromine#\ which\ in conjunction with triethylaminein re~uxing dichloromethane\ provided convenient access to trisubstituted keteniminesð57LA"607#13Ł[ The putative intermediate in this reaction is "1#\ though it is conceivable that animidoyl bromide is subsequently formed "see the following section#[ The reaction conditions arecompatible with a variety of substituents\ and some typical compounds prepared by the method arelisted in Table 1[ The method has also been used for making the exotic ketenimine "2# ð66TL2242Ł\and for producing ketenimine intermediates such as "3# en route to heterocyclic systems ð74TL0536Ł[

Scheme 2

R1

NHR3

R2

O

R1

NR3

R2

OPPh3+

Br–

(2)

•

R2

R1

NR3NEt3Ph3P, Br2

The Bestmann method lends itself to the synthesis of ketenimines bearing heteroatomic sub!stituents on carbon[ For example\ But"Br#C1C1NBut has been obtained from the correspondinga!bromo amide in 39) yield ð63JOC378Ł\ and C!phosphoryl ketenimines\ "EtO#1PO"R0#C1C1NR1

"R0�Me\ Ph^ R1�Et\ Ph#\ were made by the standard procedure in yields of 58Ð82) ð68CC899\79JOC4274\ 80S0052Ł[ Bestmann and Lehnen have even succeeded in making a bis"phosphoryl# keten!imine\ ð"EtO#1POŁ1C1C1NPh\ as a comparatively stable\ distillable liquid "76) yield# ð80TL3168Ł[The C!sulfenyl ketenimines "R0S#R1C1C1NR2 "R0�Me\ Ph^ R1�Me\ Et\ Pri^ R2�Et\ Ph# havebeen prepared in yields of 42Ð52) ð70JCS"P0#1616Ł\ and the sulfone PhSO1C"Me#1C1NEt wasalso accessible in 28) yield if re~uxing 0\1!dichloroethane was used as the solvent ð80S0052Ł[

A potentially valuable modi_cation of the Bestmann procedure uses 1) cross!linked polystyreneas a support for the phosphine ð79MI 206!92Ł[ The e}ective reagent is poly"styryldiphenylphosphinedibromide#\ which\ when used with triethylamine in re~uxing benzene\ gave high yields "69Ð89)#of trisubstituted ketenimines from secondary amides[ Polymeric phosphine oxide was easily


Table 1 Representative ketenimines\ R0R1C1C1NR2\ prepared by dehydration of secondary amides\R0R1CHCONHR2\ with dibromotriphenylphosphorane[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Ketenimine Methoda Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 Ph1C1C1N"C5H3R# "R�H\ o!Me\ p!Me# i 79Ð74 57LA"607#131 Ph1C1C1NBun i 53 57LA"607#132 R1C1C1NPh "R�Me\ EtO1C# i 34\ 49 57LA"607#133 0\3!"Ph1C1C1N#1C5H3 i 24 63JHC5224 H1C1CH"Me#C1C1N"p!C5H3Me# i 34 62JA43065 H1C1CHCH1C1N"p!C5H3Me# i Ð 71JOC28876 PhCH1C1NR "R�Me\ c!C5H00\ Ph\ 1\3\5!C5H1Me2# ii 54Ð74 79JOC26557 MeCO"R#C1C1NPh "R�Me\ Et\ Pri# iii 39Ð49 62TL40568 EtO1C"R#C1C1NPh "R�Me\ Et# iii 79\ 65 62TL4056

09 NC"Me#C1C1NEt iv 10 80S005200 "C5Me4#1C1C1NBn i 51 81JOC25101 Me1C1C1NSO10p!Tol i b 79TL2970\ 71TL1898*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa PPh2\ Br1\ NEt2^ solvents and temperatures are as follows] i\ CH1Cl1\ re~ux^ ii\ CCl3\ re~ux^ iii\ C5H5\ ³09>C^ iv\ ClCH1CH1Cl\ RT[b Characterized spectroscopically[

CN

N

O

MeO

PhPh

NO O

Me

PhPh•

N

(3)

MeO2C

N•

(4)

removed by _ltration\ after which the phosphine could be regenerated by reduction with tri!chlorosilane[

A di}erent variation uses dichlorotriphenylphosphorane\ prepared in situ from triphenylphos!phine and tetrachloromethane\ for generating trisubstituted "mostly triaryl# ketenimines fromamides in yields of 44Ð76) ð66ZC82Ł[ This combination of reagents has also been used for thesynthesis of imino ketenimines by formal 0\3 elimination from 2!aminoacrylamides "Equation "0##ð61TL0408Ł[

NBut•

EtO2C

R1N

R2

CONHBut

EtO2C

R1HN

R2

Ph3P/CCl4, NEt3, CH2Cl2, RT(1)

R1

PhPh2,6-C6H3Me2

R2

MePhMe

Yield (%)546169

"iii# Dehydrohalo`enation of imidoyl halides

Stevens and French introduced this frequently used method for preparing ketenimines in 0843ð43JA3287Ł[ Imidoyl chlorides\ prepared as isolable intermediates from secondary amides and phos!phorus pentachloride in re~uxing benzene\ undergo dehydrochlorination when treated with tri!ethylamine "Scheme 2#[ An apparent limitation is dimerization of the products\ which is promotedby triethylammonium hydrochloride formed as a by!product[ However\ the relatively mild con!ditions are conducive to the formation of rather sensitive ketenimines "e[g[\ trialkyl ketenimines\ cf[Table 2\ entry 1#[ Other workers have used this method\ occasionally varying the chlorinating agentor the base\ for preparing both trisubstituted ketenimines and C\N!disubstituted ketenimines\ anda representative selection of accessible compounds and reaction conditions is shown in Table 2[ The

448Ketenimines

last entry records a unique attempt to prepare an N!alkoxy ketenimine\ Ph"Me#C1C1NOEt^ thehighly unstable 0!azaallene rearranged to 1!ethoxy!1!phenylpropanenitrile ð81BAU1928Ł[

Scheme 3

•

R2

R1

N

R3

R1

NHR3

O

R2

R1

NR3

R2

ClPCl5, C6H6 NEt3

The imidoyl chloride method is suitable for the preparation of ketenimines bearing chiral sub!stituents on nitrogen^ for example\ compounds "4#Ð"8# were obtained from secondary amides viaimidoyl chlorides in yields of 61Ð099) ð74CPB1220\ 74CPB3580Ł[ More unusual ketenimines includethe penicillin derivatives "09a# and "09b#\ prepared in a 8 ] 0 ratio "69) yield# from an epimericmixture of the corresponding imidoyl chlorides ð63TL0404Ł[ The 5!deutero analogue of "09a# wasaccessible from the imidoyl chloride on treatment with triethylamine and deuterium chlorideð63TL0404Ł[ Similar reactions have been demonstrated for cephalosporins ð65CC405\ 66GEP"O#1617773Ł[By contrast\ treatment of penicillin derivatives such as "00# with phosphorus pentachloride andpyridine in benzene gave the ketenimine "01# directly^ no intermediate imidoyl chloride was detected"Equation "1## ð66TL2720Ł[

•

Ph

N

NO

SH

CO2CH2O2CBut

(10a)

6

•

Ph

N

NO

SH

CO2CH2O2CBut

(10b)

•

R1

R2

N

Et

(5)

HMeEtCH2=CHCH2Et

PhPhPhPh

o-C6H4OMe

R1 R2

•

R1

R2

N

(6)

MeEtH2C=CHCH2Et

PhPhPh

o-C6H4OMe

R1 R2

•

Et

Ph

N

R

OMe

(7)R = Me, Pri, Bn

•

Et

Ph

(8)

N

•

Et

Ph

H

N

(9)

NO

S

O

ONO2

HN

PhO2C

O

Ph

NO

S

O

ONO2

(11) (12)

H HN•

Ph

PhO2CPCl5, pyridine, C6H6, 5 °C

85%(2)


Table 2 Representative ketenimines\ R0R1C1C1NR2\ prepared from secondary amides\ R0R1CHCONHR2\via imidoyl chlorides\ R0R1CHC"Cl#1NR2[

• NBun

Ph

Ph

• NBun

Et

Bun

• N(C6H4R) (R = o-Me, p-OMe, p-Me)

• NPhPri

• N(C6H3-2,6-Me2)

• NPri (R = H, D, Me)

Ph

R

Entry Ketenimine Methoda Yield(%)

Ref.

1 i, then ii 69 54JA4398

2 i, then iii 57 54JA4398

3 i, then iv 58–70 54JA439866LA(700)32

4 i, then iii 39 72JOC2364

5 i, then iii 61 74JHC241

6 i, then iii 34–50 80JCS(P2)579

7 i, then v 85, 61 81CB3751

8

• NR (R = Bun, Bus)

BnMe2C

i, then v 22–8781CB375184T893• N(C6H4R) (R = H, p-Me, p-F, p-Cl, p-Br,

BnMe2C

9 i, then v 54–65 81CB3751• NPri (R = H, Me)

p-C6H4R

10 i, then v 34–48

Pri

81CB3751• NBun (Ar = p-C6H4OMe,

Ar

11 i, then vi 47

Pri

84JOC2200

12

• N(C6H3-2,6-Me2)

i, then iii 54–64• N(p-C6H4R) (R = H, Me, OMe, Cl, NO2)

But86CB3411

13 vii• NCHPh2

C6Me5

30 92JOC362C6Me5

14 i, then viiiN

O

O

•

N(c-C6H11)

b 80TL3081

15 i, then ix c• NOEt

Ph92BAU2039

p-OMe, p-NO2, p-CN, o-F, o-OMe, o-NO2, o-CN)

C6H3-3-NO2-4-OMe)

a i, PCl5/C6H6, reflux; ii, Et3N/Et2O, RT; iii, Et3N/C6H6, reflux; iv, Et3N/C6H5Me, 110 °C; v, Et3N/Et2O, reflux; vi, KOBut/THF, 0 °C;

vii, SOCl2/pyridine, RT; viii Et3N, CHCl3, reflux; ix, NaH, 18-crown-6, THF, reflux. b Not reported. c Ph(Me)C(OEt)CN was isolated (58%).

Ketenimine formation from imidoyl halides other than imidoyl chlorides is rare[ Elimination ofhydrogen ~uoride from imidoyl ~uorides with powdered potassium hydroxide in ether has beenused for preparing bis"tri~uoromethyl# ketenimines\ "F2C#1C1C1NR "R�aryl\ alkyl\ cycloalkyl#\in yields of 47Ð89) ð62BAU0639Ł[ The preparation of the ketene hydrazone "F2C#1C1C1NNMe1

450Ketenimines

by this method "34) yield# has also been claimed ð62BAU0639Ł[ Imidoyl bromides are the presumedintermediates in the rearrangementÐelimination reaction to be described in Section 2[06[0[1[1"i#below[

"iv# Dechlorination of a!chloro imidoyl chlorides

As long ago as 0896\ Staudinger failed in his attempts to prepare ketenimines "referred to by himas {imenes|# by dechlorinating a!chloro imidoyl chlorides with zinc metal ð96LA"245#44\ 19CB61Ł[ Over34 years later\ the transformation was successfully accomplished by Stevens and French ð42JA546Ł[The substrates\ prepared by treating secondary a!chloro amides with phosphorus pentachloride inboiling benzene\ were dechlorinated with sodium iodide in re~uxing acetone "Scheme 3#[ Thelimited range of ketenimines prepared in this way included N!"p!tolyl#diphenylketenimine "72[4)#ð42JA546Ł\ N!methyldiphenylketenimine "35)# and its corresponding N!"n!butyl# homologueð43JA3287Ł\ and N!isopropyldiphenylketenimine "43)# ð54JOC2607Ł[ The comparatively mild\ neu!tral conditions lend themselves to the preparation of ketenimines that are susceptible to dimerization[

Scheme 4

•

R2

R1

N

R3

R1

NHR3

O

Cl

R1

NR3

Cl

Cl

PCl5, C6H6, heat NaI, Me2CO, heat

R2R2

Few improvements to the original reaction conditions have been reported[ Lithium amalgam inether o}ers advantages over sodium iodide in acetone for preparing the bis"ketenimine# "02# fromthe corresponding bis"dichloro# precursor "50) versus 12) yield# ð54JOC2607Ł[ Various triarylketenimines\ including N!"p!nitrophenyl#diphenylketenimine\ have been obtained from a!chloroimidoyl chlorides in yields of 46Ð80) by dechlorination with copper powder in re~uxing benzeneð58JCED397Ł[ Ethylmagnesium bromide is the reagent in the unique dehalogenation shown inEquation "2# ð68LA72Ł[

• NMeBut

But

Cl

NMe

Br

But

NMe

Br

EtMgBr, Et2O–106 °C to –60 °C

+ (3)

22% 66%

N•

Cl

Cl

N•

Cl

Cl(13)

"v# Eliminations from thioamides and their derivatives

Ketenimines have been prepared from secondary thioamides by formal elimination of hydrogensul_de upon treatment with mercuric oxide ð51AG"E#401\ 69BCJ0763Ł[ Eliminations from sulfone!substituted thioamides\ "EtSO1#1CHCSNHR\ have been more reliably accomplished withdiisopropylcarbodiimide and acetyl chloride^ the reaction a}orded stable bis"ethanesulfonyl#ketenimines\ "EtSO1#1C1C1NR "R�Me\ Pri\ Ph#\ in yields of 42Ð76) ð55CB2052Ł[ Mitsunobuconditions "diethyl azodicarboxylate and triphenylphosphine# have been used for inducing elim!ination from N!aryldiphenylthioacetamides\ Ph1CHCSNHAr\ but the ketenimines Ph1C1C1NArproved to be di.cult to separate from by!products ð60BCJ0251Ł[ For formal 0\3 elimination from


2!aminothioacrylamides "Equation "3##\ both diisopropylcarbodiimide:acetyl chloride andN!methyl!benzimidoyl chloride have been explored as activating agents^ in most cases\ the unstable iminoketenimines were immediately treated with aniline to give amidines\ the yields of which "38Ð70)#indicated that the elimination step was\ in general\ e.cient ð79CB1498Ł[

YNH

SR

HNX

X

•

R

NX

X

N

Y

•PriN NPri/AcCl, NEt3, CH2Cl2,

NMe, CH2Cl2

Cl

Ph

X = H, Me; Y = H, Cl, OMe; R = Ph, CO2Et

(4)

or

A useful large!scale synthesis of N!phenyl!C\C!bis"ethoxycarbonyl#ketenimine "69) yield# byreaction of the thioamide "03# with DMF and phosgene followed by triethylamine "Scheme 4# hasbeen reported in the patent literature ð53GEP0055660\ 54MI 206!90Ł[ This reaction\ carried out on a1 M scale and presumably proceeding via an imidoyl chloride\ was less e.ciently performed withthionyl chloride "45) yield#[ Related compounds prepared by this route included the naphthalene!based bis"ketenimine# "04# ð53GEP0055660\ 54MI 206!90Ł[

Scheme 5

•

EtO2C

EtO2C

NPhEtO2C

NHPh

S

CO2Et

EtO2CNPh

CO2Et

Cl

(14)

COCl2, DMF, C6H6 NEt3

N•

CO2Et

CO2Et

N•

CO2Et

EtO2C

(15)

The reaction of imino thioesters with organometallic reagents produced ketones by a pathway inwhich ketenimines have been postulated as intermediates ð77BSF772Ł[ When the silylated iminothioether "05# was treated with n!butyllithium and one equivalent of allyl bromide "present tointercept the expelled methanethiolate anion#\ the disubstituted ketenimine "06# "R�H# was isolatedin a remarkable 72) yield via an N!lithiated enamine "Scheme 5# ð80JCS"P0#2278\ 80PS"48#030Ł[ Withtwo equivalents of base and of haloalkane\ compound "06# "R�H# apparently underwent C!lithiation followed by alkylation^ the ketenimines "06# "R�Me\ Et\ Bn\ allyl\ crotyl# were obtainedin 44Ð63) yields[ Alternative but related routes to less stable ketenimines "characterized only bylow!temperature IR and 02C NMR spectroscopy# involved "i# ~ash vacuum thermolysis of the N!silyl enamine "07#\ which yielded N!phenyl!C!methylketenimine after expulsion of TMS!SMe\ and"ii# direct ~ash vacuum thermolysis of the imino thioether "05#\ which gave N!phenylketenimineitself ð80PS030Ł[

"vi# Miscellaneous 0\1 eliminations

Heating the imino ether "08# with excess methyllithium in ether\ or with t!butyllithium in hexane\gave a high "but unspeci_ed# yield of the N\C!bis"t!butyl#ketenimine "19# "Scheme 6# ð68AG"E#677Ł[

452Ketenimines

Scheme 6R = Me, Et, Bn, allyl, crotyl

•

R

TMS

NPh

(17)

TMS

N

SMe

Ph

(16)

i, BunLi, THF, –78 °C to 5 °C

ii, RX

N

SMe

Ph

(18)

TMS

The same product was formed in moderate yield by sequential treatment of N!"t!butyl#!2\2!di!methylbutyramide "10# with n!butyllithium\ benzenesulfonyl chloride\ and again n!butyllithiumð68AG"E#677Ł[ The synthesis of 0\2!diketones from N!phenylacrylimidates and Grignard reagentsprobably also involves ketenimine intermediates that result from conjugate addition followed by anelimination akin to that shown in Scheme 6 ð74CC0662Ł[

Scheme 7

•But

NBut

(20)

But

N

OMe

But

(19)

i, BunLi ii, PhSO2Cl

iii, BunLi

MeLi, Et2O, orButLi, hexane

But

O

NHBut

(21)

a!Cyano enamines "11# underwent elimination of hydrogen cyanide when treated with methyl!magnesium iodide in ether^ trialkyl ketenimines were isolated in yields of 16Ð50) ð67JOC1569Ł[Yields were improved to 44Ð77) when methyllithium was used as the base ð71OPP102Ł[ Imidoylcyanides "12#\ which are structural isomers of "11#\ can be prepared by N!chlorination:dehydrochlorination of a!aminonitriles^ they lose hydrogen cyanide when passed in the gaseousphase over solid potassium t!butoxide heated to 009>C ð76JOC0036Ł[ The products\ C!unsubstituted!and C!monomethyl!N!alkyl ketenimines\ were isolated "59Ð54) yields# by condensation on a cold_nger\ and were stable for several days in solution[

N

CN

R2

R1

HN

CN

R3

R1

R2

(22) (23)

R1, R2 = Me, Et; R3 = Pri, But R1, R2 = H, Me

Thiolesters of N!monoalkyl a!amino thiocarboxylic acids may be dehydrated to C!alkylthioketenimines with phosphonic acid dichlorides\ RP"O#Cl1\ and triethylamine ð66JOU0878Ł[ FromBunSC"1O#CH1NHBun\ for example\ BunSCH1C1NBun was prepared in 34) yield[

2[06[0[1[1 By elimination reactions accompanied by skeletal rearrangement

In these reactions\ a substituent on the central carbon atom migrates to nitrogen[ The eliminationprocess may follow the migration\ or the two processes may be synchronous[

"i# From oximes

When treated with dibromotriphenylphosphorane and triethylamine\ the oximes of acetophenoneand desoxybenzoin underwent sequential Beckmann rearrangement and elimination ð56JOC2453Ł[The ketenimines Ph"R#C1C1NPh "R�H\ Ph# were formed in 34) and 64) yields\ respectively\perhaps via imidoyl bromides "cf[ Section 2[06[0[1[0"iii##[ Similar transformations have been


accomplished with methanesulfonyl chloride and triethylamine^ the initially formed oxime sulfonatesunderwent base!induced elimination in toluene at 099>C to give ketenimines\ including the trialkylketenimine Me1C1C1NPri\ in yields of 79Ð84) ð57AG"E#293Ł[

An interesting application of the Beckmann route\ shown in Scheme 7\ involves rearrangementof the cycloheptanone oxime "13# with triphenylphosphine and tetrachloromethane ð70CL416Ł[Elimination of hydrogen chloride from the intermediate imidoyl chloride "14# with triethylamineproduced the eight!membered cyclic ketenimine "15# in 43) yield[ There are two chirality elementsin this strained compound^ furthermore\ con_gurational inversion of the heterocumulene systemwas slow enough on the NMR time!scale to permit the observation of two distinct diastereomers\which at ambient temperature occur in the ratio 1[6 ] 0[ The barrier to interconversion is approxi!mately 08 kcal mol−0 "79 kJ mol−0#[ This is the only example to date of observable axial dissymmetryin a ketenimine system[

Bn

Bn

N OH

N

Bn Cl

Bn

N•

Bn

Bn

(24)

PPh3, CCl4, NEt380 °C

54%

(25) (26)

Scheme 8

"ii# From vinyl azides

The thermal or photochemical decomposition of vinyl azides is rarely an e.cient process forforming ketenimines ð75JOC2065Ł[ Azirines or rearranged nitriles are usually the dominant products[When the formation of ketenimines does occur\ it is by a Curtius!like rearrangement in which asubstituent on the central carbon migrates to the adjacent nitrogen with concomitant\ or perhapsprior\ expulsion of nitrogen "Scheme 8#[ Furthermore\ most ketenimines prepared by this route arehighly unstable ones whose formation has been deduced only from spectroscopic data or aftertrapping with nucleophiles[ Thus\ vapour phase pyrolysis of a!azidoalkenes\ H1C1C"R#N2\ gaveno more than about 4) of the ketenimines H1C1C1NR "R�Ph\ o!Tol\ Bun# together with otherproducts ð51JOC2446Ł\ while photolysis of b!azidoacrylates "16# yielded product mixtures containing½14) of the ketenimine "17# "Equation "4## ð55JOC2896Ł[ Ketenimine formation is promoted bystabilizing groups\ as in the case of thermolysis of "NC#1C1CHN2\ from which the tetra!methylammonium salt of dicyanoketenimine\ "NC#1C1C1NH\ could even be isolated on heatingat 59Ð69>C in aqueous acetone ð56AG"E#848Ł[ The formation of other trappable or isolable ket!enimines from vinyl azides is illustrated in Scheme 09 ð69CB0871\ 64BCJ1780\ 77JOC568Ł[ The arch!etypical ketenimine H1C1C1NH has been detected spectroscopically at low temperatures amongstthe thermolysis or photolysis products of vinyl azide itself ð77T3336Ł or of a vinyl azide precursorð78T148Ł[

R

:N• N

R

N N–

+

N

RR

:N:

Scheme 9

•

R

EtO2C

N

Me

NN3R

EtO2C EtO2C

R

(28)

+

(27)

C6H6, hν(253 nm)

93%

3 : 1

(5)

454Ketenimines

R

N3NC

EtO2C

•

NC

E tO2C

NR

NHR

OEtNC

EtO2C

N3(EtO)2P

Et

•

(EtO)2P

Et

NH

O O

(EtO)2P

Et

O

CN

C6H4-p-NO2

BrEtO2C

EtO2C C6H4-p-NO2

N3EtO2C

EtO2C

EtOH, ∆

60–84%

•

EtO2C

EtO2C

7%30%

N

C6H4-p-NO2

c-C6H12, hν+

15 : 85

R = H, Me, Ph

+KN3, MeCN, RT

Scheme 10

The related photochemical decomposition of aryl azides via singlet nitrenes and thence ringexpansion to unstable but trappable cyclic ketenimines such as "18# "Scheme 00# has been reviewedð81MI 206!90Ł[ The much slower ring expansion of 1\5!di~uorinated phenyl azides during laser ~ashphotolysis suggests that ready interception of the nitrenes may make the compounds useful asphotoa.nity labels ð82MI 206!90Ł[

NN3 Nhν

::

(29)

Scheme 11

2[06[0[1[2 From alkanenitriles\ their a!anions or their a!radicals

"i# Tautomerism of alkanenitriles

Alkanenitriles "29a# bearing at least one hydrogen atom a to the C2N functional group can inprinciple exist in equilibrium with ketenimine tautomers "29b#\ the relative importance of the latterdepending on the nature of substituents R0 and R1 "Scheme 01# ðB!69MI 206!90Ł[ Strongly electron!withdrawing groups favour the 0!azaallene\ formally at least because they stabilize the zwitterioniccanonical form "29c# by resonance[ For instance\ Arndt and Loewe speculated in 0827 on theexistence of the ketenimine tautomer of bis"p!toluenesulfonyl#acetonitrile "29b# "R0�R1�p!MeC5H3SO1# in solution ð27CB0516Ł[ A similar stable tautomer of dinitroacetonitrile is also feas!ible ð51T68Ł[ Concrete evidence for a discrete ketenimine tautomer was subsequently providedfor tricyanomethane "cyanoform\ "29b# "R0�R1�CN## ð52JOC106Ł[ Mobile substituents otherthan hydrogen may also migrate to give a preferred ketenimine isomer\ as in the quantitative re!arrangement at 049>C of trimethyl isocyanide\ TMS!NC\ via trimethylsilylacetonitrile\ to tris"trimethylsilyl#ketenimine\ "TMS#1C1C1N!TMS ð69JOM"14#274Ł[ In less favorable cases\ nitrileÐketenimine interconversion can be stimulated by using unusual conditions\ as in the formation ofH1C1C1NH by reaction of acetonitrile with excited argon atoms at 03 K ð68CPH046Ł^ or in theproduction at 0 K of the carbene ]C1C1C1NH from cyanoacetylene in a microwave spectrometerwith a pulsed discharge nozzle ð82MI 206!91Ł[ Finally\ ynamines\ too\ can participate in tautomeric


equilibria\ especially when the alkanenitrile has the general formula RCH1CN ð65T0338Ł[ Thephotochemically induced interconversion shown in Scheme 02 represents a rare instance of a proventransformation of ynamine\ via ketenimine\ to an alkanenitrile ð69CC778Ł[

(30a)

•

R2

R1

NH

R2

R1

NH+

(30b) (30c)R2

R1

N –

Scheme 12

Scheme 13

Ph

NPh NMe2 • NMe

Ph

hν (254 nm)c-C6H12, 96 h

"ii# Direct alkylation of alkanenitriles

Early work by Arndt and co!workers showed that reaction of the tosyl!substituted cyanoaceticester "20# with diazomethane at −49>C gave a mixture of the ketenimine "21# and the C!methylatedproduct "22# "Equation "5## ð25LA"410#84Ł[ Dijkstra and Backer broadened the scope of thisreaction to include the synthesis of other reasonably stable sulfone!substituted ketenimines\MeSO1"R#C1C1NMe "R�MeSO1\ 69)^ EtO1C\ 26)^ PhSO1\ 16)#\ from the correspondingsulfonylacetonitriles ð43RTC464Ł[

p-Tol-SO2

CO2Me

CN

(31)

p-Tol-SO2

CO2Me

•

(32)NMe

+ p-Tol-SO2

CO2Me

CN

(33)

CH2N2, Et2O, –50 °C(6)

In the reaction shown in Scheme 03\ direct alkylation of nitriles by the t!butyl cation yieldsnitrilium ions "23# that are subsequently deprotonated with organic bases "triethylamine or N!"t!butyl#!N?\N?!pentamethyleneisobutyramidine# to give N!"t!butyl# ketenimines in fair yieldsð77JOC07Ł[ This mild procedure provides access to the C\C!disubstituted keteniminesR1C1C1NBut"R�Ph\ 62)^ R�Me\ 4)#\ the C!monosubstituted ketenimines RCH1C1NBut

"R�Me\ Et\ Prn\ Bun\ Ph\ CO1Et\ vinyl\ 29Ð79)#\ the very labile ClCH1C1NBut "19)#\ and theC!unsubstituted compound H1C1C1NBut "14)#\ reputedly the smallest member of the keteniminefamily to be isolated on a preparative scale[

N

R1

R2

NBut FeCl4–

R1

R2

+•

R1

R2

NBut

ButCl, FeCl3CH2Cl2, 0 °C

i, base, –80 °Cii, NaOH

(34)

Scheme 14

"iii# Reaction of a!deprotonated alkanenitriles with electrophiles

The cyano group is capable of stabilizing a carbanion by mesomerism "Equation "6##[ There issome spectroscopic evidence that ion pairs with lithium as the counterion exist as N!lithio ratherthan C!lithio salts ð75AG"E#262\ 81JOC0839Ł^ and unequivocal crystallographic studies provide _rmevidence for N!lithiated {ketenimines|\ for example in the lithiated dimer "24# ð75AG"E#262Ł and thequasi!dianion complex "25# ð78AG"E#0281Ł[ Although the anions are ambident nucleophiles\ reaction

456Ketenimines

with electrophiles usually occurs at carbon unless steric or electronic factors direct the reactiontowards nitrogen[

•

R2

R1

N–

R2

R1

N– (7)

NLi

NLi

NMe2Me2N

Me2N NMe2

•

Ph

H

•

H

Ph

(35)

NLi

NLi

NMe2Me2N

Me2N NMe2

•

Ph

H

(36)

Pri

Pri

An early example of the sterically controlled N!alkylation of cyano!stabilized carbanions involvedtreatment of t!butylacetonitrile with sodium amide followed by isopropyl iodide to give the ket!enimine ButCH1C1NPri as the sole product "45)# ð59JA762Ł[ Mixtures of C! and N!alkylatedproducts were obtained in other investigations of this synthetically limited reaction ð59JA762\ 50JOC34\79T664Ł\ for example in the competing N! and C!methylthiomethylation shown in Equation "7#ð71T416Ł[ N!Acylation is even rarer^ for example\ reaction between the anion of di!t!butylaceto!nitrile and benzoyl chloride or methyl chloroformate produced "But#1C1C1NCOPh and"But#1C1C1NCO1Me in yields of 70) and 53)\ respectively ð89CB1228Ł[ A similar reaction with0!chlorothioformimidates\ ðRN1C"SMe#ClŁ\ gave unstable but spectroscopically detectableN!imidoyl ketenimines such as "26# ð74JOC660Ł[ There is but a single report of N!halogenation] theaction of bromine on the sodium salt of cyanoform yielded crystalline "NC#1C1C1NBr in 79)yield ð60JOU302Ł[ A rare base!induced prototropic shift has been reported for the conversion ofaroylmalononitriles into ArCO"CN#C1C1NH ð52CR"145#1308Ł[ The putative ferrocenyl ketenimine"27#\ supposedly obtained by protonation of the anion prepared from ferrocenylacetonitrile andmethylmagnesium chloride ð57TL3196Ł\ was subsequently shown to be the dimeric product "28# of aThorpe condensation ð60TL2256Ł[ Finally\ the curious reaction shown in Scheme 04 illustrates twodi}erent aspects of the nitrile group of "39# as a ketenimine precursor\ and contains a rare exampleof the intermediacy of one ketenimine in the synthesis of another ð64CR"C#40Ł[

R2

R1

NC

CO2Me

•

NR2

R1

+ NC

CO2Me

CN SMeR2

R1

NC

CO2Me

CN– Na+

SMe

MeSCH2Cl, THF–CH2Cl2RT or reflux

(8)

R1 R2 Yield

PhPhPhBn

PhMeEtBn

60%(20:80)65%(25:75)55%(30:70)85%(32:68)

Fe

(38) (39)

CN

NH2Fe Fe•

NH

R1

CO2Me

•

N

NR2

SMe

(37)

R1 = 2,4,6-C6H2Me3, R2 = But

R1 = Ph2C(Me), R2 = 2,6-C6H3Me2

Silylation on nitrogen represents the most generally useful way of exploiting a!anions of alkane!nitriles as precursors for ketenimines[ For example\ trimethylsilylation of the acetonitrile anion hasbeen shown to yield the remarkably stable C\C\N!tris"trimethylsilyl#ketenimine "30# ð45JA1163Ł\ not


NO

Me

O

•N

PPh3

N

N O

Me

O

N

N O

Me

O

PhPh

PhPh

PhPh

N O

Me

O

•PhPh

N PPh3

(40)

+

Br–PPh3, Br2, NEt3 (40), NEt3

76%

Scheme 15

via a trianion as was once thought ð52AG"E#506Ł\ but by sequential deprotonation and progressivesilylation ð60JA0603Ł[ The speci_c case shown in Scheme 05 also demonstrates the concurrentformation of a trisilyl ynamine "31#\ which rearranged quantitatively to the ketenimine "30# onheating at 059>C ð60JA0603Ł[ In silylation\ as in alkylation\ steric factors play a signi_cant role inswinging the reaction towards N!silyl ketenimines rather than a!C!silyl alkanenitriles ð81JOC0839Ł[Variations in the nature of the substituents on the acetonitrile framework\ in the base\ and in thesilylating agent have been explored\ and Table 3 gives an indication of some of these variations[The silylation of cyanohydrin anions "entries 01 and 02# is particularly interesting because it providesaccess to ketenimines with oxygen substituents on the carbon terminus ð81JOC0191Ł[

TMS N

TMS

TMS

• N

TMSTMS

TMS

+

160 °C

MeCN

i, 3ButLi, Et2O, –78 °C

ii, TMS-Cl, THF

20:80(42) (41)

Scheme 16

Ketenimines bearing transition metal substituents on nitrogen may be prepared by treating saltsof cyanoform with suitable metal complexes\ followed by ligand exchange if necessary[ Spectro!scopic studies "especially IR# have provided good evidence for C0N s bonding in the follow!ing keteniminato complexes] "NC#1C1C1NM"PR2#"NO#1 "M�Co\ Ni^ R�Ph\ c!C5H00#ð55ZAAC"233#174Ł^ "NC#1C1C1NFe"CO#1Cp and "NC#1C1C1NM"CO#4−NEt3¦ "M�Cr\ Mo\W# ð56JOM"7#436Ł^ trans!"NC#1C1C1NPt"H#"PPh2#1\ cis!"NC#1C1C1NPt"X#"PPh2#1 "X�Cl\ Et#\and "NC#1C1C1NIr"CO#"L#"PPh2#1 "L�SO1\ TCNE\ fumaronitrile#\ amongst othersð61JOM"28#106Ł^trans!"NC#1C1C1NM"CO#"PPh2#1 "M�Ir\ Rh# ð61JOM"28#106\ 62CB1033Ł^ "NC#1C1C1NM"CO#2"PPh2#1 "M�Mn\ Re# and polymeric "ðNCŁ1C1C1NMðCOŁ2#n ð62CB1033Ł[ A similar reactionhas been demonstrated with some main group metals\ and the complexes "NC#1C1C1NSnPh2\"NC#1C1C1NPbPh2 and "NC#1C1C1NTlPh1 have been characterized by IR spectroscopyð56ZAAC"243#58Ł[ Reaction of methyl cyanoacetate with hydroxoplatinum complexes\ Pt"OH#PhL1

"L�phosphine#\ similarly gave keteniminato complexes of the form MeO1CCH1C1NPtPhL1

ð79JOM"088#008Ł[

"iv# Perkow reaction of a!haloalkanenitriles

Chlorodiphenylacetonitrile and triethyl phosphite react under aprotic conditions to give the N!phosphoryl ketenimine "32# "80) yield# ð54JA4957Ł[ In this unusual variant of the Perkow reaction\abstraction of chlorine by the phosphite apparently yields the ion pairs "33# and "34#\ the second ofwhich decomposes to the observed product "32# and chloroethane "Scheme 06#[

Competing Perkow reactions take place when a!halo!a!cyanoesters are treated with trimethyl ortriethyl phosphite[ Both N!phosphoryl ketenimines "35# and vinyl phosphates "36# have beendetected by NMR spectroscopy ð58TL498\ 61T3320Ł[ Only the former products were formed whentriisopropyl phosphite was used[ The three examples illustrated "Equation "8## represent the onlycrystalline ketenimines in the 19 or so cases studied[ Replacing the phosphite with sodium arene!

458Ketenimines

Table 3 Synthesis of silylated ketenimines by silylation of the anions of alkanenitriles[

•

TMS

TMS

N

TMS

•

TMS

Ph

N

TMS

•

Ph

Ph

N

TMS

CN

R

Ph

CN

But

But

CN

CN

CN

Pri

TMS-O

CN

C6Me5

C6Me5

•

RMe2Si

RMe2Si

N

SiMe2R

RMe2Si N(SiMe2R)2

Entry R1R2CHCN

•

Ph

Ph

N

SiR3

Conditions Product Yield(%)

Ref.

1 MeCN NaN(TMS)2, TMS-Cl 63AG(E)617

2 PhCH2CN NaN(TMS)2, TMS-Cl 63AG(E)617

3 Ph2CHCN NaN(TMS) 2, TMS-Cl 63AG(E)617

4 MeCN ButLi, RMe2SiCl 71JA1714

6 •

R

ButMe2Si

N

SiButMe2

5

(R = H, Me, But)

7

8

9

12

•

R

Ph

N

SiButMe2

11

10

13

14

PhCH2CN

TMS-OCH2CN

•

TMS

TMS

N

TMS

NaH/DME, R3SiCl

MeCN

RCH2CN LDA, ButMe2SiCl

CN

TMS

TMS

TMS

LDA, ButMe2SiCl

TMS-OTf, Et3N

LDA, (Pri)3SiCl

LDA, TMS-Cl

LDA, TMS-Cl

BunLi/TMEDA,

ButMe2SiCl

•

(Pri)3Si

N

Si(Pri)3

LDA, TMS-Cl

LDA, TMS-Cl

+

73CR(C)1803

•

But

But

N

TMS

83–94

98–100 74SC127

• N

TMS

73–94 74JOC279983JOC4087

73 (56:43) 77S636

68

•

TMS

TMS-O

N

TMS

87TL397

90CB2339

77

86

92JOC1202

•

Pri

TMS-O

N

TMS

75

81

90CB2339

92JOC1202

(R = Me, Et, Pri, n-C8H17, Ph)

•

C6Me5

C6Me5

N

SiButMe2

(R = Me, Et, Prn, n-C6H13, H2C=CH)

92JOC1940

+

(R = Me, Et, Prn)


N

Ph

Ph

Cl N ClP(OEt)3

Ph

Ph

NP(OEt)3 Cl–•

Ph

Ph

N•

Ph

Ph

+

(44)

–

P(OEt)2

O

+

(45) (43)

P(OEt)3C6H6, ∆

91%

Scheme 17

sul_nates gave yet another variation of the Perkow reaction\ a}ording the N!sulfonyl ketenimines"37# in yields of ½39) ð61CR"C#0298Ł[

NC

R1

R2

CO2Et

Br

CN

NC

R1

R2

CO2Et

•

N P(OMe)2

O NC

R1

R2

N

O

OEt

P(OMe)2

O

+

(47)(46)

P(OMe)3, C6H6, 0 °C(9)

152030

858070

R1 = R2 = PhR1 = R2 = BnR1 = Ph, R2 = Me

R1, R2 = Ph, BnAr = Ph, p-TolNC

R1

R2

CO2Et

•

N SO2Ar

(48)

"v# Conju`ate addition to a\b!unsaturated nitriles

The addition of nucleophiles to the activated C1C bond of vinyl cyanides formally produces anintermediate carbanion a to the nitrile group[ When the reaction is quenched by adding electrophiles\the products isolated are usually those obtained from 0\1 addition^ 0\3 addition\ which results inthe formation of ketenimines\ is encountered only in exceptional cases involving highly activatedsubstrates such as 0\0!dicyanoalkenes[ The reaction partners that participate in conjugate additionare so diverse that mechanisms more complex than the simple one postulated here must frequentlybe implicated[ The route comes into its own for producing ketenimines bearing main group metallic"Pb\ Sn# or metalloidal "Si\ Ge\ As\ B# substituents on nitrogen[ Table 4 shows the range of unusualketenimines accessible from alkylidenemalononitriles[ Related reactions leading to a bis"ketenimine#and a tris"ketenimine# are illustrated in Scheme 07 ð58CC856\ 61JCS"D#676Ł[ Many of the N!metallatedketenimines are nonvolatile solids^ the water!stable tin compounds\ in particular\ probably consistof polymeric chains containing _ve!coordinate tin associated with the nitrile group of an adjacentmolecule as shown in "38# ð57LA"607#0\ 61JCS"D#676Ł[

Formal 0\3 addition of transition metal complexes of the form X0MLn to the very reactiveacceptor TCNE has been used for making keteniminato complexes of the general formulaðX"NC#1CŁC"CN#1C1NMLn[ The following complexes were prepared in this way] ðBn"NC#1CŁC"CN#1C1NFe"CO#1Cp "31) yield# ð69JOM"10#P10Ł^ ðMe1C1CHCH1"CN#1CŁC"CN#1C1NMo"CO#1ðP"OPh#2ŁCp "04) yield# ð63ICA44Ł^ and the polymeric uraniumÐketeniminato complexesðX"CN#1CŁC"CN#1C1NUCp2 "X�Cl\ Me\ Bun\ Ph# ð76ICA164Ł[ The organouranium precursorsRUCp2 "R�Me\ Bun# even add to tetracyanoquinodimethane\ yielding keteniminato complexes"49# ð76ICA164Ł[ Another unusual N!metalloketenimine "40#\ prepared in 69) yield by the additionof IrH"CO#1"PPh2#1 to excess TCNE\ has been characterized by single!crystal x!ray crystallographyð69JA2378\ 60JA1280\ 61JOM"24#392Ł[

A fascinating application of the conjugate addition route occurred during the thermolysis of the

460Ketenimines

Table

4Sy

nthe

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repr

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nim

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nto

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s\R

0 R1 C

1C

"CN

# 1[

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N# 1

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ŁC"C

N#1

C1

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Ph 1

½09

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C"C

N# 1

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H1

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Et 2\R

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ut #CH

ŁC"C

N#1

C1

NSn

Et 2

8563

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H1

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N# 1

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•N

N CN

CF3

F3C NMe2

•N

B CN

CF3

F3C NMe2

•

F3C

NC

CF3Me2N•N

CN

CF3

F3C SMe

•N

Et2Sn CN

CF3

F3C SMe

F3C

F3C CN

CN

B(NMe2)3Et2Sn(SMe)2

Scheme 18

Sn

R

N

•

F3C

CF3

SMe

N

•

CF3

N Sn

R

N

F3C SMe

R R

R R(49)

NC CNR

NC •N

UCp3

(50)

NC

(51)

Ir

NCCN

CN

CON

PPh3Ph3P•

CNNC

NC

thiadiazoline "41# in the presence of 0\1!dicyano!0\1!bis"tri~uoromethyl#ethene ð78H"18#1958Ł[ Theintermediate thiocarbonyl ylide "42# acted as a nucleophile towards the acceptor\ and a mixture ofthe seven!membered cyclic ketenimine "43# and the thiolane "44# "67 ] 11# was formed via thezwitterion "45# "Scheme 08#[ The moisture!sensitive but crystalline ketenimine is noteworthy incontaining the smallest known isolable ring to incorporate a heterocumulene system[ The relatedcyclic ketenimine "46#\ recently prepared in a similar manner in 75) yield\ has been characterizedby x!ray crystallography ð89JOC0301Ł[ The C1C1N bond is bent to about 053>\ and considerabletorsion about the 0!azaallene system is apparent[

O S

NN

OS+

NCCF3

CF3

CNO

(52)

(54)

S+

CH2–

(55)

+

F3C

F3C CN

CN

(56)

–

(53)

Scheme 19

CDCl3

40 °C

O S

F3C CNCN

CF3O

N •

S

CF3

CN

CF3

78:22

462Ketenimines

S

N•

CN

CF3

CF3

(57)

"vi# Reactions mediated by cyanoalkyl radicals

Thermal decomposition of 1\1?!azoisobutyronitrile "AIBN# gave ambident radical fragments thatdimerized to form tetramethylsuccinodinitrile "47# and a small quantity "½04)# of the isolableketenimine "48#\ which itself rearranged to "47# "Equation "09## ð44JA2609\ 48JA3767Ł[ Cage e}ectsappear to govern the recombination of the radical fragments ð59JA4283Ł[ The ketenimine "48# hasbeen prepared somewhat more e.ciently from AIBN "24) yield# upon photolysis in benzene at254 nm ð51JOC3942Ł[ Similarly\ 0\0?!azocyanocyclohexane "59# was thermally decomposed to theketenimine "50# ð59JA4275Ł[

NN

NC

CN

•NC CN +

∆ or hν

–N2

(58) (59)

(10)N

CN

NN

CN

NC

(60)

• N

NC

(61)

Oxidation of hindered a!cyano acetic esters with iodobenzene diacetate in methanol gave goodyields of the dimeric ketenimines "51#\ apparently by way of the hypervalent N!iodo ketenimineintermediates "52# "Scheme 19# ð66TL2238Ł[ These unusual intermediates are assumed to decomposehomolytically\ after which the radical fragments couple to give varying amounts of C\N! and C\C!dimers depending on the solvent used[ IR spectroscopy provided good evidence for the intermediacyof the N!iodo ketenimine "53# when the oxidation was performed on the cyanosuccinimide substrate"54# "R�H#^ spectroscopic evidence for the iodine!linked bis"ketenimine# "55# was adduced in thecase of the analogous N!methyl compound "54# "R�Me# ð66TL2242Ł[

CN

R

MeO2C

•

R

MeO2C

N

I Ph

X

•

R

MeO2C

N

CN

MeO2C

(62)

R

(63)

PhI(OAc)2MeOH, 20 °C –PhI

R Yield (%)

Ph2C(CN)Bn2C(CN)Ph2CH

857020

Scheme 20

N

•N

IN

Ph

•

N

P hPh Ph

Ph

O O O O

Me Me

(66)

N

PhPh

O O

R

(65)

CN

N

•N

I

Ph

PhPh

O O

H

(64)

OAc


"vii# Reactions of a!cyanoalkylsulfonium salts

Ketenimines have been prepared from a!cyanoalkylsulfonium salts by two distinct pathwaysaccording to whether the reaction partner acts as a nucleophile or as a base[ For example\ thereaction shown in Scheme 10 commences with nucleophilic attack of the stabilized enolate "56# onthe sulfonium salt "57#[ Homolysis of the unstable sulfurane intermediate "58# produced radicals\the recombination of which gave various dimeric products that included the ketenimine "69#ð67TL2608Ł[ By contrast\ the same sulfonium salt "57# was converted into the sulfonium ylide"60# on treatment with triethylamine^ rapid ð1\2Ł!sigmatropic rearrangement yielded both the N!"methylthiomethyl# ketenimine "61# and the nitrile "62#\ the latter the result of an e}ective SommeletÐHauser rearrangement "Scheme 11# ð67TL2608Ł[ Although the action of n!butyllithium on "57#resulted in products of the nucleophilic pathway only\ other sulfonium salts have given keteniminesfrom the ð1\2Ł!sigmatropic pathway with both triethylamine and n!butyllithium ð67CC163Ł[ Thereaction of stabilized enolates "63# with S\S!dialkylsuccinimidosulfonium salts "64# was morecomplex\ and depended on many variables\ including time\ temperature\ and the nature of thecounterion[ Scheme 12 shows examples in which products from both the homolytic and the sig!matropic pathways were formed simultaneously ð71T416Ł[ Other succinimidosulfonium salts "e[g[\"65# and "66## also gave rise to unusual ketenimines "e[g[\ "67#Ð"79## ð71T416Ł\ but in general thereactions described here were too sensitive to conditions to be synthetically useful[

S

NC

MeO2C

p-Tol

Me

Me

Ph

Ph CN

CNCO2Me

Ph

Ph CN

CNCO2MeN

•

CO2Me

Ph

Ph

NC

SMe2 PF6–

NC

MeO2C

p-Tol+

Ph

PhNC

MeO2C

CN +

(70)(69)

–

(68)(67)

Na+ THF, 20 °C

Scheme 21

S

MeO2C

p-TolSMe2 PF6–

NC

MeO2C

p-Tol

N

Me

CH2– p-Tol

MeO2C

• N

SMe+ CN

CO2Me

SMe

(68)

NEt3 ++

(71) (72) (73)

Scheme 22

2[06[0[1[3 By cleavage of heterocyclic compounds

"i# Cleava`e of aziridines

0\2\2!Triaryl!1\1!dichloroaziridines\ formed by the addition of dichlorocarbene to aromaticimines\ are easily cleaved on treatment with sodium iodide in acetone to give ketenimines in yieldsof 72Ð86)\ probably via a!chloro imidoyl chlorides "Equation "00## ð55TL796\ 56BCJ0822Ł[ The useof zinc metal with a trace of hydrochloric acid in THF has been recommended as an alternative tosodium iodide for preparing the bis"ketenimine# "70# "71) yield# ð65RTC043Ł[ Treatment of related0\2!diaryl!1\1!dibromoaziridines "71# with triethylamine in acetonitrile has yielded unusual C!bromoketenimines "72# "54Ð75) yield#\ probably by dehydrohalogenation of intermediate a!halo imidoylhalides "Equation "01## ð70CL0086Ł[

464Ketenimines

R2

R1

NC

CO2Me

•

N R2

R1

NC

CO2Me

CN SMe

SMe

R2

R 1

NC

CO2Me

R2R1 Yield

PhBnPhPh

•

N

PhBnMeEt

60%(74:13:13)30%(80:20:0)70%(97:3:0)65%(95:5:0)

R2

CNCO2Me

(74)

– Na+THF, CH2Cl2, < 0 °C

Cl–

Scheme 23

+ +

N

O

O

SMe2+

R2

R1

NC

CO2Me

CN

(75)

R1 CN

R

CO2Me

•

N

SMe

R

CO2Me

•

N

SEt

R

CO2Me

•

NSN

O

O

S

Me

Et

N

O

O

S

(79) (80)(78)X– X–

+ +

(76) (77)

XXN

Cl Cl

Ph

Ph

N

•

Ph

Ph

NaI, Me2CO, reflux

83–97%(11)

X = H, m-Cl, m-Me, p-Cl, p-Me

N

•

Ph

Ph

N

•

Ph

Ph

(81)

NR1 R2

Br Br

(82)

•

Br

R1

N

R2NEt3, MeCN, RT

65–86%

(83)

(12)

R1, R2 = Ph, p-C6H4Cl

N!Methylketenimine has been detected as the major product of the pyrolysis of N!chloro!propylenimine at 319>C "Equation "02## ð76JSP"012#365Ł[

N• N

Me420 °C(13)

Cl

"ii# Cleava`e of cyclic imino ethers

Meyers and co!workers have shown that deprotonation of dihydro!0\2!oxazines such as "73# withlithium diisopropylamide "LDA# resulted in rapid ring scission to give the lithium salt of the


ketenimine "74# ð58JA4776\ 62JOC1018Ł[ The salts could also be made by the nucleophilic addition oforganometallics to 1!vinyloxazines such as "75# ð69TL3244Ł[ The lithiated ketenimine alkoxides couldbe trapped with various electrophiles\ including water\ chlorotrimethylsilane\ dimethyl sulfate andbenzoyl chloride "Scheme 13#[ The cleavage reaction also applies to oxazoline "76#\ from which theketenimine "77# was prepared in 54) yield "Equation "03## ð62JOC1018Ł[ Under controlledconditions\ deprotonation and silylation of the oxazoline "78# gave the silylated ketenimine "89#"Equation "04## ð77AG"E#0431Ł[

LiO

N

•

(85)

MeO

N

•

TMS-O

N

•

PhCO2

N

•

O

N

(84)

(MeO)2SO2

35%

LDA, THF, 0 °C

TMS-Cl 80%

PhCOCl

30%

Scheme 24

O

N

Ph(86)

TMS-O

N

•

LDA, THF, 0 °Cthen TMS-Cl

65%

O

N

(88)(87)

(14)

TMS-O

N

•

TMS TMS

O

N

3BunLi, 3TMS-Cl

Et2O, –55 °C

(89)

(15)

(90)

"iii# Cleava`e of isoxazoles and isoxazolium salts

Irradiation of triphenylisoxazole at 143 nm or 299 nm gave a 39) yield of the isolable C!acylketenimine "80# by a pathway in which 0\1 migration of a phenyl group on to nitrogen probably

466Ketenimines

occurred through nitrene intermediates "Scheme 14# ð55CC578Ł[ A similar reaction on the bicyclicisoxazole "81# yielded the interesting but unstable ketenimine "82# "Scheme 15#\ which could also begenerated by base!induced elimination from the isoxazolium salt "83# "cf[ below# ð65JOC02Ł[

hν (254 nm)

40%N

O

Ph

Ph

PhN:

O

Ph

Ph

Ph

:

•

Ph

O

Ph

NPh

(91)Scheme 25

hν (254 nm), –77 °CNEt3, CH2Cl2

–77 °C

NO

O

•

NMe

NO

I–+

(92) (93) (94)

Scheme 26

Me

Woodward|s {{reagent K|| "84#\ a zwitterionic isoxazolium salt\ was introduced in 0850 ð50JA0909Łas the prototype of a group of useful reagents for peptide synthesis ð69T0668Ł[ The reactivity ofthese isoxazolium salts was ascribed to initial deprotonation at the unsubstituted 2 position followedby ring cleavage to form C!acyl ketenimines "85# ð50JA0996Ł\ after which interception by a car!boxylate yielded enol esters ð57JA0260Ł suitably activated for further attack "Scheme 16#[ Subsequentinvestigations by Woodward and co!workers provided _rm spectroscopic evidence for acyl ket!enimine intermediates ð55T"S#304Ł[ For preparative purposes\ this route is limited to relativelystable compounds such as N!"t!butyl#benzoylketenimine and the corresponding acetyl compound\prepared in 59) and 69Ð79) yields\ respectively\ from isoxazolium perchlorates and triethylamineð55JA2058Ł[ Isolable C!acyl ketenimines "86#Ð"099# have also been obtained from 3\4!disubstitutedisoxazolium perchlorates or tetra~uoroborates ð58JOC2340\ 69T0668Ł[ The rather unstable C!acylketenimine "85# from reagent K itself has recently been prepared in acetonitrile solution by reactionof the salt with triethylamine ð75JA4432Ł^ other sensitive acyl ketenimines have been intercepted bythe addition of cuprates ð78SC0928Ł[ Several isoxazolium salts bearing heteroatomic substituents havealso been shown to yield ketenimines on treatment with base[ These include the 4!aminoisoxazoliumprecursor "090# of the ketenimineÐamide "091# "Equation "05## ð63CB02Ł^ and 3!azido isoxazoliumsalts "092#\ from which the unique C!azido ketenimines "093#\ stable only below −59>C\ wereobtained "Scheme 17# ð72CC637Ł[

base

N

O

Et

SO3–

+N

O

Et

SO3–

+

RCO2HO–

N Et

SO3–

+

O

SO3–

• NEt

SO3–

O

NHEt

O

R

O

(96)

Scheme 27

–

(95)


•

R2

O

R1

NR3

(97) R1 = H, R2 = Ph, R3 = But, CH(Me)Ph(98) R1 = Ph, R2 = Me, R3 = Bn, Ph, But

•

O

NR

(99) R = Me, Et

•

O

NR

(100) R = Me, Et

NaOH, CCl4

N

O

NH2

Ph•

Ph

O

H2N

NMe

(102)Me

Cl–+

(101)

(16)

ButOH, HClO40 °C

17–50%N

O

R

N3 •

N3

O

R

NBut

(104)(103)

N

O

R

N3

But

+

NEt3, CH2Cl2–90 °C

ClO4–

Scheme 28R = Me, Ph

Isoxazolium salts may or may not be involved in the rapid transformation "Scheme 18# of N!"1!benzoylstyryl#hydroxylamine "094a# and its hydroxyisoxazolidine tautomer "094b# to C!benzoyl!C\N!diphenylketenimine "095#\ which was detected by IR spectroscopy ð67JCS"P0#0002Ł[ The trans!formation can be preparatively useful\ as in the synthesis of the N!"t!butyl# analogue of "095# in50) yield from t!butylhydroxylamine and 0\1!diphenylpropane!0\2!dione in chloroform at roomtemperature ð77JOC3886Ł[

EtOH, 5–10 °CCHO

Ph

PhCO+ PhNHOH

•

Ph

PhCO

NPh

(106)

N

OPh

(105b)

Ph

OHPh

N

OHOPh

Ph Ph

(105a)

Scheme 29

"iv# Cleava`e of other _ve!membered rin`s containin` two heteroatoms

N!Acyl ketenimines have been detected by IR spectroscopy amongst the pyrolysis products ofazlactones ð79AG"E#453Ł[ They are formally formed by a cheletropic reaction in which carbonmonoxide is expelled "Equation "06##[

i, 600 °C, 10–4 torrii, collect at –196 °C

• N

R

O

N

OO R

R = Me, Ph

(17)

Ph

Ph

Treatment of isoxazol!4!ones with base yielded spectroscopically detectable ketenimine!C!car!boxylate salts that spontaneously cyclized to four!membered rings ð65JA5925Ł[ In the speci_c caseshown in Equation "07#\ the moisture!sensitive potassium salt "096# could actually be isolatedð66H"6#136Ł[ Gas phase ~ow thermolysis at 699>C of a di}erent type of isoxazol!4!one\ for example

468Ketenimines

"097#\ has been used for forming the simple unstable ketenimines H1C1C1NR "R�H\ Me\ Ph#for spectroscopic studies ð79AG"E#619\ 78JCS"P1#0730Ł[

i, KOBut, THFii, hexane

• NBut

N

O

O

Ph

But

K+ –O2C

Ph

(107)

(18)

N

O

O

H

(108)

RHN

4!Iminothiazolines "098#\ formed by oxidative cyclization of 2!aminocrotonic thioamides withbromine\ underwent a formal cheletropic loss of sulfur on treatment with tributylphosphine"Scheme 29#[ The products\ imino ketenimines "009#\ were occasionally isolable ð63CB491Ł\ but inmost cases cyclized to 0\1!dihydropyrimidines ð70CB425Ł[ The 0\1!dithiole!2!imine "000# underwenta similar reaction\ but in this case the unstable thioacyl ketenimine intermediate "001# was trappedby addition of secondary amines "Scheme 20# ð75CB051Ł[

(110)

• NR4

R3

N

R2

R1

NS

R3

NR4R1

R2N

N

R3R4

R1

R2Bu3P, CH2Cl2

41–87%

(109)

Scheme 30

SS

p-MeOC6H4

N-p-Tol

• N-p-Tol

(111)

HNEt2

66%

Scheme 31

S

p-MeOC6H4

Bu3P, CH2Cl2, 0 °C

(112)

S

p-MeOC6H4

NH-p-Tol

NEt2

"v# Cleava`e of triazoles

0!Vinylbenzotriazoles undergo ~ash vacuum pyrolysis at 499Ð699>C with expulsion of nitrogengas^ N!phenyl ketenimines are the primary products\ but indoles are the major products at highertemperatures ð77JCS"P1#0960Ł[ However\ in only one reported case "Equation "08## has a ketenimineactually been isolated ð89JCS"P0#374Ł[ The photolysis of N!phenyl!0\1\2!triazoles yielded keteniminesby a di}erent path involving migration of substituents from C!4 to C!3 "Equation "19##*perhaps aWol} rearrangement of a carbene intermediate ð57JA0812Ł[ Hydrogen migration was e.cient andgave a high yield of ketenimine\ but the less mobile 4!phenyl group resulted in signi_cant amountsof the indole "002# being formed as well[ In a related case\ transient N!cyanotriazoles "003# underwentspontaneous ring!opening to N!cyano a!diazo imines "004#\ which could in turn be photolyzed tospectroscopically detectable N!cyano ketenimines "005# "Scheme 21# ð68AG"E#219\ 79TL898Ł[


i, 600 °C, 10–2 torrii, trap at –78°C

NN

N (19)• NPh

(20)

R1

PhHPh

R2

PhPhH

60 (1:1)70 (3:1)85 (40:1)

N

NN

R2

R1

Ph

• NPh

R1

R2

hν (450 W mercury lamp)C6H6

N

Ph

R2

R1

+

(113)

Yield(%)

• N

Rhν, MeOH CNN

NN

R CN

N

CNMeO

N

CN

R

N2

(114) (115) (116)

R = H, Me, Et, 2-furyl, 2-thienylScheme 32

R

Loss of nitrogen on gentle warming of the lithiated triazole "006# resulted in the formation of thelithiated ketenimine "007#\ which showed a strong IR absorption at 1039 cm−0 ð60CJC0681Ł[ Thissalt was trapped with iodomethane to give the ketenimine "008# and ketenimine dimer in 34) and08) yields\ respectively "Scheme 22#[ Other electrophiles reacted at nitrogen to give ynamineproducts[ However\ with aldehydes\ reaction presumably occurred at carbon\ since acrylamideswere obtained in good yield on work!up ð63LA0544Ł[

• NPh

PhBunLi, THF–20 °C

(118)

NN

N

Ph

Ph NN

N

LiPh

Ph Li• NPh

Ph20 °C, –N2

MeI, THF–60 °C

45%

(119)(117)

Scheme 33

2[06[0[1[4 From other ketenimines

The most useful application of this route involves replacing the silyl substituent in N!trimethylsilylketenimines with other electrophiles[ For example\ N!stannylation\ N!germylation\ and N!plum!bylation proceeded exothermically and quantitatively on treating the ketenimine "019# with tri!alkylmetal alkoxides or acetates "Equation "10## ð63JOM"60#28Ł[ The silyl substituent has also beenreplaced by an acyl group "Equation "11## ð89CB1228Ł[ In a related example "Equation "12##\ anN!stannyl ketenimine has been converted into an N!nitroso ketenimine with nitrosyl chlorideð69TL0046Ł[

• N

+ R3MX

– TMS-X

MR3

NC

But

Ph

• N

TMS

NC

But

Ph

(120)M = Ge, Sn, PbX = OMe, OAc

(21)

470Ketenimines

• NBut

PhCOCl, CH2Cl2, RT

52%

COPh

But

• NBut TMS

But

(22)

• N

NCNOCl, THF, –20 °C

NO

• N

NC Sn(But)3

(23)

Ph Ph

Ph Ph

Keteniminylidene phosphoranes "010# "see Section 2[06[1[0# are able to react with variouselectrophiles to yield both transient and stable ketenimines[ Examples are shown in Scheme 23ð63AG"E#362\ 64AG"E#42Ł[ Photolysis of hexakis"t!butyl#cyclotrisilane "011# in the presence of twoequivalents of tris"trimethylsilyl#ketenimine initiated a surprising sequence of cycloadditionÐcyclo!reversion processes\ at the end of which the novel ketenimine "012# was produced in 61) yield"Equation "13## ð81JOM"312#218Ł[

• •

R1

R2

NPhNPh

PPh3PhN

R1

R2

O

R1

R2

Ph3P • • NPh

(121)

+

R1

p-C6H4NO2Ph

R2

HCOPh

Yield (%)6458752,2'-C6H4–C6H4

70%

MeO2C PPh3

MeO2C ••

NPh

PPh3

•MeO2CNPh

MeO2CCO2MeMeO2C

Ph3P • • NPh

(121)

+

Scheme 34

• N

TMSTMS

TMS

Si(But)2(But)2Si

Si(But)2

hν, n-C6H14, RT

72%

+(But)2Si •

TMS

TMS

• N

Si(But)2TMS

TMS

N

TMS

TMS

+2

(122)

(123)

(24)

Ketenimine!bearing penicillins\ for example "013#\ have been converted into a!methoxy ket!enimines by addition of chlorine followed by treatment with lithium methoxide in methanolð66TL2720Ł[ The putative intermediate is the a!chloroimidoyl chloride "014#\ which undergoes 0\3elimination of hydrogen chloride followed by SN? displacement of the chloride ion by methoxide"Scheme 24#[ That similar products\ for example "015#\ can be prepared in the cephalosporinseries from preformed a!chloroimidoyl chlorides "Equation "14## lends credence to the proposedmechanism ð65TL0296Ł[ Direct replacement of hydrogen by the methylthio group occurred ontreatment of "016# with methyl methanethiosulfonate "Equation "15## ð66TL2720Ł[

N

S

CO2CHPh2

O

HN

H

Br

Ph

N

S

CO2CHPh2

O

MeON

H

•LiOMe, MeOH, –78 °C

60%

(126)

(25)Ph


N

SMeON

•

CO2p-Tol

S

H

CO2CH2-p-C6H4NO2

O N

SH

CO2CH2-p-C6H4NO2

O

39%

N

SH

N•

CO2p-Tol

S

H

CO2CH2-p-C6H4NO2

ON

SH

NH

CO2CH2-p-C6H4NO2

OCl

S

Clp-TolO2C

LiOMe, MeOH, –70 °C

Cl2

Scheme 35

(125)(124)

N

Cl

CO2p-Tol

S

NO

HN

•MeS-SO2Me, DMF, K2CO3, 0 °C

28%

S

CO2Bn

Ph

PhO2C

H

NO

MeSN

•S

CO2Bn

Ph

PhO2C

H

(127)

(26)

C\N!Diphenylketenimine has been deprotonated at carbon with potassium t!butoxide in THF at−59>C\ and the resulting metallated ketenimine has been trapped with aldehydes ð63LA0544Ł[Another unique transformation\ shown in Equation "16#\ involves an additionÐelimination processbetween methyllithium and a C!bromo ketenimine ð68LA72Ł[

MeLi, Et2O-hexane, –20 °C

52%•

Br

But

NBut •But

NBut (27)

2[06[0[1[5 By miscellaneous pericyclic processes

The retro DielsÐAlder reaction of 3!iminocyclohexenes at high temperatures has a certain limitedutility when the smallest members of the ketenimine family are required[ The ~ash vacuum ther!molyses illustrated in Scheme 25 have been used for making H1C1C1NH\ a ketenimine sotransient that it cannot even be trapped\ though it can be characterized by IR\ microwave\ and UVphotoelectron spectroscopy at very low temperature ð72CC127\ 73CPL336\ 78JCS"F1#630Ł[ The rathermore stable N!methyl analog has similarly been made by the cycloreversions shown in Scheme 26ð67TL352\ 75JCR"S#077Ł[ The parent ketenimine H1C1C1NH has also been prepared "along with itstautomer acetonitrile\ acrylonitrile\ and formaldehyde# by vacuum pyrolysis of 2!hydroxy!propionitrile at 799Ð0099>C by the formal pericyclic process shown in Scheme 27 ð73CPL336\ 77JA0226\89JA2668Ł[

C!Dienyl ketenimines "017# may be generated from cyclohexadienimines "018# by the photo!chemically induced electrocyclic process shown in Equation "17# ð67AG"E#354Ł[ The products werestable at room temperature in THF for several days\ but slowly reverted to imines[ N!Acyl C!dienylketenimines "029#\ formed in the same way\ could be detected by IR spectroscopy at 66 K\ abovewhich they underwent an intramolecular DielsÐAlder reaction followed by elimination of acetic acidto give bicyclic oxazines "020# "Scheme 28# ð68TL1014Ł[ A four!electron photochemical electrocyclicprocess "Equation "18## underlies the synthesis of the unique ketene!ketenimine "021#\ which couldbe kept for several days at −67>C in the dark ð60CC476Ł[

472Ketenimines

NH

+ MeCN + Diene

850 °C, 10–3 torr

NH NH

• NH 850 °C, 10–3 torr

850 °C, 10–3 torr

Scheme 36

Scheme 37

650 °C, 10–5 torr

20% + HC≡CNMe2 (80%)

NMe

• NMe

NMe2

650 °C, 10–5 torr

75% + EtCN (20%)

O

H HN

HOCN

• NH800 –1100 °C

0.1–1 PaH2O + + MeCN

Scheme 38

•Ph

Ph

Ph

NR2

Ph

R1

Ph

NR2

R1

Ph hν

∆

R1 = Me, OMe, OAcR2 = Me, Pri

(129) (128)

(28)

•Ph

N

Ph

OAc

Ph

NOAc

Ph

RO

Ph

O

R

Ph

N

O

Ph

PhR

Phhν (mercury lamp),

C6H6 RT, –HOAc

17–55%

(130) (131)R = Me, Ph, p-C6H4X(X = Me, OMe, Cl, NO2)

Scheme 39

•

•

PhN

hν (500 W mercury lamp)C6H6

∆

OPh

Ph

Ph

O

N

(132)

(29)


Ketenimines are formed as end products of the sequence of pericyclic reactions shown in Scheme39 ð62TL2616Ł[ Equilibrium at room temperature in THF favors the azetidinoð2\1!bŁpyridine inter!mediates "022#\ but heating in benzene induces sequential valence tautomerism\ ð0\2Ł!sigmatropicalkyl shift\ and _nally a cycloreversion to give pyrroles "023# and the spectroscopically characterizedketenimines "024#[ These compounds were subsequently hydrolyzed to amides\ the high isolatedyields of which "71Ð82)# re~ect the e.ciency of the entire process[

N

N

N

NN

• N

CO2Me

CO2Me

RPh

N

N

N

NMeO2C

MeO2C

R

Ph

N

NMeO2C

MeO2C

R

Ph

R

PhMeO2C

MeO2C

PhR

PhR

Ph

R

PhR

Ph

Ph

MeO2C

MeO2C

R

MeO2C

MeO2C

Ph

R

R

Ph

cycloaddition

[1,3]-sigmatropicshift of R

+

cycloeversionwith 1,2-H shift

electrocyclicreaction

electrocyclicreactionC6H6, ∆

THF, RT73–91%

+

(134) 87–92%

R

(135) 82–93%( as amide)

Scheme 40

(133) R = c-C6H11, c-C12H23, But

Flash vacuum pyrolysis of the substituted 1\2!dihydropyrrole!1\2!dione "025# produced the C!acyl ketenimine "026# via an imidoylketene "027# "Scheme 30# ð81CC376Ł[ The ketenimine\ char!acterized by 0H and 02C NMR spectroscopy at −59>C\ was stable up to about 9>C\ above whichirreversible changes took place[ The corresponding N!phenyl ketenimine was less long!lived becauseits imidoyl ketenimine isomer was rapidly and quantitatively converted into the quinolinone "028#[Related interconversions have been probed for the comparatively stable N!adamantyl ketenimine"039# ð81CC377Ł[ Flash vacuum pyrolysis of the Meldrum|s acid derivative "030# below 599>C alsoinitiated a sequence of pericyclic reactions resulting in the formation of the C!acyl ketenimine "026#"Scheme 30# ð81CC376Ł[ Above 599>C\ however\ elimination of methanethiol gave another transientbut detectable ketenimine\ "031#\ from which the unusual cumulene "032#\ e}ectively an imine ofcarbon suboxide\ was produced ð81CC0460Ł[ The higher!order heterocumulenes "032# and "033# werealso formed by pyrolysis of other heterocyclic precursors\ as shown in Scheme 31 ð81CC0460Ł[These spectroscopically characterizable compounds\ amongst a mere handful of known keteniminescontaining more than two cumulated double bonds\ were intercepted with dimethylamine to giveyet another group of labile but characterizable ketenimines "034#[

2[06[0[2 Ketenimines from "CC¦N# Precursors

2[06[0[2[0 From ketenes "or related precursors# and iminophosphoranes "or related precursors#

The synthesis of ketenimines by the reaction of iminotriphenylphosphoranes "Ph2P1NR# withketenes was pioneered by Staudinger and co!workers in the early 0819s ð19CB61\ 10HCA776Ł[ Com!pounds prepared included R1C1C1NPh "R�Ph\ Me\ EtO1C#\ Ph1C1C1NMe\ andH1C1C1NPh\ the last only being stable at low temperatures[ The analogous compoundH1C1C1NEt polymerized too rapidly to be isolated[ Unfortunately\ yields of the products werenot speci_ed[

The reaction remained undeveloped for almost half a century until it was used to prepare"CF2#1C1C1NBut "Table 5\ entry 0# ð58TL4068Ł[ A more important revival by Singer and co!workers demonstrated that thermally labile C\C!diphenyl ketenimines\ including the _rst knownketenimine bearing a chiral auxiliary on nitrogen\ were accessible under mild conditions and in fairto good yields "29Ð74)# "Table 5\ entries 1Ð5# ð63CC851\ 63JOC2679\ 66JA1511Ł[ In this work\ generalreaction conditions were also clari_ed] the iminophosphoranes "generated in situ from dibromo!

474Ketenimines

[1,3]-sigmatropicshift of H

>600 °C, 10–4 mbar–MeSH

400–600 °C, 10–4 mbar–CO2, –Me2CO

–CO2, –Me2CO

O

O

O

SMe

NHMe

O

O

O

O

•

O

•

SMe

NHMe

•O

NMe • ••O NMe

400–600 °C, 10–4 mbar–CO

[1,3]-sigmatropicshift of SMe

N

SMe

MeO

O

SMe

NMe•

O

O

SMe

• NMe

(136) (138) (137)

(141)

Scheme 41

(142)

(143)

N

SMe

HO

(139)

N•

O

Ph

(140)

O

O

O

NMe2

NHR

O

O

O

O

•

O

NMe

310 °C 10–4 mbar

–Me2NH

500–700 °C 10–4 mbar

N

NH

O

O

•RN

N

NH

O

NO

R

O • • • NR Me2N

O

• NR

Me2NH

(143) R = Me(144) R = Ph

(145)

Scheme 42

triphenylphosphorane\ a primary amine and base# reacted with ketene components "prepared inadvance or generated in situ from appropriate precursors# in inert solvents at temperatures no higherthan room temperature[ The diverse range of ketenimines subsequently made by this methodincludes N!acyl ketenimines "entries 6 and 7# ð65M426\ 89CB1228Ł\ an N!cyanoalkyl ketenimine"entry 8# ð65M426Ł\ C!phosphoryl ketenimines "entry 09# ð79JGU34Ł\ and a ~uorenylideneketenimine"entry 01# ð70CB2640Ł[

No physical or spectroscopic data were furnished for the N!vinyl ketenimines "035#\ isolated asviscous oils after short!column chromatography in a reaction sequence that ultimately yielded~uorenoð1\2\3!i\ jŁisoquinolines "Scheme 32# ð89CC718\ 80JOC3997Ł[ It is of interest that an adduct"compound "036## en route to N!vinyl ketenimines has recently been isolated from a related reaction"Scheme 33# ð81LA04Ł[


Table 5 Ketenimines\ R0R1C1C1NR2\ prepared by the reaction of ketenes\ R0R1C1C1O\ with imino!phosphoranes\ Ph2P1NR2[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Ketenimine Conditions Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 "CF2#1C1C1NBut a 58TL40681 Ph1C1C1NR "R�Bn\ But# Et1O\ 9>C 54Ð79 63JOC26792 Ph1C1C1NCHPh1 Et1O\ 9>C b 63JOC26793 "S#!"−#!Ph1C1C1NCH"Ph#"Me# Et1O\ 9>C 79Ð74 63JOC2679\ 63CC8514 Ph1C1C1NCH1"p!C5H3R# "R�Cl\ Me\ OMe\ Ph# Et1O\ 9>C 29Ð59 66JA15115 Ph1C1C1NCH1R "R�0! and 1!naphthyl# Et1O\ 9>C 29Ð59 66JA15116 Ph1C1C1NCOR "R�Ph\ "E#!PhCH1CH# C5H5\ RT a\ c 65M4267 Ph1C1C1NCOR "R�OMe\ OEt# CH1Cl1\ 9>C 65\ 79 89CB12288 Ph1C1C1NC"CN#Me1 C5H5\ RT a\ c 65M426\ 73T782

09 "EtO#1POC"Ph#1C1NR "R�Me\ Ph# THF\ 9>C 29\ 59 79JGU3400 Ph1C1C1NCH1!TMS C5H5\ re~ux 82 73JOC157701 "1\1?!C5H30C5H3#C1C1N"p!C5H3Br# Et1O\ 11>C 59 70CB2640*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Yield not given[ b Rearranges to Ph1CHPh1CCN[ c Characterized spectroscopically[

OMe

O R1

N CO2EtPh3P

OMe

O R2

CO2EtN•

R2

R3

N

OH

MeO CO2Et

R3

H

R1

Scheme 43

•R3

R2

O

150 °C

R2 = Ph

R1 = H, Me, PhR2 = Ph, p-TolR3 = Et, Ph, p-Tol

(146)

toluene, RT

N

ArC6H6, 20 °C

Ph3PN

R

Ar

PhPh3P

–O

R

N

•

Ar

Ph

R R

• O +

Ph

R

R –Ph3PO

(147)

ArPhp-C6H4Cl

Ph

RPhPh

Yield of (147) (%)7756

30

Scheme 44

N!Amino ketenimines "ketene hydrazones#\ notable for their rarity\ have been prepared bySchweng and Zbiral from trimethylsilylketene and N!aziridinyl iminophosphoranes "Scheme 34#ð65M426Ł[ The unstable products\ amongst them the unusual compound "037#\ were characterizedby IR spectroscopy[ Attempts to prepare other N!amino ketenimines from diphenylketene werefrustrated by the spontaneous decomposition of the desired products to a!amino nitriles "Scheme35# ð65M426Ł[ A unique ketenimine azine\ Ph1C1C1N0N1CPh1\ has been prepared in 59)yield from diphenylketene and the corresponding triphenylphosphazine ð50CB1366Ł[ Interestingly\Staudinger had failed to isolate products from this reaction some 39 years earlier ð10HCA786Ł[

Capuano and co!workers have demonstrated that reactive ketenes\ generated in situ by a Wol}rearrangement following the expulsion of nitrogen from 1!diazo!0\2!diketones\ may be interceptedby iminophosphoranes "Scheme 36# ð72CB630\ 76LA072Ł[ Several of the resulting C!acyl ketenimines"e[g[\ ArCO"Ar#C1C1N"p!Tol#\ Ar�Ph\ p!C5H3Cl\ p!C5H3OMe# were isolated in good yield

476Ketenimines

•

TMS

N

N

R2

R1

HPh

Ph3P N

N

R2

R1

HPh

• O

CH2Cl2

TMS

R1 = R2 = H, Ph

Scheme 45

NN

•

TMS

(148)

• O

CH2Cl2

R = Me, 25%; Ph, 30%N N

Me

RPh3P

N N

Me

R• N

Me

RPh

NC

PhPh

Ph

Scheme 46

Ph

Ph

"41Ð80)#\ while others were characterized by IR spectroscopy before conversion into variousheterocyclic products[ A similar reaction occurs with 1!diazo!2!sulfonylketones\ resulting in theformation of C!sulfonyl ketenimines "Scheme 37# ð72CB630Ł[

N2 xylene100 °C, –N2R2R1

O O

R1

O

•

R2

O

R1

O

•

R2

NR3

Ph3P=NR3

Scheme 47

PhSO2

N2

•

PhSO2

Ph

O •

PhSO2

Ph

NAr

xylene 100 °C, –N2 Ph3P=NAr

Ph

OArp-Tol2,6-C6H3Me2

Yield (%)7466

Scheme 48

Variations on the basic reaction described in this section encompass both reaction partners[ Forexample\ the iminophosphorane can be replaced by the phosphoramidate anion "038#\ as reportedby Wadsworth and Emmons "Equation "29## ð51JA0205\ 53JOC1705Ł[ Ukrainian workers have similarlyprepared "EtO#1POC"Ph#1C1NR "R�Me\ Ph# from sodium phosphoramidates and phos!phorylketenes in yields of 49Ð59) ð79JGU34Ł[ Alternatively\ the ketene can be substituted by adi}erent 0!heteroallene^ Bo�deker et al[ have shown that both ketenes and ketenimines react withN!pyridyl iminophosphorane "049# to a}ord the N!"1!pyridyl# ketenimine "040# "Equation "20##ð79ZC100Ł[ Under the reaction conditions\ the ketenimine spontaneously dimerized to give hetero!cyclic products[ Finally\ several ketenimines have been made by a unique method involving reactionof bis"tri~uoromethyl#thioketene with iminosulfuranes "Equation "21## ð58USP2351378\ 61JOC0236Ł[


(MeOCH2)2, 20 °CN

(EtO)2P

O

•

Et

Ph

O R •

Et

Ph

NR+–

Na+

RPhBun

c-C6H11

Yield (%)621858

(149)

(30)

(150)

N

•

N

N

Ph3P

N

• X+

(151)

C6H6 orC6H3Me3, ∆Ph

Ph Ph

Ph

X = O or NPh

(31)

CH2Cl2, RT•

F3C

F3C

S •

F3C

F3C

NR+ RN S NR

Yield (%)17382048

RMePhBun

But

(32)

2[06[0[2[1 From haloalkenes or haloalkynes and amines or amine derivatives

Most of the procedures in this section exploit the fact that tri~uoromethyl substituents on alkenesimpart pronounced electrophilic character to the double bond[ When the alkene also bears a leavinggroup b to the activating substituent\ nucleophilic displacement can occur[ In particular\ aminesand amine derivatives displace the ~uoride ion from activated 0\0!di~uoroalkenes "041# to produceimidoyl ~uorides "042# "see Section 2[06[0[1[0"iii##\ from which ketenimines "043# can be formed onaddition of base "Scheme 38#[

baseCF2

X

F3C

•

X

F3C

NRRNH2

NHR

X F

F3C

(152) (153) (154)

Scheme 49

Gambaryan and co!workers were the _rst researchers to investigate the reaction between per!~uoroisobutene "041# "X�CF2# and nitrogen sources[ With the iminophosphorane Ph2P1NPh\per~uoroisobutene gave "F2C#1C1C1NPh in 23) yield ð54BAU620Ł\ while primary amines in thepresence of triethylamine similarly yielded "F2C#1C1C1NR "R�Me\ 18)^ Et\ 43)^ Ph\ 86)^p!C5H3OMe\ 78)# ð62BAU0639Ł[ The outcome of the reaction between per~uoromethacrylic esters"044# and aniline depended on the base used^ the intermediate imidoyl ~uoride "045# and itsenamine isomer "046# were isolated in the presence of pyridine\ but ketenimines "047# resulted whentriethylamine or powdered potassium hydroxide was present "Scheme 49# ð64BAU0163Ł[ Otherworkers have shown that reaction of per~uoroisobutene with the potassium salt of ben!zenesulfonamide gave the isolable salt "048#\ from which the imidoyl ~uoride "059# and\ ultimately\the ketenimine "050# could be produced\ as shown in Scheme 40 ð64JFC"5#116\ 65BAU462Ł^ and thatmethyl per~uoromethacrylate produced MeO1C"F2C#C1C1NMe "53) yield# on reaction withN!methylhexamethyldisilazane ð75JOU0539Ł[

The basic process has been extended to per~uoro!1!methylpent!1!ene "051# "Scheme 41#ð63CC023Ł[ After initial displacement of ~uoride by various amines\ the putative intermediate~uoroalkenyl imines "052# reacted with a second equivalent of amine to give C!imino ketenimines"053#[ However\ if aromatic amines without ortho substituents were used\ the ketenimines cyclizedto 3!arylaminoquinolines[ Reaction of "051# with t!butylamine a}orded a mixture of the two

478Ketenimines

CF2

F3C

RO2C

•

F3C

RO2C

NPhPhNH2, Et2O

base

NPh

F3C F

RO2C

(155) R = Me, Et (156) (158)

NPh

HO

RO

F3C F(157)

+ +

11%73%65%

41%--

48%--

Pyridine (R = Et)KOH (R = Et)NEt3 (R = Me)

Scheme 50

HCl, CH2Cl2

90%CF2

F3C

F3C KNHSO2Ph, MeCN–40 °C to 20 °C

95%

(CF3)2C CF

NSO2Ph–

K+

•

F3C

F3C

NSO2Ph

CF3

F3CN

F

SO2Ph

Et3N•BF3Et2O, 20 °C

35%

(159)

(160) (161)

Scheme 51

ketenimines "053# "R�But# "34) yield# and "054# "19) yield#\ perhaps because "051# isomerizes toper~uoro!1!methylpent!0!ene ð70JFC"06#154Ł[ An analogous reaction between the sul_de!bearingper~uoroalkene "055# and t!butylamine yielded a mixture of the ketenimines "056# and "057# andthe imidoyl ~uoride "058# "Scheme 42#[ The tetra~uoroethene hexamer "069# reacted with primaryamines to form the expected ketenimines "060# "Scheme 43#\ but piperidine\ a secondary amine\gave an imidoyl ~uoride "061# from which limited quantities of the ketenimines "062# and "063#could be formed on thermolysis ð74JCS"P0#1074Ł[

R = But

R = 2,6-C6H3Me2F3C

F3CRNH2

NR

F2C C2F5

F3C

(162) (163)

F

C2F5

NR

• C2F5

F3C

(164)RN

Scheme 52

F

• CF2CF3

F3C

(165)ButN

F

ButNH2, Et2O–50 °C to 40 °C

NBut

CF(CF3)2

(F3C)2CFS

(166)

NBut

• CF(CF3)2

(F3C)2CFS

(167)ButN

F

• CF(CF3)2

(F3C)2CFS

ButN

F

F

ButN

(169)(168)

F3C

(F3C)2CFS F

CF(CF3)2 F2C

(F3C)2CFS F

CF(CF3)2

F

+ +

19% 24% 19%

Scheme 53


F5C2

F5C2

CF3

F

F5C2

F3C

N

F

•

F5C2

F5C2

CF3

F

F5C2

F3C

N(CH2)5F

(172)

•

F5C2

F5C2

CF3

F

F5C2

F3C

N(CH2)3CH CH2120 °C

+

(173)11%

(174)8%

Scheme 54

Yield of (171) (%)66216657

REtPhNH2CH2CH2OH

CF2

F5C2

F5C2

CF3

F

F5C2

F3C

•

F5C2

F5C2

CF3

F

F5C2

F3C

NRpiperidine, Et2O, 18 °C

52%

RNH2, Et2O0 °C to reflux

(170)(171)

Isocyanates reacted with per~uoromethacryloyl ~uoride "064# to yield a range of cycloadducts\amongst them the 0\2!oxazin!1!ones "065#[ Pyrolysis of these was accompanied by loss of carbondioxide and a ð0\2Ł!sigmatropic shift of ~uoride\ and led to ~uorinated ketenimines "066# in goodyields "Scheme 44# ð62JFC"2#80Ł[

•

F3C

F3C

NRO

F3C F

F2C N

O

F3C

R

F

O

FF

, ∆ 200 °C

R = Me (78%), Bun (67%)

(175)

O•RN

(177)(176) + other products

Scheme 55

There is but a single report of ketenimine production from activated chloroalkenes and aminesð81PS"62#074Ł[ When the phosphorus!containing chloroalkene "067# was treated with primary amines\ketenimines "068# were detected spectroscopically "Scheme 45#[ Only with t!butylamine\ however\could the ketenimine be isolated "87) yield#[ In most cases\ the ketenimine added another equivalentof amine\ thereby forming bisamino compounds "079#[

•

PEtO

EtO P

O

O

EtO

EtO

NRCCl2

PEtO

EtO P

O

O

EtO

EtO(178) (180)(179)

RNH2, Et2ORT

R = But, 98%

PEtO

EtO P

O

O

EtO

EtO

NHR

NHR

RNH2, Et2ORT

Yield of (180) (%)9388905084

REtPrn

–CH2CH2–p-Tol1,2-C6H4

Scheme 56

Ketenimines may also result from the reaction of amines with chloroalkynes[ For example\perchlorobutenyne "070# reacted with branched aliphatic primary amines\ giving the unstable butdistillable ketenimines "071# or "072# in poor yield "8Ð07)# "Scheme 46# ð79CB700Ł[ Simple primaryamines RNH1 "R�Prn\ Bun\ Me1CHCH1\ c!C5H00# also apparently gave ketenimines\ but their

480Ketenimines

formation could be inferred only by hydrolysis to amides[ A more reliable reaction between chloro!alkynes and amines used chloroethynyl phosphonates\ "RO#1POC2CCl\ as substrates ð72JGU194\74JGU15Ł[ The reactions were performed with two equivalents of amine in dry ether at temperaturesbelow −4>C\ and it appears that ynamine intermediates may be involved[ The range of phos!phorylated aldoketenimines prepared in this way is shown in Table 6[

Cl

Cl

Cl

•NR

(182)NN

•

Cl

•

ClCl

ClCl

Cl

(183)

Scheme 57

Cl

Cl

Cl Cl

Cl

Cl

Cl NHR

RNH2, Et2ORT

(181)

RPri

EtCH(Me)But

Yield of (182) (%)16119

Table 6 Preparation of ketenimines\ R0R1POCH1C1NR2\ bythe reaction of R0R1POC2CCl with primary amines\ R2NH1

ð74JGU15Ł[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Ketenimine Yield

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 "RO#1POCH1C1NBut "R�Me\ Et\ Prn# 75Ð0991 "R1N#1POCH1C1NBut "R�Me\ Et# 82Ð0992 "MeO#"Et1N#POCH1C1NBut 723 "MeO#1POCH1C1N"0!adamantyl# 844 "MeO#1POCH1C1N!TMS 18a

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa "Me2Si#1NNa was used as the base[

2[06[0[3 Ketenimines from "C¦CN# Precursors

2[06[0[3[0 From phosphorus ylides and isocyanates or related compounds

Staudinger and Meyer are credited with the _rst synthesis of a ketenimine\ Ph1C1C1NPh\which they made from phenyl isocyanate and diphenylmethylenetriphenylphosphorane ð08HCA524\19CB61Ł[ No yield was quoted\ and no e}orts were made to extend the synthesis to other ketenimines[It was not until 0848 that Trippett and Walker showed that ketenimine formation is not the usualoutcome of reactions between phenyl isocyanate and ylides ð48JCS2763Ł[ For instance\ reaction withthe nonstabilized ylide Me1C1PPh2 stopped at the betaine stage "073# "Scheme 47#[ Furthermore\betaines from nonstabilized ylides bearing at least one hydrogen on the methylene carbon thenrearranged to give new ylides "074#[ While reaction of nonstabilized ylides with isocyanates hassince proved to be possible "vide infra#\ it still appears that ylides containing an a hydrogen do notgive ketenimines on reaction with isocyanates[

Staudinger|s reaction remained\ with rare exceptions ð58JA5001\ 69JOC751Ł\ almost entirely un!explored until Fro�yen used it for preparing a range of ketenimines from various isocyanates"Table 7# ð63ACS"B#475Ł[ Reaction conditions varied according to the nature of the ylide and themethod by which it was generated[ Stabilized ylides "e[g[\ entry 2# required milder conditions than


N

O

Ph3P

R2

Ph

HN •

Ph

O

NPh–O

R2

PhP

R1

Ph3P=CR1R2

R1R2 = H, Me

R1 = H

(184) (185)

Scheme 58

+

nonstabilized ylides "e[g[\ entry 7#\ a _nding attributed to the relative di.culty of inducing theelimination of triphenylphosphine oxide from the betaine intermediates formed in the latter cases[In general\ however\ yields of ketenimines were in the range 24Ð89)[ Other workers subsequentlyextended the reaction to the synthesis of ~uorenylideneketenimines "entries 09 and 08# ð79BCJ1471\78JCS"P0#1039Ł\ N!acyl ketenimines "entries 00 and 07# ð70CB0865\ 74LA1294Ł\ and vinyl ketenimines"entries 01Ð04# ð71LA79Ł[ In many of these cases\ spectroscopic characterization alone con_rmedthe formation of the 0!azaallene system^ the ketenimines either underwent other reactions\ or weredeliberately converted into other products[ Fleeting ketenimines such as "075# and "076# couldnot even be detected spectroscopically\ but underwent immediate cyclization to give a variety ofheterocyclic products ð78JCS"P0#1039Ł[ Finally\ because higher ketenimines "extended 0!aza!cumulenes# are rare in the literature\ it is signi_cant that one of the earliest applications of theisocyanate:ylide reaction involved the presumed intermediacy of Ph1C1C1C1C1NMe duringthe reaction of Ph1C1C1C1PPh2 with methyl isocyanate ð58JA5001Ł[

Table 7 Ketenimines\ R0R1C1C1NR2\ prepared by the reaction of ylides\ R0R1C1PPh2\ with isocyanates\O1C1NR2[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Ketenimine Conditions Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 MeO1C"Ph#C1C1NBut 092>C 81 69JOC7511 Ph1C1C1NC"CF2#2 Et1O\ RT 61 62DOK"101#5172 MeO1C"Me#C1C1NAr "Ar�Ph\ p!Tol\ 0!naphthyl# C5H5\ RT 79Ð84 63ACS"B#4753 MeO1C"Me#C1C1NR "R�Et\ But# C5H5\ re~ux 89 63ACS"B#4754 PhCO"Me#C1C1NR "R�Ph\ Et# C5H5\ RT 89 63ACS"B#4755 Ph1C1C1NEt C5H5\ 099>C 74 63ACS"B#475

"autoclave#6 Ph1C1C1NR "R�Ph\ 0!naphthyl\ c!C5H00# C5H5\ re~ux 79Ð89 63ACS"B#4757 Me1C1C1NAr "Ar�Ph\ 0!naphthyl# Mesitylene\ 039>C 24Ð39 63ACS"B#4758 EtO1C"CN#C1C1NPh C5H5\ re~ux 9 63ACS"B#475

09 "1\1?!C5H30C5H3#C1C1NR "R�Ph\ p!Tol\ C5H5\ re~ux 46Ð87 79BCJ1471p!C5H3Cl\ 0!naphthyl\ c!C5H00#

00 EtO1C"Me#C1C1NCOR "R�Ph\ OEt# C5H5\ RT a 70CB086501 PhCH1CH"Me#C1C1NPrn C5H5\ RT 84 71LA7902 PhCH1CH"Me#C1C1NAr "Ar�Ph\ p!Tol# C5H5\ RT a 71LA7903 PhCH1CH"Ph#C1C1NPh C5H5\ RT a 71LA7904 PhCH1CHCH1C1NPrn C5H5\ RT a 71LA7905 BunCO"R#C1C1NPh "R�Bun\ n!C4H00\ n!C5H02# C5H5\ RT a 72CB169706 EtO1C"Me#C1C1NR "R�Ph\ C"1N!xylyl#But# Toluene\ RT a 74LA129407 EtO1C"Me#C1C1NCSPh Toluene\ 09>C a 74LA129408 "1\1?!C5H30C5H3#C1C1NCH1CHPh C5H5\ re~ux 77 78JCS"P0#1039*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Yield not given[

•

Ph

NPh

N

Bn

(186)

•

Ph

NPh

(187)

Several variations on the basic procedure\ described above\ exist[ Phosphorus ylides other thantriphenylphosphoranes remain unexplored apart from the halophosphoranes "077#\ which reacted

482Ketenimines

with phenyl isocyanate to a}ord C!phosphinoyl ketenimines "078# in 34) yield "Equation "22##ð79TL2872Ł[ The HornerÐWittig reaction between anions derived from dialkyl alkylphosphonatesand phenyl isocyanate represents another successful route to ketenimines\ and some examples areshown in Table 8 ð70JCS"P0#1616\ 75JHC486Ł[

•

R

NPh

(But)2P

O

(189)

P

X

But

But

(188)

PhN=C=O, petroleumether, –20 °C

45%

X = Cl, Br; R = Me, Prn

(33)R

Table 8 Preparation of ketenimines\ R0R1C1C1NPh\ from the reaction of phenyl isocyanatewith phosphonate anions\ "ðEtOŁ1POCR0R1#− Na¦[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Keteniminea Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 EtO1C"PhS#C1C1NPh 72 70JCS"P0#16161 Ph"PhS#C1C1NPh 32 70JCS"P0#16162 Me"PhS#C1C1NPh 9 70JCS"P0#16163 EtO1C"R#C1C1NPh "R�Ph\ Me\ Me1C1CHCH1# b 75JHC4864 Me1C1CHCH1"MeO1C#C1C1NPh 43 75JHC486*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐa Formed by reacting phosphonates and isocyanate in benzene or THF in the presence of sodium hydride[ b Yield notreported\ but detected spectroscopically[

Phosphorus ylides undergo successful reaction with cumulenes other than isocyanates[ Capuanoand Djokar prepared a number of N!imidoyl ketenimines\ EtO1C"Me#C1C1NC"1NAr#Ar\ fromstabilized ylides and N!imidoyl isothiocyanates ð74LA1294Ł[ Unfortunately\ ylides were not speci_ed[Diphenylcarbodiimide has also been reported to react with alkylidenetriphenylphosphoranesð69JOC1965Ł^ however\ only IR spectroscopic evidence was obtained for the otherwise well!knownproduct Ph1C1C1NPh[ It appears that ylides containing an a hydrogen also react with diphenyl!carbodiimide to produce labile ketenimines\ RCH1C1NPh "R�Ph\ EtO1C#\ that undergo furtherreaction with another equivalent of ylide ð69JOC1965Ł[

2[06[0[3[1 By alkylation of isocyanides

"i# Reaction with activated multiple bonds

Reaction of isocyanides with two equivalents of hexa~uoro!1!butyne in inert solvents a}ordedmoderate "½ 29)# yields of the isolable cyclopropropenyl ketenimines "089#\ possibly by way ofthe carbenes "080# "Scheme 48# ð58JA3650Ł[ The course of the reaction could be altered in alcoholicsolvents\ in which the carbene intermediates were intercepted to give imino ethers "081# in additionto ketenimines "082# "e[g[\ reaction in methanol\ illustrated in Scheme 48# ð58JA3650\ 62JOC0208Ł[ Areaction between aryl isocyanides and dimethyl acetylenedicarboxylate discovered by Takizawa andco!workers probably also involves initial formation of a carbene\ which in this case was trapped bya second equivalent of isocyanide to produce the bis"ketenimine# "083# in low yield before ultimatelyyielding cyclopentene triimine hydrate "084# "Scheme 59# ð58TL2396Ł[ Aspects of both precedingsyntheses are probably involved in forming the unusual bicyclobutane!bis"ketenimine# "085# fromthe reaction of t!butyl isocyanide with dimethyl acetylenedicarboxylate ð63T1442Ł[ The productcan be explained as arising from the coupling of two intermediates\ the cyclopropene!substitutedketenimine "086# and the ketenimine!carbene "087# "Scheme 50#[

Cyclopropenes bearing electron!withdrawing substituents react with t!butyl isocyanide to a}ordvinyl ketenimines "088#\ representative examples of which are shown in Equation "23# ð68AG"E#56\68CB2055Ł[ Ketenimines have been postulated as intermediates in the reactions of cyclopropenonesor cyclobutanone with isocyanides ð58TL2392Ł[


F3C CF3

CN XN X

OMe

F3C

CF3

N X

•

CF3F3C

MeO

H2, 3.4 bar, PtO2EtOH

+

• NR

F3C

CF3

F3C

F3C

• NR

F3C

CF3

F3C

F3C

MeOH, 1.7 barRT

+

(192) (193)

Rc-C6H11PhBut

Yield of (190)(%)293335

XNO2ClHMeOMe

Yield (%) 80 (100:0) 73 (81:19) 94 (70:30) 84 (72:28) 94 (71:29)

Scheme 59

• NR

F3C

CF3

F3C CF3

F3C CF3

:

, CHCl2, 2.4 bar

(191)

CN R

RT

(190)

Scheme 60

C6H6, 0-5 °C

9%CO2MeMeO2C CN Br+

Br N

•

MeO2C CO2Me

•

N Br

MeO2C CO2Me

ArN NAr

HO NHAr

(194) (195)

CN-Ar

ButNC, C6H6, RT

X X

CO2MeMeO2C MeO2CCO2Me

•

NBut

Yield (%)62826353

X–CH2CMe2CH2CH2

(199)

(34)

484Ketenimines

MeO2C CO2Me

CO2Me

• CO2MeButN

CO2Me

CO2Me

•

CO2Me

NBut

•

MeO2C

ButN

MeO2C

MeO2C

CO2Me

CO2MeMeO2C

•MeO2C

NBut

:ButNC, Et2O

–20 °C

12%

(196)

Scheme 61

+

(197) (198)

Reaction of two equivalents of 1\3\3!trimethylpent!1!ene with three equivalents of hydrogencyanide in the presence of hydro~uoric acid has been reported to a}ord the ketenimine "199# by acomplex pathway formally involving both isocyanide "190# and iminium ion "191# formation asshown in Scheme 51 ð60JOC2331Ł[ More easily understood is an e.cient synthesis of keteniminesfrom 1!acylaziridines "192# and t!butyl isocyanide in which initial ring cleavage to azomethine ylides"193# precedes attack by the isocyanide "Scheme 52# ð64CC23Ł[

i, HCN, HF, CH2Cl2

ii, MeSO3H, crystallizeiii, KOH

ButN

CN

CNBut

(201) (202)

+

60%

But

•

N

NC

N

But

H

(200)

Scheme 62

But

ButNC, CCl4

N

Ph

Ph NPh

•

NBut

Yield (%)9266

XOEtNEt2

X

O

X

O

Ph

NPhX

O+

–

(203) (204)

Scheme 63

Ph

The oddest ketenimine synthesis of all "Equation "24## involves combination of t!butyl isocyanideand ~uorenylideneborane "194# in a 2 ] 0 ratio to give the 0\1!azaborolidine!ketenimine "195# in 40)yield ð82CB0440Ł[ The structure of "195# has been con_rmed by x!ray crystallography[


3ButNCtoluene, RT

51%BN

N

B

•

ButN

NBut

N

But

(206)(205)

(35)

"ii# Reaction with carbenes

An early attempt to react dichlorocarbene "generated from chloroform and an alkoxide ion# withcyclohexyl isocyanide produced no dichloroketenimine\ Cl1C1C1N"c!C5H00#\ but only dich!loroacetimidates resulting from the capture of the reactive intermediate by the alkoxide ð53AG"E#641Ł[Later workers also failed to isolate dihaloketenimines from the alkylation of isocyanides withdihalocarbenes no matter how these intermediates were generated^ however\ various heterocyclicproducts isolated suggest that the ketenimines were formed transiently ð64BCJ1176Ł[ It was only in0889 that IR spectroscopic evidence was obtained for transitory dichloroketenimine intermediates\Cl1C1C1NR\ formed from chloroform\ potassium t!butoxide\ and the isocyanides RNC "R�iso!butyl\ s!butyl\ t!butyl\ n!pentyl\ benzyl\ phenyl# ð89JOU0531Ł[

The _rst successful preparation of ketenimines from carbenes dates from 0858\ when two inde!pendent research groups reported essentially identical procedures for preparing N!cyclohexyl!C\C!diphenylketenimine "14Ð49) yield# by photolysis of diphenyldiazomethane in the presence ofcyclohexyl isocyanide ð58CC0266\ 58TL4982Ł[ The t!butyl analogue was similarly prepared in 39Ð49)yield ð58TL4982Ł[ A poor thermolytic variation has since been used for making Ph1C1C1N"1\5!xylyl#\ but other N!aryl analogues lacking ortho substituents underwent cyclizations with a secondequivalent of isocyanide ð64BCJ1176Ł[ The thermolytic route has been more successful for makingMeO1C"Ph#C1C1NBut from methyl phenyldiazoacetate and t!butyl isocyanide ð69JOC751Ł[

In 0878\ Bertrand and co!workers\ requiring evidence for the carbene character of the stabletrimethylsilylmethylenephosphine "196#\ showed that its reaction with t!butyl isocyanide followedby sulfuration a}orded the unique ketenimine "197# in 89) yield "Scheme 53# ð78AG"E#510Ł[

CNBut

•

TMS

[(Pri)2N]2P

NBut

:

(207)

S

•

TMS

[(Pri)2N]2P

NButS8

90%[(Pri)2N]2P TMS

(208)Scheme 64

"iii# Reaction with transition metal or`anometallic compounds

The reaction of isocyanides with transition metal carbene complexes provides a useful methodfor preparing metal complexes of ketenimines "198# according to the general Equation "25#[However\ this equation fails to highlight the large range of structural types "109#Ð"103# encompassedby the simple formula "198#[ While only those complexes in which the metal is s bonded to thecarbon or nitrogen of the ketenimine "i[e[\ in which the C1C1N unit remains intact# fall strictlywithin the scope of the present review\ various other complexes are proven intermediates en routeto metal!free ketenimines[ The comprehensive review by Aumann should be consulted for furtherdetails and references ð77AG"E#0345Ł[

(R1XC • NR2)MLnR1XC MLn N R2

(209)

+ C (36)

486Ketenimines

•

LnM

R

N

R

•

R

R

N

R

•

R

R

N

MLn

MLn

(210) (211) (212)

MLn

R

RN

R

MLn

NR

(213) (214)

R

R

In 0857 Aumann and Fischer reported that the chromium carbene complex "104# reacted withcyclohexyl isocyanide to give an air!sensitive compound ð57CB843Ł\ the structure of which was latershown to be the h0!ketenimine complex "105# by x!ray crystallography ð75CB2030Ł[ With a twofoldexcess of isocyanide\ the ketenimine ligand "106# could be displaced from the intermediate complexand isolated in 67) yield "Scheme 54# ð67CB0112Ł[ Other nucleophiles such as pyridine also liberatedthe ketenimine ð74CB841Ł[ The voluminous subsequent publications by Aumann and co!workerscontained examples of the N!bonded ketenimine complexes "R0XC1C1NR1#MLn\ in which X isOR\ SR\ SeR\ NR1\ or N1CR1\ and MLn is Cr"CO#4\ Mo"CO#4\ W"CO#4\ Mn"C4H3Me#"CO#1\ orFe"CO#3 ð77AG"E#0345\ 82CB0756Ł[ However\ only in a few instances was the ketenimine then liberatedfrom the metal template on which it was constructed "e[g[\ from a tungsten complex with acetonitrileð76CB0828Ł\ and from a manganese complex with excess isocyanide ð77CB0974Ł#[ Two especiallyinteresting examples*a C!amino ketenimine "107# generated from an "aminocarbene#chromiumcomplex ð78CB0028Ł\ and a C!phenylthio!C!vinyl ketenimine "108# generated from an alkenyl!"thiocarbene#chromium complex ð89CB1942Ł*are shown in Scheme 55[

•

MeO

N(c-C6H11)•

MeO

N

c-C6H11

Cr(CO)5

MeO

Cr(CO)5

(215) (216) (217)

c-C6H11NCC6H14, 0°C

c-C6H11NC–(CO)5CrCN(c-C6H11)

78%

Scheme 65

•

Ph

N

N

RCr(CO)5

Ph

H2N

Cr(CO)5

Ph

PhCO2

•

Ph

N

NRPh

PhCO2

(218)

i, PhCOCl, NEt3ii, CN-R

Cr(CO)5

PhS

Ph

•

PhS

N(c-C6H11)

Ph

CN-R

R = But (92%), c-C6H11 (95%)

2 CN-R, Et2O

84%

(219)

Scheme 66

Insertion of isocyanides into vinylidene and allenylidene complexes of transition metals shouldin principle open up routes to higher 0!azacumulenes analogous to those described above[ In fact\the only higher 0!azacumulene complexes described to date appear to be the unstable\ readilyhydrolyzed manganese complexes "119# and "110#\ prepared as shown in Equations "26# and "27#ð78JOM"268#292Ł[ The free ligands have not been detached from the metal[ Transient vinylideneÐtitanium complexes "111#\ trapped by alkynes as the titanacyclobutenes "112#\ are implicated in thesynthesis shown in Scheme 56 ð81CC24Ł[ In this case the metallacycles reacted with isocyanides togive isolable "and previously undocumented# C!allenyl ketenimines "113# in yields of 79Ð86)[Other h3!complexed vinyl ketenimines "e[g[\ "114#\ "115#\ and "116##\ made by treating a variety oforganometallic precursors with isocyanides\ have been characterized crystallographically but notdissociated from the metal template ð79JOM"089#C28\ 89CC296\ 82JA8735Ł[

• Mn(CO)2Cp • • NR CN-R, Et2O, 20 °C

(220)R = But, c-C6H11, Bn

(37)

Ph Ph

Mn(CO)2Cp


• • Mn(CO)2Cp • • • NButMn(CO)2Cp CN-But, Et2O, 20 °C

Ph

Ph

Ph

Ph

(38)

(221)

•

R1

TiCp2

HMPA, RT

(223)

TiCp2 •

R2

•

R3

NButR1

R3R2

R1

R1 = Prn, n-C5H11, PhR2 = H, Prn, n-C5H11, PhR3 = Prn, Ph, TMS

(224)

(222)

CN-But

n-C6H14, RT

R13 steps

R2 R3

Scheme 67

80–97%

•

CO2Me OMe

N(c-C6H11)

Fe(CO)3

•

NBut

Fe(CO)3

•

TMS SO2Ph

NBut

(227)

Ph EtO2C

(225)

Co

(226)

The insertion of isocyanides into h1!acyl organometallic complexes\ which are also close relativesof Fischer carbene complexes\ di}ers from the processes described above in that the metal remainsattached to oxygen in the product[ The acylthorium complex "117#\ for instance\ reacted quan!titatively with one equivalent of isocyanide to yield gummy ketenimines "118#\ which reacted in turnwith a second equivalent of reagent to yield complexes "129# as tractable solids "Scheme 57# ð75JA45Ł[An analogous zirconium!complexed ketenimine "120# has been detected by NMR spectroscopy\though it rapidly decomposed when the synthesis "Equation "28## was tried on a preparative scaleð76JA1938Ł[

CN-R, RT

~100 %

OTh

•

NRCN-R

CpCp

ClBut

OTh

•

NR

Cl

Cp

ButCp CN-R, RT

~100 %(Cp)2Th(Cl)(η2-COCH2But)

(228) (229) (230)R = Ph, But, 2,6-C6H3Me2

Scheme 68

CD2Cl2, RT

~100%CN TMS

O

•

N

Cp2Zr

Cl

O

TMS

Cp2Zr

Cl

+

(231)

(39)

488Ketenimines

The synthesis of ketenimines from isocyanides and carbenes has been approached from a di}erentperspective by Werner and co!workers\ who treated isocyanide complexes of cobalt with diaryldiazoalkanes as an external carbene source "Scheme 58# ð89AG"E#164\ 80CB174Ł[ Intermediate ket!enimine complexes were found to have either the h1!C\C or h1!N\C structures "121# or "122# dependingon the substituents on carbon[ These complexes could not be disrupted with additional isocyanide\but on treatment with iodine\ ketenimines "123# and "124# were liberated in yields of 37Ð69)[

• NMe

Co

N

Cp PMe3

Ar

Ar

Me

N2

•NRCo

Me3P

Cp

NR

CpCo(CNMe)(PMe3)

(232)

I2, Et2O, RT

50–70%

(234)Ar = Ph, p-Tol, p-C6H4Cl

Ar2CN2Me2CO, –78 °C to RT

54–67%

CpCo(CNR)(PMe3)Me2CO, –78 °C to RT

52–68%R = Me, c-C6H11

CH(Me)Ph

I2, Et2O, RT

R = Me (48%) CH(Me)Ph (68%)

+

(233) (235)

Ar

Ar

Scheme 69

Several alternative syntheses of ketenimines on palladium templates are known ð66TL0998\79SC122Ł[ They involve insertion of isocyanides into Pd0C s bonds "e[g[\ Equation "39##\ p!allylpalladium complexes "Equation "30##\ or diene complexes "Equations "31# and "32##[ s!Bondedintermediates such as "125#\ previously isolated by other workers ð69JOM"12#164\ 60ICA366Ł\ areimplicated in the reaction pathway\ and a ready b elimination of H0PdLn with 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# then a}ords the desired product[ The process has been madecatalytic in palladium as shown in Equation "33#\ and this variation a}ords aryl and vinyl ket!enimines in moderate yields[ An insertion of isocyanides into s!bonded platinumÐallene complexes"126# has been used for making the unusual but stable metallated vinyl ketenimines "127# in48Ð78) yields "Equation "34##\ whereas the corresponding palladated vinyl ketenimines were toounstable to be isolated ð82OM2753Ł[

• NBut

NBut

PdHal

CNBut

dbu, C6H6, RT

i,

ii, ButNCPd(CNBut)2 (40)R1

R2

R1

R2

(236)

R1

PhPrn

Me

HalR1

R2

R2

HH

Me

Yield (%)826227

)2

PdCl2

i, ButNCii, dbu

55%• NButPd

Cl

)2

(41)

OMe

•NBut

PdCl

Cl

PdCl

MeOH, Na2CO3

OMe i, ButNCii, dbu

50%)2

(42)


)2

•

NBut

MeO

Pd

Cl Cl

Pd

Cl

MeOMeOH, Na2CO3

i, ButNCii, dbu

38%

(43)

• NR2

X =

R1R1 Cl

R1

PhPhp-TolH2C=CHPhCH=CH

R2

But

XX

But

But

+ C N R

Yield (%)6557402020

(44)

Pd(OAc)2 (cat.)dbu, THF– +

CN-R3

THF, reflux; orC6H5Me, RT

• NR3R1

Pt

X

R2

•

Pt

X

R1

MeMe

MeMe

R2

MeMe

EtMe

R1

R2

Yield (%)8978797959

(45)

(237) (238)

R3

But

But

But

But

2,6-Xylyl

XBrClBrBrBr

-(CH2)5-

PPh3

Ph3PPPh3

Ph3P

2[06[0[3[2 Formal cycloaddition processes

0\2!Dipolar cycloaddition of aromatic nitrile oxides to phosphorus ylides gave rise to 3\4!dihydro!0\1\4l4!oxazaphospholenes "128#\ which decomposed either spontaneously or on heating to giveketenimines\ amongst other products ð58CB0705\ 58CB0722Ł[ For example\ use of the stabilized ylide"139# gave only the ketenimine "130# "Scheme 69#\ whereas azirines "131# were the major productsfrom a nonstabilized ylide ð58CB0705Ł[

PhC≡N-OC6H6 • NPh

EtO2C

PPh3

EtO2C

C6H6, 8 °C

PPh3

ON

EtO2C

Ph

68%

+–

PPh3

ONPh

PPh3X N O–

++

X = H (20% + 80%) Cl (8% + 92%)

XN• XN

+

(240) (239) (241)

(242)Scheme 70

X = H (74%) Cl (85%)

Haszeldine and co!workers have shown that oxazetidines "132#\ isolated from the reaction oftri~uoronitrosomethane with bis"tri~uoromethyl#aminoallenes "133#\ give excellent yields of N!tri~uoromethyl ketenimines "134# upon ~ow pyrolysis ð69CC345\ 62JCS"P0#0450Ł[ The overall process\shown in Scheme 60\ is e}ectively a metathesis reaction[

Formal ð1¦1Ł cycloaddition has been invoked to explain the reaction of alkyl isocyanates

590Ketenimines

•

R1

R2

NCF3N O

R1

R2

F3C

N CF3

F3C

•

R1

R2

CF3N

F3C

R1 = R2 = H, 100%R1 = H, R2 = N(CF3)2, 98%R1 = R2 = N(CF3)2, >90%

R1 = R2 = H, 47%R1 = H, R2 = N(CF3)2, 89%R1 = R2 = N(CF3)2, 32%

, ∆

Scheme 71

N O 200–300 °C, –HCON(CF3)2

CF3

(244) (243) (245)

with 0!diethylaminopropyne "Scheme 61# ð61TL0028\ 66JOC3150Ł[ Electrocyclic ring opening of theiminooxete intermediate "135# leads to the formation of isolable C!carbamoyl ketenimines "136# inmoderate to good yields[

O

Et2N

NR•

Et2N

OEt2N

O=•=NR, RTC6H6 or CCl4

(246) (247)

NR

Scheme 72

RMeEtBun

c-C6H112,6-C6H3Me2

Yield of (247) (%)7867514535

2[06[0[4 Keteniminium Salts

Although salts of ketenimines are of some consequence as reactive intermediates in ð1¦1Łcycloadditions ðB!65MI 206!90\ 77CRV682Ł\ very few have actually been isolated as stable intermediates\or even characterized spectroscopically[ These salts are generally formed in situ under conditionsthat favour their immediate conversion into cyclobutanone products[ They are e}ectively in equi!librium with enamines bearing various heteroatomic substituents on the a position "Equation"35##^ their interception by suitable reaction partners often constitutes the sole evidence for theirintermediacy[ a!Chloroenamines\ for instance\ have frequently been used as synthetic equivalentsfor keteniminium salts ðB!65MI 206!90\ 82HOU"E04:1#0523Ł[ Secondary amides provide a more accessiblesource\ since treatment with tri~uoromethanesulfonic "tri~ic# anhydride and collidine in an inertsolvent provides a simpler route to keteniminium intermediates via a!tri~yloxy enamines ð77CRV682Ł[Some representative intramolecular and intermolecular cycloadditions involving transient ket!eniminium salts prepared by these two methods are shown in Scheme 62[ In those rare cases inwhich the keteniminium intermediates could actually be detected in solution\ the counterionspresent were hexa~uorophosphate ð69JOC2869Ł\ tetra~uoroborate ð61JA1769Ł\ or trichlorozincateð63AG"E#156Ł\ as shown in Equation "36#\ for example[ The ethynylogous guanidinium salt "137#represents a special case in which resonance e}ects play a part in stabilizing a keteniminium system"Scheme 63# ð63JA3601Ł[

X

NR3R4R2

R1

•

R2

R1

NR3R4 X–+

X = Cl, OSO2CF3

(46)

• NAgBF4, CH2Cl2, –60 °C +

Cl

NMe2 Me

MeBF4

– (47)


i, Tf2O, collidine, CHCl3, ∆ii, NaOH

50%

OH

H

O NMe2

O

N

O

N

i, Tf2O, collidine, ClCH2CH2Cl, ∆ii, H2O

65%

i, Tf2O, 2,6-(But)2Py, ClCH2CH2Cl, 20 °Cii, H2O

OH

H

Cl

N

MeO

i, cyclopentene, ZnCl2, CH2Cl2, 20 °Cii, NaOH

70%, >97% ee

Scheme 73

88%, 98% ee

+

⟨82JA2920⟩

⟨81AG(E)879⟩

⟨85JA2192⟩

⟨90TL4467⟩

• • NMe2 ClO4–

(248)

+Cl

NMe2

Me2NNMe2 ClO4

–

Me2N+

+

ClO4–

Scheme 74

Me2N

Et3N, MeCN

Transient keteniminium intermediates may also be involved in reaction of the nucleophilic b!carbon site of ynamines with electrophiles "Equation "37##[ There is no conclusive evidence for theintermediacy of the salts\ although in most cases the isolated product strongly suggests a ket!eniminium precursor[ Relevant reviews should be consulted for examples of reactions assumed toproceed through such keteniminium salts ð65T0338\ 82HOU"E04:2#2393Ł[

•

El

R1

N+El+ X–

R1 N

R2

R3 R3

R2:

X– (48)

The only truly isolable keteniminium salts bear bulky substituents that help to retard decompo!sition[ Equation "38# shows an example in which N!methylation of a hindered ketenimine a}ordeda salt that survived recrystallization ð67JOC490Ł[ N!Methylation with trimethyloxonium tetra~uo!roborate or hexachloroantimonate\ or with methyl ~uorosulfonate\ has subsequently been exploitedin the synthesis of a wider range of isolable keteniminium salts "138#Ð"140#\ one of which\ compound"141#\ has even been examined by single!crystal x!ray di}raction ð71CB061Ł[

•

But

But

N+MeOSO2F, Et2O, RT

55% Me

Et–OSO2F•

But

But

NEt (49)

2[06[1 P\ As\ Sb\ AND Bi ANALOGUES OF KETENES AND THEIR DERIVATIVES"R1C1C1P0R\ ETC[#

Antimony and bismuth analogues of ketenes have not been prepared to date[ The arsenicanalogues "0!arsaallenes# are also unknown\ though a few higher 0!arsacumulenes have beenprepared[ This section is thus dominated by the comparatively well!explored trivalent "l2# andpentavalent "l4# phosphorus analogues of ketenes and higher cumulenes[ Reviews by Matthewsand Birum ð58ACR262Ł\ Bestmann ð66AG"E#238Ł\ Bestmann and Zimmermann ð71HOU"E0#648Ł\ andMarkovskii and Romanenko ð75JGU110Ł deal wholly or in part with the chemistry of these phos!phorus compounds[

592P\ As\ Sb\ and Bi Analo`ues

(251)(249) (250)

X– = FSO3–, SbCl6–R = Pri, X– = FSO3

–, SbCl6–

R = But, X– = FSO3–, BF4

–

•

R

But

N

Me

Bn

•But

N

Me

Bn

•

But

N

Me

Bn

SbCl6–

•

But

N

+

+

Me

But

X–+

But

X– +

SbCl6–

(252)

2[06[1[0 0l4!Phosphaallenes and 0l4!Phosphacumulenes

0l4!Phosphaallenes "alkenylidene phosphoranes# "142a# are mesomers of ylides "142b#\ a rep!resentation preferred by some authors[ Similar representations are possible for higher 0l4!phos!phacumulenes\ X1C1C1PR2 "X�C\ O\ S\ N\ P#[ With heteroatomic termini\ further resonanceforms\ for example "143#\ contribute to the stability of the structure "Scheme 64#[ Much experimentaland theoretical work has been devoted to assessing the relative importance of these canonical forms[The present review side!steps this issue\ and includes all compounds for which a formal C1P bondcan be drawn[ However\ several x!ray crystallographic investigations have shown that the CCPangle is not linear\ but varies between 015> and 057> depending on substituents ð74CB0619Ł[ This_nding is compatible with the C1C1P formalism if ppÐdp bonding is countenanced[

Y • • PX3 Y •

PX3

PX3Y

+

+–

(254)

Scheme 75

• PX3

PX3+

–

(253a) (253b)

R1

R2

–

R1

R2

2[06[1[0[0 From precursors containing the CCP triad

The simplest route to alkenylidene phosphoranes is by deprotonation of vinylphosphonium salts[This process was _rst described by Gilman and Tomasi\ who prepared Ph1C1C1PPh2 "used in situin a Wittig reaction# from Ph1C1CHPPh2

¦ Br− and phenyllithium ð51JOC2536Ł[ Bestmann and co!workers later deprotonated the phosphonium salt "144#\ formed as shown in Scheme 65\ to thecrystalline ketene acetal "145# ð58AG"E#105\ 62CB1590Ł[ On prolonged heating in toluene\ "145#was converted into the cyclic vinyl phosphorane "146#\ which underwent further elimination toyield the cyclic phosphaallene "147# ð66AG"E#766Ł[ Deprotonation of vinylphosphonium salts hasalso been used for preparing alkylthio analogs\ "RS#1C1C1PPh2 "R�Me\ Et\ Prn\ Bun^ 38Ð60)#ð70TL0570Ł\ and EtOCH1C1PPh2 "58)# ð71CB050Ł[ While isolable 0l4!phosphabutatrienes\R1C1C1C1PPh2\ have yet to be prepared by this method\ both Ph1C1C1CHPPh2

¦ Br− andHC2CCH1PPh2

¦ Br− reacted with base to form products whose structures imply the intermediacyof Ph1C1C1C1PPh2 and H1C1C1C1PPh2\ respectively ð58JA5001\ 62TL0384Ł[

Acylmethylenetriphenylphosphoranes may also be deprotonated to give formal 0!phosphaallenes\as in the conversion of PhCOCH1PPh2 into the reactive enolate Ph"LiO#C1C1PPh2 with lithiumÐHMPA ð64T0220Ł[ However\ when a leaving group is present on the b position\ 0!phosphacumulenesmay be formed instead[ For example\ sodium hexamethyldisilazide induced elimination of MeXHfrom MeX1CCH1PPh2 "X�O\ S# in benzene at 59Ð54>C\ yielding the ketenylidene phosphoranesX1C1C1PPh2 "X�O\ 79)^ X�S\ 65)# ð64AG"E#523\ 79CB163Ł[ The former product has alsobeen isolated from the reaction of MeO1CCH1PPh2 with n!butyllithium and Me2MCl "M�Si\Sn#\ probably by rapid elimination of Me2M0OMe from a metallated intermediate ð63JOM"66#C11Ł[


•

EtO

EtO

PPh3+

O

EtOPPh3

EtO

EtOPPh3 BF4

–

NaNH2, NH3

48%

PEtOPh

PhPEtOOEt

Ph

Ph

Et3O+ BF4–

CH2Cl2

68%

i, AcClii, NaN(TMS)2

82%

toluene, ∆3 d 81%

(255) (256)

(258) (257)

Scheme 76

In a related reaction\ base!induced elimination of ethanol from b!ethoxyallylidenephosphoranes"148#\ formed from the previously mentioned acetal "145# and active methylene compounds\ pro!duced the stable 0!phosphabutatrienes "159# in moderate yields "Scheme 66# ð79CB163Ł[

•

R2

R1

•R1CH2R2, C6H6

PPh3

R2

R1

OEt

PPh3•

EtO

EtO

PPh3

NaN(TMS)2, C6H6

(256) (259) (260)

Scheme 77

R1 = Ph, R2 = CN, 65%R1 = p-MeOC6H4, R2 = CN, 47%R1 = Ph, R2 = CO2Me, 59%R1–R2 = –CH=CHCH=CH–, 51%

2[06[1[0[1 From "C¦CP# precursors

Birum and Matthews\ pioneers in this _eld\ found that hexaphenylcarbodiphosphorane "150#readily formed inner salts "151# "×82) yield# on treatment with carbon dioxide and relatedheterocumulenes "Scheme 67# ð55CC625Ł[ These salts underwent elimination of Ph2P1X whenheated in DIGLYME\ thereby giving rise to a variety of 0!phosphacumulenes[ The stableO1C1C1PPh2 was obtained from carbon dioxide "08) yield# ð55TL4696\ 57JA2731Ł\S1C1C1PPh2 from carbon disul_de ð55TL4696Ł\ and the more labile ArN1C1C1PPh2

"Ar�Ph\ p!Tol\ p!C5H3NO1# from aryl isothiocyanates ð57CI"L#542\ 57JA2731Ł[ More conventionalWittig reactions of Ph2P1C1PPh2 with hexa~uoroacetone ð56CC026\ 56JOC2443Ł and benzophenoneð71ACH24Ł gave the 0!phosphaallenes "F2C#1C1C1PPh2 and Ph1C1C1PPh2\ respectively[

Ph3P • PPh3 X • • PPh3

Ph3P PPh3

X Y–

–Ph3P=Y

+

X • Y

(261) (262)

Scheme 78

A useful preparation of higher 0!phosphacumulenes by Bestmann and co!workers involves acyl!ation of methylenetriphenylphosphorane with thio or imino analogues of phosgene "152#\ or with0\0!dichloroalkenes "Scheme 68#ð63AG"E#162\ 64TL3914\ 79CB2258Ł[ The 2 ] 0 stoichiometry of the processimplies that two equivalents of ylide function as base\ _rst deprotonating the initially formedphosphonium salts "153#\ and then\ after methylation\ inducing a b elimination of the sort describedin Section 2[06[1[0[0 above[ Compounds prepared by this procedure are presented in Table 09[


Methylenetriphenylphosphorane also reacted with isothiocyanates to produce "154# "Scheme 79#^methylation followed by base!induced b elimination subsequently gave keteniminylidene phos!phoranes "155# in good yield ð82CB1040Ł[

Scheme 79

X

Hal HalH2C PPh33 +

X

Hal

(263) (264)

PPh3 Hal–

X • • PPh3 + 2 Ph3PMe Hal–

+

+

Table 09 Preparation of 0l4!phosphacumulenes\ X1C1C1PPh2\ by the reaction of X1CY1 withmethylenetriphenylphosphorane\ H1C1PPh2[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐEntry Reactant Product Yield Ref[

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ0 "MeO1C#1C1CCl1 "MeO1C#1C1C1C1PPh2 08 64TL39141 MeO1C"CN#C1CCl1 Me1OC"CN#C1C1C1PPh2 40 64TL39142 "1\1?!C5H30C5H3#C1CBr1 "1\1?!C5H3\C5H3#C1C1C1PPh2 79 64TL39143 S1CCl1 S1C1C1PPh2 59 79CB22584 RN1CCl1 RN1C1C1PPh2 "R�Me\ c!C5H00# 57Ð69 79CB22585 "p!C5H3X#N1CCl1 "p!C5H3X#N1C1C1PPh2 "X�H\ Cl\ Me# 58Ð74 79CB22586 "1\3!C5H2Cl1#N1CCl1 "1\3!C5H2Cl1#N1C1C1PPh2 62 79CB2258*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

RN • SPPh3

RHN

S

H2C PPh3 +

(265)

PPh3

RN

SMe

RN • • PPh3

i, MeI, CHCl3, 0 °Cii, NaOMe, MeOH, RT

67–75%

C6H6, RT

84–95%

NaN(TMS)2C6H6, RT to 50 °C

(266)

Scheme 80

R = Me 71%

Ph 86%

Prn 69%

2[06[1[1 0l2!Phosphaallenes and 0l2!Phosphacumulenes

These unsaturated compounds tend to dimerize to 0\2!diphosphetanes ð75CB1355Ł unless thephosphorus atom bears a sterically protecting substituent "invariably 1\3\5!tri!"t!butyl#phenyl\denoted by Ar � in the following# to inhibit further reaction[

2[06[1[1[0 By the Peterson reaction and related ole_nations

Peterson ole_nation has been used by the research groups of both Ma�rkl and Yoshifuji in anumber of di}erent ways for preparing 0l2!phosphaallenes and 0l2!phosphacumulenes[ In thesimplest case\ the lithiated silylphosphine "156# reacted with ketenes to give 0!phosphaallenes "157#in moderate yield "Equation "49## ð73TL0798\ 74PS"14#126\ 76PS"29#416\ 77AG"E#0259Ł[ Alternatively\ 0!phosphaallenes could be formed by treating the lithiated l2!phosphaethenes "158# with aldehydesor ketones "Equation "40## ð78TL728Ł[ The product formed from benzaldehyde is axially dissym!metric\ and can exist as two enantiomers\ "R#!"169# and "S#!"169#[ These have recently been separatedby HPLC on a chiral column and their CD spectra recorded^ the compounds racemized whenexposed to light ð89TL1200Ł[ Tri!"t!butyl#cyclopropen!0!yl has also been used as a sterically encum!


bering group to inhibit dimerization of phosphaallene products "160# formed in a Peterson!likeelimination "Equation "41## ð82S0136Ł[

• P

Ar*

P Ar*

Li

ButMe2Si , THF, –78 °C

(268)

R

R

(267)

•

RPhTMS

R

R

Yield (%)5840

Ar* = 2,4,6-C6H2(But)3

O

(50)

• P

Ar*

P

TMS

Li

–78 °C to RT(51)

Ar*

(269)

R

Ph

Ar* = 2,4,6-C6H2(But)3

O

Yield (%)4516

R

Ph

RPhH

• P

Ph

H

But

But

But

:

• P

H

Ph

But

But

But

:(R)-(270) (S)-(270)

NaOH, THF, 70 °C

P

TMS-O

TMS

ButBut

But

R

R• P

ButBut

But

R

R

RPh2,4,6-C6H2Me3

Yield (%)9052

(271)

(52)

Lithiation of the alkynylphosphine "161# with n!butyllithium yielded a spectroscopically detectableion pair*apparently not a lithioallene*that underwent Peterson ole_nation with dialkyl and diarylketones "Scheme 70# to produce fair yields of 0!phosphabutatrienes "162# ð78TL2828\ 89TL3318Ł[ Thelabile phosphacumulenes from acetone and cyclohexanone immediately dimerized at the terminalC1C bond\ giving 0\1!bis"phosphaallenyl# cyclobutanes "163# ð78TL2828Ł\ whereas products fromhalogenated aromatic aldehydes or diaryl ketones dimerized at the P1C head to give 0\2!diphos!phetanes "164# ð89TL3318Ł[

• • P

Ar*

R1

R2

PTMS

Ar*

H

P

P••

Ar*

Ar*

R2

R1R1

R2

•P

•P

R1

R2

R2

R1

Ar*

Ar*

R1, R2 = aromatic

31–62%

(274)

(275)

(272) (273)

Scheme 81

i, BunLi, THFii, R1R2C=O –78 °C to RT

48–70%

R1, R2 = Me, 15%R1–R2 = (CH2)5, 48%

:


Ma�rkl and co!workers have also investigated variants of the Peterson ole_nation in whichchlorotrimethylsilane is eliminated[ For example\ the reaction between the lithiated tri!methylsilylallenes "165# and the sterically crowded Ar�PCl1 yielded 0!phosphabutatrienes "166# bysequential displacement of the chloride ion and elimination of TMS!Cl "Equation "42##ð75AG"E#0992Ł[ Propargylic rearrangements must have occurred during the synthesis of 3\3!bis"tri!methylsilyl#!0!phosphabutatriene "167# from 0\2!dilithiated bis"trimethylsilyl# allene "168# andAr�PCl1 "Equation "43## ð81TL0870Ł[ The monolithiated allene "179# and Ar�PCl1 initially producedalkynes "170# as a mixture of geometrical isomers^ subsequent lithiation of "170# followed by additionof electrophiles then gave 0!phosphacumulenes "171# "Scheme 71#[ This variant of the Petersonole_nation also works with the lithiated phosphaallene "172#\ from which the 0\3!diphos!phabutatriene "173# was obtained as an "E#:"Z# mixture "67 ] 11# via the isolable 0!phosphaallene"174# "Scheme 72# ð77AG"E#0259Ł[

• • P

Ar*

(277)

Ar*PCl2 THF, –78 °C to RT

R2

R1

•

R2

R1

TMS

Li

R2

TMSPh

TMS

(276)

R1

TMSPhMe

Yield (%)1045

10(E), 1(Z)

(53)

• • P

Ar*

(278)


26% TMS

TMS

•

TMS

Li

TMS

Li(54)

(279)

• • P

Ar*

(282) R = TMS, Me


R

TMS

•

TMS

TMS

Li

(280)

P

Ar*

TMS(281)

BunLiTMS-Cl, or MeI

Scheme 82

• • P

Ar*

(284) (E):(Z) = 78:22

Ar*PCl2 THF, –78 °C to RT P

*Ar• P

Li

Ar*

(283) (285)

18-crown-6toluene, ∆

TMS• P

Ar*TMS

Cl

Ar*P

Scheme 83

2[06[1[1[1 By other routes

A conceptually simple route to l2!phosphaallenes and l2!phosphacumulenes involves exchangeof the phosphorus moiety in l4 precursors with a suitable l2!phosphine[ Ma�rkl and Bauer haveaccomplished this transformation by the action of 1\3\5!tri"t!butyl#phenylchlorophosphine on l4!phosphaallene "175# "n�9# or l4!phosphacumulenes "175# "n�0#\ prepared in situ by deprotonationof phosphonium salts "see Section 2[06[1[0[0# "Scheme 73# ð82TL1804Ł[ The geometry of the unsym!metrical product "176# "R0�Me\ R1�Et# is uncertain[

Just as ketenimines can be made by the reaction between alkylidenetriphenylphosphoranes andisocyanates "see Section 2[06[0[3[0#\ 0!phosphaallenes are accessible in low yield from Ph2P1CR0R1

and O1C1PAr�\ the phosphorus analogue of an isocyanate ð73AG"E#508\ 75CB1355Ł[ Productsprepared by this route include Ph1C1C1PAr� "29) yield#\ PhCH1C1PAr� "18)#\ andEtO1CCH1C1PAr� "13)#[

Yoshifuji et al[ have accomplished a one!carbon homologation of phosphaethenes and 0!phos!phaallenes with dichlorocarbene "Equations "44# and "45## ð89CL716\ 80CC013Ł[ Organolithiumreagents cleaved the intermediate dichlorophosphiranes "177# and "178# to the desired products inmoderate yields[ The reaction of the symmetrical diphosphene "189# with the unsaturated carbene


•n

BunLi, THF

n

Ar*PHCl

(286)

R1

R2

(287)

PPh3 Br–

Scheme 84

• •

R1

R2

PPh3n = 0. R1 = R2 = Ph, 19%n = 1, R1 = Me, R2 = Et, 26%n = 1, R1 = R2 = Et, Pri, Ph, 32–53%

+

• •n

R1

R2

PAr*

Me1C1C] has been shown to produce a 6 ] 2 mixture of the diphosphirane "180# and the 0!phosphaallene "181# "Equation "46## ð80TL2576Ł[

CHCl3, KOBut, pentane, RT

35% from (E), 47% from (Z)

ButLi, Et2O, –78 °C

62%

(288)

P

Ar*

• PAr*P

Cl Cl

Ar*Ph

Ph

Ph(55)

• P

Ar*

• PAr*•P

Cl Cl

Ar*

Ph

PhPh

Ph

(289)

BunLi, Et2O, –78 °C

68%

CHCl3, NaOH, BnNEt3+ Cl–

hexane, RT

35%

Ph

Ph

(56)

+P P

Ar*

• PAr*P P

Ar* Ar*

Ar*

BunLi, Et2O, 0 °C

(290) (291)70%

(292)30%

Cl

(57)

The reaction of alkynyllithium compounds with 1\3\5!tri"t!butyl#phenylchlorophosphine in THFprovides a short but ine.cient route to 0!phosphaallenes\ which are tautomers of the initiallyformed alkynylphosphines "182# "Scheme 74# ð77TL352Ł[ The alkynes were isolated in yields of 30Ð32) when alkynylmagnesium bromides were used in diethyl ether[ A similar reaction with TMS!protected propargyl alcohols "183# led to the formation of 0!phosphaallene silyl ethers "184#\ twoof which were hydrolyzed to the free alcohols "185# "Scheme 75# ð77TL1824Ł[ When a stereogeniccentre complemented the chiral axis\ diastereomers of "184# "R0�R1# were detected by NMRspectroscopy[ Chromatography of products bearing aryl substituents on the carbon terminus wasaccompanied by spontaneous elimination of trimethylsilanol\ and 0!phosphabutatrienes "186# wereformed[

Ar*PHCl

THF, –78 °C to 0 °C• PAr*LiR PR

Ar*

H R = Ph, 37%,

But, 35%, Me, 17%

(293)Scheme 85

R

Treatment of the quadricyclane "187# with copper"II# chloride in deuteriated benzene givesrise to the phosphaallene "188#\ characterized by NMR spectroscopy ð82BSF074Ł[ The postulatedmechanism "Scheme 76# assumes that corner metallation of a cyclopropane ring is followed bycleavage of the C!00C!1 bond to form the intermediate "299#[ After a Grob!type fragmention ofthe C!30C!6 bond and elimination of copper\ the resulting cyclopentadien!4!yl phosphaallene "290#rearranges to the more stable 0!substituted isomer "188#[


• • P

Ar*

(297)

chromatography

R1, R2 = Ph, 63%R2

R1

• PAr*

P

Ar*

HTMS-O

R2

R1

R2

O-TMSR1

Li

TMS-O

R2

R1

• PAr*

R2

OHR1

Ar*PHCl THF, –78 °C to 0 °C

R1, R2 = H, alkyl, aryl

2 N HCl, MeOH

R1, R2 = H, Me

(294)

(295) (296)

Scheme 86

•

PAr*

PAr* P

Ar*

Cu

PAr*

1

+

Cu

27

+

4

(298) (300) (301) (299)

CuCl2, C6D6

Scheme 87

•P

Ar*

2[06[1[1[2 Transition metal complexes of 0l2!phosphaallenes and 0l2!phosphacumulenes

The coordination chemistry of compounds containing phosphorusÐcarbon multiple bonds hasbeen reviewed ð77CRV0216Ł[ Complexes of 0l2!phosphaallenes are rare[ With the exception of a fewh1!P\C complexes\ the bonding mode is invariably h0!P\ that is\ with the metal coordinated to thelone pair on phosphorus\ as shown in "291#[ Synthesis simply involves heating or irradiating theligand with a metal carbonyl[ Crystallographically characterized complexes include h0!ð"Ph1C1C1PAr#Ni"CO#2Ł "52) yield# ð75JOM"296#82Ł and h0!ð"Ph1C1C1PAr#W"CO#3Ł "25)yield# ð89HAC228Ł[ The chromium and molybdenum analogs of the latter were identi_ed by NMRspectroscopy ð75JOM"200#C52Ł\ as was the tungsten complex "292# "19) yield# ð82S0136Ł[ The onlyknown h0 complex of a 0l2!phosphabutatriene\ "293#\ made in 82) yield\ was also characterizedcrystallographically ð82JOM"350#70Ł[

• P

M

But

But

But• P

W(CO)5• • P

W(CO)5Ph

PhBut

But

But

(302)

ButBut

But

M = Ni(CO)3, Cr(CO)5, Mo(CO)5, W(CO)5

(303) (304)

Ph

Ph

Ph

Ph

2[06[1[2 0!Arsacumulenes

By the end of 0882 there were only two documented syntheses of 0!arsacumulenes[ Bestmann andBansal prepared the ketenylidene l4!arsorane "294# by elimination of methanol from the stabilizedarsenic ylide "295# "Equation "47## ð70TL2728Ł according to the method previously described for thecorresponding phosphorus analogue ð64AG"E#523Ł "cf[ Section 2[06[1[0[0#[ Ma�rkl and Reithingerhave adapted one of the previously discussed Peterson ole_nation procedures "cf[ Section 2[06[1[1[0#for preparing the unstable 0l2!arsabutatriene "296# as shown in Scheme 77 ð89TL5220Ł[ The productdimerized spontaneously to the 0\2!diarsetane "297#[


• AsPh3•

NaN(TMS)2toluene, RT

60%O

O

MeOAsPh3

(306) (305)

(58)

• • AsC(TMS)3

Ph

PhAs

As••

C(TMS)3

C(TMS)3

Ph

PhPh

Ph

(308) (307)

i, THF, –78 °Cii, NaOH, H2O–MeOH

52%•

Ph

Ph TMS

LiAs OMe

Cl

(TMS)3C

Scheme 88

•

Ph

Ph

As OMe

(TMS)3C

+

But, Et2O, –78 °C

47%


3.18Nitriles: General Methods andAliphatic NitrilesMICHAEL NORTHUniversity of Wales, Bangor, UK

2[07[0 GENERAL METHODS FOR NITRILE SYNTHESIS 500

2[07[0[0 Synthesis via Substitution Reactions 5012[07[0[0[0 Nucleophilic substitutions 5012[07[0[0[1 Electrophilic substitutions 503

2[07[0[1 Synthesis via Addition Reactions 5032[07[0[1[0 Addition to CC multiple bonds 5032[07[0[1[1 Addition to CX multiple bonds 504

2[07[0[2 Synthesis via Elimination Reactions 5062[07[0[2[0 Elimination from carbonyl derivatives 5062[07[0[2[1 Elimination from carboxylic acid derivatives 5062[07[0[2[2 Elimination from nitro compounds 5192[07[0[2[3 Elimination from amines and amino acids 519

2[07[0[3 Synthesis from other Nitriles 5192[07[0[4 Miscellaneous Methods of Synthesis 510

2[07[1 ALIPHATIC NITRILE SYNTHESIS 511

2[07[1[0 Saturated Unsubstituted Nitriles 5112[07[1[1 b! and More Remotely Unsaturated Nitriles 511

2[07[1[1[0 Aliphatic nitriles with one double bond 5112[07[1[1[1 Aliphatic nitriles with more than one double bond 5132[07[1[1[2 Aliphatic nitriles with aryl or heteroaryl substituents 5142[07[1[1[3 Aliphatic nitriles with one or more C2C triple bonds 515

2[07[1[2 Halo!substituted Aliphatic Nitriles 5162[07[1[3 Aliphatic Nitriles Bearin` an Oxyèn!based Functional Group 516

2[07[1[3[0 a!Oxyènated nitriles 5162[07[1[3[1 b!Oxyènated nitriles 5212[07[1[3[2 More remotely oxyènated nitriles 522

2[07[1[4 Aliphatic Nitriles Bearin` a Sulfur!based Functional Group 5232[07[1[5 Aliphatic Nitriles Bearin` a Se! or Te!based Functional Group 5252[07[1[6 Aliphatic Nitriles Bearin` a Nitroèn!based Functional Group 5262[07[1[7 Aliphatic Nitriles Bearin` a P!\ As!\ Sb! or Bi!based Functional Group 5282[07[1[8 Aliphatic Nitriles Bearin` a Si! or B!based Functional Group 5282[07[1[09 Aliphatic Nitriles Bearin` a Metal Functionality 539

2[07[0 GENERAL METHODS FOR NITRILE SYNTHESIS

A number of reviews dealing with the synthesis of nitriles have been published\ though many ofthese deal with only one of the various approaches for the preparation of this functional group\ andare referenced in the appropriate section of this chapter[ However\ two general reviews of nitrilesynthesis can be found in Rappoport|s 0869 book ðB!69MI 207!90Ł and Mowry|s 0837 reviewð37CRV078Ł[ The latter of these\ although somewhat dated\ provides a thoroughly comprehensive

500

501 Nitriles] General and Aliphatic Nitriles

review of the more classical methods of nitrile synthesis[ The general methods used in the synthesisof nitriles can be classi_ed as] by substitutions\ by additions\ by eliminations\ synthesis from othernitriles and miscellaneous methods[ Each of these is discussed in turn[

2[07[0[0 Synthesis via Substitution Reactions

Nitriles can be prepared by substitution reactions involving both nucleophilic and electrophiliccyanide sources\ although the former are far more common[ For reactions involving nucleophilicsubstitutions\ cyanide "CN−# can be used either as the sodium or potassium salt^ HCN is also anexcellent nucleophile[ Various electrophilic cyanide sources are known\ including cyanogen "C1N1#and cyanogen bromide "BrCN#[

2[07[0[0[0 Nucleophilic substitutions

The synthetic utility of displacement reactions by cyanide is enhanced by the fact that in additionto forming at least one functional group\ the reaction is also a carbonÐcarbon bond!formingreaction[ Substitution can occur at sp2\ sp1\ or sp hybridised centres^ however\ the last two reactionslead to a\b!unsaturated or aryl nitriles\ and are discussed in Chapter 2[08 so only displacementreactions at sp2 hybridised carbon centres is discussed in this chapter[

Cyanide will displace a wide variety of leaving groups and the reaction is almost always an SN1displacement\ hence primary carbon atoms react more easily than secondary and tertiary[ In thecase of secondary and tertiary centres\ the basicity of the cyanide anion means that elimination ofthe leaving group to give an alkene is sometimes a serious side reaction[ A further side reaction canarise from the ambident nature of the cyanide anion ð53AG"E#459Ł\ as substitution can occur oneither carbon or nitrogen\ giving nitriles and isonitriles respectively\ as shown in Scheme 0[ Inpractice\ however\ use of NaCN or KCN results only in the formation of cyanides by SN1 displace!ment[ Use of heavy metal cyanides such as silver cyanide\ however\ gives the isonitrile via a moreSN0 type reaction due to complexation of the halide with the heavy metal "cf[ Chapter 2[07[A21#[

R CN R X R NCNaCN AgCN

Scheme 1

"i# Displacement of halide

The reaction of cyanide salts with alkyl halides was _rst reported in 0743 ð0743JPR"50#59Ł\ and isnow one of the most common ways of introducing a nitrile group into an organic compound[ Thereaction is often conducted in an alcoholic solvent ð30OSC"0#425\ 44OSC"2#261Ł\ and follows thereactivities expected for an SN1 reaction[ Thus\ when comparing the halogens\ the order of reactivityis iodide×bromide×chloride\ and ~uorides are inert[ It is possible to selectively displace onehalogen in the presence of a less reactive one\ as illustrated by the synthesis of 3!chlorobutyronitrilefrom 2!chloropropyl bromide and KCN ð30OSC"0#045Ł[ The reactivity of alkyl chlorides may beincreased by adding a catalytic amount of sodium iodide to the reaction ð20IEC241Ł[ Neopentylhalides are inert to reactions with the cyanide ion ð02M0782\ 22JA3050Ł\ whilst halides a! to oxygenð28JA0463\ 30JA1685Ł and nitrogen ð39JIC370Ł atoms\ as well as benzylic ð0770CB0534\ 30OSC"0#096\34JA0138Ł\ and allylic ð25MI 207!90\ 30OSC"0#35\ 42JA2329Ł halides react easily[ The last named\ however\may give products arising from allylic rearrangement ð21HCA143\ 33JA434Ł\ and from migration ofthe double bond into conjugation with the nitrile ð0778JA78\ 96LA"240#243\ 12CB0061Ł[ Halides adjacentto a carbonyl group are also often easily replaced "esters ð93JA0434Ł^ acids ð30OSC"0#070\ 30OSC"0#143Ł^ketones ð23CB28\ 33JA107Ł#[ However\ in the last case\ elimination and reduction can be serious sidereactions "ð37CRV078Ł and references therein#[ Another problem with a!haloketones is competitiveattack of the cyanide ion at the carbonyl group "see Section 2[07[0[1[1#\ followed by displacementof halide by the cyanohydrin\ leading to a!epoxynitriles "Equation "0## ð22JA3188\ 28G267\ 30G30\33JA295Ł[

502General Methods

R1R2

O

Cl

ONC

R1R2

CN–(1)

Where necessary\ a variety of methods are available for increasing the nucleophilicity of thecyanide anion[ Thus\ use of hexamethylphosphoramide "HMPA# as the solvent\ and NaCN ratherthan KCN\ results in coordination of the HMPA to the sodium ions\ and the formation of highlynucleophilic naked cyanide ð67JOC0906Ł[ A similar e}ect can be obtained for KCN by using amixture of HMPA and 07!crown!5 ð67JOC0906Ł\ or just 07!crown!5 ð63JOC2305Ł[ For primary andsecondary alkyl chlorides which normally react with cyanide only very slowly\ use of DMSO as thesolvent and temperatures of 89Ð059>C result in improved yields ð59JOC146Ł\ as do glycolic solventssuch as diethylene glycol and polyethylene glycol!299 ð45ACS0086Ł[ Adsorption of NaCN or KCNonto alumina also gives a highly reactive cyanide source ð68JOC1918\ 79SC168Ł[ The use of lithiumcyanide has been reported to give superior results due to its greater solubility in organic solvents\such as acetonitrile and DMF ð53JOC0869Ł[

Although the displacement of halides by cyanide is often a straightforward reaction\ one problemthat is sometimes encountered is _nding a suitable solvent for both the organic halide and NaCN[Alcohols are not always suitable solvents since alcoholysis of the halide can be a side reactionð37CRV078Ł\ and solvents such as HMPA and DMSO can cause puri_cation di.culties particularlyfor large!scale reactions[ One solution to this problem is to use a two!phase organic:aqueous solventsystem\ and a phase!transfer catalyst such as a quaternary ammonium salt ð62JA2502Ł\ polysorbate!79 ð78JOC3365Ł\ or 07!crown!5 ð64TL60Ł[ The crown ether catalyses both solid:liquid reactions "e[g[\BnBr:dry KCN#\ and liquidÐliquid reactions carried out in an acetonitrile:water solvent system[ Afurther possibility is to use sonication to induce a reaction between an alkyl halide dissolved intoluene\ and solid KCN and alumina as described by Ando et al[ ð73CL614Ł[ The yield of nitrileobtained in this way is reported to be higher than that obtained using 07!crown!5 as a phase transfercatalyst[ An alternative approach is to use acetone cyanohydrin as the cyanide source\ since in thepresence of 0\4!diazabicyclo ð4[3[9Łundec!4!ene "dbu# or tetramethylguanidine this reagent convertsalkyl halides into nitriles ð82SC1212Ł[

Tertiary alkyl halides are not susceptible to substitution under standard SN1 conditions\ andunder SN0 conditions give the isonitrile[ One solution to this problem has been developed by Reetzet al[ ð70AG"E#0906\ 72T850Ł[ Thus\ reaction of a tertiary alkyl halide with TMS!CN in the presenceof a catalytic amount of SnCl3 results in formation of the corresponding nitrile with retention ofstereochemistry as shown in Equation "1#[ The reaction is thought to proceed via the correspondingisonitrile\ with the SnCl3 isomerising this functionality to the nitrile product[ Other groups whichare susceptible to SN0 type reactions such as a!chloro ethers also undergo this reaction "cf[ Section2[07[1[3#[

Cl CNTMS-CN/SnCl4

(2)

"ii# Displacement of oxy`en `roups

Alcohols can be displaced by cyanide in a one!pot procedure using TMS!Cl\ NaCN\ and catalyticNal in acetonitrile:DMF ð70JOC1874Ł[ The method gives good to excellent yields with primary\secondary and tertiary alcohols^ an example is shown in Equation "2#[ An alternative processinvolves a Mitsunobu!type reaction using PPh2\ diethyl azodicarboxylate "dead# and HCNð65HCA1099Ł^ acetone cyanohydrin can be used instead of HCN in this reaction ð82SC1370Ł[ Forprimary alcohols\ the use of HCN can be avoided by utilising a reagent system composed of Bun

2P:CCl3:KCN:07!crown!5 ð79S0996Ł\ or Ph2P:CCl3:NaCN:DMSO ð56JOC744Ł[ A more common pro!cedure for the displacement of an alcohol is to _rst form the corresponding tosylate or mesylateand then displace the sulfonate with cyanide ð41LA"464#0\ 45JA349\ 47JOC686\ 51JCS843Ł[ Alcohols orDMF are often chosen as the solvent for this reaction[


OOH

OCN

TMS-Cl/NaCN/NaI(3)

2[07[0[0[1 Electrophilic substitutions

Cyanogen chloride reacts with the sodium salts of malonic acid and acetoacetate derivatives togive the cyano derivatives ð0778AC"R#111\ 0785CB0060\ 0788CB532Ł[ However\ use of cyanogen bromideoften results in formation of the bromo derivatives instead[ Primary aliphatic Grignard reagentsalso react with cyanogen chloride to give nitriles\ but secondary and tertiary Grignard reagents givethe corresponding chlorides instead ð00CMR"041#277\ 01CMR"044#33\ 03CMR"047#346\ 15BSF0478Ł[ Thisproblem can be overcome by using cyanogen instead of cyanogen chloride\ in which case all aliphaticGrignard reagents give nitriles ð00MI 207!90\ 01MI 207!90\ 03MI 207!90\ 04AC"R#17\ 19AC"R#253Ł[ A widevariety of highly functionalised organozinc compounds have been shown to react with Ts!CNto give the corresponding nitriles with good yields ð82TL3512Ł[ Arylisocyanoates ð54CB2551Ł andcyanamides ð41CB286Ł also react with Grignard reagents to give nitriles[

2[07[0[1 Synthesis via Addition Reactions

2[07[0[1[0 Addition to CC multiple bonds

HCN adds to unactivated alkenes only with di.culty\ requiring high temperatures and pressures\and the reaction is generally not synthetically useful ð37CRV078Ł[ Nevertheless\ a number of organ!ometallic catalysts for this reaction have been discovered\ and are the subject of a number of reviewsð66OR"14#144\ B!71MI 207!90\ 74MI 207!90Ł[ Co1"CO#7 catalysed addition of HCN to unactivated alkenesoccurs in a sealed tube at 029>C ð43JA4253Ł[ Best results are obtained with terminal alkenes\ andMarkovnikov addition to the alkene is observed[ PdðP"OPh#2Ł3\ and NiðP"OPh#2Ł3 catalyse theaddition of HCN to both norbornene and ethene with yields of exo!1!cyano!norbornane up to 72)from reactions carried out at 019>C in benzene ð58CC001Ł[ The mechanism of this reaction has beeninvestigated ð70CC0987Ł\ and it has been shown that the HCN adds in a cis fashion to the alkene[Jackson and co!workers have modi_ed the above palladium and nickel catalysts by introducingthe chiral 1\2!O!isopropylidene!1\2!dihydroxy!0\3!bis"diphenylphosphino#butane "diop# ligand "0#\giving catalysts "diop#1Pd\ and "diop#1Ni respectively ð68JA5017\ 71AJC1930Ł[ The addition of HCNto norbornene catalysed by these chiral catalysts\ gave exo!1!cyanonorbornane in up to 84) yieldand 15) ee[ Linear alkenes gave mainly the product of anti!Markovnikov addition\ and thereaction has been shown to be susceptible to steric hindrance\ as attempted hydrocyanation of6\6!dimethylnorbornene was unsuccessful[ The mechanism of the reaction has been investigatedð71AJC1942\ 71TL0510\ 77OM0650Ł\ and the corresponding platinum catalyst "diop#1Pt was found notto be e}ective as a catalyst[

O

O

PPh2

PPh2

(1)

Anti!Markovnikov addition of HCN across an alkene can be achieved via a hydrozirconationreaction as shown in Scheme 1 ð76TL184Ł[ Thus\ addition of zirconocene hydrochloride to an alkenegives the alkyl zirconocene chloride "1# in which the zirconium adds to the least hindered end of thealkene[ Treatment of compounds "1# with either t!butyl or TMS!isocyanide results in insertion intothe carbon zirconium bond giving the imine derivative "2#[ Treatment of compounds "2# with iodinethen gives the nitriles\ the best yield being obtained with t!butyl isocyanide derivatives[ The reactionis normally highly regiospeci_c[ However\ internal alkenes are isomerised to terminal alkenes underthe reaction conditions\ and so give terminal nitriles[ Aromatic or heteroaromatic alkenes give

504General Methods

signi_cant amounts of the more hindered nitrile\ as shown by 1!vinyl furan which gives 1!furyl!propionitrile "3# as the sole product "see also Section 2[07[1[1[2#[

R1 Cp2Zr

Cl

HCp2Zr

R1

Cl

R1

NR2

Cp2Zr

Cl

NCR1

Scheme 2

CN

R2 I2

R2 = But or TMS

OCN

(3)(2)

(4)

+

Unlike unactivated alkenes\ cyanide adds with ease to both electron!de_cient conjugated alkenesðB!81MI 207!90Ł\ and electron!rich enol ethers and enamines[ However\ as these reactions inevitablylead to nitriles containing heteroatoms\ they are dealt with in the appropriate sections later in thischapter[

2[07[0[1[1 Addition to CX multiple bonds

The addition of cyanide to carbonyl compounds giving a!hydroxynitriles "cyanohydrins# wasdiscovered as early as 0721 when Winkler reacted HCN with benzaldehyde and obtained man!delonitrile ð0721LA"3#135Ł[ Since then\ numerous variations to the reaction conditions have beeninvestigated\ so that conditions are available under which aromatic and aliphatic aldehydes\ andaliphatic and monoaromatic ketones give good yields of the corresponding cyanohydrinsð0761LA"053#144\ 95CB0745\ 05CB0272\ 33OSC"1#18\ 34JOC330\ 44OSC"2#325Ł[ However\ the addition of HCNto a carbonyl group is reversible\ and for diaromatic ketones\ the position of equilibrium is towardsthe carbonyl compound and HCN[ In many cases\ an advantageous procedure involves _rst formingthe bisul_te adduct of the carbonyl compound and then reacting this with cyanide ð0785CZ89\05CB0272\ 21MI 207!90Ł[ For modi_cations leading to optically active cyanohydrins\ see Section2[07[1[3[0[

The addition of TMS!CN to aldehydes and ketones was _rst reported simultaneously by Evanset al[ ð62CC44\ 62TL3818Ł\ and by Lidy and Sundermeyer ð62CB476Ł[ With aldehydes\ the additionoccurs at RT\ but for ketones the reaction either needs to be conducted above 099>C\ or needs tobe catalysed[ The catalyst can be either a base "tertiary or hindered secondary amines\ phosphines\triphenylarsine and triphenylantimony ð80CL426Ł\ calcium ~uoride ð78CL0282\ 82BCJ1905Ł\ solid cal!cium or magnesium oxide ð82BCJ1905Ł\ KCN:07!crown!5 ð62TL3818\ 72TL3448Ł or Bu3NCNð62TL3818Ł# or a Lewis acid such as zinc iodide ð62CC44\ 73TL3472Ł\ TMS!OTs ð70T2788Ł\ a lanthanidetrichloride "SmCl2\ CeCl2\ and LaCl2#\ Eu"fod#2 ð76TL4402Ł\ ðHC"Py#2W"NO#1"CO#Ł"SbF5#1ð82TL1164Ł\ or ferric or tin montmorillonite ð78CL0282\ 82BCJ1905Ł[ Yb"CN#2 also catalyses thisreaction\ despite not being a Lewis acid\ allowing the formation of cyanohydrins from acid sensitiveketones ð80CL0336Ł[ Additionally\ zinc iodide and solid KCN can be used together in a combinedacid base catalyst ð67S108Ł[ Probably the most widely used catalyst is zinc iodide\ which has beenreported to catalyse the addition of TMS!CN ð67TL2662Ł\ t!butyldimethylsilyl cyanide "TBDMS!CN#\ and t!butyldiphenylsilyl cyanide "TBDPS!CN# ð82JOC048Ł to even sterically hindered ketones\and in the case of TMS!CN to give cyanohydrin silylethers from ketones which do not form stablecyanohydrins ð63JOC803Ł[ However\ 07!crown!5:KCN has been reported to give even better results\especially with ketones ð72TL3448Ł[ For the lanthanides\ depending upon the catalyst used theproduct is the cyanohydrin\ the cyanohydrin silyl ether\ or a mixture of both in a combined yieldof 24Ð87)[ Best results are obtained with aromatic aldehydes\ and the worst results occur withaliphatic ketones[ This method has been extended to chiral a!hydroxy\ and a!amino aldehydesð81CL0058Ł\ and Eu"fod#2 was found to catalyse the formation of the syn!diastereomer "Equation"3##[ Good results have been obtained with benzyl!protected hydroxy aldehydes and with dibenzyland butoxycarbonyl!protected amino aldehydes\ and the degree of diastereoselection increases asthe steric bulk of the side chain R of the aldehyde increases[ The diastereoselective addition of TMS!CN to a!dibenzylamino aldehydes has also been investigated by Reetz et al[\ who found that use of


TiCl3\ or MgBr1 as catalysts gave the chelation controlled product\ whilst BF2\ ZnBr1 and SnCl3catalysts gave the diastereomeric products ð77TL2184Ł[

R

X

O

RCN

X

OH

TMS-CN/Eu(fod)3 (4)

TMS!CN adds to a\b!unsaturated ketones in the presence of a variety of Lewis acid catalysts\ togive either the cyanohydrin resulting from 0\1!addition\ or the 3!ketonitrile resulting from 0\3!addition to the enone ð66OR"14#144\ 72T856Ł[ The product is determined by the structure of theketone\ although in some cases it is possible to isomerise the kinetically formed 0\1!adduct to thethermodynamically more stable 0\3!adduct by prolonged reaction[ See also Section 2[07[1[3[2[

Acetone cyanohydrin can also be used as the cyanide source\ providing a catalyst is present[Evans and Truesdale originally introduced the use of the cyanide ion as the catalyst at 019Ð039>Cð62TL3818Ł\ though Lewis acid catalysts have since been found to be more e}ective[ Catalysts basedon lanthanide alkoxides ð82CL264Ł\ titanium and zirconium alkoxides\ and aluminum alkyls havebeen used ð89CL0060Ł\ although with aluminum as the metal\ better results are obtained usingligands which contain a phenol\ imine and an amide ð80CL034Ł[ Diethylaluminum cyanide is alsoan e}ective cyanide source\ and has been reported to be advantageous in electronically di.cultcases ð61JA3543Ł[

If cyanide is allowed to react with a carbonyl compound in the presence of a primary or secondaryamine\ then the product is the a!aminonitrile[ This procedure was discovered in 0749\ and is calledthe Strecker reaction ð0749LA"64#16Ł[ Numerous reaction conditions have been developed for thisreaction\ allowing the preparation of a!aminonitriles derived from aromatic and aliphatic aldehydes\aliphatic and monoaromatic ketones ð0779CB271\ 95CB0070\ 97CB1814\ 20JCS0280\ 20JCS0783\ 44OSC"2#164Ł[A modi_ed procedure in which sodium hydrogensul_te is _rst added to the aldehyde to form thebisul_te adduct has been reported to give higher yields in some cases ð62OSC"4#326\ 76TL436Ł[ Themechanism of the Strecker reaction has been the topic of considerable debate[ However\ from asynthetic point of view\ the most important point is that it is possible to treat a cyanohydrin withan amine and obtain an a!aminonitrile[ This is often synthetically more convenient than thetraditional one!pot Strecker reaction ð23JA1086\ 23JPR164\ 33OSC"1#18Ł[ A chiral version of the Streckerreaction has also been reported ð82BSF402Ł\ in which cyanide and ammonia are _rst reacted with achiral ketone to give a chiral aminonitrile[ This then functions as a chiral ammonia equivalent in asecond Strecker reaction with an aldehyde giving optically active aminonitriles after a hydrolyticworkup to cleave and regenerate the ketone!derived chiral auxiliary[ A number of other examplesof chiral Strecker reactions based on the use of chiral auxiliaries on the nitrogen atom have beenreported ð69CJC0770\ 60CB2483\ 79CB609\ 79LA101\ 74LA455Ł[

With hindered ketones\ the Strecker reaction sometimes gives the cyanohydrin rather than theaminonitrile[ However\ it has been reported that sonication of the reaction mixture ensures for!mation of the aminonitrile ð75TL2174Ł[ Alumina has been shown to be a good catalyst for theStrecker synthesis of a!aminonitriles\ providing the reaction mixture is sonicated ð76CL576Ł[ Themethod works well for aldehydes and acetophenone\ and has the advantage of a much simplerworkup procedure compared to more classical methods^ the solids are _ltered and the solvent"acetonitrile# is evaporated to leave the aminonitrile[ Aminonitriles can also be prepared from theTMS ethers of cyanohydrins by treatment with an amine ð73TL3472Ł[

Diethyl phosphorocyanidate can be used as a cyanide source for the Strecker reaction and thishas the advantage that the reaction can be carried out in an organic solvent under entirely anhydrousconditions\ allowing the preparation of water!sensitive aminonitriles ð68TL3552Ł[ Mai and Patilð74SC046Ł have reported a general procedure for the preparation of a!aminonitriles from a widerange of aldehydes\ methyl ketones and amines using TMS!CN as the cyanide source[ Thus\treatment of the aldehyde or ketone with the amine for 0 minute at 099>C in the absence of a solventresults in formation of the iminium salt which when treated with TMS!CN for a further minute at099>C gives the a!aminonitrile[ The only limitation of this method appears to be that ammoniacannot be used as the amine due to its volatility[

A reaction related to the Strecker synthesis is the addition of HCN to a preformed carbonnitrogen double bond[ Suitable substrates for this reaction include imines ð23JA1984\ 35JA736Ł\ oximesð31JOC053\ 32JPR160\ 33JA0541Ł\ hydrazones ð0785CB51Ł and semicarbazones ð23JPR06\ 66JOC1990\77OSC"5#223Ł[ The Lewis acid catalysed addition of TMS!CN to preformed imines and oximes hasalso been reported ð64ABC460\ 64CL220Ł[ The most e}ective Lewis acid was found to be Znl1\ and by

506General Methods

use of imines with a chiral auxiliary on the nitrogen atom\ chiral aminonitriles could be obtainedð64CL626Ł[

With a\b!unsaturated aldehydes\ the Strecker reaction carried out under traditional conditionsoften fails ð57JBC"132#5998\ 63ACS"B#206Ł[ However\ by using TMS!CN as the cyanide source\ andreacting it with a preformed imine\ then good yields of b\g!unsaturated!a!aminonitriles can beobtained ð73JOC1521Ł[

2[07[0[2 Synthesis via Elimination Reactions

2[07[0[2[0 Elimination from carbonyl derivatives

The dehydration of oximes is one of the most common ways of preparing nitriles\ and a largenumber of reagents have been found to carry out this transformation\ some of which are set out inTable 0[ As Table 0 shows\ many of the reagents which dehydrate oximes also dehydrate amides"see Section 2[07[0[2[1#[ This reactivity can be explained by considering the similarity between thestructure of an oxime and the tautomeric form of an amide as indicated in "4# and "5#[ Botteghi etal[ have examined the dehydration of chiral oximes to nitriles\ and report that many of the reagentsthat carry out this transformation "Ac1O\ HCO1H\ SeO1\ dicyclohexylcarbodiimide "dcc#\ causepartial racemisation[ However\ they found that carbonyl diimidazole dehydrated oximes withoutcausing any racemisation ð71SC14Ł[

N

R

OHN

R OH

H

(5) (6)

Dimethylhydrazones can be oxidised to nitriles in moderate to excellent yields using eithermcpba\ or H1O1 and SeO1 ð78S112Ł[ Alternatively\ reaction with methyl iodide gives the hydrazone!ammonium salt which on treatment with NaOMe eliminates trimethylamine and Hl\ giving thenitrile ð51JOC3261Ł[

Aldehydes can be converted directly into nitriles in one!pot procedures involving reaction with anumber of hydroxylamine!based reagents[ Examples include hydroxylamine hydrochloride andselenium dioxide in pyridine ð68S611Ł\ hydroxylamine and formic acid in re~uxing water ð68S001Ł\O!aminobenzoylhydroxylamine:BF2 ð77SC1068Ł\ O!"1\3!dinitrophenyl#hydroxylamine:KOHð64JOC015Ł\ O\N!ditri~uoroacetylhydroxylamine:pyridine ð48JA5239Ł and hydroxylamine sulfateð65HCA1675Ł[ Alternatively\ reaction of dimethylhydrazine with an epoxide gives the reagent "6#which has been shown to react with various functionalised aldehydes leading to nitriles ð67S290Ł[Reaction of an aldehyde with ammonia and an oxidising agent such as iodine ð55BCJ743Ł\CuCl1:O1:NaOMe ð52RTC646Ł\ or lead tetraacetate ð54CI"L#877Ł also results in formation of thenitrile[

N OHHN +–

(7)

MeMe

2[07[0[2[1 Elimination from carboxylic acid derivatives

Heating an acid in the presence of anhydrous ammonia results in the formation of the nitrile viadehydration of the ammonium salt ð35MI 207!90Ł[ Alternatively\ a dehydrating agent such as ethylpolyphosphate ð72S031Ł or MsCl:pyridine ð71OPP285Ł can be used[ Acids can also be converted intonitriles in a one!pot procedure involving treatment with phosphorus pentachloride and TsNH1

ð44OSC"2#535Ł[ Alternatively\ treatment of a carboxylic acid with O!methyl hydroxylamine andPPh2:CBr3 followed by photolysis gives the corresponding nitrile ð82SC0950Ł[ When a carboxylicacid is heated to 049Ð299>C in the presence of a nitrile\ an equilibrium is established in which theoriginal acid is converted into a nitrile[ The yield of this process can be improved if the original


Table 0 Reagents for the dehydration of amides or oximes to nitriles[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐRea`ent Amide dehydration Oxime dehydration Comments*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐTFA 68S45Ac1O 96CB1698 44OSC"2#589TFAA:pyridine 66TL0702 66TL0702 Pyridine is not always needed

89T7156[CH2COCl 0773CB0460 Other acid chlorides can also be used[CCl2COCl 74S073 72S637 Very mild conditions[2\4!NO1C5H2COCl 34JA050 34JA0634COCl1 91CB2536 Pyridine is usually the reaction solvent[CCl2OCOCl 75TL1192 75S0926 Tolerates many other functional groups[PhOCOCl 60CJC0210 Other chloroformates can also be used["Imidazole#1CO 73CPB1459 62CC514 With amides allyl bromide is a coreagent[DCC 50JOC2245 59BCJ0271\ 63CB0110 Other dimides can also be used[p!Cl!C5H3!SCOCl 69CC0903Tf1O:Et2N 65TL592Ph2P

¦OTf Tf− 64TL166 PPh2¦Tf1OSOCl1 0782LA"163#201 0783BSF0956Me1N

¦1CHCl Cl− 79SC368 73TL2254 DMF¦ðSOCl1 or "ClCO#1Ł

Me1N¦1CCl1 Cl− 63S452

TsCl or PhSO1Cl 44JA0690 64S491 Pyridine or Et2N is added[ClSO1NCO 68S116 68S116ClSO1F 79S548SCl1:Et2N 68ZN"B#400 Other similar sulfur compounds were

also used["1!Py#OSO1"!1!Py# 75TL0814 Also converts thioamides into nitriles[Me1S:Cl1 64SC312Me2N

¦SO1− 67S691

MeSCH1NMe1¦I− 64SC188

Burgess reagent 77TL1044 Tolerates many other functional groups[PCl4 33OSC"1#268P1O4 44OSC"2#382 07M139POCl2 34OS"14#52 67ZN"B#0922 For oximes\ similar reagents were also

used["EtO#2P:I1 68TL0614 68TL0614Catechol!PCl2 52CB0276PPh2:CCl3:Et2N 60CB0929 60CB1914 Also converts thioamides into nitriles[PPh2!polymer 66S30 66S30Pl2:Et2N or P1I3 67S894\ 79CC433P"NEt1#2 62CL466 Also converts thioamides into nitriles[Esters of PPA 71S480\ 78SC0320 50BCJ88"Cl1PN#2 61CJC2746 62JOC0959Cyanuric chloride 79S546 61CC0115 Reagent is cyclo"ClCN#2[TiCl3:organic base 60TL0490AlCl2:NaCl 39JA0321BF2 26JA0191Ag1O:Etl 82TL0470 Non!acidic conditions[Cu"OAc#1 72S639 Acts catalytically[Rh carbonyl clusters 77CL174 At 7 atm under a CO atmosphere[MeCH1C"OEt#1:BF2 50JOC1191CCl1 62TL1010 62TL10101\3!NO1C5H2F:KOtBu 64SC188SeO1 67S692 Can be used catalytically[Electrochemically 78JOC1138*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

{donor| nitrile is a dinitrile ð60JOC2949Ł[ Treatment of a carboxylic acid with chloro!sulfonylisocyanate\ followed by a tertiary amine\ also results in conversion of the acid into a nitrileð56CB1608\ 69OS"49#07Ł[ Dithioacids are converted into nitriles on treatment with hydroxylamine inpyridine ð21BSB085Ł

Esters are converted into nitriles by treatment _rst with hydroxylamine to give the hydroxamicacid\ then with phosphorus tribromide as shown in Scheme 2 ð76S057Ł[ An alternative one!potprocedure involves treatment of an ester with two equivalents of aminodimethylaluminum\ givingnitriles in 49Ð80) yield ð68TL3896Ł[ A variety of TMS esters are converted into nitriles by treatmentwith P1O4\ "TMS#1NH\ and Nal at 89>C ð76IJC"B#396Ł[

Acid chlorides can be converted into nitriles in a one!pot procedure by treatment withH1NSO1NH1\ and good!to!excellent yields are obtained for a variety of acid chlorides ð71TL0494Ł[

508General Methods

Scheme 3

O

R OEt

O

R NHOHR CN

H2NOH•HCl

70–98%

2PBr3

83–94%

Treatment of acid halides with the chlorophosphazine "7# "the reagent also contained 14) of theeight!membered ring derivative#\ similarly gives nitriles in 4Ð84) yields ð62TL2714Ł[

P

NP

N

PN

ClCl

Cl

Cl Cl

Cl

(8)

A very large number of reagents have been reported to dehydrate unsubstituted amides to nitriles\some of which are shown in Table 0[ For simple nitriles\ it is often su.cient to strongly heat theamide and collect the nitrile by distillation as it forms ð44OSC"2#657Ł[ However\ many solids such assilica\ pumice and alumina are known to catalyse the dehydration ð37CRV078Ł[ The Burgess reagent"CH2O1CN−SO1N¦Et2# dehydrates even highly functionalised amides to nitriles in 71Ð81) yieldsat RT in dichloromethane ð77TL1044Ł[ For small!scale reactions\ probably the reagent of choice istri~uoroacetic anhydride "TFAA# "either with pyridine ð66TL0702Ł or without ð89T7156Ł#\ whichdehydrates amides under very mild conditions at RT or below[ Furthermore\ the reagent causes noracemisation of labile\ chiral centres ð89T7156Ł\ and gives only volatile by!products[ Chloro!sulfonylisocyanate has also been reported to dehydrate chiral amides to nitriles without causingracemisation ð71SC14Ł[ For large!scale dehydrations\ or for dehydrating unfunctionalised amides\POCl2 ð96CB1698\ 23CB0651Ł or SOCl1 ð0782LA"163#201Ł is probably the reagent of choice[ In the caseof POCl2\ a number of di}erent reaction conditions involving addition of NaCl or P1O4 or use ofvarious solvents have been reported to result in increased yields ð37CRV078Ł[ Whilst both oxalylchloride and thionyl chloride act as dehydrating reagents in their own right\ addition of DMF tothe reaction mixture results in a much more reactive dehydrating agent[ It is thought that in bothcases the chloroiminium salt "8# is the actual dehydrating agent ð79SC368Ł[

N

Cl

Me

Me

(9)

+

Cl–

N!Alkylated amides can also be converted into amides\ by a process called the Von Braunreaction[ Thus\ N!t!butylamides are converted into nitriles upon treatment with POCl2 ð72OPP186Łor PCl4\ and N!TMS amides are converted into nitriles on treatment with an acid chloride ð61TL1946Ł[Secondary amides are also converted into nitriles on treatment with Wilkinson|s reagent"RhCl"PPh2#2# at 149>C ð69TL0852Ł[ Primary\ secondary and tertiary amides are all converted intonitriles by treatment with bis"trimethylsilyl#amine at 079>C ð69JOC2142Ł[ Treatment of a primaryamide with two equivalents of TMS!Cl gives the N\O!bis!TMS adduct "09#\ which on treatmentwith either a basic "Bu3NF# or acidic "FeCl2\ ZnCl1\ AlCl2\ or iron phthalocyanine# catalyst isconverted into the nitrile in 84Ð099) yield ð75TL236Ł[

N-TMS

R O-TMS

(10)

1\1?!Dipyridyl sul_te converts both amides and thioamides into nitriles ð75TL0814Ł\ as does CCl1ð62TL1010Ł and PPh2:CCl3 ð60CB0929Ł\ whilst diethyl carbonate:N!methylmorpholine selectively


converts thioamides into nitriles ð74JOC1212Ł as does HgCl1:MeNH1 ð48JCS3939Ł[ Imino ethers areconverted into nitriles on treatment with sodium ethoxide ð57TL50Ł[

2[07[0[2[2 Elimination from nitro compounds

Aliphatic nitro compounds can be converted into nitriles by a number of reagents\ many of whichare phosphorus"III# compounds[ Thus\ the reaction with Pl2:Et2N occurs at RT in CH1Cl1 ð79CC433Ł\and the same authors also report the use of P1I3 for this transformation ð68TL2884Ł[ Phosphorustrichloride in pyridine has been reported to convert a variety of nitriles including unsaturated\aryl\ and a!oxygenated derivatives into nitriles ð66JOC2845Ł[ Olah et al[ have reported that thistransformation can also be achieved either by treatment with hexamethylphosphorus triamide"HMPT# in re~uxing dichloroethane\ or by reagents of the type R2N¦SO1

− in re~uxing dichloro!methane ð68S25Ł[ POCl2 is the only phosphorus"V# compound reported to dehydrate nitro groupsto nitriles ð69ACS2313Ł[ A rhodium cluster compound has been used to convert nitropropaneinto propionitrile ð74CL0228Ł[ Treatment of sodium borohydride with sulfur gives a reagent ofcomposition NaBH1S2 which reduces aliphatic nitro compounds to nitriles ð60CJC1889Ł[ Treatmentof a nitro compound with KH followed by bis"TMS#!sul_de\ then photolysis also results in nitrileformation ð80JCS"P0#0382Ł[

2[07[0[2[3 Elimination from amines and amino acids

Dehydrogenation of an amine to a nitrile can be e}ected in the gas phase by a variety of catalystsincluding nickel\ copper\ zinc sul_de and cadmium sul_de ð37CRV078Ł[ Hydrocarbons are formedas by!products[ However\ this can be suppressed by carrying out the dehydrogenation in the presenceof ammonia or oxygen[ A variety of similar processes have been developed in which the amine isgenerated in situ by the dehydrogenation catalyst from a precursor such as an amide\ aldehyde\alcohol\ alkene or alkyne ð37CRV078Ł[ A number of these processes are of considerable industrialimportance[

Oxidation of an amine with Pb"OAc#3 ð54TL350Ł\ IF4 ð50JOC1420Ł or NiO1 ð52CPB185Ł results information of the nitrile[ Treatment of an amine with a brominating or chlorinating agent underbasic conditions results in the formation of the corresponding nitrile by an N!halogenation:dehydrohalogenation mechanism ð0784AC"R#178\ 0784CB0571Ł[ The amine can also be generated insitu by a Ho}mann degradation\ and this then provides a method for the conversion of an amideinto a nitrile with one less carbon atom ð0773CB0393\ 0773CB0819\ 0775CB0322\ 0775CB0711Ł[ In a relatedreaction\ a!amino acids react with chloramine!T ð05BJ"09#208\ 05PRS121\ 06BJ"00#68Ł\ sodium hypo!bromite ð51B42Ł or N!bromosuccinimide "NBS# ð50JBC"125#604Ł to give nitriles by an oxidativedecarboxylation process[

2[07[0[3 Synthesis from other Nitriles

The acidity of the protons adjacent to a nitrile group provides an easy way of converting arelatively simple nitrile into a more complex one\ and a comprehensive review has been written onthis subject ð73OR0Ł[ A number of bases can be used to deprotonate nitriles\ including sodiumhydroxide ð44OSC"2#110\ 44OSC"2#112\ 63AG"E#554Ł\ sodamide ð44OSC"2#108\ 57JOC2391Ł\ BunLið57JOC2391\ 70CCC0571\ 72TL2498Ł and LDA ð75JOC2996\ 82T7312Ł\ though with the weaker basespolyalkylation of the resulting anions is sometimes a problem and the reagent of choice is probablyLDA or a similar lithium amide base[ The resulting carbanions have been reported to react withvarious electrophiles including alkyl halides ð44OSC"2#108\ 63AG"E#554\ 79T664\ 82T7312Ł\ alkyl tosylatesð72SC24Ł\ esters ð34JA1041\ 72TL1948Ł\ aldehydes ð57JOC2391Ł\ ketones ð57JOC2391\ 70CCC0571\ 75JA0200\76TL0500Ł and cyanohydrins ð72TL2498Ł[ Nitrile carbanions will also react intramolecularly\ withalkyl halides giving cyclic nitriles ð44OSC"2#112\ 63AG"E#554Ł\ with epoxides providing a route tocyclic g!hydroxynitriles ð78TL3656Ł\ and with esters giving cyclic b!ketonitriles ð76TL353\ 76TL3534Ł[Electrolysis of an aryl halide in acetonitrile results in formation of the acetonitrile enolate whichreacts with ketones and esters to give b!hydroxy and b!ketonitriles respectively ð82T4980Ł[

The protons of an alkyl cyanoacetate are very acidic\ and will undergo a variety of alkylationreactions ð46OR"8#096\ 82T7312Ł\ including Michael additions with suitable a\b!unsaturated carbonyl

510General Methods

derivatives ð75TL2242Ł\ and reductive alkylation by aldehydes in the presence of KHFe"CO#3ð64JCS"P0#0162Ł[ Mitsunobu and co!workers have reported that the same compounds react withdiols in the presence of PPh2 and diethyl azodicarboxylate "dead# to give cyclic a!carboxynitrilesð65TL1344Ł[ Alkyl dicyanoacetates are readily methylated under phase!transfer catalysis ð78S501Ł\and react with other nucleophiles under basic conditions ð77S870Ł[

a\b!Unsaturated nitriles are readily prepared by a variety of methods "Chapter 2[08#\ and a varietyof reagents are available to reduce them to the corresponding saturated nitriles[ For nitriles thatcontain no other reducible functional groups\ the reagents of choice are probably sodium borohy!dride ð65BCJ1532\ 67CJC30Ł or Wilkinson|s catalyst ð58JOC2573Ł[ With some a\b!unsaturated nitriles\sodium borohydride in conventional solvents is not an e}ective reducing agent[ However\ additionof methanol and pyridine has been reported to give a more reactive reducing agent ð77SC570Ł\ ashas a combination of NaBH3 and PdCl1 ð63JOC2949Ł[ For more functionalised nitriles\ reducingagents speci_c for a\b!unsaturated carbonyl derivatives including nitriles have been reported[ Theseinclude] Mg in MeOH ð64JOC016Ł^ Mo"CO#5 and phenylsilylhydride ð76JOC1465Ł^ NaHFe1"CO#7ð67JA0008Ł^ Fe"CO#4:NaOH ð61JOC0431Ł^ Rh5"CO#05:CO:H1O ð62CL268Ł^ diphenylsilane\ zinc chlo!ride and Pd"PPh2#3 ð75JA6203Ł^ copper hydride complexes ð79JOC056Ł^ Pd:C:Et2NH¦HCO1

−

ð67JOC2874Ł^ NaHCr1"CO#09 ð65S485Ł^ CrSO3:DMF:H1O ð55JA3853Ł^ and sodium hydrophosphiteð74JOC2397Ł[

Acrylonitrile and other a\b!unsaturated nitriles are also very good Michael acceptors for bothradicals and carbanions\ and both have been widely used to prepare a!unsubstituted nitriles[ Suitableradical sources include thioacyl imidazoles ð76TL3534Ł\ xanthates ð73AG"E#58Ł\ alkyl halides ð75JA139\76CC0996\ 76JOC2548\ 89TL1864Ł\ organomercury compounds ð74T3914Ł and nitroalkanes ð74CL524\74JA3221Ł[ Amongst the carbanion sources that have been used are enamines ð73JOC0202Ł\ cyanideð0767LA"080#22Ł\ hydrocarbons with acidic protons such as cyclopentadiene ð34JA590Ł and enolatesof esters\ aldehydes\ ketones\ nitriles\ cyanohydrins\ nitro compounds and sulfones ð37CRV078\77OSC"5#755Ł[ In addition\ a\b!unsaturated nitriles are good alkene components for both DielsÐAlderð31CRV208\ 36JA462Ł and 0\2!dipolar cycloadditions ð72TL2336\ 73JOC165Ł\ thus providing access to awide variety of cyclic nitriles[

2[07[0[4 Miscellaneous Methods of Synthesis

Isonitriles can be thermally isomerised to the thermodynamically more stable nitriles[ By employ!ing ~ash vacuum pyrolysis\ or short contact ~ow pyrolysis\ the rearrangement can be made to occurwithout isomerising any double bonds in the isonitrile\ and with complete retention of con_gurationat the isonitrile centre as shown in Equation "4# ð76CB0Ł[

Ph

NC

Ph

CN

flash vacuum pyrolysis, 550 °C, 10–2 torror short contact flow pyrolysis, 350 °C

95%, 95% ee(5)

Aldehydes can be converted into the chain extended nitrile via the a\b!unsaturated nitro compoundas shown in Scheme 3[ Ketones are converted into the chain!extended nitriles on treatment withtosylmethyl isocyanide "TsMIC# in the presence of potassium t!butoxide "Equation "5## ð62TL0246\66JOC2003Ł\ or by treatment with carboethoxyhydrazine:HCN followed by Br1:NaOMe ð66JOC1990\77OSC"5#223Ł[ The same chain!extending transformation can be carried out by treating either analdehyde or a ketone with 1\3\5!triisopropylphenylhydrazine followed by KCN in re~uxing methanolð66CC179Ł[ An alternative procedure involves treating a carbonyl compound with TMS!formamidine"00# and sec!BuLi\ giving the enamine as shown in Scheme 4[ Exchange of the formamidinefor N\N!dimethylhydrazine followed by Ho}mann elimination with methyl iodide:base gives thecorresponding nitriles ð82TL4728Ł[ Electrochemical reduction of the nitro alkene in the presence ofTiCl3 gives the nitrile ð76S520Ł[

O

R RNO2 R CN

MeNO2

TiCl4/Et4N+TsO–

+5– 6 e–

64–95%

Scheme 4


O

R1

R2

CN

R1

R2

TosCH2N=C

KOBut(6)

R1

R2

CN

R1

R2

TMS NMe

NBut

R2

R1

N Me

NBut

O +BusLi

i, Me2NNH2 ii, MeI

iii, NaOMe

(11)

Scheme 5

a!Amino ketones can be converted into imine derivatives\ as shown in Scheme 5\ which thenundergo a fragmentation reaction giving nitriles ð52HCA0089Ł[

O

R3

NR2R1

NX

R3

NR2R1

R3 CN

X = OH, O2CMe, O2CPh

Scheme 6

2[07[1 ALIPHATIC NITRILE SYNTHESIS

2[07[1[0 Saturated Unsubstituted Nitriles

A number of routes for the synthesis of unfunctionalised aliphatic nitriles have been developedusing organoboranes as the starting material[ Addition of a trialkylborane to methylcopper gives areagent which enables the boron alkyl groups to undergo a Michael addition to acrylonitrile\ asshown in Equation "6# ð65TL144Ł[ Trialkylboranes also react with CuCN\ Cu"OAc#1\ and Cu"AcAc#1\to give alkylnitriles in good!to!excellent yield ð78CC155Ł[ The same reaction can be achieved bytreating a trialkylborane with NaCN and lead tetraacetate ð73CC287Ł[ Electrolysis of a trialkylborane"R2B# in acetonitrile results in transfer of the alkyl groups to the acetonitrile\ giving nitriles of theform RCH1CN ð64CL412Ł[ Hydroboration of an alkene with 8!borabicycloð2[2[0Łnonyl "8!BBN#gives a trialkylborane\ which in the presence of potassium 1\5!di!t!butyl!3!methylphenoxide reactswith chloroacetonitrile to give the nitrile in which two carbon atoms have been added to the alkeneð71TL1966Ł[ In the same way\ trialkylboranes react with dichloroacetonitrile to give a!branchednitriles in which two groups have been transferred from boron to the acetonitrile[ The reaction canalso be carried out in two steps\ using two di}erent alkylboranes\ thus allowing two di}erent alkylgroups to be introduced ð58JA5743\ 69JA4680Ł[ Trialkylboranes also react with diazoacetonitrile givingalkylnitriles ð57JA5780Ł[

CN CNR

[R3BMe]Cu

84–93%(7)

2[07[1[1 b! and More Remotely Unsaturated Nitriles

2[07[1[1[0 Aliphatic nitriles with one double bond

Treatment of an allyl alcohol with HCN in the presence of CuCl and NH3Cl results in formationof the b\g!unsaturated nitrile ð40LA"461#38Ł[ Allylic acetates and carbonates are converted into b\g!unsaturated nitriles by treatment with TMS!CN\ and Pd"PPh2#3 ð82JOC05Ł[ The reaction proceedsvia a p!allyl complex\ which is attacked by cyanide anion at the least hindered end[ Allyl phos!phonates are converted into b\g!unsaturated nitriles on treatment with cyanide anions^ the reactionproceeds without allylic transposition and has no e}ect on the double!bond geometry ð70BCJ518Ł[

512Aliphatic Nitrile

Allyl methyl ethers are converted into b\g!unsaturated nitriles by treatment with TMS!CN in thepresence of p!methoxyphenyldiphenylmethyl perchlorate ð76CL0056Ł[ The reaction proceeds largelywithout allylic displacement[ An alternative transformation of allyl ethers involves oxidation to theallyl cation with 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#\ followed by cyanation withTMS!CN in the presence of a catalytic amount of lithium perchlorate giving b\g!unsaturatedcyanohydrins as shown in Equation "7# ð76CL0700Ł[ Best results "×79)# are obtained with methylethers\ t!butyldimethylsilyl "TBDMS# and phenyl ethers give much lower yields[

R3

R2 OR1

R3

R2 OR1

NCddq/TMS-CN

LiClO4(cat.)(8)

b\g!Unsaturated nitriles can be deprotonated with a suitable base such as LDA\ and the anionsthen react with alkylating agents exclusively in the a!position\ providing a route to a!functionalisedb\g!unsaturated nitriles ð64TL3536Ł "see also Section 2[07[0[3#[ a\b!Unsaturated nitriles\ which arereadily prepared by a variety of routes "see Chapter 2[08#\ can also be deprotonated "LDA:HMPA#\to give the same delocalised carbanion obtained from b\g!unsaturated nitriles\ and again alkylationoccurs a! to the nitrile ð64JOC0051\ 68JOC299Ł[ The readily prepared a!cyano allyl esters "01# undergoa palladium!catalysed Carroll reaction\ leading to b\g!unsaturated nitriles as shown in Equation"8# ð76JOC1877Ł[ Vinylboranes react with chloroacetonitrile in the presence of potassium 1\5!di!t!butylphenoxide to give the corresponding b\g!unsaturated nitriles stereospeci_cally as shown inEquation "09# ð70JOC118\ 75JOC287Ł[

OR CN

O

R CN

Pd(PPh3)4, 100 °C

(12)R = H, or Bun

(9)

R1

BR22

But

O–K+

But R1

CN

+ ClCH2CN (10)

g\d!Unsaturated nitriles can be prepared from allyl halides by reaction with cyanomethylcopperas shown in Equation "00# ð61TL376Ł[ The reaction is highly speci_c for allyl halides\ as alkyl halidesand benzyl halides fail to react[ In a similar reaction\ allyl halides react with iodomethylzinciodide and either CuCN or an a!copper nitrile derivative to give g\d! and d\o!unsaturated nitriles\respectively\ as indicated in Equation "01# ð78JA5363Ł[ The azo!Claisen rearrangement of allyl amidesis initiated by a variety of dehydrating agents such as TFAA\ triethylphosphite:iodine\ PCl4:Et2Nor COCl1:Et2N to give g\d!unsaturated nitriles as shown in Scheme 6 ð54JOC1453\ 82TL0342Ł[ Inaddition to simple allyl amides\ a!aryl\ oxygen\ halide\ ester and nitrogen containing amides alsoundergo this rearrangement\ giving a variety of functionalised g\d!unsaturated nitriles ð80TL068Ł[The same rearrangement can be brought about starting from b\g!unsaturated azides by reactionwith PPh2 and a ketene "Scheme 7# ð80TL3930\ 82T4042Ł[

Br

Br

Br

CN

+ CuCH2CN (11)

R2X

R3

R1

R2 Br

R3

R1

ICH2ZnI/CuX

69–91%

X = CN, CH2CN, MeCHCN

(12)


NH N• CN

O

R R R

Scheme 7

R2

R1 N•

R4

R3

R3

R2 R1

CNR4

R2

R1 NPPh3

R2

R1 N3•

R4

R3

OPPh3

Scheme 8

The ~uoride!initiated Michael addition of allyl silanes onto a\b!unsaturated nitriles provides aroute for the synthesis of d\o!unsaturated nitriles "Equation "02##[ The reaction is e}ective in bothinter! ð75JOC0634Ł\ and intramolecular senses ð75JOC0642Ł[ 0!Nitrocycloalkenes undergo a one!pot reaction with trimethylsilylmethylmagnesium chloride followed by PCl2 to give terminallyunsaturated nitriles as shown in Equation "03# ð82CC558Ł[

R

CNTMS

R

CN

+F

–

(13)

NO2

CN( )n

( )n

i, TMSCH2MgCl

ii, PCl3(14)

2[07[1[1[1 Aliphatic nitriles with more than one double bond

Very few {speci_c| methods have been reported for the preparation of nitriles with more than onedouble bond\ as these compounds are prepared by general methods\ or by the methods describedin Section 2[07[1[1[0 for nitriles with one double bond[ One example\ however\ is the azo!Claisenrearrangement of N!propargylamides leading to b!allenic nitriles "Scheme 8# ð54JOC1453Ł[

•N

•

CN

N

O

N

Cl

H

COCl2 Et3N

Scheme 9


2[07[1[1[2 Aliphatic nitriles with aryl or heteroaryl substituents

The direct introduction of a cyanomethyl group onto an aromatic ring can be achieved by thepalladium!catalysed coupling of an aryl halide and cyanomethyltributyltin as illustrated in Equation"04# ð73CL0400Ł[ The reaction works well with electron!rich aromatic systems\ but fails with electron!de_cient species[ Alternatively\ in the presence of Cul and HMPA\ aryl halides react with the enolateof alkyl cyanoacetates to give the a!arylmalonate derivatives\ which on heating with aqueous sodiumhydroxide decarboxylate give a!arylnitriles\ as shown in Scheme 09 ð72CL082Ł[ In the umpolun` ofthis reaction\ arylzinc chlorides react with bromoacetonitrile in the presence of a Ni"AcAc#1 catalystand cyclohexyldiphenylphosphine to give a!arylnitriles in 26Ð81) yield ð76S39Ł[ Treatment of ano! or p!hydroxy substituted benzyl alcohol with NaCN in DMF at 009>C results in substitution ofthe alcohol by cyanide\ giving the benzylnitrile ð65JOC1491Ł[ The reaction is thought to proceed viaa methylenequinone intermediate as shown in Scheme 00[ Dimethyl!o! or p!"hydroxybenzyl#aminescan be displaced by KCN\ presumably by the same mechanism ð62T0820Ł[

BrCN

Bu3SnCH2CNPdCl2[P(o-tol)3]2

(15)

Ar

CO2Et

CN

Ar

CN

CO2Et

CN

ArX + –CuI/HMPA NaOH

Scheme 10

CN

HOO

OH

HO

Scheme 11

NaCN110 °C

As illustrated above\ there are a number of routes for the preparation of compounds of the typeArCH1CN^ however\ more substituted a!arylnitriles are not so readily prepared by these methods[Grigg et al[ have reported that treatment of an arylmethylenenitrile with an alcohol in the presenceof a ruthenium catalyst "RuH1"PPh2#3# results in coupling to give the arylmethinenitrile\ as shownin Equation "05# ð70TL3096Ł[ Cainelli et al[ have shown that in the presence of KHFe"CO#3 and analdehyde\ phenyl acetonitrile undergoes a reductive alkylation giving a!alkyl!a!arylnitrilesð64JCS"P0#0162Ł[ Arylmethylnitriles react with alcohols in the presence of sodium to give the a!aryl!a!alkylnitriles ð55TL0498\ 56CPB0700\ 60JOC1837Ł[ Arylmethylenenitriles can be deprotonated with BuLi"see also Section 2[07[0[3# to give a lithium anion that undergoes Michael addition to a\b!unsaturatedketones\ providing access to a range of functionalised a!arylnitriles ð70T0816Ł[ Nitrile!stabilisedlithium anions add to arene chromiumtricarbonyl species giving a variety of a!arylnitriles afteroxidative elimination of the chromiun^ an example is shown in Equation "06# ð71JOM"139#C4\82TL0288Ł[ The same anions also add to electron!de_cient nitrobenzene derivatives ð77LA192Ł[

CN

Ar

RArCH2CN + ROH

RuH2(PPh3)4(16)

N

Bn

NTs Me

CN

N

Bn

NTs Me

(CO)3Cr

CNLi

i,

ii, I2

(17)


Cyanide will add to aryl alkenes such as cyanostilbene\ giving 1\2!diphenylbutandinitrileð11JCS0588Ł[ Ni"PTol2#3 has been used to catalyse the Markovnikov addition of HCN to aryl alkenesleading to a!arylacetonitrile derivatives ð74JOC4269Ł\ and a total synthesis of naproxen has beenachieved in this way as highlighted in Scheme 01[ The addition of HCN to styrene derivatives is notso facile\ but use of ZnCl1 as a cocatalyst increases the yield in these cases "see also Section2[07[0[1[0#[

MeO

CO2H

MeO MeO

CN

naproxen

HCN/Ni(PTol3)4

Scheme 12

Treatment of an aryl halide and a nitrile with sodium and liquid ammonia results in formationof the a!arylnitrile via addition of the nitrile anion to a benzyne intermediate ð72JOC3286\ 74JOC0223\76JOC0222\ 76JOC1508Ł[ The reaction is also e}ective in an intramolecular sense ð51JOC2725\ 62OSC"4#152\70JOC3599Ł\ giving cyclic!a!arylnitriles with a 3Ð6 membered ring fused to the aromatic ring[ Nitrileenolates also react with aryl and heteroaryl halides in a photochemical reaction\ giving a!arylnitrilesð65JOC2260Ł[

Treatment of methylthioacetonitrile "see Section 2[07[1[4# with N!chlorosuccinimide "NCS# resultsin formation of the a!chloro derivative[ FriedelÐCrafts reaction with an aromatic compound givesthe a!aryl!a!thiomethylacetonitrile which on reductive desulfurisation gives the arylacetonitrile\ asshown in Scheme 02 ð71CPB2463Ł[ Deprotonation of a!cyanomethylphosphonate "see Section2[07[1[7# with NaH:HMPA followed by addition of an aryl iodide and Cul results in formation ofthe a!aryl!a!cyanophosphonate[ On thermolysis\ the phosphate group is eliminated and substitutedby an alkyl group from the phosphate ester\ as shown in Scheme 03 ð74CL0668Ł[

Scheme 13

Ar

MeS CN

Cl

MeS CNMeS CN Ar CNZn/AcOH

ArH/SnCl4or TiCl4NCS

P

CN

O

RO

RO P

CN

O

RO

RO

Ar

CN

Ar

R

i, NaH/HMPAii, ArI/CuI ∆

Scheme 14

a\a!Diarylnitriles can be prepared by treating a diarylketone with tosylhydrazine followed bysodium hydride and TMS!CN ð78OPP243Ł[ The reaction is a variation on the method of Orere andReese discussed in Section 2[07[0[4[ The lactone "02# reacts with KCN by opening of the lactonering to give o!carboxyphenylacetonitrile as shown in Equation "07# ð44OSC"2#063Ł[ Fer!rocenylacetonitrile can be prepared by displacement of trimethylamine from N\N!dimethyl!aminomethylferrocene methiodide with KCN ð62OSC"4#467Ł and b!arylnitriles can be prepared bythe Michael addition of aryl cuprates to alkyl a!cyanoacrylates ð75TL4208Ł[

O

O

CN

CO2H

KCN

(13)

(18)

2[07[1[1[3 Aliphatic nitriles with one or more C2C triple bonds

No speci_c methods for the synthesis of alkyne containing nitriles have been reported\ and thesecompounds are prepared by the methods discussed in Section 2[07[0[


2[07[1[2 Halo!substituted Aliphatic Nitriles

Few speci_c methods for the preparation of halonitriles have been reported\ and many of thegeneral methods of nitrile synthesis described in Section 2[07[0 are applicable to these compounds[Chloroacetonitrile is prepared by the dehydration of chloroacetamide by P1O4 ð52OSC"3#033Ł\ andthe same route can be used to prepare other halogenated acetonitrile derivatives including tri~uoro!acetonitrile ð82T0430Ł[ Other a!chloronitriles can then be prepared from dichloroacetonitrile byreaction with one equivalent of a trialkylborane and potassium 1\5!di!t!butylphenolate at 9>Cð69JA4680Ł[ Barton et al[ have reported that radicals generated by the decarboxylation of carboxylicacid derivatives will add to a!chloroacrylonitrile to give a!chloronitriles ð73TL0944Ł[ Treatment of acyanohydrin with thionyl chloride also gives a!chloronitriles ð60JCS"C#1040Ł[ a!Fluoronitriles can beprepared from cyanohydrins by treatment with diethylaminosulfur tri~uoride "DAST# ð80JA5207Ł[Reaction of tri~uoroacetonitrile with phenylmagnesium bromide\ followed by reaction of the iminewith HCN\ gives the a!amino!b!tri~uoronitrile "Scheme 04# ð82T0430Ł[ Epoxides of a\b!unsaturatednitriles react with HF to give b!~uorocyanohydrins ð82SC1278Ł[

NH

Ph CF3 Ph CF3

CNH2NCF3CONH2 CF3CN

P2O5 PhMgBr HCN

Scheme 15

Active methylene compounds containing a nitrile group can be photolysed in the presence ofbromine to give a!bromonitriles ð89S657Ł and reaction of a cyanohydrin ether with NBS results information of the corresponding a!bromocyanohydrin ether ð65JOC1735Ł[ The addition of cyanogenchloride to an enol ether results in formation of b!chlorocyanohydrin ethers ð65JOC1735Ł\ anda!iodomalononitriles undergo radical additions to alkenes\ leading to g!iododinitriles ð81JA3325Ł[

2[07[1[3 Aliphatic Nitriles Bearing an Oxygen!based Functional Group

2[07[1[3[0 a!Oxygenated nitriles

The principal method for the preparation of a!hydroxynitriles is the addition of cyanide anion tocarbonyl derivatives[ This is a very general reaction and is discussed in Section 2[07[0[1[1\ thoughthe preparation of optically active cyanohydrins is discussed later in this section[ The carbanions ofO!protected cyanohydrins can be formed\ and used to prepare functionalised cyanohydrin deriva!tives ð72T2196Ł[ Reaction of a vinyl ether or vinyl acetate with HCN in pyridine gives the cor!responding cyanohydrin derivatives ð37CRV078\ B!69MI 207!90Ł[ Reaction of a carbonyl compoundwith LiCN and diethylphosphoroyl chloride results in direct formation of the cyanohydrin diethylphosphate ð82T3216Ł[ b\g!Unsaturated cyanohydrins can be prepared by the TaCl4:Zn!inducedaddition of an alkyne to an acyl cyanide ð81BCJ0432Ł[ Ortho!esters react with HCN to givea!cyanoacetals^ tertiary amide acetals\ and ester diaminals react similarly to give a!cyano!a!ami!noethers ð60CB813Ł[ a!Chloro! and a!acetoxyethers react with TMS!CN in the presence of catalyticSnCl3 to give the corresponding cyanoethers with retention of con_guration\ as shown in Equation"08# ð72T850Ł[ Acetals\ ketals and ortho!esters similarly react with TMS!CN in the presence ofBF2OEt1\ SnCl1\ or ferric or tin montmorillonite giving a!cyanoethers and a!cyanoacetals respec!tively^ however\ this reaction does not appear to be stereospeci_c ð70TL3168\ 72T856\ 82BCJ1905Ł[

O

OAc OAc

XAcO

O

OAc OAc

CNAcO

TMS-CN/SnCl4

X = Cl or OAc

(19)

a\b!Unsaturated nitriles are epoxidised by treatment with mcpba\ giving a\b!epoxynitrilesð68JOC56Ł[ These compounds can also be prepared by the Darzens condensation between chloro!acetonitrile and an aldehyde in the presence of NaOH and a crown ether ð63AG"E#554Ł[ Treatmentof an acid chloride with TMS!CN and pyridine gives the a!cyano!cyanohydrin silylether "03#


ð62CB476\ 62TL0338Ł^ similarly\ phosgene gives tricyanomethyl!TMS!ether "04# and oxalyl chloridegives adduct "05# ð62CB476Ł[

O-TMS

NC

NC

R

(14)

NC

TMS-O O-TMS

CN

CNNC

(16)

O-TMS

NC

NC

NC

(15)

A number of methods are available for the preparation of optically active cyanohydrins\ basedon one of four basic methodologies] "i# use of a chiral catalyst "including enzymes# for the asymmetricaddition of HCN to aldehydes and ketones "this area has been reviewed ð82SL796Ł#^ "ii# resolutionof racemic cyanohydrins^ "iii# addition of HCN to optically active carbonyl derivatives^ and "iv#addition of nucleophiles to chiral acyl cyanides[

The _rst catalyst to be discovered for the asymmetric addition of HCN to aldehydes was theD!oxynitrilase enzyme isolated from almonds in 0897 by Rosenthaler ð97MI 207!90Ł[ This enzyme"EC 3[0[1[09# which constitutes 9[3) by weight of almonds\ will catalyse the asymmetric additionof HCN to a wide range of aromatic ð76AG"E#347\ 89S464\ 89T868\ 80JA5881\ 80SC0276\ 80TL1594\ 81TA0112\82CB668Ł\ heteroaromatic ð76AG"E#347\ 89T868\ 80SC0276Ł and aliphatic aldehydes ð76AG"E#347\ 89S464\89T868\ 80JA5881\ 80SC0276\ 80TL1594\ 81TA0112\ 82CB668Ł as well as methyl ketones ð89S464\ 80TL1594\82CB668Ł[ The natural substrate for this enzyme is benzaldehyde ð54AG"E#0968Ł\ which is convertedinto "R#!mandelonitrile in 87) yield with 88) ee[ In early synthetic work with this enzyme\ anaqueous solvent was used\ and this is often the optimum condition[ However\ the enzyme can alsobe immobilised onto cellulose ð76AG"E#347Ł\ used in organic solvents ð89S464\ 80TL1594\ 82CB668Ł\ orcrude almond meal can be used ð77TL3374\ 89T868\ 80SC0276Ł\ and in some cases these conditions givesuperior enantiomeric excesses[ It is also possible to use acetone cyanohydrin as an in situ source ofHCN ð80JA5881\ 81TA0112Ł[

Oxynitrilase enzymes have been isolated from a variety of other sources\ but synthetic inves!tigations have only been conducted on the enzyme derived from Sor`hum bicolour "EC 3[0[1[00#ð89AG"E#275\ 89TL0138Ł\ and that derived from Hevea brasiliensis ð82TL3658Ł[ These enzymes havecomplementary activity to the oxynitrilase derived from almonds\ as they always gives the"S#!enantiomer of the cyanohydrin[ However\ the Sor`hum!derived enzyme has a much narrowersubstrate speci_city than the almond!derived enzyme\ catalysing the addition of HCN only tobenzaldehyde derivatives ð89AG"E#275\ 89TL0138Ł[ Again\ the enzyme can be used in aqueousð89AG"E#275Ł or organic solvents ð89TL0138Ł\ and can be immobilised on Eupergit C ð89AG"E#275Ł[The enzyme from Hevea brasiliensis has been reported to give "S#!cyanohydrins from both aromaticand aliphatic aldehydes in transcyanation reactions with acetone cyanohydrin as the cyanide sourceð82TL3658Ł[

In 0868\ Inoue and co!workers reported that cyclic dipeptides "diketopiperazines# containing ahistidine residue catalysed the asymmetric addition of HCN to benzaldehyde giving optically activemandelonitrile ð68MAC0978Ł[ The optimum catalysts were found to be cyclo!ð"S#!His!"S#!PheŁ "06#ð70CC118\ 71MAC468Ł\ and cyclo!ð"S#!His!"S#!LeuŁ "07# ð78CL1008Ł\ which catalysed the formation of"R#! and "S#! mandelonitrile respectively[ Catalyst "06# has been used to catalyse the asymmetricaddition of HCN to a large number of carbonyl compounds[ Aromatic ð75BCJ782\ 77AJC0586\89JOC070Ł\ heteroaromatic ð77AJC0586\ 89JOC070Ł\ and aliphatic ð74MAC0644\ 77AJC0586\ 89JOC070Łaldehydes as well as ketones ð77AJC0586Ł were all found to be converted into optically activecyanohydrins with ee|s of 4 to 86)[ Acetone cyanohydrin can be used as an in situ source of HCNwith catalyst "06#^ however\ this results in lower enantiomeric excesses in the cyanohydrins ð75CL820Ł[The diketopiperazine "06# can also be incorporated into an insoluble polymer\ though this resultsin a considerable decrease in asymmetric induction to a maximum of 07) ee ð83SC092Ł[ Althoughthe catalyst "07# has been studied less extensively than diketopiperazine "06#\ it has been observedthat not only does it give the opposite enantiomer of the cyanohydrin to the peptide "06#\ but thatit also gives the highest enantiomeric excesses with aliphatic aldehydes ð78CL1008Ł^ this is again incontrast to "06# which reacts best with aromatic aldehydes[

A number of organometallic reagents based on chiral complexes of titanium\ aluminum\ tin andmagnesium have also been found to catalyse the asymmetric addition of HCN or TMS!CN toaldehydes^ the various results are collected in Table 1[ Narasaka et al[ have described the use of thetitanium complex "08# in the asymmetric addition of TMS!CN to aldehydes ð76CL1962\ 77BCJ3268\89CL0504Ł[ It was found to be necessary to use a full equivalent of the complex "08# in the presenceof 3Aý molecular sieves[ Oguni and co!workers have described a very similar catalytic system basedupon the modi_ed Sharpless catalyst ð89CC0253\ 81JCS"P0#2024Ł[ However\ in contrast to the complex


NH

HN

O

O

N

NH

NH

HN

O

O

Ph

N

NH

(18)(17)

"08#\ only a catalytic amount of the Sharpless complex is required to catalyse the asymmetricaddition of TMS!CN to aldehydes[ The same research group ð80CC0641\ 82JOC0404Ł has reportedthat the titanium complexes of chiral imino alcohols such as "19# also catalyse the asymmetricaddition of TMS!CN to aldehydes[ The tin"II# complex "10# of "¦#!cinchone was investigated byMukaiyama and co!workers ð80CL430Ł and found to catalyse the asymmetric addition of TMS!CNto aldehydes[ Corey and Wang have reported that a mixed catalyst system based on the magnesiumcomplex of a chiral bisoxazoline catalyses the asymmetric addition of TMS!CN to aldehydes\ bestresults being obtained with aliphatic aldehydes ð82TL3990Ł[

O

O

Ph OH

PhPh

OH

PhPh

N

CF3SO3SnO N

H

But

OHN

OH

(19) (21)(20)

/TiCl2(OPri)2

The above methods all rely upon the use of TMS!CN as a cyanide source[ However\ Inoue andco!workers ð80TL3222\ 81CL1332\ 81JA6858Ł have reported that the titanium complex of the peptidederived ligand "11# "and related ligands derived from other amino acids# catalyses the asymmetricaddition of HCN to aldehydes giving the "R#!enantiomer of the cyanohydrin[ Based on molecularmodelling studies ð81JA6858Ł of the postulated catalytic intermediate\ the authors were able to designa new ligand "12# derived from "S#!valine\ the titanium complex of which catalyses the formationof "S#!cyanohydrins[ Interestingly\ although the titanium complexes of the ligands "11# do notcatalyse the asymmetric addition of TMS!CN to aldehydes\ the corresponding aluminum complexesboth of the peptides "11#\ and of the amino acid derivatives "13# do so\ but they do not catalyse theasymmetric addition of HCN to aldehydes ð80SL452\ 81JOC5667Ł[ The aluminum complexes of avariety of other N!protected amino acids and peptides were also found to catalyse the addition ofTMS!CN to aldehydes ð81JOC5667Ł[

NH

O

N

OH

Br

BrNH

CO2Me

PhO

N

OH

(23)

NH

O

N

R

OH

(22)

(24) R = Pri

R = Bui

R = Ph


Table 1 Comparison of organometallic derivatives as catalysts for the asymmetric addition of cyanide toaldehydes[

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐAldehyde Catalyst Yield ee "con_`uration#

")#*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐBenzaldehyde "08# 68 85 "R#

Sharpless 73 80 "R#"19# 56 74 "R#"11# 77 77 "R#Bisoxazoline:Mg 77 41 "S#

1!Methylbenzaldehyde "12# 85 81 "S#2!Methoxybenzaldehyde "19# 65 45 "R#

"11# 60 74 "R#"12# 68 86 "S#

2!Phenoxybenzaldehyde "19# 56 68 "R#"11# 45 80 "S#

3!Methylbenzaldehyde Sharpless 68 54 "R#"19# 57 60 "R#

3!Methoxybenzaldehyde Sharpless 77 66 "R#"19# 51 80 "R#

3!Cyanobenzaldehyde "19# 59 19 "R#1!Naphthaldehyde Sharpless 79 59 "R#

"19# 65 62 "R#"11# 44 89 "R#"12# 52 61 "R#

Furfural "11# 19 76 "S#1!Thiophenecarboxaldehyde Sharpless 73 72 "R#

"19# 59 68 "R#Butanal "19# 62 46 "R#Heptanal "11# 60 55 "R#

Bisoxazoline:Mg 77 84 "S#Nonanal "08# 74 82

"10# 78 61Decanal "08# 72 74 "R#

"19# 37 55 "R#Undec!09!enal "08# 81 82Dodecanal "19# 37 55 "R#1!Methylpropanal "19# 69 23 "R#

"10# 56 841\1!Dimethylpropanal "19# 47 69 "R#

"10# 38 72Bisoxazoline:Mg 46 89 "S#

1!Ethylbutanal Bisoxazoline:Mg 75 80 "S#1\1!Dimethylpent!3!enal "10# 16 82Phenylethanal "08# 55 662!Phenylpropanal "08# 77 80

"19# 74 39 "R#Cyclohexanecarbaldehyde "08# 66 57

"19# 61 54"11# 74 43"10# 68 85Bisoxazoline:Mg 83 83 "S#

Sorbaldehyde Bisoxazoline:Mg 13 73 "S#Propenal "19# 43 52 "R#1!Methylpropenal "19# 51 74 "R#

"11# 89 61E!But!1!enal "19# 69 78 "R#E!1!Methylbut!1!enal "19# 57 85 "R#

"11# 11 262!Methylbut!1!enal "19# 52 78 "R#

"11# 63 69Hex!1!enal "11# 82 74 "R#

Bisoxazoline:Mg 48 76 "S#Hex!1\3!dienal "11# 67 59E!1!Ethylhex!1!enal "11# 17 59Hept!1!ynal "11# 67 59Oct!1!enal "11# 72 78 "R#Geranial Bisoxazoline:Mg 20 52 "S#Cinnamaldehyde "19# 70 61 "R#

"11# 71 70 "R#"12# 39 51 "S#

*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ


A number of enzymatic systems have been reported to resolve racemic cyanohydrins[ In particular\lipases can be use to enantioselectively esterify\ transesterify\ or saponify cyanohydrins ð77TL5846\78TL0806\ 80LA36Ł[ Usually\ the maximum yield from such a reaction would be 49)^ however\ it hasbeen reported that the lipase from Pseudomonas is compatible with the reaction conditions underwhich quinidine\ anion!exchange resins\ or polymer!supported cinchona alkaloids reversibly catalysethe transcyanation of aldehydes with acetone cyanohydrin ð81BCJ000\ 81JOC4532Ł[ Thus\ in thepresence of isoprenylacetate\ the enzyme catalyses the enantioselective esteri_cation of the"S#!cyanohydrin\ which disturbs the equilibrium established in the transcyanation\ and eventuallyresults in high yields of "S#!cyanohydrin acetates "Scheme 05#[

OAc

R CN

OH

R CN

OH

R CN

R

O

AcO

quinidine

acetonecyanohydrin

+

lipase /

Scheme 16

Johnson and co!workers have reported that the TiCl3!catalysed addition of TMS!CN to chiralacetals followed by hydrolysis of the chiral auxiliary gives optically active cyanohydrins\ as illustratedin Scheme 06 ð72JOC1183\ 73TL480Ł[ Condensations of esters with optically active sulfoxides giveb!ketosulfoxides "14# as shown in Scheme 07 ð81JOC6124Ł[ Addition of cyanide "from diethyl!aluminum cyanide# to the carbonyl group of compounds "14# is controlled by the chirality of thesulfoxide\ giving cyanohydrins with ×85) de[ Reetz et al[ have investigated the TiCl3!catalysedaddition of allyl silanes and silyl enolethers to a! and b!benzyloxyacyl nitriles "15# and "16#\respectively ð74AG"E#878Ł[ In all cases\ a greater than 85) de was observed\ with the major isomerbeing the product of chelation!controlled addition of the silyl derivative to the acyl cyanide[

O

O

R

CN

O

R

OH

OH

R CN

TMS-CN/TiCl4

Scheme 17

R1S

Tol

O O

R2

R1 OEt

O

R2 STol

O

R1S

Tol

O

R2

OHNC

+LDA

Scheme 18

Et2AlCN

(25)

OBn CN

OO

CNBnO

(27)(26)

Optically active benzylic and allylic cyanohydrins can be converted into the opposite enantiomerunder Mitsunobu conditions "triphenylphosphine\ dead\ 3!nitrophenylacetic acid#\ followed byacidic hydrolysis of the resulting ester ð82T0952Ł[ However\ alkyl cyanohydrins are esteri_ed withretention of con_guration under these conditions[ By contrast\ aliphatic cyanohydrins can beinverted by treatment of a sulfonyloxy derivative with acetate followed by hydrolysis of the cyano!hydrin acetate ð82CB668Ł[ Under these conditions\ aromatic cyanohydrins are partially racemised[


2[07[1[3[1 b!Oxygenated nitriles

For racemic b!hydroxynitrile synthesis based on lithium enolates of nitriles see Section 2[07[0[3[Reactions between bromoacetonitrile and zinc result in formation of the corresponding zinc enolate\which then reacts with aldehydes and ketones in the presence of TMS!Cl to give b!silyloxynitrilesð89TL1194Ł[ Treatment of a nitrile with a boron tri~ate such as 8!BBN tri~ate results in formationof the boron enolate of the nitrile which reacts with aldehydes leading to b!hydroxynitrilesð71CL0390Ł[ A chiral b!hydroxynitrile synthesis has been reported ð81TA566Ł in which cyano!methylzinc bromide adds to aldehydes in the presence of N!methyl!diphenylprolinol "DPMPM#"17# giving b!hydroxynitriles in 63Ð82) ee[

N

Me

Ph

PhOH

(28)

Treatment of TMS!acetonitrile with an aldehyde or ketone in the presence of a ~uoride ormethoxide catalyst also gives b!silyloxynitriles ð78JCS"P0#0581Ł[ Alcohols react with a\b!unsaturatednitriles via a Michael addition to give b!oxynitriles ð34JA0494\ 34JCS424Ł\ and the reaction can alsobe made to occur intramolecularly ð78T2620Ł[ Cyanide will react with both epoxides ð58BCJ0234\62OSC"4#503\ 74JOC0446Ł\ and b!chloro alcohols ð30OSC"0#145Ł giving b!hydroxynitriles[ The use oflithium cyanide ð81TL0320Ł\ or acetone cyanohydrin in the presence of triethylamine ð81TL2170Ł asthe cyanide source\ allows the use of nonaqueous conditions which are tolerated by many otherfunctional groups[ The transfer of cyanide from acetone cyanohydrin to epoxides is also catalysedby lanthanoid"III# alkoxides ð82CL864Ł[ Diethylaluminum cyanide can also be used as the cyanidesource\ as can the complex of triethylaluminum and HCN ð69JCS"C#1254\ 78JOC0184Ł[ In each case\cyanide reacts at the least hindered end of the epoxide\ with inversion of con_guration at the epoxidecentre[

Epoxides also react with TMS!CN\ though only in the presence of a catalyst\ which can be eithera base\ such as 07!crown!5:KCN ð89JOC1905Ł or solid calcium or magnesium oxide ð89CL370Ł^ or aLewis acid\ such as Ti"OPri#3 ð74JOC0446\ 77JMOCL12Ł\ Et1AlCN ð76JOC556Ł\ Et1AlCl ð71JOC1762Ł\AlCl2 ð62TL0338Ł\ a lanthanide trichloride "LaCl2\ CeCl2 and SmCl2# ð76TL4402Ł\ an alkyl lanthanideð89TL5198Ł or Yb"CN#2 ð89TL5198Ł[ If a Lewis acid catalyst is used\ then the catalyst must be derivedfrom a hard metal\ as soft Lewis acids instead give the isonitrile ð76JOC0902Ł[ In each case\ thecyanide ion is delivered to the less hindered end of the epoxide\ and reacts with inversion ofcon_guration at that carbon\ whilst chirality elsewhere in the epoxide is preserved ð80TA326Ł[Ti"OPri#3 is only a moderate catalyst for this reaction\ and often the reaction requires extendedheating to go to completion[ However\ Oguni and co!workers have reported that addition of 09mol) of the ligand "18# to the reaction mixture results in a substantial rate enhancement\ with goodyields being obtained at room temperature ð81SL552Ł[

But

OHN

OH(29)

Alkenes can be converted into b!hydroxynitriles via a 0\2!dipolar cycloaddition with carbo!ethoxyformonitrile oxide as shown in Scheme 08[ Saponi_cation followed by thermal decar!boxylation!induced fragmentation of the intermediate isoxazoline results in the formation ofb!hydroxynitriles[ The reaction is stereoselective\ the stereochemistry of the b!hydroxynitrile beingdetermined by the geometry of the alkene ð72JOC255Ł[

b!Hydroxynitriles can be resolved via the enantioselective hydrolysis of the thioacetylesters usinglipase!P ð78CL0494Ł[ The presence of a sulfur atom in the cyanohydrin ester has been found to beessential in order to obtain a good enantiomeric excess[ Attempts to use bakers| yeast for theasymmetric reduction of 2!ketobutyronitrile\ has resulted in concomitant introduction of an ethylgroup\ giving the a!ethyl!b!hydroxynitrile\ as shown in Equation "19# ð78TL2700Ł[ However\


R2 CN

R1 OH

NO

CO2Et

R1

R2R2

R1

N+–O

CO2Et

+

i, NaOHii, ∆

Scheme 19

1!substituted!2!ketobutyronitriles are reduced by bakers| yeast\ giving a mixture of syn and antioptically active b!hydroxynitriles in which the substituent in the 1!position determines the syn:antiratio ð78BCJ2740Ł[

CN

O

CN

OH

CN

OH

Et Et

+Baker's yeast

88%(20)

b!Ketonitriles can be prepared from ketones by forming the corresponding kinetic enolate withLDA\ and then allowing the enolate to react with tosylcyanide ð70TL4900Ł[ Yields are between 45)and 79) for cyclic ketones\ but linear methyl ketones give only low yields[ Ketone enolates alsoreact with cyanogen chloride to give b!ketonitriles ð69JOC050Ł[ This transformation can also beachieved under nonbasic conditions by reacting a ketone with chlorosulfonylisocyanate ð62S571Ł[In a related reaction\ enamines react with arylisocyanates ð54CB2551Ł or cyanogen chlorideð48JA4399Ł to give b!ketonitriles after an acidic workup[ The dianion of a b!ketonitrile cannot beprepared directly from the b!ketonitrile[ However\ the dianion can be generated by treatment of anisoxazole with sodium methoxide as shown in Scheme 19 ð34JA0634Ł[ The dianion can then bealkylated regiospeci_cally at the g!position to give substituted b!ketonitriles ð67TL3110Ł[ The dianionof cyanoacetic acid can be prepared with butyllithium\ and reacts with acid chlorides to giveb!ketonitriles after a decarboxylative acidic workup ð72S297Ł[ Similarly\ TMS a!cyanocarboxylatesare deprotonated by LDA and react with mixed anhydrides to give b!ketonitriles as illustratedin Equation "10# ð68TL0474Ł[ b\g!Epoxynitriles can be prepared from b\g!unsaturated nitriles byepoxidation with mcpba ð64JOC0051Ł[

CN

O

R1

E

R2

CN

O

R1

R2

NO

R1

R2

E+2LDA

or NaOMe–

–

Scheme 20

R1

NCR2

O

R1

NC CO2-TMS

i, LDA ii, R2CO2CO2Etiii, H3O+

(21)

2[07[1[3[2 More remotely oxygenated nitriles

Oxetanes react with TMS!CN in the presence of diethylaluminum chloride\ giving g!hydroxy!nitriles in which the cyanide ion adds to the least hindered end of the oxetane ð71JOC1762Ł[g!Ketonitriles can be prepared by the cyanide!catalysed addition of aromatic aldehydes to a\b!unsaturated nitriles ð77OSC"5#755Ł[

Additions of HCN or TMS!CN to a\b!unsaturated carbonyl compounds are catalysed by Lewisacids and bases\ and can give either a g!ketonitrile\ by Michael addition of cyanide onto the enonesystem ð33OSC"1#387\ 79TL278\ 72T856\ B!81MI 207!90Ł\ or the cyanohydrin by 0\1!addition to the carbonyl"cf[ Section 2[07[1[3[0#[ The addition of HCN to conjugated carbonyl compounds has been com!prehensively reviewed ð66OR"14#144\ B!81MI 207!90Ł[ The g!ketonitrile is the thermodynamic productof this reaction\ whilst the cyanohydrin is formed under kinetic control\ so with some carbonylcompounds it is possible to isolate either product by adjusting the reaction conditions ð72T856Ł[With other carbonyl compounds however\ only the g!ketonitrile has been isolated ð79TL278Ł[ The


use of {naked| cyanide generated from acetone cyanohydrin in the presence of 07!crown!5 and acatalytic amount of KCN is reported to always add 0\3! to a\b!unsaturated nitriles givingg!ketonitriles ð66TL0006Ł[ Other reagents which favour formation of the g!ketonitrile include calciumcyanide ð56JCS"C#1354Ł\ diethylaluminum cyanide and triethylaluminum:HCN ð61JA3524\ 61JA3533Ł[In the presence of TMS!Cl\ diethylaluminum cyanide gives g!silyloxy enolethers of nitriles ð67SC120Ł[Diethylaluminum cyanide also reacts with cyclopropylketones in a Michael!type reaction to give 4!ketonitriles ð71CJC714Ł[ By using TMS!CN as the cyanide source for addition reactions to a\b!unsaturated ketones\ it is possible to obtain either the cyanohydrin "by using a solid base as thecatalyst#\ or the g!ketonitrile by utilising a solid acid catalyst ð82BCJ1905Ł[

Additions of cyanide to other conjugated C1C double bonds also occur^ they are base catalysed\and take place via a Michael!type addition giving the product where the nitrile is introduced b! tothe electron!withdrawing group ðB!81MI 207!90Ł[ Suitable Michael acceptors include esters\ alkylidenemalonates ð26JA633Ł and other nitriles ð11JCS0588Ł[

v!Cyanoaldehydes can be prepared from cycloalkenes as shown in Scheme 10 for 6!cyanoheptanalð62OSC"4#155Ł[ The key step is the Beckmann _ssion of an a!methoxyoxime[

NOH

OMe

O CN i, NOClii, MeOH/Et3N PCl5

Scheme 21

2[07[1[4 Aliphatic Nitriles Bearing a Sulfur!based Functional Group

a!Thionitriles can be prepared by the reaction of a nitrile enolate "including a!heteroatom!substituted nitrile enolates# with a disul_de ð62CL176\ 78LA192\ 89SL624Ł or with sulfenyl chlorideð65JOC1735Ł^ reaction of the enolate of an a!thionitrile with an alkylating agent ð61TL1280\ 62SC154\65TL2688\ 68H"01#570^ 76BSB"85#292\ 76S341Ł^ reaction of an a!chlorosul_de with TMS!CN in the presenceof SnCl3 ð89SC0832Ł^ or by treating bromo! or chloroacetonitrile with the sodium salt of a thiolð72BCJ146\ 73JA6789\ 73JOC2170Ł[ An electrolytic version of the latter reaction has also been reportedð89S730Ł[ Other sulfur electrophiles such as thiocyanates ð89S657Ł\ sodium benzenesul_nateð73BCJ502\ 76CL776\ 76S45Ł\ sodium sul_te ð60JCS"C#1040Ł\ diphenyldithiophosphinic acid ð68CL612Ł\N\N!dialkyl dithiocarbamates ð65TL1856Ł\ and thioamides ð74H"12#2958Ł also react with haloaceto!nitriles providing access to a wide variety of S!substituted!a!thionitrile derivatives[ In the case ofthioamides\ the sulfur atom can be alkylated twice\ providing a route to di"cyanomethyl#sul_desð68SC458Ł[ Reaction of chloroacetonitrile with dithiocarbonates "29# in the presence of 0\1!diam!inoethane also results in the formation of a!thionitriles ð76H"15#802Ł[ Sodium trithiocarbonate reactswith chloroacetonitrile in the same way\ providing a route to cyanomethyl thiol although this isreported to be unstable and explosive ð78SC0422Ł[ Thioacetals react with TMS!CN in the presenceof SnCl3 ð73TL2290Ł\ with Hg"CN#1 in the presence of iodine ð89H"29#728Ł\ or with cyanogen iodideð67OPP100Ł to give a!thionitriles by substitution of one of the sulfur groups[ Similarly\ reaction of avinyl sul_de with an alcohol in the presence of TiCl3\ gives an a!thiocarbocation which then reactswith TMS!CN to give an a!thionitrile ð76CL0852Ł[

S

ArS OEt

(30)

Oxidation of a!thionitriles can give either the sulfoxide ð70S193\ 72BCJ146\ 73JA6789Ł or sulfoneð76S341Ł\ depending upon the oxidising agent[ Optically active a!cyanosulfoxides can be preparedeither by the oxidation of the corresponding sul_de with a chiral oxaziridine ð81JA0317Ł or themodi_ed Sharpless catalyst ð74NJC0Ł\ or by reaction of a nitrile enolate with a menthyl sul_nateð70JCS"P0#503Ł[ Nitrile enolates also react with sultines to give a!cyanosulfoxides\ and use of a chiralsultine leads to the formation of optically active a!cyanosulfoxides ð70JOC4397Ł[ Optically activea!cyanosulfoxides can also be prepared from suitable a!cyanovinylicsulfoxides by an intramolecularene reaction\ creating up to three new chiral centres with ×86) de as shown in Equation "11#ð82T0720Ł[ a!Cyanosulfoxides undergo a stereospeci_c Pummerer rearrangement on treatment with


acetic anhydride\ giving a!thio!a!acetoxynitriles "Scheme 11# ð66TL0226\ 72BCJ146Ł[ Treatment of a"b!arylethyl#cyanomethylsulfoxide with TFAA results in cyclisation of the Pummerer intermediateas illustrated in Equation "12# ð77CPB0587Ł[ a!Cyanosulfoxides can be oxidised to the correspondinga!cyanosulfones by treatment with mcpba^ the latter can then be deprotonated\ and react with 0\0!dinitroalkanes to give b!nitro!a!cyanosulfones ð67TL652Ł\ and with alkyl halides to give a!alkylated!a!cyanosulfones ð74BCJ654\ 74JOC1139Ł[ An alternative synthesis of ~uorinated a!cyanosulfonesinvolves deprotonating acetonitrile with LDA\ and reacting the resulting carbanion with aper~uorosulfonyl ~uoride ð80S0194Ł[ The ~uorinated a!cyanosulfones can then be converted intovinylcyanosulfones which undergo DielsÐAlder reactions to give cyclic a!cyanosulfones ð80S0194Ł[Vinyl"aryl#sulfones can be converted into a!"arylsulfonyl#nitriles as shown in Scheme 12 ð67CPB673Ł[Thus\ treatment with iodoazide followed by elimination of Hl gives the b!sulfonylvinylazide whichwhen heated eliminates nitrogen giving a!"arylsulfonyl#nitriles[ Cyanomethyl"aryl#sulfones can alsobe prepared from arylsulfonyl chlorides and bromoacetonitrile by treatment with the compound"20# ð89SC1180Ł[ Addition of methylsulfenyl chloride to acrylonitrile gives 2!chloro!1!methyl!thiopropionitrile ð65JOC1735Ł[

S

CN

Tol

OS

CN

Tol

O

Et2AlCl(22)

CNSR

CNSR

O

OAc

Ac2OCNRS

mcpbaCNClRS– Na+ +

Scheme 22

RR

S CN

O

S

CN

TFAA(23)

ArSO2N3

I

ArSO2 ArSO2N3

ArSO2 CN

Scheme 23

dabco 65 °CIN3

P Te–Na+

EtO

O

EtO

(31)

a!Cyanosulfoxides react with arenes in the presence of TiCl3 and TFAA to give a!aryl!a!cyano!sulfoxides ð74TL366Ł[ Deprotonation of an a!cyanosulfone with NaH:Cul followed by addition ofan aryl iodide also gives a!aryl!a!cyanosulfones ð76CL776Ł[

The ylides of a!cyanosulfones act as sources of the corresponding carbenes which react withalkenes to give cyclopropyl!a!cyanosulfones ð80CC369Ł[ The same reaction can be achieved startingfrom a!chloro!a!thionitriles by treatment with SnCl3 followed by Et2N ð75JCS"P0#0652Ł[ Methylcyanodithioformate reacts as a dieneophile in the DielsÐAlder reaction\ giving cyclic\ a\a!dithio!nitriles as shown in Equation "13# ð64JCS"P0#079\ 76JOC1331Ł[ Radicals generated from carboxylicacids via a Barton decarboxylation undergo addition to acrylonitrile and its derivatives to givea!pyridylthionitriles ð76T3186\ 81TL4906Ł[ The same chemistry can be used to prepare b!cyclic!a!pyridylthionitriles by utilising v!tellurio!a\b!unsaturated nitriles as starting materials ð80TL3602Ł[Chlorination of phenylthioacetonitrile with sulfuryl chloride gives a!chloro!a!phenylthioacetonitrile


which reacts with alcohols in the presence of silver ions to give a!oxygenated!a!phenyl!thioacetonitriles ð80JA0933Ł[

R

R

S

NC SMe

S

R

RCN

SMe+ (24)

a\a!Diethylthionitriles can be prepared from diethylthioacetaldehyde "21# as shown in Scheme 13ð72CJC1995Ł[ Thus formation of the oxime and dehydration with methane sulfonylchloride givesdiethylthioacetonitrile "22#\ which can then be deprotonated with potassium hydride to give acarbanion which reacts with alkyl halides\ alkyl sulfonates\ and a\b!unsaturated aldehydes leadingto a variety of a\a!diethylthionitriles[ Dehydration of a\a!dimethylthioamides also gives a\a!dimethylthionitriles\ as shown in Equation "14# for the synthesis of the naturally occurring insectantifeedant dithyreanitrile ð82TL0974Ł[

EtS

EtS O

CN

EtS

EtS

R

EtS

EtS

NC

Scheme 24

i, NH2OHii, MeSO2Cl

i, KHii, RX

(32) (33)

NH

NH2

OMeS

MeS

OMe

NH

CNMeS

MeS

OMe

POCl3

pyridine(25)

b!Thionitriles can be prepared by the Michael addition of thiols onto b\g!unsaturated nitrilesð36JA1217\ 44OSC"2#347\ 65JOC1735\ 67S591Ł[ Other sulfur!based nucleophiles such as benzenesul_natealso add to b\g!unsaturated nitriles ð75TL4988Ł[ Cyanide undergoes Michael additions to vinyl!sulfones\ also giving b!cyanosulfones ð37CRV078Ł[ Tosyl cyanide undergoes AIBN!initiated radicaladditions to alkenes\ leading to b!cyanosulfones "Equation "15## ð76TL1742Ł[ With conjugated dienes\0\3 addition occurs providing access to b\g!unsaturated d!cyanosulfones[ b\g!Unsaturated nitrileg!silylenol ethers react with PhSCl to give b!phenylthio!g!ketonitriles as shown in Equation "16#ð67SC120Ł[

Ts

CN

TsCN/AIBN(26)

AIBN = 2,2-azobisisobutyronitrile

NC O-TMS

R

NC O

R

SPh

PhSCl(27)

2[07[1[5 Aliphatic Nitriles Bearing a Se! or Te!based Functional Group

The reaction of chloroacetonitrile with selenocyanate gives the corresponding a!selenonitrilederivative as shown in Scheme 14\ reaction with 1!ethoxybutadiene then gives the selenodinitrileð77JA7560Ł[ A variety of other selenium!based nucleophiles also react with chloroacetonitrile togive a!selenonitriles ð66CL724\ 75CC313\ 77JCS"P0#0802Ł[ a!Selenonitriles can also be prepared fromcyanohydrins by treatment with methanesulfonyl chloride followed by sodium phenylselenide


ð71JCS"P0#0292Ł[ a!Selenonitriles can be deprotonated by NaOH in the presence of tetra!butylammonium iodide to give carbanions which then react with alkyl halides leading to moresubstituted a!selenonitriles[ The process can be repeated\ giving a\a!disubstituted!a!selenonitrilesincluding cyclic derivatives ð66CL724Ł[

NC SeCl CN CN

O

NCSe CN

EtO

Scheme 25

NCSe–

Selenoacetals "23#\ react with TMS!CN in the presence of SnCl3 as a Lewis acid\ to givea!cyanoselenides "24# as shown in Equation "17# ð82SL010Ł[ Only selenoacetals with simple alkyl andaryl substituents have been investigated[ However\ seleno!ortho!esters "25# react similarly to givea!cyanoselenoacetals "26# as shown in Equation "18#[ Treatment of the anion of malononitrilederivatives with phenylselenyl bromide results in formation of a!phenylselenodinitriles which canthen undergo a radical addition to alkenes giving g!phenylselenodinitriles ð81JA3325Ł[ Reaction of amalononitrile derivative with dialkylselenium dichlorides results in formation of the a!cyano!selenium ylides ð61JOM"31#288Ł[ Electrolysis of an a!arylselenonitrile in the presence of Et2N and HFresults in the formation of a!~uoro!a!arylselenonitriles ð81TL2050Ł[

R2 R3

SeR1R1Se

R2 R3

CNR1SeTMS-CN

SnCl4

(34) (35)

(28)

(29)R2 SeR1

SeR1R1Se

R2 SeR1

CNR1SeTMS-CN

SnCl4(36) (37)

Phenylselenyl cyanide adds to unactivated alkenes in the presence of SnCl3 to give b!phenylselenylnitriles "27# ð71CC760Ł[ The reaction is a trans addition across the double bond as shown in Equation"29# for the case of cyclohexene[ Phenylselenyl cyanide also adds stereo! and regiospeci_cally toenamines giving b!seleno!a!aminonitriles ð71TL0250Ł without the need for a Lewis acid catalyst[Similarly\ in the presence of BF2 phenylselenotoluenesulfonate adds to acrylonitrile giving 1!phenyl!seleno!2!tosyl!propionitrile ð70JOC2138Ł[

CN

SePh

PhSeCN

SnCl4

(30)

(38)

Reaction of dibutyltellurium with chloroacetonitrile gives dibutyl"cyanomethyl#telluroniumchloride\ which reacts with organolithium reagents to give alkyldibutylcyanomethyltelluriumð80JCS"P0#0820Ł[ Other a!halonitriles also react with dibutyltellurium leading to tellurium salts ð80MI207!90Ł[

2[07[1[6 Aliphatic Nitriles Bearing a Nitrogen!based Functional Group

For the synthesis of a!aminonitriles by the Strecker synthesis see Section 2[07[0[1[1[ Isoquinolinesystems will undergo a Strecker!type reaction with TMS!CN and benzoyl chloride\ giving thea!aminonitriles as shown in Equation "20# ð79S273Ł[ Dihydropyridinium salts react similarly withcyanide\ giving b\g!unsaturated!a!aminonitriles ð79JA0953Ł[ Addition of HCN to 0\0!diaminoalkenes occurs easily to give a\a!diaminonitriles ð54AG"E#840\ 60CB813Ł[


NH

N

NH

N

CN

Ph

O

TMS-CN/PhCOCl(31)

Tertiary amines are oxidised to iminium salts by chlorine dioxide[ Addition of NaCN then givesa one!pot procedure for the conversion of amines into a!aminonitriles\ as shown in Equation "21#ð77JA3718Ł[ Alternatively\ the amine can be oxidised to the nitrile oxide with hydrogen peroxide\which on treatment with TFAA gives the iminium salt\ and addition of KCN gives the a!aminonitrileð79SC384\ 71H"08#1004Ł[ This transformation can also be achieved electrochemically[ Thus\ electrolysisof a tertiary amine in methanol:water in the presence of NaCN gives the a!aminonitrile ð58JA3070\66JOC1862Ł[ A related process for secondary amines involves chlorination to give the N!chloroamine\followed by elimination to the imine and addition of HCN\ as shown in Scheme 15 for piperidineð68TL660Ł[ Cyclic a!methoxyamides and carbamates react with TMS!CN in the presence ofBF2 =Et1O or SnCl3 to give a!aminonitriles "Equation "22## ð70TL030\ 82T66Ł[ Thioamides react withalkyl halides to give the S!alkylated salt which then reacts with KCN to form a!thio!a!aminonitrilesð66JCS"P0#0700\ 76BSB"85#292Ł[ a!Hydroxylaminonitriles can be prepared by the oxidation of secondaryamines with hydrogen peroxide and sodium tungstate\ followed by the addition of cyanide to theresulting nitrone ð76TL5358Ł[ Aminomalononitrile "H1NCH"CN#1# can be prepared from malono!nitrile by formation of the oxime with sodium nitrite followed by reduction of the oxime to theamine with aluminum ð62OSC"4#21Ł[

N

R3

R2 R1

N

R3

R2 R1

CN

i, ClO2ii, NaCN

67-83%(32)

NH

N

Cl

N NH

CN

Scheme 26

HCN

N

CO2Me

CO2BnMeO N

CO2Me

CO2BnNCTMS-CN/TiCl4

(33)

The a!protons of an a!aminonitrile can be deprotonated by a suitable base\ provided the aminogroup is suitably protected[ Reactions with electrophiles then provide a versatile route to a varietyof functionalised a!aminonitriles ð68S016\ 89CJC0294\ 89JCS"P0#2254\ 82SL488Ł[ b\g!Unsaturated!a!aminonitriles react similarly ð76TL5068Ł[

Amines react with a\b!unsaturated nitriles via a Michael addition\ to give b!aminonitriles ð31CB020\31JA0298\ 33JA614\ 34JA0960\ 34JOC166\ 44OSC"2#82\ 54JOC2578\ 70S264Ł[ In appropriate cases\ the aminecan react with more than one molecule of the a\b!unsaturated nitrile\ giving di! and trialkylatedamines[ This reaction has been recently reviewed ðB!81MI 207!90Ł[ Cyanide undergoes Michaeladditions to nitroalkenes giving b!nitronitriles ð32CB0164\ 36JCS0499Ł\ and to a\b!unsaturated nitrilesleading to butanodinitrile derivatives ð0767LA"080#22Ł[ N!Tosylaziridines react with TMS!CN in thepresence of catalytic Yb"CN#2\ Y"CN#2\ or Ce"CN#2 ð89TL5268Ł\ or with acetone cyanohydrin in thepresence of lanthanoid"III# alkoxides ð82CL864Ł to give b!N!tosylaminonitriles in which cyanideattacks the least hindered end of the aziridine[ When the boron enolate of a nitrile is formed withEt1NBCl1\ followed by the addition of an aromatic aldehyde\ the product is not the expectedb!hydroxynitrile\ but the b!diethylaminonitrile "Equation "23## ð68SC442Ł[ v!Aminonitriles can beprepared from cyclic a!aminoketones by Beckmann fragmentation of the derived imine or oximederivatives "see Scheme 5 for an acyclic example# ð52HCA0089\ 82SL479Ł[

NC

R R

NC NEt2

Ar

Et2NBCl2

ArCHO(34)


2[07[1[7 Aliphatic Nitriles Bearing a P!\ As!\ Sb! or Bi!based Functional Group

a!Cyanophosphonates are valuable synthetic intermediates for the formation of a\b!unsaturatednitriles via the WadsworthÐEmmons reaction "see Chapter 2[08#[ They can be prepared by theArbuzov reaction from an a!bromonitrile ð50JA0622\ 65JOC1735Ł\ or by reaction of a nitrile enolatewith diethyl chlorophosphate ð76S300Ł[ Displacement of the tosylate of a hydroxymethyl!phosphonate by cyanide anion provides an alternative route to a!cyanophosphonates^ this is aparticularly useful way of introducing 02C! or 03C!labelled cyanide into these compoundsð80JCS"P0#254Ł[ The alkene "28# undergoes Michael additions to give a!cyanophosphonates as shownin Equation "24# ð89TL1794Ł[ a!Aryl!a!cyanophosphonates can be prepared from nitroalkenes andsilylphosphites by treatment with TiCl3 and zinc "Equation "25## ð76SC842Ł[ The enolate of ana!cyanophosphonate can be formed\ and reacts with alkyl dihalides\ giving cyclic a!cyano!phosphonates ð89PS"43#060Ł^ with Tf1NF to give a!~uoro!a!cyanophosphonates ð81JCS"P0#202Ł^ andwith phenylsulfenyl chloride leading to a!phenylthio!a!cyanophosphonates ð65JOC1735Ł[

NH

NHBOCHN

O

CN

P(OEt)2

O

NH

NBOCHN

O

P(OEt)2

CN

O

+

(39)

(35)

ArNO2

PO(OEt)2

Ar CN+ (EtO)2PO-TMS

i, TiCl4

ii, Zn(36)

Cyanomethyl!containing phosphines can be prepared by a number of routes[ Thus\ reaction oflithioacetonitrile with a diaryl "or dialkyl# chlorophosphine ð76S827Ł\ reaction of cyanomethylzincbromide with an alkylchlorophosphine ð72ACS"B#528Ł\ reaction of chloroacetonitrile with anaryl"trimethylsilyl#phosphine ð65ACS"B#688\ 72ACS"B#528Ł and reaction of chloroacetonitrile with adialkyl"ethoxy#phosphine\ followed by deoxygenation of the resulting trialkylphosphine oxide withPh1SiH1 ð64ACS"B#752Ł\ all give cyanomethylphosphine derivatives[ Treatment of phosphorustrichloride with tributyl"cyanomethyl#tin gives tri"cyanomethyl#phosphine ð68JCR"S#285Ł[b!Cyanophosphines and phosphonium salts can be prepared by the Michael addition of suitablephosphines onto a\b!unsaturated nitriles ð77OSC"5#821\ 77T5096Ł[

Reaction of the TMS ketene acetal of methyl cyanoacetate with trichloroarsine results in for!mation of the corresponding a!dichloroarsine methyl malononitrile as shown in Equation "26#ð80TL1644Ł[ Reaction with PCl2 similarly gives methyl a!dichlorophosphine!a!cyanoacetateð75TL4500Ł[ Treatment of malononitrile or methyl cyanoacetate with triphenylarsine oxide resultsin elimination of water to give the a!cyanoarsonium ylides ð62T0586Ł[

NC OMe

O-TMS AsCl2

NC CO2Me+ AsCl3 (37)

Triphenyl"cyanomethyl#phosphonium chloride is prepared by the reaction of chloroacetonitrilewith triphenylphosphine ð71IJC"B#0935Ł[ Tributylantimony reacts with bromoacetonitrile to givetributylcyanomethylantimonium bromide ð80JOC0270Ł[

2[07[1[8 Aliphatic Nitriles Bearing a Si! or B!based Functional Group

a!Silylnitriles can be obtained by reaction of a nitrile enolate with a silyl chloride ð73BCJ1657\74TL4724Ł[ Thus\ TMS!acetonitrile is prepared by the reaction of chloro! or bromoacetonitrile withTMS!Cl in the presence of zinc powder ð68JCS"P0#15Ł[ The enolate of a!silylacetonitrile can then beformed\ and undergoes alkylation ð73JOC2593\ 81SC1118Ł and Michael additions ð73TL0488Ł\ givingmore functionalised a!silylnitriles[ Treatment of phenylthioacetonitrile with LDA\ followed by"chloromethyl#trimethylsilane results in formation of 1!phenylthio!2!TMS!propionitrileð70JCS"P0#145Ł[ Treatment of an a!tertiary aminonitrile with TMS!Cl gives the ammonium salt which


on treatment with LDA rearranges to the corresponding a!amino!a!trimethylsilylnitrile\ as shownin Scheme 16 ð76JOC1316Ł[ An alternative a!silylnitrile synthesis involves the use of Wilkinson|scatalyst to catalyse the addition of a trialkylsilane to an a\b!unsaturated nitrile ð63TL3994Ł[ Reactionof acetonitrile with TMS!OTf results in the formation of the tris!TMS!acetonitrile\ as shown inEquation "27# ð66S525Ł[ Mono! and di!substituted nitriles react similarly to give the di! and monosilylderivatives\ respectively[ Reaction of MeSCH1CN with TMS!OTf and triethylamine\ however\results in the formation of a!TMS!a!MeS!acetonitrile in which only one TMS group has been addedð77SC1000Ł[ Reaction of a TMS!ketone with TMS!CN and TMS!OTf results in formation of theO!TMS!a!TMS!cyanohydrin ð81JOC2220Ł[

Me

N CNPh NPhN CNPh

TMS

MeTMS Me

CN

Scheme 27

+

TMS-Cl LDA

CN

TMS

TMS

TMSMeCN + TMS-OTf (38)

Reaction of acrylonitrile with a TMS dialkylphosphite "or with a trialkylphosphite and TMS!Cl#gives dialkyl 1!cyano!1!"TMS#ethanephosphonates ð71S804\ 72S806Ł[ Treatment of the lithium anionof a nitrile with borane gives the lithium "a!cyanoalkyl#trihydroborate salt^ the lithium can then betransmetallated to other alkali metals by treatment with the appropriate ~uoride salt ð78IC381Ł[

2[07[1[09 Aliphatic Nitriles Bearing a Metal Functionality

A number of bases will replace the acidic protons a! to a nitrile by a metal as described in Section2[07[0[3[ However\ the resulting a!metal nitriles are usually reacted in situ\ and not isolated[ Theanions of a!heteroatom substituted nitriles can also be formed\ and these are discussed in the sectionof this chapter appropriate to the particular heteroatom[ However\ sodium hexamethyldisilazidedeprotonates nitriles giving the a!sodium derivatives which can be isolated ð56JOM"8#014Ł[ Acetonitrilecan be deprotonated with butyllithium\ giving cyanomethyllithium "39# as shown in Scheme 17[This can be transmetallated by treatment with Cul\ giving cyanomethylcopper ð61TL376Ł[

Me CN Li CN Cu CN

(40)

Scheme 28

BuLi CuI

Treatment of tributyltin methoxide with trimethylsilylacetonitrile under Lewis acid catalysisresults in the formation of cyanomethyltributyltin "Equation "28## ð56PNA"154#828Ł[ Tributyltinhydride also undergoes a Michael addition to acrylonitrile\ giving b!tributylstannylproponyl nitrileð74JOM"174#062Ł[

Bu3Sn OMe TMS CN Bu3Sn CN TMS-OMe+ + (39)


3.19a,b-Unsaturated and Aryl NitrilesMILTON J. KIEFELMonash University, Vic., Australia

2[08[0 GENERAL METHODS 530

2[08[1 NITRILES BEARING AN a\b!VINYLIC BOND 532

2[08[1[0 a\b!Alkenic Nitriles without Further Unsaturation 5322[08[1[1 a\b!Alkenic Nitriles with Further Unsaturation 5352[08[1[2 a\b!Alkenic Nitriles with Halo!substituents 5382[08[1[3 a\b!Alkenic Nitriles with Oxy`en!based Substituents 5492[08[1[4 a\b!Alkenic Nitriles with Sulphur!based Substituents 5432[08[1[5 a\b!Alkenic Nitriles with Se! and Te!based Substituents 5452[08[1[6 a\b!Alkenic Nitriles with Nitro`en!based Substituents 5452[08[1[7 a\b!Alkenic Nitriles with P!\ As!\ Sb! and Bi!based Substituents 5482[08[1[8 a\b!Alkenic Nitriles with Si! and B!based Substituents 5592[08[1[09 a\b!Alkenic Nitriles with Metal Substituents 550

2[08[2 NITRILES BEARING AN a\b!ARYL OR !HETARYL SUBSTITUENT 550

2[08[2[0 General Methods 5502[08[2[1 Benzonitrile and Substituted Benzonitriles 5532[08[2[2 Polycyclic Aromatic Nitriles 5562[08[2[3 Heterocyclic Aromatic Nitriles 558

2[08[3 NITRILES BEARING AN a\b!TRIPLE BOND 563

2[08[0 GENERAL METHODS

Nitriles represent one of the classical functional groups of organic chemistry[ The importance ofthe carbonÐnitrogen triple bond lies in its ease of introduction into molecules\ as well as itsexceptional reactivity due to a unique combination of unsaturation\ polarizability and low stericdemand[ Many synthetic chemists have taken advantage of these characteristics of the nitrilegroup in order to synthesize complex molecules\ in particular in the preparation of heterocycliccompounds[

The synthesis of a\b!unsaturated and aryl nitriles is similarly of great interest to organic chemists\the former especially so since they are versatile reagents which have been extensively used in thesynthesis of heterocycles[ Since this account is devoted solely to the synthesis of a\b!unsaturatedheterocycles and aryl nitriles\ and not to the use of such compounds as intermediates\ the interestedreader is directed to several excellent review articles to become more acquainted with this _eldð37CRV078\ B!69MI 208!90\ 72H"19#408\ B!72MI 208!90\ B!72MI 208!91\ 80COS"5#114Ł[ Given the comprehensivenature of these outstanding articles\ as well as the space limitations of this chapter\ this account willfocus on general strategies towards a\b!unsaturated and aryl nitriles\ together with presentingdevelopments in this _eld since 0874[

There are several general methods for the preparation of a\b!unsaturated nitriles[ These include]"i# the alkenation of either aldehydes or ketones "Wittig or WittigÐHorner condensations# andmodi_cations of this theme\ including cyanomethylation via acetonitrile^ "ii# from vinyl halides vianucleophilic displacement with cyanide ion^ "iii# from a\b!alkynenitriles by direct reduction or via

530

531 a\b!Unsaturated and Aryl Nitriles

vinyl cuprates^ and "iv# by elimination\ such as in the dehydration of oximes[ Whilst speci_c examplesof these general approaches towards a\b!unsaturated nitriles will be presented throughout thischapter\ it is appropriate at this stage to give an overview of these techniques[

The alkenations of aldehydes and ketones with cyanomethylenetriphenylphosphoraneð50JCS0155Ł or diethyl cyanomethylenephosphonate ð62T1326Ł typically give the best results whenaromatic carbonyl compounds are employed ðB!72MI 208!90Ł\ although a few e.cient methods withaliphatic carbonyl compounds have been reported ð60JOC1915\ 61TL558\ 63S758\ 66S518\ B!72MI 208!90Ł[A modi_cation of this approach involves the use of cyanomethyldiphenylphosphine oxide in thepresence of base "Equation "0## ð66S015Ł[ In this way\ E!1!alkenenitriles are prepared with ×89)selectivity for aromatic aldehydes and ½64) selectivity for aliphatic aldehydes and in excellentchemical yield "generally ×89)#[ 0\1!Diketones can also react under Wittig conditions with cyano!methylenetriphenylphosphorane to give the corresponding dialkene nitrile ð65T1868\ 66S455Ł[

RCHO +

O

PPh

Ph

CNButOK

THF or DMFR

CNCNR

+ (1)

trans cis

Vinyl halides generally have low reactivity towards nucleophilic displacement ð80COS"5#114Ł[ Forthe preparation of vinyl nitriles\ the use of copper cyanide with base under high temperatures"×199>C# is typically required ðB!69MI 208!90Ł[ However\ the use of potassium cyanide in thepresence of catalytic Pd"9# and 07!crown!5 "Equation "1## requires much milder conditions "59Ð099>C# ð66TL3318Ł[ The reaction is highly stereospeci_c and high yielding "74Ð87)#[

(2)

R2

R1 R3

Br R2

R1 R3

CN+ KCN

Pd(PPh3)4, 18-crown-6

benzene

a\b!Alkenic nitriles can also be prepared readily from a\b!alkynenitriles "see Section 2[08[3 forthe preparation of nitriles bearing an a\b!triple bond#[ Lithium aluminum hydride adds in a transmanner to alkynenitriles to provide the alanate "0# "Scheme 0#\ which upon acidi_cation leads tothe E!a\b!unsaturated nitrile "1# ð68S329Ł[ Addition of an organocopper"I# reagent to an alkynenitrilegives the a!cyanocuprate "2# "Scheme 1# which upon acidi_cation provides the 1!alkenenitrile "3#ð67S343Ł[ It is worth noting that in this instance\ the R0 and CN groups "Scheme 1# are cis to eachother "cf[ Scheme 0#[ Furthermore\ addition of an organocuprate to an alkyne provides the vinylcuprate "4a# "Scheme 2# which\ upon exposure to cyanogen chloride in THF\ gives the corresponding1!alkenic nitrile in ×89) yield ð66S673Ł[

R CN RCN

AlH2

CN

R R

CN

Scheme 1

LiAlH4 H+

(1) (2)

R1 CNR2

CN

(4)

R1

Scheme 2

R2CN

R1

Cu X

(3)

R2[CuX]M

THF or Et2OM

H+

R1R2

R1

Scheme 3

R2H

R1

Cu X

(5a)

[R2CuX]MgHal

THF or Et2OMgHal

ClCN

THF

CN

532Bearin` an a\b!Vinylic Bond

Elimination processes are also of interest as a general route into a\b!unsaturated nitriles[ Thedehydration of oximes\ an important method for the synthesis of saturated nitriles\ can also beapplied to the preparation of unsaturated nitriles[ In one reported example\ allylic nitro compoundsare deoxygenated with carbon disulphide under phase transfer conditions to provide the cor!responding allylic oxime which is then dehydrated to an a\b!alkenic nitrile "Scheme 3# ð89SC854Ł[Saturated nitriles can themselves be transformed into a\b!unsaturated nitriles via oxidative elim!ination of an intermediate a!phenylselenonitrile with hydrogen peroxide "Scheme 4# ð63TL1168Ł[

NO2

CN

Scheme 4

NOHK2CO3, CS2, H2O

TBAB, CH2Cl2

NaOH (aq.), CS2

CNCNCN

SePh i,

ii, PhSeSePh

LiN

Scheme 5

H2O2

2[08[1 NITRILES BEARING AN a\b!VINYLIC BOND

2[08[1[0 a\b!Alkenic Nitriles without Further Unsaturation

As mentioned above\ the alkenation of aldehydes or ketones is an important route intoa\b!unsaturated nitriles[ The two!carbon homologation of 06!keto!androstane to 19!keto!pregnanehas been achieved via the intermediate a\b!unsaturated nitrile "5# "Scheme 5#[ Thus\ exposure of theketone "4# to the anion of 1!"diethylphosphono#!propionitrile a}orded the alkenic nitrile "5# inexcellent yield "66)# ð65JOC0762Ł\ which was then elaborated to the progesterone "6#[ In anotherWittigÐHorner alkenation\ of either an aldehyde or ketone\ the use of a cyanophosphonate inthe presence of catalytic tetrabutylaminium iodide in an aqueous two!phase system provides thecorresponding unsaturated nitriles ð63S758Ł[ This simple procedure a}ords crotonitrile "40) yield#and 2!methyl!1!butenenitrile "51) yield#\ the former as a mixture of geometrical isomers "50 ] 28#in favour of the E!isomer[

O

(EtO)2P CN

Scheme 6

NaH

(5) (6)

O

RO RO

CN

steps

O

O

(7)


Moderate yields of several simple alkyl a\b!unsaturated nitriles from carbonyl compounds havealso been achieved using either O!ethyl S!cyanomethyl dithiocarbonate "7# or S!cyanomethyldiethyl phosphorothioate "8#\ also in a two!phase system employing catalytic methyl!trioctylammonium chloride "Scheme 6#[ It is believed that the reaction proceeds via the thiirane "09#which\ upon extrusion of sulphur\ produces the nitriles in 25Ð68) yield ð68S789Ł[ Generally higheryields result from the use of the dithiocarbonate "7#[

EtO S CN

S R1

(EtO)2PS CN

O R1

+

+

R2 R3

O

R2 R3

O

NaOH, H2O, MeCN

(C8H17)3N+Me Cl–

SR2

R3 CN

R1(8)

(9)

(10)

–S

R3

R2 R1

CN

Scheme 7

R1 = H, Me; R2 = H, alkyl; R3 = alkyl

The reaction of chloroacetonitriles and aldehydes mediated by tri!n!butylstibine at 019>Cfurnishes a\b!alkenic nitriles in yields typically ×89) ð78SC72Ł\ but generally as 0 ] 0 mixtures oftrans ] cis isomers[ Similarly\ treatment of cyclic ketones under these conditions "Equation "2## yieldsthe corresponding unsaturated nitriles\ though in more moderate yield "22Ð49)#[ Thistransformation is believed to proceed via the chloro!alkoxy!tri!n!butylstiborane "00# whichthen decomposes to the a\b!unsaturated nitrile and chloro!hydroxy!tri!n!butylstiborane "01#ð78SC72Ł[

(3)OCN

Bun3Sb

Cl CN

( )n ( )n

n = 1, 2

Bun3Sb

O

HCl

CN

R1 R2OH

Cl

Bun3Sb

(11) (12)

Acetonitrile can itself be used in the direct conversion of aliphatic ketones into a\b!alkenic nitrilesð66S518Ł[ The use of potassium hydroxide pellets as base in acetonitrile solution overcomes manyof the problems usually associated with this type of reaction\ most notably the aldol condensationof the ketone under the polar\ protic conditions normally required for this transformation[ Thereaction gives moderate to excellent yields "29Ð79)# of a\b!unsaturated nitriles^ lower yields resultfrom ketones which are easily enolized "e[g[\ acetophonone# ð66S518Ł[ Interestingly\ the reactionbetween acetonitrile and cyclohexanone "Equation "3## provides the a\b!unsaturated nitrile con!taminated with the b\g!unsaturated nitrile ð66S518Ł[ The latter component constituted about 19)of the product\ and could be easily separated from the desired conjugated nitrile[ This result iscontrary to the reaction between cyclohexanone and cyanoacetic acid which provides only theb\g!unsaturated product after decarboxylation of the intermediate cyanoacrylic acid ð40OS"40#14Ł[

(4)

OCN CNMeCN, KOH

+

4.5 : 1

As mentioned in Section 2[08[0 above\ the oxidative elimination of a!phenyl!selenonitriles is ane.cient route into alkenic nitriles ð63TL1168Ł[ Similarly\ the direct cyanoselenylation of aldehydeswith aryl selenocyanates in the presence of tri!n!butylphosphine leads to cyanoselenides of the type"02# "Scheme 7# ð66JA4109Ł[ Oxidative elimination of aryl selenoxide with hydrogen peroxide then


leads to a\b!unsaturated nitriles in excellent chemical yield\ but as 0 ] 0 mixtures of geometricalisomers[

R CHOR

SeAr

CNR

CN

Scheme 8

(13)

ArSeCN, Bu3P, THF H2O2

R = acyclic or cyclic alkyl

Electrooxidative cleavage of the C0S bond in the ethylthiol "03# "Equation "4##\ using bromideion as the electrolyte\ results in the smooth formation "56Ð67) yield# of simple alkyl and branchedalkyl a\b!unsaturated nitriles ð75TL3066Ł[ As with the oxidative elimination of selenoxides\ thisoxidative elimination process results in essentially 0 ] 0 mixtures of cis ]trans isomers[

(5)R

CN

SEt

RCN

(14)

Br –, MeOH

Reductive eliminations can also lead to alkenic nitriles "Equation "5##[ Thus\ exposure of thea!cyano!b!nitrosulphone "04# to sodium sulphide in DMF at room temperature provides the cor!responding a\b!unsaturated nitriles in good yield ð67TL652Ł[ In this way several acyclic and cyclicalkyl substituted a\b!alkenic nitriles have been prepared\ again as 0 ] 0 mixtures of geometricalisomers[ The direct dehydrocyanation of 0\1!cyclobutenedicarbonitrile "05# with sodium hydroxideat ×199>C results in moderate yields of 0!cyclobutanecarbonitrile ð62JOC364Ł[ The same productcan be obtained by the dehydrochlorination of 1!chlorocyclobutanecarbonitrile during exposure tobase under much milder conditions "009>C# ð62JOC364Ł\ although problems with the formation ofthe requisite chloronitrile substrate ð51JOC311Ł make this approach impractical on a preparativescale[

(6)

O2N

R1

R2

R3

SO2Ar

CN

R2

R1 R3

CN

(15)

Na2S, DMF

CN

CN

(16)

The use of alkynes in the preparation of a\b!unsaturated nitriles has already been mentioned inthe introductory remarks[ Further to this\ hydroboration of alkynes with bis"0\1!dimethyl!propyl#borane in THF gives the corresponding alkenyldialkylborane "06# "Scheme 8# which\ uponexposure to copper"I# cyanide and copper"II# acetate in HMPA\ produced the desired E!1!alkenicnitriles "07# in excellent yield ð80CC637Ł[ The presence of a small amount of water in the _nal stepof this transformation is essential for cyanoalkene formation ð63BCJ1400\ 78CC155Ł[

R1 R1

BR22

R1

CN

Scheme 9

(17) (18)

CuCN, Cu(OAc)2, HMPT, H2OR22BH, THF

The palladium"9# catalysed decarboxylation*dehydrogenation of allyl a!cyanocarboxylates "08#to a\b!unsaturated nitriles proceeds with generally high e.ciency for both cyclic and acyclic allyla!cyanocarboxylate substrates "Equation "6## ð75CC007Ł[ It has been found that when the allyla!cyanocarboxylate is substituted with two di}erent alkyl groups "e[g[\ "19##\ then the two isomers"10# and "11# result from this reaction in almost equal amounts ð75CC007Ł[


(7)R

CN

O OR

CNPd0, PPh3, EtCN, ∆

(19)

O O

CN

(20)

CN

(21)

CN

(22)

In the early 0889s it was found that the reactions of organozinc halides with p!toluenesulphonylcyanide provide an excellent entry into a\b!unsaturated nitriles ð82TL3512Ł[ This method is illustratedin Equation "7#[

(8)Cl ZnI Cl CNTsCN, THF, 0 °C to 25 °C

72%

2[08[1[1 a\b!Alkenic Nitriles with Further Unsaturation

In an elegant one!step synthesis of 1!cyano!0\2!butadienes\ the WittigÐHorner alkenation hasbeen utilized to great advantage[ Thus\ diethyl 1!lithio!1!cyano!1!trimethylsilylethanephosphonate"12# is condensed with an aldehyde "R0�Et\ Pri\ Ph\ Ar# or carbonyl compound "R0�R1�Ph# toprovide the intermediate 1!cyano!1!alkenephosphonate "13# "Scheme 09#[ Without isolation "13# islithiated "lithium diisopropylamide "LDA## a to the phosphorus and then reacted with a furtherequivalent of carbonyl compound to give the desired 1!cyano!0\2!butadiene "14# "Scheme 09#[ Inpractice only one addition of LDA "1 equivalents# and one addition of carbonyl compound "1[9equivalents# to the starting phosphonate is required\ and yields of the 1!cyano!0\2!butadienes aretypically above 64) ð72S806Ł[ Dienenitriles have also been prepared by the treatment of aldehydeswith trimethylsilyl cyanide ð75CB1489\ 75CB2233Ł[

(EtO)2P

O

CN

LiTMS

(EtO)2P

O

CN

R1 R2

(EtO)2P

O

CN

R1 R2

Li

R1 R2

O

Scheme 10

(23)

–78 °C

R1 R2

O

LDA

(24)

(25)

–78 °C

CN

R1

R2R1

R2


In a HornerÐEmmons reaction of a phosphononitrile with aldehydes "Equation "8##\ it has beenfound that a bulky isopropyl group on the a!carbon of the phosphononitrile results in excellentZ!selectivity of the resulting a\b!unsaturated nitrile ð83TL0470Ł[ The in~uence of solvent on the Z ]Eratio was found to be signi_cant\ with the lower polarity solvents "Et1O\ toluene# giving the highestZ!selectivity "up to 24 ] 0^ cf[ the use of THF as solvent which results in a Z ]E ratio of 1[1 ] 0#[ Thismethodology has been applied successfully to the total synthesis of the natural product plaunotol"15#[ The key step in the total synthesis of "15# involved the HornerÐEmmons reaction between thephosphononitrile "16# and the aldehyde "17# to provide the alkenic nitrile "18# ð83TL0470Ł[


(9)P(OEt)2

CN

O

+

CHO

CN

OH

OH

NC P(OEt)2

O

CHO OR

(26) (27)

OR

CN

(28) (29)

Many examples of the synthesis of a\b!alkenic nitriles with further unsaturation involvecompounds containing an aromatic ring\ often deriving from aromatic carbonyl compoundsðB!72MI 208!90Ł[ In one such example\ involving cyanophosphates "29#\ the cyanophosphorylationof aromatic ketones with diethyl phosphorocyanide in the presence of lithium cyanide a}ords "29#"Scheme 00#[ Treatment of the cyanophosphates "29# with boron tri~uoride etherate then leads tothe a\b!unsaturated nitriles in good to excellent overall yield "50Ð83)# from the ketone ð73TL316Ł[Interestingly\ the cyanophosphate "20#\ derived from an aliphatic ketone\ remains intact under thedephosphorylation conditions[

ArR1

R2

O

ArR1

R2

ONC

P(OEt)2

O

ArR1

R2

CN

O

(EtO)2PCN

Scheme 11

LiCN

BF3•Et2O

(30)

Ar

OCN

P(OEt)2

O

(31)

The reactions of aromatic carbonyl compounds with an organotellurium ylide also results in theformation of 1!alkenic nitriles ð77JOC3751Ł[ Thus\ condensation of various para!substituted aromaticketones with the cyanodibutyl telluronium ylide "21# gives the corresponding aryl a\b!unsaturatednitrile "22# in good yield "50Ð72)# and high E!selectivity "up to 013 ] 0 E ]Z#[

R

CNBun

Te+ –CHCN

Bun

(32) (33)

Organometallic chemistry when applied to aryl halides also furnishes a\b!unsaturated nitriles[ Inthis case\ the Heck reaction involving the palladium!catalysed coupling of an aryl iodide withacrylonitrile provides the corresponding aryl a\b!unsaturated nitrile in 76Ð83) yield "Equation"09## ð78JOM"260#286Ł[ This process gives mixtures of E! and Z!isomers\ although slightly in favourof the Z!geometry[

(10)Ar I + CNAr

CNPd(OAc)2, H2O, K2CO3, 80–100 °C


The interest in organic molecules as synthetic metals ð73NAT008Ł has led to the synthesis offour thiophene!fused tetracyanoquinodimethanes "e[g[\ "23##[ These compounds were prepared in04Ð26) yield by the titanium tetrachloride mediated condensation of the corresponding quinonewith malononitrile "19 equivalents# in chloroform containing pyridine "39 equivalents# ð75CC0668Ł[

SS

NC CN

NC CN

(34)

Reaction of the anion of 3!cyano!2!oxo!tetrahydrothiophene "24#\ "which can be considered as asynthetic equivalent to the a!acrylonitrile anion "25##\ with an alkyl halide leads to the C!alkylatedproduct "26^ R�ArCH1\ HC2C0CH1# "Equation "00##[ Exposure of "26# to 4) aqueous sodiumhydroxide results in a hydroxide promoted fragmentation via a series of inverse DieckmanÐMichaelreactions to give various substituted benzyl a\b!unsaturated nitriles together with the acetylenica\b!alkenic nitrile "27# "Equation "00## ð74S858Ł[ Only low to moderate yields "18Ð49)# of substituted1!alkenic nitriles result from this transformation\ although the ease of availability of the substratesand the mild reaction conditions make this a viable route into acrylonitrile syntheses[

(35) (36)

S

O CN–

CN–

(11)

S

OR

CN

CN

R

(37)

NaOH (aq.)

CN

(38)

a\b!Unsaturated nitriles containing an additional triple bond can also be prepared from thereaction of potassium cyanide with the quaternary salt of pyridazine 0!oxide "28#\ formed by thereaction of pyridazine 0!oxide with either dimethyl sulphate or benzoyl chloride "Scheme 01#[ Asbefore\ only poor yields of the desired b!ethynylacrylonitriles "19Ð29)# were achieved ð62T1326Ł\and as mixtures of geometrical isomers[ The reaction is believed to proceed via the dihydro derivative"39# which undergoes electrocyclic opening to "30# which leads to the alkyne products upon elim!ination of N1 and R2

0OH[ The intermediacy of the dihydro compound "39# is supported by itsslow conversion to the cyanopyridazine "31# "when R0�H# under the reaction conditions ð62T1326Ł[

N NR1 R2

O

N NR1 R2

OR3

+

R2

CNR1

Scheme 12

(39)

Me2SO4

or PhCOCl

KCN

R1 = Ph, Me; R2 = H, Me


N N

OR3

R1

R2

CN

N R2

CNR1

N

OR3

N N

R CN

(40) (42)(41)

The preparation of cyanoallenes "Equation "01## can be achieved by the treatment of substituted1!propynols with potassium cyanide and HBr in the presence of copper cyanide and copperð57JCS"C#180\ 80COS"5#114Ł[ Alternatively\ the propynol can _rst be converted into the halide and thentreated with copper cyanide ð80COS"5#114Ł[

(12)

R

R

HO •

R

R

CNCuCN, KCN, HBr, [Cu], 76 h

R = alkyl

2[08[1[2 a\b!Alkenic Nitriles with Halo!substituents

a!Halo!a\b!unsaturated nitriles are useful intermediates in organic synthesis[ They are generallyprepared by condensation reactions between a carbonyl compound and an a!halophosphoraneð50CB1885Ł[ In one such example\ dichloromethylenetriphenylphosphorane has been successfullyused in the preparation of 1!aryl!2\2!dichloroacrylonitriles[ Thus\ exposure of 1!arylacrylonitriles"Equation "02## "R�H\ Me\ CI\ MeO# to triphenylphosphine in a large excess of carbon tetra!chloride provides the desired aryl!2\2!dichloroacrylonitriles in 59Ð69) yield ð62JOC368Ł[ However\the reaction fails when aliphatic acyl cyanides are used as substrates[

O

CN

R

CN

R

Cl

Cl∆, 2–4 h

Ph3PCl

Cl(13)

An alternative method for the preparation of a!halo!a\b!alkenic nitriles involves the use of thereadily available arsonium salt "32#[ Treatment of the arsonium bromide "32# with iodine in pot!assium carbonate a}ords the iodoarsonium iodide "33# which\ without isolation\ was reacted witha variety of aldehydes "R�Ar\ alkyl# to give the corresponding a!iodo!a\b!unsaturated nitriles ingood to excellent yield "47) when R�alkyl^ 79Ð86) when R�Ar# "Scheme 02# ð78SC1528Ł[

Ph3As CN

Br–

+ Ph3As CN

I–

+

I

R I

CN

Scheme 13

I2, K2CO3 RCHO, K2CO3

(43) (44)

The use of a novel intramolecular Wittig reaction has been developed for the synthesis ofb!per~uoroalkyl!a\b!alkenic nitriles ð80JCS"P0#376Ł[ It was found that per~uoroacylmethylene!triphenylphosphoranes were highly stable and did not react with aldehydes under Wittig conditions[To overcome this problem\ treatment of the per~uoroacylcyanomethylenetriphenylphosphorane"34^ Rf�CF2 or C2F6# with an aryl or alkynyl lithium reagent leads to the ylide anion "35# "Scheme03#[ Acidi_cation of "35# results in a spontaneous intramolecular Wittig reaction to give the desired~uorinated a\b!unsaturated nitrile in excellent yield "89Ð85)# ð80JCS"P0#376Ł[ The products from


this transformation are predominantly the E!isomers\ and in no examples did the authors observenucleophilic attack at the cyano group in "34#[

Ph3P

CN

O

Rf

Ph3P

CN

–O

R

RfRf

CNR

Scheme 14

(45) (46)

RLi H+

Rf = CF3, C3F7; R = aryl, alkynyl

The reaction of a!chlorocarbonyl compounds with lithium trimethylsilylacetonitrile in a Peterson!type reaction is a convenient route into 2!chloro!0!cyano!prop!0!enes "Scheme 04# ð89SC1140Ł[ Theyields from this process are generally good "56Ð79)#\ although the products are mixtures ofgeometrical isomers[ One advantage of this method over other routes into 2!chloro!0!cyano!prop!0!enes\ for example the 0\1!elimination from 2!chloro!0!cyano!1!hydroxypropanes "see ð55BSF0204Ł\and references therein#\ is the ready availability of the a!chlorocarbonyl substrates and the ease ofhandling of lithium trimethylsilylacetonitrile ð89SC1140Ł[ 2!Chloro!0!cyano!prop!0!enes can also beprepared by the free radical chlorination of a!ethylenic nitriles ð63JOC1596Ł[ For example\ treatmentof crotononitrile with t!butyl hypochlorite under radical generating conditions "hn and 1\1?!azo!bisisobutyronitrile "AIBN## gave the corresponding allylic chlorinated product as a mixture ofcis ] trans isomers[ The ratio of the geometrical isomers obtained in this way was dependant uponthe concentration of the substrate\ and favoured the cis product at lower concentrations ð63JOC1596Ł[

TMS CNTMS CN

LiR1 CN

Cl

R2

LDA, THF, –78 °C

R1R2

Cl

O

Scheme 15

–78 °C

R1 = H, alkyl; R2 = alkyl, aryl

Treatment of the `em!dicyanoepoxide "36^ R�Ar\ alkyl# with Li1NiBr3 leads to the bromo!enolate "37# which can then be trapped with acetic anhydride providing various 1!acetoxy!2!bromo!1!propene nitriles "Scheme 05# ð75TL4380Ł[ The yields for this transformation are excellent "68Ð87)#\ and the product is predominantly the Z!isomer when R�aryl "typical Z ]E ratio around2 ] 0#\ although 0 ] 0 mixtures of geometrical isomers result when R�alkyl[

O

RCN

CN

R

Br OLi

CN R

Br OAc

CN

Scheme 16

(47) (48)

Li2NiBr4, THF Ac2O, pyridine

R = Ar, alkyl

2[08[1[3 a\b!Alkenic Nitriles with Oxygen!based Substituents

a\b!Unsaturated nitriles containing oxygen!based substituents are versatile synthetic inter!mediates[ Their preparation from carbonyl compounds is the most widely reported method of accessinto this class of compound\ typically employing HornerÐWittig type chemistry\ or the aldol!likecondensation with alkoxyacetonitriles[

a!t!Butoxy!a\b!unsaturated nitriles "38# have been prepared using diethyl t!butoxycyano!methylphosphonate "49# with sodium hydride in a HornerÐEmmons reaction with several carbonyl


compounds ð65JOC1735\ 66JA071Ł[ Of the many examples studied\ both with aldehydes "R0�H# andketones "R�R0�"CH1#4!\ 1!methylcyclohexanone\ 1!cyclohexenone\ etc[# the chemical yields areexcellent "69Ð88)#[ It was found that the only limitation of this method is that\ due to the stericbulk of the phosphonate "49#\ only ketones with three or more a!hydrogens will react ð66JA071Ł[Indeed\ this {limitation| can be exploited\ as in the case of the regiospeci_c reaction of the phos!phonate "49# with 4a!androstane!2\06!dione which gives a 81) yield of the a!t!butoxy!a\b!alkenicnitrile "40#[

(51)

H

O

NC

ButO

R2

R1 CN

OBut

(49)

O

(EtO)2P

OBut

CN

(50)

The reaction of saturated aliphatic aldehydes with acrylonitrile in the presence of tri!butylphos!phine "9[1 equivalent# and triethylaluminum "9[0 equivalent# at 79>C in dichloromethane underpressure a}ords 1!"0!hydroxyalkyl#acrylonitriles "41# ð73SC0156Ł[ The reaction is e.cient "69Ð89)isolated yield# for saturated aliphatic aldehydes\ but the same reaction with benzaldehyde yieldsonly 16) of the desired product[ It is believed that the reaction proceeds via the initially formedbetaine "42# which then reacts with the aldehyde to form "43# ð54JOC0246\ 69JOC2934Ł[ Eliminationof tri!butylphosphine from "43# gives the hydroxy substituted acrylonitrile "41#[

+ –

(54)

CN

HO

RBu3P

CN+

HO R

–

(52)

CN

(53)

Bu3P

Rearrangement of O!silylated cyanohydrins can also be exploited to prepare b!substituted!a!silyloxyacrylonitriles ð75SC506Ł[ Thus\ exposure of an a\b!unsaturated aldehyde to trimethylsilylcyanide in the presence of catalytic potassium cyanide and 07!crown!5 leads to the cyanohydrin"44^ R0�PhCH1\ CH2\ C2H6\ H^ R1�H\ CH2# "Scheme 06#[ Without isolation\ the cyanohydrin istreated with catalytic "4)# 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu# and isomerizes to theb!substituted!a!""trimethylsilyl#oxy#acrylonitrile[ The yields for this process are excellent "61Ð84)from the a\b!unsaturated aldehyde#\ though the products are mixtures of geometrical isomersð75SC506Ł[

R1

R2

CHO

R1

R2

CN

O-TMS R1

R2

CN

O-TMS

Scheme 17

(55)

TMS-CN, KCN, 18-crown-6 dbu

R1 = PhCH2, Me, C3H7, H; R2 = H, Me


Aldehydes can also be used in the preparation of g!hydroxy!a\b!alkenic nitriles[ Reaction ofa!"phenylsulphinyl#acetonitrile with aldehydes in the presence of piperidine in methanol a}ords theg!hydroxy!a\b!unsaturated nitriles in excellent yield and exclusively as the E!isomers "Equation "03##ð73JA6789Ł[ Ketones also undergo this reaction ð73JA6789Ł[ In a further application of this methodNokami and co!workers have employed an optically active 1!"arylsulphinyl#acetonitrile "45# toprovide optically active 3!hydroxyalk!1!enenitriles "46^ R�aliphatic# in good chemical yield "42Ð66)# and high enantiomeric excess "49Ð79) ee# ð75TL4098Ł[


R CHO

PhS CN

O R CN

OH(14)

piperidine, methanol+

(57)(56)

ArS CN

OR CN

OH*

*

3!Hydroxyalk!1!enenitriles can also be prepared by an aldol!like condensation between ana!chlorocarbonyl compound and the dilithiated anion derived from treatment of acetonitrile withLDA "Scheme 07# ð72S186Ł[ Under the basic reaction conditions the intermediate epoxide "47^R0�H\ Me\ Et\ Ph^ R1�Me\ H# isomerizes spontaneously to the hydroxy!substituted a\b!unsatu!rated nitrile "Scheme 07#\ formed in 40Ð76) yield from the a!chlorocarbonyl substrate[ Similarly\the lithiated anion of acetonitrile when exposed to the a!methylene lactone "48# in THF at −67>Cproduces the diene "59^ R�H\ Et\ Ph# ð75CC0129Ł[ The anion derived from methoxyacetonitrilereacts with arylaldehydes to provide the corresponding a!methoxy!a\b!unsaturated nitriles in goodyield "Equation "04## ð62CC670\ 72T0440Ł[

LDA, THF HMPTR1

R2

O

Cl

+ MeCN

O

R1R2

CNR1 CN

R2

OH

Scheme 18

(58)

R1 = H, Me, Et, Ph; R2 = Me, H

(60)(59)

O O

R

O

R

CN

(15)ArCHO + MeO CNAr OMe

CN

NaH, DMF, 110 °C

1!Alkoxy!1!alkene nitriles can also be prepared from vinyl ethers[ In a one!pot\ three!stepsequence\ bromination of vinyl ethers followed by cyanide displacement leads to bromonitriles ofthe type "50#[ Piperidine induced dehydrobromination then leads to the desired 1!alkoxy!a\b!alkenicnitriles in 59Ð84) yield ð75S437Ł[ Scheme 08 is illustrative\ and the sequence is applicable to bothcyclic and acyclic vinyl ethers[ The aluminum chloride catalysed DielsÐAlder reaction betweena\b!unsaturated acyl cyanides and simple alkenes also gives 1!alkoxy!1!alkenic nitriles "Equation"05## ð71AG"E#748Ł[ Acyl cyanides can also undergo a self!condensation reaction under mild\ basicconditions to provide lactones of the type "51# ð72TL1736Ł[

O O

Br

CN O CN

(61)

i, Br2, CCl4

ii, CuCN, ∆

NH

Scheme 19


(16)

O CN O CN

+AlCl3

(62)

OO CN

The Knoevenagel condensation of aromatic aldehydes or cyclohexanones with ethyl cyanoacetate\catalysed by amino groups immobilised on silica gel\ results in excellent yields of the correspondinga!carboxyethyl!a\b!unsaturated nitriles "e[g[\ "52## ð78JCS"P0#094Ł[ Angeletti et al[ found that the bestcatalyst for this condensation was a 2!aminopropyl functionalized silica gel[

(63)

Ph

CN

CO2Et

a!Carboxy!a\b!alkenic nitriles also result from exposure of methyl cyanoacetate to magnesiummethoxide in methanol ð83TL334Ł[ The resulting 2!hydroxy!1!methoxycarbonyl glutaconic dinitrile"53# "67) yield# is di}erent from that product\ viz "54#\ arising from exposure of methyl cyanoactateto sodium methoxide ð60ZN"B#0013\ 72S367Ł[ A further route into a!carboxy!b!hydroxy!a\b!unsatu!rated nitriles stems from the pyrolysis of 1\4!diazo!2\5!dihexynyl!0\3!benzoquinones "Scheme 19#ð73CC0955Ł[ The resulting\ highly reactive\ hexynylcyanoketene "55# upon exposure to alcoholundergoes an addition and subsequent rearrangement to the allene "56#[ In the presence of furtheralcohol "56# produces the a\b!unsaturated nitrile "57# ð73CC0955Ł[

(64)

HO

CN

CO2Me

CNH2N CN

CO2MeMeO2C

(65)

C6H6, 80 °C R2OH

R1

R1

N3

N3

O

O

•

NC

R1

O

(67) (68)

•

R1 CN

CO2R2

R2O

CN

CO2R2

R1

(66)

Scheme 20

R2OH

In a general and stereoselective synthesis of Z!b!silyloxyacrylonitriles ð75TL1916Ł\ exposure of4!substituted isoxazoles "58^ R0�Me\ Ph# "Scheme 10# to LDA results in the formation of theenolate "69#\ which can then be trapped in situ with either trimethyl! or t!butyldimethyl!chlorosilaneto give the Z!b!silyloxy!a\b!alkenic nitriles in 61Ð81) yield[

The b!cyanoenone "60# has been prepared in 76) yield from the dinitrile "61# "itself prepared byradical cyclization of propargyliodomalononitrile# via ozonolysis and subsequent base treatmentð89JA8390Ł[

The palladium!catalysed allylic etheri_cation of the b\g!unsaturated nitrile "62# with phenoxy!


ONR1 R1

O–

CN

R23SiO

R1

CN

Scheme 21

(69) (70)

LDA, –78 °C R23SiCl, –78 °C

R1 = Ph, Me

(71)

NC

O H

H

H

H

(72)

NCNC

tributyl tin in THF results in an 78) yield of the corresponding g!phenoxy!a\b!unsaturated nitrile"63# ð74JOC2447Ł[ The product is predominantly the E!isomer[ Interestingly\ the same reaction withmethoxytributyl tin provides only a 44) yield of the g!methoxy!a\b!alkenic nitrile ð74JOC2447Ł[

(73)

Ph CN

OAc

Ph CN

OPh

(74)

2[08[1[4 a\b!Alkenic Nitriles with Sulphur!based Substituents

In a general synthesis of a!thio!a\b!alkenic nitriles\ exposure of carbonyl compounds to thePeterson reagent cyano"methylthio#methyltrimethylsilane "64# "Equation "06## in the presence ofLDA leads to the corresponding thiosubstituted a\b!unsaturated nitriles in good to excellent yield"30Ð84)# ð77SC1000Ł[ Higher yields "67Ð84)# are obtained with arylaldehydes "R0�Ar^ R1�H#whilst more moderate yields "30Ð67)# result from the use of ketones "both aliphatic and cyclic#ð77SC1000Ł[

R1 R2

O+ TMS

CN

SMe R2

R1 CN

SMe

(17)LDA, –78 °C

(75)

As in the preparations of a!alkoxy!a\b!alkenic nitriles from the reactions of carbonyl compoundswith the anion derived from alkoxyacetonitrile "Section 2[08[1[3\ ð62CC670\ 72T0440Ł#\ the anionderived from methylthioacetonitrile reacts with carbonyl compounds to form a!methylthio!a\b!unsaturated nitriles "Equation "07## ð61JOC0239\ 67CPB0763\ 67TL1572Ł[ Acetonitrile itself can be con!densed with thioesters in the presence of butyllithium to form the lithiated intermediate "65#ð62LA0526Ł[ Subsequent methylation of "65# gives 2!substituted!2!methylthio!1!alkenic nitriles in30Ð79) yield but as mixtures of geometrical isomers "Scheme 11# ð62LA0526Ł[

R1 R2

O+ NC SMe

R2

R1 CN

SMe(18)

Triton B or NaOEt

R1 = alkyl, Ph, Ar; R2 = H, alkyl


R1 OR2

S

R1 S–

CN

Li+

R1 SMe

CN

Scheme 22

MeCN, BuLi MeI or CH2N2

(76)

Bromination of the a!thioether nitrile "66# leads to the bromothionitrile "67# "Scheme 12# which\without isolation\ can be treated with triethylamine resulting in dehydrobromination to give thecorresponding a!ethylthio!a\b!unsaturated nitrile in 54Ð79) yield ð67TL1572Ł[ The eliminativedeoxygenation of a!cyanosulphoxides "68^ R�alkyl#\ by treatment with trimethylsilyl tri~ate in thepresence of hexamethyldisilazane\ leads to the a!thiophenyl!a\b!unsaturated nitriles "79# in excellentyield "63Ð76)# ð74TL1284Ł[ a!Alkylthioacrylonitrile derivatives can also be prepared by therearrangement of a!chloro!b!alkylthionitriles induced by lithium bromide in N\N!dimethyl!formamide ð45CB0152\ 63LA0550Ł[

R2

R1 SEt

CN R2

R1 SEt

CN

Br

R2

R1 SEt

CN

Scheme 23

(77) (78)

Br2 Et3N

R1 = alkyl, Ph; R2 = H, alkyl

(79)

NC

S

O

Ph R

NC

PhS R

(80)

In an e.cient synthesis of b!alkylthio!a\b!alkenic nitriles "Equation "08##\ exposure of substitutedmalononitriles to sodium alkylthiolate gives the desired b!amino!b!alkylthio!a\b!unsaturated nitrileð77S702Ł[ Yokoyama and Sato have also reported the reduction of 2\2!bis"alkylthio#methyl!enemalononitriles "70# with sodium borohydride to give the bis"alkylthio#!a\b!unsaturated nitrile"71# ð77S702Ł[ The reaction is believed to proceed via the alkylthiomalononitrile "72#\ which reactswith alkylthiolate anion to furnish the desired unsaturated nitrile "71#[

(19)CN

NC

R1

NC

R1 SR2

NH2

R2SNa, H2O

NC

NC SR

SR

H2N SR

CN

SRNC

SR

CN

(82)(81) (83)

The addition of thiols to allenylnitriles can also be used to prepare b!thio!a\b!alkenic nitriles[Thus\ treatment of allenylnitriles "73^ R0�R1�alkyl# "Scheme 13# with thiols in the presence of acatalytic amount of base gives the b!thio!b\g!alkenic nitriles "74# as a mixture of geometrical isomersin excellent yields "89Ð84)# ð73T1030Ł[ Heating "74# at 199>C a}ords an equilibrium mixture of theb!thio!a\b!alkenic nitrile "75# and the starting b\g!alkenic nitrile "74#\ although the latter constitutes


only a minor "¼09)# portion of the mixture[ A similar equilibrium can be obtained by heating theunconjugated nitrile "74# in ethanol in the presence of sodium ethoxide ð73T1030Ł[ Once again it isthe desired b!thio!a\b!unsaturated nitrile "75# which constitutes ca[ 89) of the equilibrium mixture[

•

R1

R2

CN

R2

R1

SR3

CN

R2

R1

SR3

CN

Scheme 24

(84) (85) (86)

R3–SH, EtO– heat or NaOEt

R1 = R2 = alkyl; R3 = alkyl, aryl

2[08[1[5 a\b!Alkenic Nitriles with Se! and Te!based Substituents

Whilst the oxidative elimination of selenoxides is a commonly used route into a\b!alkenic nitriles\the preparation of a\b!unsaturated nitriles containing a selenium!based substituent is far lesscommon[ As already mentioned in Section 2[08[1[0\ cyanoselenations of aldehydes\ followed byoxidative elimination of selenoxide produces a\b!unsaturated nitriles ð66JA4109Ł[ However\ reactionsof a\b!unsaturated ketones with phenylselenocyanide in the presence of tributylphosphines give riseto g!phenylseleno!a\b!unsaturated nitriles in modest yield ð66JA4109Ł^ Equation "19# is illustrative[

(20)

O CN

SePh

PhSeCN, Bu3P

Reaction of the novel selenamidoacetonitrile "76#\ prepared by reaction of malononitrile withhydrogen selenide in the presence of base\ with 0\2!diketones in triethylamine leads to the3\5!disubstituted!2!cyanopyridine!1"0H#!selenone "77# in excellent yield "Scheme 14# ð74S87Ł[ Thesame product also results from the reaction of "76# with 1!chloro!2!cyanopyridines in the presenceof either selenourea or sodium hydrogen selenide "Scheme 14#[

R R

O O

N

R

R

CN

Cl

NCNH2

Se

NH

R

R

CN

Se

Scheme 25

Se or NaHSeH2N

H2N

Et3N

(87) (88)

To this author|s knowledge\ there have been no reports of a\b!alkenic nitriles containing telluriumsubstituents[

2[08[1[6 a\b!Alkenic Nitriles with Nitrogen!based Substituents

Tetracyanoethylene "TCNE# "78# is perhaps the best known and certainly the most widely useda\b!alkenic nitrile with nitrogen based substituents[ A comprehensive review of the synthesis andchemistry of TCNE has appeared ð75S138Ł[ In the early 0889s\ an excellent review detailing thesynthesis of b!enaminonitriles "89# and their use in heterocyclic synthesis has been publishedð82CRV0880Ł[ An earlier report on the synthesis of cyano compounds "ðB!72MI 208!90Ł and references


therein# has a section devoted to enaminonitriles[ The importance of the synthesis of enaminonitrilesand their subsequent use in the preparation of heterocycles is re~ected in all these accounts\ and theinterested reader is encouraged to consult these comprehensive articles[

(89)

NC

NC CN

CN R

H2N CN

(90)

For the preparation of simple b!enaminonitriles "89#\ the most commonly employed method isthe dimerization of substituted nitriles[ The dimerization of acetonitrile with sodium metal in organicsolvent leads to "89^ R�Me# in quantitative yield "ð42CJC0100\ 58AG"E#347\ 82CRV0880Ł and referencestherein#[ The 0858 production also reports the synthesis of simple b!enaminonitriles\ in moderateyield\ from the lithium aluminum hydride reduction of substituted malononitriles "Equation "10##ð58AG"E#347Ł[

(21)R CN

CN

R CN

NH2

LiAlH4

40%

The synthesis of a!amino!a\b!alkenic nitriles has received considerable attention "ðB!72MI 208!90Łand references therein#[ One common method for access into this class of compound involvesdeprotonation of saturated a!aminonitriles with strong base ð59JA0675\ 56CC107Ł[ Alternatively\deprotonation of "80# with lithium diisopropylamide in THF at −67>C followed by silylation\ basetreatment and exposure to formaldehyde\ yields the desired a!amino!a\b!alkenic nitrile in 64) yield"Equation "11## ð67S786\ 68S016Ł[ Another popular method for the synthesis of a!cyanoenaminesinvolves cyanation of enamines themselves ðB!72MI 208!90Ł[ In one example\ reaction of an enaminewith cyanogen bromide a}ords the b!cyanobromide "81#\ which upon exposure to triethylamine\eliminates hydrogen bromide to give the desired a!amino!a\b!unsaturated nitrile "Scheme 15#ð66S384Ł[

(22)

CN

N

Me

Ph

CN

N

Me

Phi–iv

i, LDA; ii, TMS-Cl; iii, LDA; iv, H2CO

(91)

NR1R2 NR1R2

CN

Br

NR1R2

CN

Scheme 26

(92)

BrCN Et3N

a!Amino!a\b!alkenic nitriles can also be prepared from carboxyamides[ Exposure of N!diethyl!acrylamide to sodium benzenesul_nate leads to the amide "82a# which is treated with P3S09 to givethe thioamide "82b# "Scheme 16#[ Reaction of the thioamide "82b# with dimethyl sulfate andthen potassium cyanide gives the a!cyanoenamine "83# in 59) yield as the E!isomer ð73TL2364Ł[

NEt2

O

PhSO2 NEt2

X

PhSO2 NEt2

CN

Scheme 27

PhSO2Na i, Me2SO4

ii, KCN

(93) a; X = Ob; X = S

(94)


The g!phenylsulphonyl!a!cyanoenamine "83#\ in the presence of a strong base\ acts as a syntheticequivalent of an a!carboxyl vinyl anion ð73TL2364Ł[ Exposure of an aldehyde to an amine\ followedby chlorination and subsequent treatment with potassium cyanide also gives a!amino!a\b!alkenicnitriles "Equation "12## ð68S630Ł[

(23)

R2

R1 O

R2

R1 NHR3

CN

i, R3NH2 ii, NCS

iii, KCN

In a synthesis of a!amino!b!alkoxy!a\b!unsaturated nitriles\ exposure of acetals to two equivalentsof t!butylisocyanide in the presence of titanium tetrachloride leads to the imidoyl intermediate "84#which then undergoes nucleophilic addition of isocyanide to ultimately give alkoxycyanoenaminesof the type "85# "Scheme 17# in moderate yield "25Ð58)# ð75TL2494Ł[ Interestingly\ Pellissier etal[ have reported that treatment of the same acetal with t!butylisocyanide in the presence ofdiethylaluminum chloride leads to the b!alkoxy!a!iminonitrile "86# "52Ð89) yield#[ If R2�H\ theiminonitrile "86# can undergo an acid!catalysed isomerization to the a!cyanoenamine "85# ð78TL060Ł[

R1

OR2

OR2

R1

OR2

NBut

R1

OR2

ButN NBut

R1

R2O NHBut

CN

Scheme 28

ButNC, TiCl4 ButNC

(95) (96)

R1 = H, alkyl, Ph; R2 = Me

R2O

R1

R3

NBut

CN

(97)

b!Amino!a\b!alkenic nitriles are also valuable synthetic intermediates[ Commonly\ substitutionof a halogen with either cyanide ð62S098\ 65T2952Ł or with amines ð53JOC0799\ 55CRV050Ł leads to thisclass of compound ðB!72MI 208!90Ł[ In a general synthesis of b!amino!a\b!unsaturated nitriles\nucleophilic displacement of vinyl bromides by amines in carbon tetrachloride at room temperaturegives good to excellent yields "59Ð89)# of the desired products "Equation "13## ð77S025Ł[ Thereaction proceeds with retention of double bond geometry\ although the Z!isomer does slowlyisomerize to the more thermodynamically favoured E!isomer under the reaction conditions[

(24)

Br

R1 CN

R22N

R1 CNHNR2

2, CCl4

(E)

The nucleophilic displacement of vinyl halides with cyanide ion also proceeds in high yield[Thus\ exposure of the vinyl bromide "87# to potassium cyanide in dimethyl sulfoxide gives theb!amino!a\b!alkenic nitrile "88# ð62S098Ł[ Compounds of the type "88# have also been prepared byusing phase!transfer catalysis ð67S781\ 67S783Ł[

Br

Ar1 Ar2

NHAr3 NC

Ar1 Ar2

NHAr3

(98) (99)

The reaction of carbonyl compounds under Wittig conditions has been successfully employed inthe synthesis of b!amino!a\b!alkenic nitriles[ Thus\ treatment of succinimides with cyano!methylenetriphenylphosphorane gives the corresponding 1!cyanomethylene!4!pyrrolidones "099# in


poor to moderate yields "12Ð59)# ð60CB1736Ł[ The best result "59) yield# occurs with succinimideitself "R�H#\ whilst the yields fall substantially with any substitution on the nitrogen[

NOCN

R

(100)

b!Amino!a\b!unsaturated nitriles can also be prepared via the decarboxylation of enamino esters[Whilst it has been reported that enamines like "090# can be formed by the treatment of enaminoesters "091# with aqueous base ð58AG"E#232\ 65CPB2900Ł\ the same reaction with cyanoesters of thetype "091^ Z�CN# results in a retro!condensation to give a pyrrolidinone and ethyl cyanomalonateð70JOC2560Ł[ This problem has been overcome by heating cyanoesters of the type "091^ Z�CN^R0�Me\ H^ R1�H# at high temperature "199Ð149>C# with acidic alumina for 0 h "Equation "14##[This transformation is highly temperature dependent ð74SC362Ł[

N

R1

R2

ZN

R1

R2

Z

(101)

RO2C

(102)

N

R1

R2EtO2C

NCN

R1

R2

NC

(25)Al2O3, 200–250 °C

2[08[1[7 a\b!Alkenic Nitriles with P!\ As!\ Sb! and Bi!based Substituents

There are very few publications detailing the synthesis of a\b!alkenic nitriles containing P!\ As!\Sb! and Bi!based substituents[ Indeed\ apart from reports on the preparation of a\b!unsaturatednitriles with phosphorus substituents\ it appears that a\b!alkenic nitriles with arsenic\ antimony orbismuth!based substituents are unknown[

In one report\ detailing the preparation of 1!cyano!0\2!butadienes "Section 2[08[1[1\ ð72S806Ł#\diethyl 1!lithio!1!cyano!1!trimethylsilylethanephosphonate "092# is condensed with an aldehyde togive the 1!cyano!1!alkenephosphonate "093# "Equation "15##[ Whilst the cyanophosphonate "093# ishighly reactive and usually reacts in situ\ it has been isolated in moderate yield[

(EtO)2PCN

O LiTMS

(EtO)2PCN

OR

(103) (104)

R

O

(26)–78 °C

Reactions of a\b!unsaturated carbonyl compounds with diethyl phosphorocyanidate in thepresence of lithium cyanide produces 1!diethylphosphonoxy!1!methyl!2!butenenitriles "094# "Sch!eme 18#[ Subsequent allylic rearrangement of "094# with boron tri~uoride etherate provides theg!phosphonoxy!a\b!alkenic nitrile "095# ð75CPB3519Ł[ Interestingly\ the Z!isomer of "095# results

O

RO

PO

R

CN

EtO OEt

R OP(OEt)2

CN O

(105) (106)

O

(EtO)2PCN, LiCN

Scheme 29


from a\b!alkenic ketones whilst the E!isomer of "095# predominates when a!b!alkenic aldehydes areused[ The high Z!stereospeci_city in the former case can be explained by considering the ð2\2Ł!sigmatropic rearrangement of the low energy conformer of the initially formed "094# ð75CPB3519Ł[

2[08[1[8 a\b!Alkenic Nitriles with Si! and B!based Substituents

There are a few reports of the synthesis of a\b!alkenic nitriles containing silicon!based substituentsin the literature\ and in many of these reports such compounds are formed as intermediates in thepreparation of more elaborate molecules[ In one example\ silylation of trimethylsilylacetonitrilegives the tris"trimethylsilyl#ketenimine "096# "Scheme 29# which reacts with aldehydes in the presenceof boron tri~uoride etherate to a}ord E!1!trimethylsilylalk!1!enenitriles "098# ð71CC45Ł[ Compoundsof the type "098# can be desilylated with ~uoride ion\ and the anion thus formed quenched with acarbonyl compound to give E!1!"0!hydroxyalkyl#alk!1!enenitriles "097# ð72CC069Ł[

TMS CN • N-TMS

TMS

TMS

R1

TMS

CNR1 CN

HO

R2

R3

Scheme 30

(107) (108)(109)

R1–CHO i, Bun4NF

ii, R2COR3

The exposure of an arylalkyne "009# to trimethylsilyl cyanide in the presence of catalytic palladiumchloride and pyridine results in the addition of triethylsilyl cyanide across the carbonÐcarbon triplebond to give b!cyano!b!arylalkenylsilanes of the type "000# "Equation "16## ð74CC727Ł[ The additionof the trimethylsilyl cyanide stereoisomer proceeds with high regio! and stereoselectivity to give theproduct "000# in generally high yield "up to 89)#[ As an aside\ the addition of trimethylsilyl cyanideto allenes\ under either palladium or nickel catalysis\ gives E! and Z!isomeric mixtures of thecorresponding b!trimethylsilyl!b\g!unsaturated nitriles "001# ð75TL0730Ł[

(27)Ar + TMS-CNNC

Ar

TMS

(110) (111)

PdCl2, pyridine

R TMS

CN

(112)

In an alternative\ yet complementary approach\ exposure of silylated alkynes to hydrogen cyanidein the presence of a nickel catalyst produces the corresponding E!silylalk!1!enenitriles "002# and"003# in good to excellent yield "Equation "17## ð72AJC0864\ 74CC3Ł[ It has been found that whent!butyldimethylsilyl alkynes are employed\ the steric bulk of the silicon substituent directs the nitrileaddition away from the silicon bearing carbon\ and thus favours the formation of "002# "up to 87 ] 1in favour of "002##[ If a silicon group requiring less steric bulk is employed "viz trimethylsilyl# then\in some cases "003# is the predominant product ð74CC3Ł[

(28)R13Si R2

R13Si R2

CN

R13Si R2

NC

+

(113) (114)

HCN, Ni0

R2 = H, Me, Bu, Ph

Reports detailing the synthesis of a\b!alkenic nitriles containing boron!based substituents havenot appeared[

550Bearin` an a\b!Aryl

2[08[1[09 a\b!Alkenic Nitriles with Metal Substituents

a\b!Alkenic nitriles with metal substituents are highly reactive species and as such have not beenisolated[ Such species are therefore considered as transient intermediates and will not be discussedhere[ However\ it is worth remembering that such species\ formed by deprotonations ofa\b!unsaturated nitriles with strong base\ are valuable intermediates in the preparations of sub!stituted a\b!alkenic nitriles "ðB!72MI 208!90Ł and references therein#[

2[08[2 NITRILES BEARING AN a\b!ARYL OR !HETARYL SUBSTITUENT

2[08[2[0 General Methods

The reactions between an aryl halide and a metal cyanide remain one of the most popularand convenient methods for the preparation of a\b!aryl nitriles "Equation "18##[ Typically thetransformation depicted in Equation "18#\ usually referred to as the RosenmundÐvon Braun reactionð08CB0638\ 20LA"377#000Ł\ is achieved by heating the aryl halide with copper"I# cyanide at 049Ð149>Cwith or without solvent[ Several excellent articles provide a comprehensive introduction to thecyanation of aromatic halides ðB!72MI 208!90\ B!72MI 208!91\ 76CRV668Ł^ the latter article contains morethan 199 examples\ as well as a detailed discussion of the mechanism ð74CJC000Ł[

(29)Ar X + CuCN Ar CN + CuX150–250 °C

Furthermore\ several reviews ðB!69MI 208!90\ B!72MI 208!90\ B!72MI 208!91\ 80COS"5#114Ł provide anexcellent introduction to the synthesis of aromatic nitriles in general\ and readers interested in thistopic are urged to consult these comprehensive articles[ Once again\ space limitations dictate thatthis section focuses on general strategies towards the synthesis of aryl and hetaryl nitriles\ and inparticular on developments since 0874 in the synthesis of such compounds[

The substitution of a halide by cyanide ion is the most common route into a\b!aryl nitrilesð76CRV668Ł[ Indeed\ the preparation of aromatic nitriles by the substitution of a variety of functionalgroups is the favoured method of many workers ðB!72MI 208!91Ł[ As detailed above\ the directcyanation of aromatic halides with copper"I# cyanide requires relatively forcing conditions "049Ð149># ð76CRV668Ł[ In an attempt to carry out this transformation under far milder conditions\several researchers have investigated the use of complexes of sodium or potassium cyanide withtransition metals or metal!triphenylphosphine ð76CRV668Ł[ It is considered that reactions with suchmetal complexes proceed as illustrated in Scheme 20\ and may involve an oxidative one!electrontransfer ð60JOM"17#176Ł[

Ar X + M Ar CN + M + X–Ar M X

Scheme 31

–CN

Complexes of palladium and nickel are particularly useful for this reaction[ For example\reactions of an aryl halide with sodium cyanide in the presence of tris"triphenylphosphine#nickel"9#"Equation "29## in either methanol\ ethanol or acetone at 29Ð59>C give the corresponding a\b!arylnitriles in excellent yield "×89)# ð62JOM"43#C46Ł[ Other nickel catalysts\ including trans!chloro!bis"triphenylphosphine#nickel "NiCl1"PPh2#1# have also been used and provide aryl nitriles in excel!lent yields "×79)# ðB!63MI 208!90\ 68JOM"062#224\ B!72MI 208!90\ 76CRV668Ł[ Similarly\ conversions ofchloro! and iodoaryl compounds into aryl cyanides have been achieved in 71Ð80) yield usingtetrakis"triphenylphosphine# palladium"9# and potassium cyanide in re~uxing THF ð64CL166Ł[

(30)X + NaCNR

CNR

Ni(PPh3)3

X = Cl, Br, I

In an adaptation of these transition metal catalysed aromatic cyanations\ it has been found thatthe reactions of aryl iodides with trimethylsilyl cyanide and catalytic tetrakis"triphenylphosphine#palladium"9# in triethylamine at re~ux provide the corresponding a\b!aryl nitriles in high yield"Equation "20## ð75JOC3603Ł[ Under these conditions both aryl bromides and aryl chlorides fail to


react[ Catalysis of aryl iodide displacement by palladium"II# salts\ especially palladium"II# acetate\also results in high yields of aryl nitriles ð64BCJ2187Ł[ Aryl halides also react with palladium"II# saltsin the presence of sodium cyanide on alumina giving aryl nitriles in excellent yield ð68JOC3332Ł[Various cobalt complexes have also been used to catalyse the aromatic substitution of a halide witha nitrile ð72JOM"132#84\ 76CRV668Ł[

(31)I + TMS-CNR

CNR

Pd(PPh3)4, Et3N

R = H, Me, Br, Cl, MeO, MeO2C

It must be remembered that in all these metal catalysed substitution processes\ the nature andposition of other substituents on the aromatic ring has an e}ect on the outcome of the reactionð76CRV668\ 80COS"5#114Ł[ In general terms\ the aromatic ring may carry various substituents "but notnitro groups because of the interaction between the nitro group and the metal catalyst#\ althoughortho!substituents tend to give rise to lower yields of the corresponding a\b!aryl nitriles ð76CRV668Ł[

Functional groups other than halogens\ including oxygen\ hydrogen\ nitrogen and organometallicgroups\ may also be substituted by cyanide ion ðB!72MI 208!90\ B!72MI 208!91Ł[ Examples of these lesscommonly used\ but nevertheless important\ transformations will be presented in the followingsection "see 2[08[2[1#[

The preparation of aromatic nitriles via elimination reactions is perhaps the other general syntheticapproach towards these compounds[ The dehydration of oximes "Equation "21## is by far the mostcommon of these elimination reactions\ and several reagents have been used ðB!72MI 208!91Ł[ Forexample\ the {phosphonium anhydride| species "004# resulting from the reaction of two equivalentsof triphenylphosphine oxide with one equivalent of tri~ic anhydride\ dehydrates aryl oximes to arylnitriles in 4 min at room temperature in ×89) yield ð76JOC3026Ł[

(32)Ar CNAr

N OH –H2O

OTf

Ph3P

O

Ph3P

OTf

(115)

The direct transformation of aryl aldehydes into nitriles via the oxime may be performed with avariety of reagents ðB!72MI 208!91Ł[ In one report with several examples of the preparation ofsubstituted benzonitriles from the corresponding aldehydes ð63CB0110Ł\ the intermediate oxime isnot isolated but treated with dicyclohexylcarbodiimide in the presence of copper"II# ions andtriethylamine[ The yields are excellent for this transformation "×69)#[ Similarly\ the conversionof aromatic aldehydes into aryl nitriles can be achieved using ortho!"1!aminobenzoyl#hydroxylamineand BF2 =OEt1 "Scheme 21# ð77SC1068Ł[

COONH2

NH2

NH2

O

O

N Ar

BF3

Ar CN

Scheme 32

+ Ar CHO

+–

BF3•OEt2, EtOH

The direct conversion of 1\3\5!trinitrotoluene into the corresponding benzonitrile derivative"Scheme 22# can be achieved via the oxime nitrite intermediate "005# using nitrosyl chloride inpyridine ð62JOC3252Ł[

Aromatic amides can be transformed e.ciently under very mild conditions to aryl nitriles "63Ð76) yield# by the use of chlorosulphonyl isocyanate in the presence of triethylamine ð68S116Ł[ Theprocess is depicted in Scheme 23 and is believed to proceed via the intermediate "006#[

Another important elimination process which is used in the preparation of aryl nitriles is the


Ar MeAr

NOH

Ar

NONOAr CN

Scheme 33

NOCl, pyridine –HNO2

(116)

Ar NH2

O

Ar NH

O–

N–

H

N

O

Ar

O SO2

Cl

Ar CN

Scheme 34

Et3N Cl–SO2–NCO Et3N

(117)

Beckmann fragmentation of ketoximes "Scheme 24# ðB!72MI 208!91Ł[ The requirement for thisfragmentation to succeed is that the substituent on the a!carbon "A# must be able to stabilize\ orbear\ a positive charge[ This fragmentation is often performed using thionyl chloride\ as exempli_edby the transformation shown in Scheme 25 ð62JA1812Ł[ Despite some conjecture as to the role ofsulfur in this particular case ð57JA3813Ł\ it is believed ð62JA1812Ł that the sulfur is capable ofstabilizing the adjacent cation in the intermediate "007#[ Similarly\ the Beckmann fragmentation ofb!trimethylsilylketoximes\ e[g[\ "008# "Equation "22##\ catalysed by boron tri~uoride etherate\ pro!vides the corresponding aryl nitrile in 84) yield ð77T1302Ł[

N

A

Ar

OH N

A

Ar

X Ar CN

Scheme 35

S

NOH

S

CN

S

CN

Cl

Scheme 36

+

(118)

SOCl2, C6H6, RT SOCl2

(33)

NOAc

TMS

CN

(119)

BF3•Et2O

Rearrangement reactions can also be used to prepare aryl nitriles\ although less frequently thanthe substitution or elimination processes detailed above[ The simplest of such rearrangements isthat involving the isothiocyanide to nitrile transformation ð68COC"1#417Ł\ which occurs irreversiblyat temperatures above 049>C "Scheme 26#[

Ar N C S Ar N : Ar CN

Scheme 37

(PhO)3P


2[08[2[1 Benzonitrile and Substituted Benzonitriles

The substitution of various functional groups\ especially halides "Section 2[08[2[0#\ by cyanideion is the most widely used method for the preparation of benzonitriles[ The substitution of diazogroups by cyanide ion\ _rst reported by Sandmeyer in 0773 ð0773CB0522Ł\ represents an importantroute into aryl nitriles "Equation "23## ð80COS"5#114Ł[ The many reports of this transformation varymainly in the type of copper cyanide complex employed ð80COS"5#114Ł[ In a modi_cation of thisgeneral approach\ treatment of aromatic diazo sul_des with tetrabutylammonium cyanide leads tothe corresponding benzonitriles ð76T3514\ 89T1194Ł[

(34)Ar N2+ Ar CN

[CuCN], ∆

The boron trichloride mediated cyanation of anilines with trichloroacetonitrile or with methyl!thiocyanate "Scheme 27# gives ortho!cyanoanilines in moderate yield after basic workup ð89SC60Ł[Similarly\ phenols undergo this same FriedelÐCrafts type reaction to give ortho!cyanophenols in60Ð77) yield ð89SC60Ł[

R

NH2

R

NH2

CNR

N

N

BCl

H

SMe

Scheme 38

MeSCN, BCl3 base

Substitution of a hydrogen in nitroarenes containing an additional activating group by cyanideion can be accomplished under photolysis conditions in the presence of oxygen "Equation "24##ð55JA1773Ł[ The photochemically assisted substitution of anisole with potassium cyanide in poly!ethylene glycol and dichloromethane gives mixtures of ortho! and para!cyanoanisoles ð79CC0142Ł[

(35)

NO2

OMe

NO2

OMe

CN

+ KCNH2O, ButOH, O2, hν

Cyanation of 3!nitrobenzophenone with potassium cyanide in dimethyl sulfoxide results in theformation of 2!cyano!3!hydroxybenzophenone "Equation "25##[ It is assumed that the nitro groupis displaced by hydroxide after substitution of the cyanide ortho to the nitro group ðB!72MI 208!91Ł[

(36)

NO2

COPh

OH

COPh

CNKCN, DMSO, 3 h, 100 °C

The displacement of aromatic organometallic groups by cyanide ion has also been employed togood e}ect in the synthesis of benzonitriles[ Thus\ electrophilic thallation of aromatic substrateswith thallium tris"tri~uoroacetate# "Scheme 28# followed by exposure to copper"I# cyanide in aceto!nitrile leads to various aryl nitriles in good to excellent yield "42Ð73)# ð73TL4362Ł[ The reaction isbelieved to proceed via an initial one!electron transfer from Cu"I#\ producing an unstable Tl"II#species which then undergoes homolysis of the carbon to thallium bond leading to an aryl radical"Scheme 28# ð73TL4362Ł[ Similar organometallic displacement reactions have been performed onarylthallium acetate substrates with copper cyanide in pyridine ð61T2914Ł\ and an aryltin specieswith cyanogen chloride ð61JOM"35#156Ł[

Another substitution process involving metallated aromatic compounds involves the reaction ofbenzylic organozinc halides with tosyl cyanide "Equation "26##[ The transformation is completely


R

TlTfO OTf

R

TlTfO •

R

•

R

CN

Scheme 39

CuCN, e– transfer CuIICN CuIICN

regioselective\ can tolerate a variety of other functional groups\ and produces benzonitriles in 56Ð64) yield ð82TL3512Ł[

(37)R

ZnBr

R

CN

TsCN

67–75%

Alternatively\ metallated alkyl nitriles can be used in the preparation of benzonitriles[ Thus\addition of a!lithioalkyl nitriles to the benzyne derived from aryloxazolines results in cyclization togive the benzocyclobutanone imine "019# which then fragments to give 1!alkyl!2!cyanobenzoic acidsin high yield "Scheme 39# ð73TL1830Ł[

Oxz

CN

Li ROxz

CN

R

Li

OxzR

N

Li

EtOH

Oxz

R

CN

CO2H

R

CN

Scheme 40

+

hydrolysis

(120)

The substitution of alkoxy groups by cyanide can be achieved by the anodic oxidation ofcyanide!ion solutions containing alkoxy substituted aromatic substrates ð58JA3070\ B!72MI 208!91Ł[Electrooxidation of 1\1\5\5!tetramethylpiperidinyl!0!oxy "TEMPO# forms the nitrosonium ion "010#which reacts with benzylic amines to give the intermediate imine "011# "Scheme 30#[ The imine "011#then reacts with a further nitrosonium ion "010# to give various benzonitriles "68Ð80) yield#ð72JA5621Ł[ Benzylic amines can also be oxidized directly to benzonitriles in moderate yield "24Ð30)# with copper"I# chloride and oxygen in the presence of pyridine ð66S134Ł[

N

O

+

N

O

+ Ar NH2 Ar NH+ Ar CN

Scheme 41

(121) (122)

The preparations of benzonitriles from carbonyl compounds or their derivatives o}er manyalternative strategies ðB!72MI 208!91Ł[ The addition of trimethylsilyl azide to aromatic aldehydes inthe presence of zinc chloride gives the corresponding benzonitriles in 51Ð86) yield ð73CL662Ł[Aromatic carboxylic acids can be converted directly into the corresponding nitriles with reagentssuch as aminosulphonic acid and urea\ or with methanesulphonamide and phosphorus pentachloride


ðB!72MI 208!91Ł[ Chlorosulphonyl isocyanate reacts with carboxylic acids to give N!chloro!sulfonamides "Scheme 31# which decompose to nitriles in N\N!dimethylformamide ð56CB1608Ł[

MeO OMeMeO OMe

HN

O

SO2Cl

MeO OMe

CN

Scheme 42

ClSO2NCO DMF

Amides are also a common source of benzonitriles ðB!72MI 208!91Ł[ The thermal decompositionof aryl amides in the presence of a catalyst above 149>C leads to benzonitriles ð69JOC2142\ 69TL0852Ł[A series of substituted aryl nitriles have been prepared by the reaction of aromatic N!methoxyamides with carbon tetrachloride or carbon tetrabromide and triphenylphosphine in acetonitrile togive the intermediate N!alkoxyimidoyl halides "012^ X�Cl\ Br# "Scheme 32#\ which on exposure tozinc in acetic acid a}ord the desired benzonitriles in generally excellent yield ð80S649Ł[ Similarly\aryl N!hydroxyimidoyl chlorides lead to aryl nitriles upon exposure to the hydridoundeca!carbonyltriferrate anion ðHFe2"CO#00Ł− in benzene at re~ux ð62JOC3254Ł[

Ar NH

OMe

O

Ar NOMe

XAr CN

Scheme 43

CX4, Ph3P, MeCN Zn, AcOH, DMF

(123)

X = Cl, Br

Exposure of O!alkyl!3!nitrobenzaldoximes to sodium hydride in N\N!dimethylformamide"Scheme 33# a}ords the corresponding 3!alkoxybenzonitriles\ resulting from displacement of thenitro group by the initially eliminated alkoxy group ð72JOC2094Ł "cf[ Equation "25##[ The yields forseveral 3!alkoxy substituted benzonitriles prepared by this eliminationÐaromatic substitution pro!cess are above 71)[ Similarly\ benzaldimines react with diisopropyl peroxidocarbonate to givebenzonitriles via a benzimidoyl radical intermediate ð69CC0590Ł[

NOR

NO2

CN

NO2

+ RONa

CN

OR

Scheme 44

NaH, DMF

Other nitrogen containing functional groups which can be converted into nitriles include theoxidation of aromatic hydrazones "Scheme 34# ð55JOC3099Ł and the preparation of benzonitriles bythe ring cleavage of heterocycles ðB!72MI 208!91Ł[ In the latter case\ mainly _ve! and six!memberednitrogen heterocycles are used as substrates\ and oxidative\ thermal and photochemical processesare usually involved ðB!72MI 208!91Ł[ For example\ lead tetraacetate oxidation of the triazole "013#"Scheme 35# gives the corresponding nitrene "014# which then eliminates molecular nitrogen toproduce two moles of benzonitrile ð69TL2740Ł[

NNMe2

Ar N

Ar

NMe2

–O

+ Ar CN

Scheme 45

30% H2O2


NN

N PhPh

NH2

NN

N PhPh

:N:

Scheme 46

2PhCNPb(OAc)4 –N2

(124) (125)

Cycloaddition reactions can also be used to prepare benzonitriles[ In one example\ the ð3¦1Ł!cycloadduct "015# eliminates hydrogen cyanide leading to various substituted biaryl!1!carbonitrilesin 54Ð79) yield "Scheme 36# ð89JOC1434Ł[

Ar

CN

CN+ NR2

Ar

CN

CN CN

Ar

Scheme 47

C6H6 –HCN

(126)

2[08[2[2 Polycyclic Aromatic Nitriles

Syntheses of polycyclic aromatic nitriles are not widely reported in their own right\ since manyof the methodologies presented in the previous two sections "see 2[08[2[0 and 2[08[2[1# are as equallyapplicable to polycyclic systems as they are to simpler aromatic systems[ As detailed earlier\ additionsof cyanide ion are a useful procedure for the synthesis of aromatic nitriles[ For example\ additionof cyanide ion to ~uorene derivatives results in the formation of a stabilized carbanion system "016#which is then oxidized to the polycyclic aromatic nitrile "Scheme 37# ð69JOC29Ł[

PhPh

Ph

PhPh

PhNC

–

PhPh

PhNC

Scheme 48

(127)

–CN [O]

The addition of cyanide ion to carbonyl compounds is also a convenient route into aromaticnitriles[ Reaction of 8!benzoylanthracene with sodium cyanide at 79>C in N\N!dimethylformamidefollowed by the addition of a mild oxidant leads to 8\09!dicyanoanthracene ð62JOC370Ł[ Alter!natively\ the reaction between 5!methoxytetralone and trimethylsilyl cyanide in the presence ofcatalytic boron tri~uoride a}ords the cyanohydrin derivative "017# "Scheme 38# ð72JOC4023Ł[Exposure of "017# _rstly to phosphoryl chloride in pyridine and then to aromatization conditions"09) palladium on carbon with sulphur# then gives the aryl nitrile "018#[ Similarly\ the bis"trimethyl!silyl cyanohydrin# "029#\ obtained by the addition of trimethylsilyl cyanide to the correspondingdiketone\ upon exposure to phosphoryl chloride in pyridine leads to the biscyano aromatic com!pound "020# ð68CL0316Ł[

The use of nitrogen based precursors is also a common avenue into polycyclic aromatic nitriles"see Section 2[08[2[1#[ The reaction of aromatic diazosul_des with tetrabutylammonium cyanideunder photolytic conditions furnishes dicyanonaphthalenes in good yield ð89T1194Ł[ The photo!induced cyanide ion displacement of aryl nitro groups "Equation "27## a}ords moderate yields ofthe corresponding aryl nitrile compounds ð69TL3690Ł[


Scheme 49

MeO

O

MeO

O-TMSNC

MeO

CN

(128) (129)

TMS-CN, BF3 i, POCl3, pyridine

ii, Pd on C, S

O-TMSNC

NC O-TMS

CN

CN

(130) (131)

(38)

NO2 CN

hν, –CN

The thermal\ potassium hydroxide!induced ring opening of the bis"tosylhydrazone# "021# gives0\7!dicyanonaphthalene in moderate yield ð79CC680Ł[ Pyrolysis of the 0\1\4!thiadiazole!0\0!dioxide"022# results in the extrusion of sulfur dioxide with concomitant ring cleavage to provide the bisaryl nitrile "023# ð63S11Ł[

NTsN N NTs

NS

N

O

O

(132)

CN

CN

(134)(133)

Treatment of aryl substituted acetamides with a hypochlorite liquid triphasic system results inthe loss of one carbon via a Hofmann rearrangement "Equation "28## producing aryl nitriles inmoderate yield ð83S0016Ł[

(39)

NH2

O

CNNaOCl, NaBr, TBAHSO4

benzene, H2O, Na3PO4

The reaction of bianthrone with malononitrile in pyridine a}ords the extensively conjugated18\18\29\29!tetracyanobianthraquinodimethane "TBAQ# "024# in 61) yield ð75TL1300Ł[ TBAQ wasprepared as part of a study aimed at developing new electron acceptors with enhanced conductivity"see for example ð73NAT008Ł#[

(135)

NC CN

NC CN


Cycloaddition reactions also provide a route into polycyclic aromatic nitriles[ Condensationbetween the benzylic nitrile "025# and the diene "026# in the presence of a base at elevated tem!peratures gives rise to the polycyclic aromatic nitrile "027# "Equation "39## ðB!72MI 208!90Ł[ Acry!lonitrile itself can act as the dienophile in cycloaddition reactions[ Thus\ reaction between "028# andacrylonitrile in tetrahydrofuran at re~ux gives the aryl nitrile "039# after aromatization of theintermediate adduct "Scheme 49# ð61JCS"P0#1943Ł[

CN

+Me

N+

NMe2

R

CN

R

(40)

(136) (137) (138)

base

i, 50–70 °Cii, 145–205 °C

MeClO4

–

N

O–

MeCN

O

CN

Me

+

Scheme 50

NO

Me2N

NC

i, MeI, EtOAc

ii, Ag2O, H2O

THF, reflux+

(139) (140)

2[08[2[3 Heterocyclic Aromatic Nitriles

Methods for the preparation of heterocyclic aromatic nitriles are generally similar to those usedin the synthesis of other aromatic nitriles "Sections 2[08[2[0 and 2[08[2[1#[ The most widely usedmethod involves the cyanation of heterocyclic aromatic substrates[ An excellent review provides avaluable insight into the displacement of a heterocyclic aromatic halide with cyanide ion "see alsoSection 2[08[2[0# ð76CRV668Ł[ Such transformations are typically performed at elevated temperatures"049Ð149>C#\ usually with copper"I# cyanide and either with or without solvent[ The variety ofheteroaryl nitriles which can be prepared in this way is enormous\ with over eighty examples in thisaccount alone ð76CRV668Ł[ Other comprehensive articles also give details concerning alternativemethods for the cyanation of heterocyclic aromatic substrates ð68H"01#708\ B!72MI 208!90Ł[ Threefurther reviews also provide many examples of other avenues for the preparation of heteroarylnitriles[ One report concentrates on the use of cyanoacetamide "030^ X�O# and cyanothioacetamide"030^ X�S# in heterocyclic synthesis in general ð75H"13#1912Ł\ whilst the other two focus on the useof nitriles in heterocyclic synthesis ð72H"19#408\ 76H"15#386Ł[ These three articles contain severalexamples of the synthesis of heterocyclic aromatic nitriles[

NCNH2

X

(141)X = O, S

Apart from the displacement of a heteroaryl halide with cyanide ion ð76CRV668Ł there are othermethods involving a variety of reagents for the direct cyanation of heterocyclic aromatic substratesð68H"01#708\ B!72MI 208!90Ł[ The cyanation of pyrrole with triphenylphosphineÐthiocyanogen complex"Equation "30## a}ords 1!cyanopyrrole in 79) yield ð79JCS"P0#0021Ł[ Cyanation of indoles can alsobe achieved with this reagent ð79JCS"P0#0021Ł\ although only if there are no electron!withdrawinggroups on the indole ring[ Indoles can also be cyanated with the powerful electrophile chlorosulfonylisocyanate ð67S263Ł[ This same reagent has also been used for the cyanation of pyrroles ð70CJC1562Ł\thiophenes ð69OS"49#41Ł and furans ð72T2770Ł[ Moderate to excellent yields of the correspondingheteroaryl nitriles are obtained in all of these examples[ The reaction proceeds through a chloro!sulfonyl carboxamide intermediate\ such as "031# in the pyrrole series\ which liberates HCl andSO2 upon the addition of N\N!dimethylformamide ð70CJC1562Ł[ Importantly\ the nature of other


substituents on the heterocyclic ring can alter the position of cyanation[ Thus\ if a deactivatinggroup is in the 1!position of pyrrole "e[g[\ 1!carboxyaldehyde# the product is the corresponding3!cyanopyrrole ð70CJC1562Ł[ Several examples of 1!substituted furans "032^ R�H\ Me\ CH1OH\CH1OAc\ CH1OMe# give 4!cyanofurans upon exposure to chlorosulfonyl isocyanate ð72T2770Ł[ If1\4!disubstituted furans are employed then 2!cyanofurans result ð72T2770Ł[

(41)NH

CNNH

+ Ph3P(SCN)2

CH2Cl2, –40 °C

NH

HN

SO2Cl

OO

(142)

R

(143)R = H, Me, CH2OH, CH2OAc, CH2OMe

Diethyl phosphorocyanidate in the presence of lithium cyanide reacts with 2!acylindoles "033# toa}ord 1!cyano!2!indoleacetonitriles in excellent yield "Scheme 40# ð75CPB3434Ł[ In the several exam!ples reported\ either R0 or R1 is hydrogen[ Indeed 0!methyl!2!acetylindole "033^ R0�R1�Me# isrecovered unchanged when exposed to these conditions[

N

R1

OR2

N

R1

R2

OCN

P(OEt)2

O

N

R1

NCR2

CN

(EtO)2P

O

CN

Scheme 51

–CNLiCN

N

R1

NCR2

CN

(144)

R1 = H, Me, Et, Ph, CH2Ph; R2 = H, Me, Ph

The reaction of aryl organozinc halides with p!toluenesulphonyl cyanide leading to aromaticnitriles has already been mentioned "Section 2[08[2[1#[ The same article ð82TL3512Ł also reports thatvarious heteroaryl organozinc iodides "indoles\ thiophenes\ benzothiazoles# a}ord the correspondingnitriles in high yield under the same conditions[

1!Cyanoergolines "034# have been prepared by the electrochemical cyanation of ergolines inmoderate yield "30Ð37)# ð72TL1730Ł[ The reaction is performed in methanolic aqueous sodiumcyanide solution using a platinum electrode[

N CN

R1

N MeH

R2

H

(145)


Trimethylsilyl cyanide is a valuable reagent in the preparation of heteroaryl nitriles[ For example\treatment of pyridine N!oxide with trimethylsilyl cyanide in the presence of triethylamine in aceto!nitrile a}ords 1!cyanopyridine in high yield "Scheme 41# ð72S205Ł[ Only traces of 3!cyanopyridineare reported from this reaction[ This modi_cation of the ReissertÐHenze reaction can be performedon a variety of substituted pyridine N!oxides\ including alkyl\ hydroxy\ carboxy and carboxamidogroups[ Quinoline N!oxides also react under these conditions to give 1!cyanoquinoline[ The sametransformation can also be carried out with trimethylsilyl cyanide in the presence of dimethyl!carbamyl chloride\ resulting in excellent yields "83Ð099)# of substituted 1!cyanopyridinesð72JOC0264Ł[ The reaction is believed to proceed as depicted in Scheme 42 ð72JOC0264\ 80COS"5#114Ł[

N

O

+ TMS-CN NCN

H

O-TMSN CN

Scheme 52

Et3N, MeCN –TMS-OH

N

O

Me2N Cl

ON

O

O

NMe2

N

O

O

NMe2

Scheme 53

+ H

CN+ +TMS-CN –Me2NH, –CO2

N CN

Trimethylsilyl cyanide also reacts with alkynes in the presence of a palladium or nickel catalystleading to 1!cyano!4!aminopyrroles "Equation "31## ð75TL3190Ł[ Diarylacetylenes "035^ R�Ar# givethe corresponding cyanopyrroles in 64Ð76) yield\ whilst arylalkynes "035^ R�H# a}ord onlymoderate yields of cyanopyrroles[

Ar R + TMS-CNPdCl2 or NiCl2

NH

R

NC

Ar

N(TMS)2

(42)

(146)

R = Ar, H

Other metal catalysts can also be employed in heteroaryl nitrile synthesis[ Thus\ exposure ofa!hydrazononitriles "e[g[\ "036## to anhydrous aluminum chloride produces 3!amino!2!cyano!cinnoline "037# ð76H386Ł[

N

CN

CN

PhNH

NN

NH2

CN

(147) (148)

Carbonyl compounds have been widely used as substrates in the synthesis of heterocyclic aromaticnitriles[ In one example\ reaction of o!phthalaldehyde with primary amines\ followed by the additionof potassium cyanide gives 0!cyano!1!substituted!isoindoles in moderate to excellent yield "Scheme43# ð74CL0376Ł[ o!Hydroxybenzaldehyde undergoes a Knoevenagel condensation with malononitrileon an AlPO3ÐAl1O2 catalyst in the absence of solvent to produce the benzopyran "038# via theinitial intermediate "049# "Scheme 44# ð73JOC4084Ł[ Similarly\ a!hydroxyketones condense withmalononitrile to produce furan derivatives ð76H386Ł[


CHO

CHO

N

CNH

HCN

RN

CN

R

Scheme 54

i, NaHSO3 (aq.) ii, RNH2

iii, KCN

OH

CHO CN

CN OH

CN

CNAlPO4-Al2O3

H3O+O NH

CN

O O

CN

+

Scheme 55

(150)

(149)

Diketones or their derivatives are also valuable substrates in heteroaryl nitrile synthesis[a!Chloroacetylacetone reacts with malononitrile to a}ord the cyanofuran "040# ð51CB170Ł\ whilst1!acylcyclohexanones react with cyanoacetamide in diethylamine leading to a mixture of the cyano!isoquinoline "041# and the cyanoquinoline "042# ð76H"15#386Ł[ The oximino ketone "043#\ preparedfrom the enol ester "044# "Scheme 45#\ upon exposure to thionyl chloride leads to the 1!cyano!imidazole "045# ð62JHC788Ł[ Similarly\ the 1!cyanobenzimidazole "046# results from thionyl chlorideinduced fragmentation of the corresponding oximino ketone ð62JHC788Ł[ The imidazole derivative"045# can also be prepared by the mild thermal decomposition of the oximino pyruvate "047#ð62JHC788Ł[

O

O

CN

NH2

N

OH

CN

RN

CN

R

OH

(153)(151) (152)

N

N Ph

O

O

Ph

MeO2N

N

N

MeO2N NOH

O

Ph

N

NCN

MeO2N

Scheme 56

(155) (154) (156)

HOSO2NO2 SOCl2

N

NCN

RN

N

MeO2N N OH

O OEt

O

(157) (158)


Glyoxal a!oximes have also been used as precursors to cyano substituted imidazoles[ In a three!step procedure the nitroimidazole "048# is reacted with dimethylformamide dimethyl acetal leadingto the enamine "059# which on exposure to sodium nitrite in acetic acid gives the glyoxal a!oxime"050# "Scheme 46#[ Tri~uoroacetic anhydride treatment of "050# then a}orded 3!cyano!0!alkyl!4!nitroimidazole "051^ R�alkyl# ð74JOC4781Ł[ Similarly prepared was the isomeric 4!cyano!0!alkyl!3!nitroimidazole "052#\ and in both instances the chemical yields were high for each step in thesequence ð74JOC4781Ł[

N

N

RO2N N

N

RO2N

Me2N

Me2NCH(OMe)2, H+ NaNO2, AcOH, H2O

(161) (162)

N

N

RO2N

OHC

NOH

N

N

RO2N

NC

(159)

Scheme 57

(160)

R = alkyl

N

NNC

O2N

R

(163)

3!Cyanoimidazoles "053# have also been prepared by exposure of the corresponding 3!"tri~uoro!methyl#imidazole to dilute ammonium hydroxide solution "Scheme 47# ð75JOC2117Ł[ The yields fora variety of substituted cyanoimidazoles "053^ R�heteroaryl# prepared in this way are generallyexcellent[

N

NR

F3C

N

NR

NC

(164)

N

NR

F

F

Scheme 58

NH4OH

H H

1!Cyano!0!hydroxyimidazoles "054# can be prepared by the thermal decomposition of 1!azido!pyrazine!0!oxides "055# ðB!72MI 208!91Ł[ Similarly\ 1!azidopyridine!0!oxides produce 1!cyano!0!hydroxypyrroles "056# ðB!72MI 208!91Ł[ The thermal decomposition of azidoindoles has also beenused as a route into cyanoindole derivatives[ Thus\ exposure of either 1!chloro! or 1!phenylsulfonyl!2!phenylsulfonyl indoles "057# to sodium azide in N\N!dimethylformamide at 89>C results inmoderate to high yields of 2!cyanoindoles "058# "Scheme 48# ð74TL0716Ł[ It is believed that thereaction proceeds via the intermediate Schi} base "069#[

N

N

OH

CNN

OH

CN

(165)

NN

O

(166) (167)

N3


N

R

X

SO2Ph

N

H

N

SO2Ph

N N

::

R

CN

SO2Ph

N

R

NaN3, DMF

(169)

N

H

R

CN(170)

(168)

Scheme 59

X = Cl, SO2Ph

2[08[3 NITRILES BEARING AN a\b!TRIPLE BOND

A general review of the chemistry of a!cyanoalkynes has been published ð66RCR263Ł[ a!Cyanoal!kynes "060# can be prepared by the dehydration of amides at elevated temperature in the presenceof phosphorus pentoxide although the yields are poor ðB!60MI 208!90\ 66RCR263Ł[ Similarly\ dicyano!alkyne "061# results from the dehydration of the diamide "062# ð57T0418Ł\ although in a moderate39) yield[ Cyanoalkyne can also be prepared by the dehydration of the oxime of propargyl aldehydewith acetic anhydride ð50USP2995837Ł[

R CN NC CN

O

H2N NH2

O

(173)(172)(171)

Chlorination of acrylonitrile and pyrolysis of the resulting dichloro intermediate "063# "Scheme59# leads to a!cyanoalkyne itself in 39) yield ð69JOC564Ł[ Similarly\ pyrolysis of the trichloro!acrylonitrile derivative "064# at 899>C gives the b!chlorocyanoalkyne "065# in 64) yield ð69JOC564Ł[

CN ClCN

ClCN

Scheme 60

Cl2 1000 °C

(174)

CNClClCN

ClCl

(175) (176)

The pyrolysis of b!ketoalkylidenetriphenylphosphoranes of the type "066# under far milder con!ditions "119>C# also provides a route to a\b!alkynic nitriles "067# ð51JCS1222Ł[ The phosphoranes"066# can be prepared conveniently by the reaction of cyanomethylenetriphenylphosphorane withacid chlorides[ This procedure was later extended to include the preparation of dialkynic nitrilesð53JCS432Ł[ Thus\ pyrolysis of the b!ketoalkylidenephosphorane "068#\ this time prepared by thereaction of the corresponding a\b!alkynic acid chloride with cyanomethylenetriphenylphosphorane\at 179Ð299>C furnishes dialkynic nitriles of the type "079# "Equation "32##[

564Bearin` an a\b!Triple Bond

CNR–O

R CN

PPh3

(177) (178)

+

Ph3P

CN

O

RNC R (43)

(179) (180)

280–300 °C

In 0882 a novel synthesis of a\b!alkynic nitriles was published ð82TL4800Ł involving the iodine!catalysed cyanation of terminal alkynes with cuprous cyanide "Equation "33##[ The yields for thistransformation are generally good to excellent "42Ð73)# with the best results when R�aryl"Equation "33##[ Importantly\ the authors found that the use of dimethyl sulfoxide with acetonitrilein the ratio of 2 ] 0 was the ideal solvent system for this reaction\ with di}erent proportions of thesetwo solvents or other solvents "e[g[\ THF\ THF and HMPA\ benzene# resulting in signi_cantlylower yields of the desired a\b!alkynic nitriles[

(44)R R CNCuCN, TMS-Cl, NaI (cat.), H2O

DMSO/MeCN (3:1)

R = aryl, alkyl

Terminal alkynes can also be transformed into a\b!alkynic nitriles via reaction with coppercyanide in the presence of bis"trimethylsilyl#peroxide "Equation "34## ð80TL1058Ł[ It is believed thatthe reaction involves a formal transfer of CN¦ from CuCN to the terminal alkyne in an umpolungfashion via the intermediate hypo species TMS0O0CN ð80TL1058Ł[

(45)R CNTMS-O O-TMS + CuCNR

THF

The reaction of metallated alkynides with cyanogen chloride to furnish a\b!alkynic nitriles is aclassical method for the preparation of these compounds ð04BSF117\ 15AC"P#4\ 62RTC556Ł[ An obviousproblem with such an approach is the use of the highly toxic cyanogen chloride[ In an attempt toovercome this problem it has been found that the reaction of cyanogen bromide "which is easier tohandle than cyanogen chloride# with the alkynyl cuprate "070# in diethyl ether:acetonitrile at 24>Cproduces phenylpropynenitrile in 59) yield "Equation "35## ð65S337Ł[ Lower temperatures result inpoorer yields of the desired a\b!alkynic nitriles ð65S337Ł[ In a further modi_cation of this generalroute into a\b!alkynyl nitriles\ phenyl cyanate "071# "prepared by the reaction of phenol withcyanogen bromide in the presence of triethylamine# reacts with lithiated alkynides at −69>C indiethyl ether to give a\b!alkynic nitriles "Equation "36## ð79S049Ł[ The reaction is quite general withalkyl\ cycloakyl\ aryl and alkoxy substituted lithiated alkynides all providing the corresponding a\b!alkynic nitriles in excellent yield "69Ð84)#[

(46)CNCu

(181)

BrCN

(47)R CNR Li + Ph–O–CN

(182)

R = alkyl, cycloalkyl, aryl, alkoxy

Metallated alkynides can also react with p!toluenesulphonyl cyanide "TsCN# leading toa\b!alkynic nitriles ð82TL3512Ł[ In this case alkynic organozinc iodides are found to react smoothlywith TsCN in THF under very mild conditions "9Ð14>C\ 1 h# to give the desired alkynic nitriles inexcellent yield "70Ð89)# "Equation "37## ð82TL3512Ł[


(48)R CNR ZnI + TsCNTHF, 0 °C to 25 °C

R = alkyl

The utility of a\b!alkynic nitriles in organic synthesis has been aptly demonstrated by the synthesisof bongkrekic acid "072# ð73JA351Ł via the alkynic nitrile "075#[ The nitrile "075# was itself preparedin a novel two!step procedure starting with the a!cyanoketone "073# "Scheme 50#[ Thus\ exposureof the cyanoketone "073# to sodium hydride and then tri~ic anhydride _rst led to the enol tri~ate"074#[ Elimination of the elements of tri~ic acid from "074# with sodium hydride in diethyl etherand dimethyl sulfoxide next gave the a\b!alkynic nitrile "075# in a 54) yield from the cyanoketone"073# ð73JA351Ł[ Reaction of "075# with dimethylcopper lithium then gave the Z!a\b!alkenic nitrile"075# which was _nally elaborated to the bromoalkyne "077#\ the immediate precursor to bongkrekicacid "072#[

CO2H

CO2H

OMe

CO2H

(183)

CN

O

OMe

TIPS

CN

OTf

OMe

TIPS

NaH, Et2O, DMSONaH, Tf2O

(187)(186)

Me2CuLi stepsOMe

TIPS CN

OMe

TIPS

Scheme 61

CN

(185)

(188)

OMe

Br

CO2Me

(184)


3.20N-Substituted Nitriles and OtherHeteroanalogues of Nitriles of theType RCZR. MICHAEL PATONUniversity of Edinburgh, UK

2[19[0 N!SUBSTITUTED NITRILES 566

2[19[0[0 General Methods for the Formation of Nitrilium Betaines 5662[19[0[1 Nitrile Ylides 5672[19[0[2 Nitrile Imides 579

2[19[0[2[0 Generation of transient nitrile imides 5792[19[0[2[1 Preparation of stable nitrile imides 570

2[19[0[3 Nitrile Oxides 5722[19[0[3[0 From aldoximes 5722[19[0[3[1 From nitromethyl compounds 5732[19[0[3[2 From a!nitroalkanoate esters 5732[19[0[3[3 From furazan N!oxides 5742[19[0[3[4 Generation of fulminic acid and heteroatom!substituted analo`ues 574

2[19[0[4 Nitrile Sul_des 5752[19[0[5 Nitrilium Ions 576

2[19[1 N!SUBSTITUTED ANALOGUES OF NITRILES BEARING A HETEROATOMOTHER THAN NITROGEN 576

2[19[1[0 Phosphaalkyne Synthesis 5762[19[1[1 Methods for the Synthesis of AlkylidyneÐTransition Metal Compounds 589

2[19[1[1[0 Synthesis from nonalkylidyne precursors 5892[19[1[1[1 Modi_cations of alkylidyneÐmetal complexes 580

2[19[0 N!SUBSTITUTED NITRILES

2[19[0[0 General Methods for the Formation of Nitrilium Betaines

The most important N!substituted nitriles from a synthetic point of view are the nitrilium betainesðB!73MI 219!90Ł[ These are propargyl!allenyl type 0\2!dipoles with nitrogen as the central atom andcan be represented as RC2N¦

0Z−tRC−

1N¦1Z where Z�CR1\ NR\ O\ etc[ They undergo

concerted inter! and intramolecular 0\2!dipolar cycloaddition reactions with a variety of double!and triple!bonded dipolarophiles "Scheme 0#\ and are thus uniquely well suited for the constructionof _ve!membered heterocycles incorporating the C1N0Z unit[ Their 0\4! and 0\6!electrocyclisationreactions also have great synthetic potential ð79AG"E#836\ 80S070Ł[ Four classes of nitrilium betainewill be discussed in this chapter] the nitrile ylides "RC2N¦

0C−R1#\ nitrile imides"RC2N¦

0N−R#\ nitrile oxides "RC2N¦0O−# and nitrile sul_des "RC2N¦

0S−#[ The cor!responding nitrile selenides "RC2N¦

0Se−# are also known and have been characterised spec!troscopically with the aid of matrix isolation techniques ð66ACS"B#737Ł^ their chemistry\ however\

566

567 Nitriles and Other Heteroanalo`ues of Nitriles

has not yet been exploited synthetically and they are therefore omitted from the survey[ Methodsfor the formation of nitrilium ions "RC2N¦R# are considered in the _nal section[ The generationand reactions of the nitrilium betaines and mechanistic aspects of their chemistry have been describedin depth as part of wider reviews ð80COS"3#0958\ 80COS"3#0000Ł\ and also in a two!volume monographon 0\2!dipolar cycloaddition chemistry edited by Padwa ðB!73MI 219!90Ł[ Reference to reviews speci_cfor the individual classes of nitrilium betaine is made in the appropriate sections of this chapter[

N ZX

YR

N Z–RN

R

Z

X Y X Y

N ZX

YR

–

+

Scheme 1

+

As most nitrilium betaines usually exist at ambient temperature only as short!lived intermediates\it is common practice in synthetic applications for them to be generated in situ in the presence ofthe dipolarophile[ In this way\ side reactions which compete with cycloaddition are minimised[ Nosingle method is applicable for the generation of all four classes of nitrilium betaine[ There are\however\ two approaches which are common to more than one type and are widely used[ These areoutlined in the following paragraphs[

The most widely used route "Equation "0## involves the dehydrohalogenation of the appropriatelysubstituted imino compounds "RCX1NZH#[ Thus nitrile ylides\ nitrile imides and nitrile oxidescan be conveniently formed from imidoyl halides "RCX1N0CHR1#\ hydrazonoyl halides"RCX1N0NHR# and hydroximoyl halides "RCX1N0OH#\ respectively[ The elimination of HXis usually carried out by treatment with base but can sometimes be accomplished by thermolysisalone[

N Z–RN

X

R

ZH base and/or heat

–HX

+ (1)

X = Cl, Br; Z = CR2, NR, O

The second generally applicable approach involves thermally or photochemically induced frag!mentation "with expulsion of a stable moiety such as carbon dioxide or nitrogen# of a _ve!memberedheterocyclic compound which already incorporates the C1N0Z moiety "Equation "1##ð68AG"E#610Ł[ This is the method of choice for nitrile sul_des and is also widely used for nitrile ylidesand nitrile imides[

N ZX

YR

N Z–R+heat or hν

–X = Y

XY = CO2, N2, etc.; Z = CR2 NR, S

(2)

2[19[0[1 Nitrile Ylides

Nitrile ylides are versatile intermediates which a}ord via their 0\2!dipolar cycloaddition reactionsa variety of C1N0C containing _ve!membered heterocycles[ They are Type I dipoles underthe Sustmann classi_cation for which cycloaddition is predominantly dipole!HOMO:dipolarophile!LUMO controlled[ ð0¦1Ł!\ ð0¦2Ł! and ð2¦5Ł!Cycloadditions ðB!73MI 219!91Ł\ and ð0\4Ł! and ð0\6Ł!electrocyclisation reactions ð79AG"E#836\ 80S070Ł have also been reported[ Their chemistry has beenreviewed ðB!65MI 219!90\ 66H"5#032\ B!73MI 219!91Ł and they have also been discussed as parts of widersurveys ð89MI 219!90\ 80CRV152Ł[ Nitrile ylides undergo several side reactions which compete withcycloaddition and thus in~uence the choice of synthetic method[ They readily dimerise in a head!to!head manner to give 1\4!diaza!0\2\4!hexatrienes "0# "Scheme 1#[ Photocyclisation a}ords1H!azirenes\ and for formonitrile ylides 0\2!hydrogen shifts yield the isomeric isonitriles[ 0\3!Shiftsand protonation at carbon have also been reported[

The original route described by Huisgen ð51AG"E#49Ł involving base!mediated de!hydrochlorination of imidoyl chlorides "Scheme 2# remains one of the methods of choice for the in

568Substituted Nitriles

NX

YR

NR+

RR R

R–X Y

NR

RNR

R

R

R(1)

Scheme 2

situ generation of arenenitrile ylides[ The precursors are easily prepared from N!monoalkylatedcarboxamides by treatment with SOCl1\ PCl4 or COCl1 and\ provided the proton at the alkyl groupattached to nitrogen is su.ciently acidic\ formation of the nitrile ylide is readily induced by additionof a base such as triethylamine[ The process is faster in the presence of a dipolarophile and isbelieved to involve an equilibrium between imidoyl halide and HCl:nitrile ylide\ the latter beingpresent only at low concentration[ It has been reported ð61CB0147Ł that triethylamine hydrochloridealso causes tautomerism between the regioisomeric imidoyl chlorides Ar0CCl1NCH1Ar1 andAr0CCH1N1CClAr1\ thus leading to the generation of both nitrile ylide isomersAr0C2N¦

0C−HAr1 and Ar0CH−0N¦

2CAr1[

NY

XR

NR

RR

R

R

NR

N

R

RR

N

X

R

(3) X = O, Y = CO(4) X = CO, Y = O(5) X = O, Y = PR3(6) X = S, Y = PR3

+ –

base

R

R

–HX

heat or hν

hν

–X Y

:

R

R

Scheme 3

1H!Azirenes undergo photochemical\ but not thermal\ ring opening at C"1#0C"2# to a}ord nitrileylides "Scheme 2# and\ as there are e.cient methods available for the synthesis of such azirenesbearing a wide range of substituents\ this is a valuable strategy for the generation of this class of0\2!dipole ð73JOC2063Ł[ It is\ for instance\ suitable for low!temperature spectroscopic studies[ Theprocess can be reversible\ and with light of longer wavelength "249 nm#\ benzonitrile ylides aretransformed back into 2!phenyl!1H!azirenes[ Benzonitrile ylides are also formed on photolysis of0!azido!0!phenylalkenes\ presumably via the 1H!azirene as intermediate ð63HCA0271Ł[ The photo!chemistry of nitrile ylides has been reviewed ð65ACR260\ B!71MI 219!90Ł[

Additions of a singlet carbene or carbenoid to a nitrile represent an elegant alternative methodfor nitrile ylide generation ð80CRV152Ł[ The reactions are particularly useful for alkyl! and acyl!substituted nitrile ylides for which some of the traditional methods are unsuccessful[ For example\singlet methylene\ generated by photolysis of either diazomethane or diazirene\ combines withacetonitrile to a}ord acetonitrile methanide "CH2C2N¦

0CH1−# ð75JA5628Ł[ Rhodium acetate!

mediated fragmentation of a!diazoketones and acetates in the presence of nitriles leads to C!acyland C!alkoxycarbonyl analogues ð81CL1086Ł[ The _rst stable nitrile ylide "1# was prepared by thisapproach in 0873^ its unusual stability is attributed both to the steric bulk of the C!adamantylsubstituent inhibiting dimerisation and to charge delocalisation at the N!terminus into the cyclo!pentadienyl ring ð73TL394Ł[

N

CF3

CF3

F3C

F3C+–

(2)


Nitrile ylides are formed on thermal or photochemically!induced fragmentation of several hetero!cyclic systems "Scheme 2#[ Carbon dioxide is expelled on photolysis or thermolysis of 1! and2!oxazolin!4!ones "2# and "3#\ which are readily prepared bearing a variety of substituents startingfrom amino acids[ The temperature required "099Ð129>C# depends on the nature of the substituentsð60CB2705\ 77HCA0066Ł\ 2!oxazolin!4!ones generally fragmenting more readily than their 1!oxazo!linone isomers[ Similarly 1\2!dihydro!0\3\1l4!oxazaphospholes "4# and !thiazaphospholes "5# ther!mally or photochemically extrude triakyl phosphate and thiophosphate respectively ð79CB1588\75AG"E#74Ł[ 1\1!Bis"tri~uoromethyl#!2!oxazolin!4!one:P"OMe#2 acts as a synthon for formonitrilehexa~uoro!1!propanide ð76S813Ł[ Benzonitrile bis"tri~uoromethyl#methanide is formed togetherwith phenyl isocyanide on ð2¦0Ł cycloreversion of azetidinimine "6# ð62AG"E#044Ł[

N

Ph NPh

CF3

CF3

(7)

HNNCO2Et

NPh

(8)

N

PhS

R TMS

(9)

Alternative approaches to nitrile ylides include oxidative photofragmentation of dihydrotriazolederivative "7# ð63HCA0271Ł and silver ~uoride!induced desilylations of silylthioimidates "8#ð75JA5628Ł[ The synthetic potential of addition of electrophiles to isonitriles is illustrated by theformation of triphenylboron nitrile ylide anion Ph2B−

0C2N¦0C−R1 ð57LA"602#0Ł[ Stable

iminocarbene complexes such as "CO#4W1CMe0N1CHPh have been shown to be useful nitrileylide synthons ð89OM1756Ł[ Organometallic analogues of the form ð"CO#4M0C2N¦

0

CH−CO1EtŁ have also been described ð76CB1920Ł[

2[19[0[2 Nitrile Imides

The chemistry of the nitrile imides "nitrile imines# has been the subject of intensive investigationsince the original report in 0848 by Huisgen et al[ of their generation and formation of 0\2!dipolarcycloadducts ð48JOC781Ł[ They are regarded as Sustmann Type II dipoles with contributions fromboth dipole!HOMO:dipolarophile!LUMO and dipole!LUMO:dipolarophile!HOMO interactions[The value of their cycloaddition reactions in heterocyclic synthesis\ particularly for the preparationof pyrazoles and 1!pyrazolines\ is well documented ð79JHC722\ 73MI 219!92Ł and their chemistry hasbeen the subject of a recent review ð83AG"E#416Ł[ Various _ve! and seven!membered heterocyclesnot readily accessible by other means have also been prepared via their electrocyclisation reactionsð79AG"E#836\ 80S070Ł[ Until the early 0889s they were regarded solely as short!lived reactive inter!mediates[ Evidence for their existence was based on trapping experiments and spectroscopic studiesat low temperatures using matrix isolation techniques[ However\ with a greater understanding ofthe factors in~uencing their stability\ methods for the preparation of a variety of more stableand isolable analogues have been developed\ thus allowing their structures and properties to beinvestigated[

The nitrile imides\ like the other nitrilium betaines\ undergo several rearrangement and dim!erisation processes[ Photolysis induces rearrangement to carbodiimides\ possibly via an intermediate0H!diazirene "Scheme 3#[ Isomerisation to diazoalkanes and photofragmentation to the parentnitrile have also been reported[ In the absence of a dipolarophile head!to!head dimerisation a}ordsthermally and photochemically labile 0\1!bisazoethenes "09#[ Symmetrical head!to!tail 0\1\3\4!tetra!zine dimers "00# are sometimes also formed\ but these are thought to result from an alternativepathway involving combination of the nitrile imide and its precursor[ For synthetic purposes it isnecessary for most nitrile imides to be prepared in situ in order to avoid these side reactions[ In thefollowing section the methods used for generating short!lived nitrile imides and the new approachesdeveloped for the synthesis and isolation of stable analogues are described[

2[19[0[2[0 Generation of transient nitrile imides

The _rst de_nitive report of nitrile imides ð48JOC781Ł described the generation of benzonitrileN!phenylimide both by base!mediated dehydrochlorination of N!phenylbenzohydrazonoyl chloride


N NR2R1 +

N NR2

NNR1

R1

(10)

N

N

R1 R2N •

R1

N

R2

R2

N2

R2

R1

N N

NN

R1

R2

R1

R2

hν

hν

(11)Scheme 4

–

and by thermal decomposition of 1\4!diphenyltetrazole\ and these remain two of the most usedapproaches to this class of nitrilium betaine[

Hydrazonoyl chlorides are readily prepared by a variety of methods including treatment ofhydrazides with PCl4 ðB!68MI 219!90Ł\ Ph2P:CCl3 ð76JHC466Ł or POCl2:pyridine ð65ZOR0565Ł andby chlorination of aldehyde hydrazones ð61RCR384Ł^ use of Ph2P:CBr3 provides access to thecorresponding bromides ð64CJC0222Ł[ Coupling of diazonium salts with halogenated methylenecompounds and with diazo compounds can be used for the preparation of C!acyl and C!alkoxy!carbonyl analogues ð48OR"09#032Ł[ Addition of a base such as triethylamine a}ords the nitrile imideby a pathway which is believed to involve initial removal of the NH proton followed by loss ofhalide ion ð61JCS"P1#33Ł[ Base!induced elimination of nitrous acid from a!nitro aldehyde hydrazoneshas also been investigated "Scheme 4#\ and in some cases hydrazones can be oxidised to nitrileimides directly\ for example with lead tetraacetate ð57CI"L#326\ 58JCS"C#1476Ł[

N NN

NR1

N NR2R1

–CO2

+

NNHR2

X

R1

–

base–HX

heat or hν

–N2

R2

N NX

OR1

R2

O

NO

NR1

OR2

O

NN

–O

R1

R2

hν

–CO2hν

+

heat or hν

–XO2

(14) X = C(16) X = S

(12)

(13)(15)

Scheme 5

X = Cl, Br, NO2

Tetrazoles "01# provide another valuable source of nitrile imides[ They are accessible by severalroutes including oxidation of formazans\ treatment of aldehyde hydrazones with aryl azides anddiazotisation of amidrazones ð73CHEC"4#680Ł[ Photolysis\ or thermolysis in an inert solvent resultsin extrusion of nitrogen^ the temperature required ranges from 059 to 119>C depending on theelectron donatingÐwithdrawing properties of the imide substituent[ The ~ash vacuum pyrolysistechnique coupled with low!temperature matrix isolation has also been used ð74AG"E#45Ł[ Thermalor photochemically!induced fragmentation of various other diazoles a}ords nitrile imide derivedproducts ð68AG"E#610\ B!73MI 219!92Ł] for example\ the decarboxylation of the mesoionic compound"02# and the oxadiazolinones "03# and "04#\ and extrusion of sulfur dioxide from the oxathiadiazole"05#[

2[19[0[2[1 Preparation of stable nitrile imides

The _rst stable nitrile imide "06#\ which was reported by Bertrand and co!workers in 0877ð77JA1552Ł\ was prepared by treatment of the lithium salt of a thiophosphinoyldiazomethane with


a chlorophosphane "Equation "2##^ it is not air sensitive and is thermally quite stable[ Subsequentlya range of organometallic analogues has been synthesised bearing boryl\ germyl\ phosphino\thiophosphinoyl\ silyl and stannyl substituents "R0C2N¦

0N−R1 where R0�R1B\ R1P\ R1P"S#\R2Si and R1�BR1\ GeR2\ PR1\ SiR2#[ The kinetic stablity of this class of compounds is attributedprimarily to steric factors\ although pushÐpull substituents can decrease the polarity of the nitrileimide framework and further enhance their stability[ The various synthetic approaches to stablenitrile imides have been surveyed by Bertrand and Wentrup ð83AG"E#416Ł[

(Pri2N)2P(S)C(Li) N2 + (Pri

2N)2PCl LiCl + (Pri2N)2P(S)C N NP(NPri

2)2+

(17)(3)

–

The original route employing diazolithium precursors has proved to be general and a wide rangeof stable nitrile imides have been similarly prepared by combination of chlorosilanes\ chloroboranesand chlorophosphanes with the lithium salts of phosphino!\ boryl! and silyl! as well as thiophos!phinoyl!diazomethanes[ Electrophilic attack can occur at carbon yielding a substituted diazo com!pound\ or at nitrogen to form the nitrile imide ð81JA5948Ł[ The balance between the two processeshas been shown to depend on steric factors\ bulky electrophiles reacting preferentially at nitrogenand less sterically demanding analogues at carbon[ Diazo compounds can also result from iso!merisation of the thermodynamically less stable nitrile imide "Scheme 5#[

N2

Li

R

NR NE

N2

E

R

+ E+

N - attack

C - attack

–

Scheme 6

+

Trialkylstannyldiazo compounds also prove to be versatile precursors of stable nitrile imides\with substitution possible at both carbon and nitrogen termini[ For example\ bis"stannyl!diazo#methane "07# reacts with chloroboranes and chlorophosphanes to a}ord the bisboryl andbisphosphinyl substituted nitrile imides "08# and "19# respectively "Equation "3## ð81JA5948Ł[ Ofparticular interest is the preparation by this route of the stable organic C\N!ditrityl analogue "10#[

N2

Me3Sn

Me3SnNR NR+

–+RCl

(19) R = B(NPri2)2

(20) R = P(NPri2)2

(21) R = CPh3

(4)

(18)

Some chemical modi_cations have also been performed on carbon and nitrogen substituentswithout destroying the CNN skeleton^ for example\ a C!phosphino group can be converted into thecorresponding C!thiophosphinoyl by treatment with elemental sulfur ð80OM2194Ł[ An alternativeapproach to stable nitrile imides involves replacement of boryl groups at both carbon and nitrogentermini ð81S32Ł[ Reaction of the bis"diisopropylamino#boryl compound "11# with methyllithiumfollowed by a chlorophosphane a}ords the C!phosphino derivative "12# "Scheme 6#\ and the diboryl!substituted analogue "13# is formed by a similar two!step sequence[

NR12P NBR1

2–+

NR12B NBR1

2–+

NR22B NBR2

2–+

i, MeLiii, R1

2PCl i, MeLi ii, R2

2BCl

iii, MeLiiv, R2

2BCl(23) (22) (24)

Scheme 7

R1 = PriN, R2 = (c-C6H11)2N

The stable organometallic nitrile imides described above are of interest in their own right andhave allowed the structure\ bonding and properties of the CNN framework to be examined in detail[In some cases they also provide further scope\ as yet not fully realised\ for the synthesis of heterocyclic


compounds via the reactions of their substituents[ Whereas phosphorusÐcarbon bonds in thecycloadducts are not readily cleaved\ the corresponding boronÐcarbon and siliconÐcarbon bondsare more susceptible to substitution[ C!Silyl and C!boryl nitrile imides may therefore provide usefulbuilding blocks for the preparation of _ve!membered heterocycles incorporating the C1N0N unit[

2[19[0[3 Nitrile Oxides

The nitrile oxides are the group of nitrilium betaines which have been studied in greatest detail[Not only do they provide access via their 0\2!dipolar cycloaddition reactions to a wide variety ofC1N0O!containing heterocyclic systems but\ together with the manipulation of the isoxazolesand 1!isoxazolines resulting from their reactions with alkynes and alkenes\ respectively\ nitrile oxidecycloaddition chemistry has been developed into a versatile method for the stereocontrolled synthesisof natural products and analogues ð73ACR309\ 74MI 219!90\ 77MI 219!90\ 89H"29#608\ 80CHE280Ł[ Function!ality accessible by this approach includes b!hydroxyketones\ a!enones\ 0\2!diols\ g!aminoalcohols\0\2!diones\ b!aminoketones and b!amino!a!enones[ They are mainly Type II dipoles and for appli!cations in heterocyclic synthesis a very wide range of double! and triple!bonded unsaturation can_ll the role of dipolarophile[ The chemistry of nitrile oxides has been the subject of several reviewsand monographs ðB!60MI 219!90\ B!73MI 219!92\ B!77MI 219!91Ł[ Like the other nitrilium betaines\ thenitrile oxides undergo several reactions which compete with cycloaddition and therefore imposeconstraints on the method of preparation\ including dimerisation to furazan N!oxides "furoxans\14# at ambient temperature\ thermal or photochemically!induced rearrangement to the isomericisocyanates\ and 0\2!addition with nucleophiles "Scheme 7#[ Although it is possible to isolate somenitrile oxides\ particularly those with bulky substituents "e[g[\ mesitonitrile and triphenylacetonitrileoxides#\ it is usual in synthetic applications for the nitrile oxide to be generated at low concentrationin the presence of the dipolarophile in order to minimise the side reactions[ The two most usedmethods involve the dehydrohalogenation of hydroximoyl halides derived from aldoximes anddehydration of nitromethyl compounds[ In contrast to the chemistry of nitriles\ for which treatmentof an alkyl halide with a metal cyanide is an important synthetic route\ the analogous reaction withmetal fulminates does not provide a general approach to nitrile oxides\ the isomeric isocyanateusually being isolated[

N O–R+

NOH

Nu

R

NuHheat or hν

N OY

XR

N OY

XR

RN • O

NO

N

R R

O–+

X YX Y

Scheme 8

(25)

2[19[0[3[0 From aldoximes

The route to benzonitrile oxide described by Werner and Buss a century ago ð0783CB1082Łinvolving chlorination of benzaldoxime followed by base!mediated dehydrochlorination of theresulting hydroximoyl chloride continues to be widely used "Scheme 8#[ Hydroximoyl chlorides canbe prepared by direct chlorination of aldoximes using chlorine in an inert solvent[ However\ thisprocedure limits the functionality which the oxime and ultimately the nitrile oxide can carry[ Alkeneand acyl substituents\ and electron!rich aromatic rings are incompatible^ for example\ thiophene!1!aldoxime on treatment with chlorine a}ords 4!chloro!1!thienohydroximoyl chloride[ Alternativemilder reagents now in widespread use include nitrosyl chloride ð57BCJ1843Ł\ N!bromosuccinimideð58JOC1905Ł and N!chlorosuccinimide ð73T1874Ł[ The dehydrochlorination step\ originally carriedout with aqueous sodium bicarbonate or sodium hydroxide\ is now usually accomplished by additionof triethylamine\ the resulting triethylamine hydrochloride by!product being readily removed by


_ltration[ Slow addition of the base ensures a low concentration of the nitrile oxide and minimalformation of furazan N!oxide dimer[ The reaction is believed to involve removal of the oximeproton by the base with concomitant loss of halide ion ð66JCS"P0#0346Ł^ a similar but cation!like mechanism has been proposed for silver salt!induced eliminations[ Alternative hydrohalidescavengers include molecular sieves ð89H"20#0582Ł\ potassium ~uoride ð80H"21#366Ł and its dihydrateð82JCS"P0#1040Ł[ O!Alkoxycarbonyl! and O!trimethylsilyl!hydroximoyl chlorides have also beenexamined ð72JOC1679\ 80BCJ207Ł[ It is reported that the formation of ethoxycarbonylformonitrileoxide from ethyl chloro"hydroxyimino#acetate:alumina is accelerated by microwave radiationð83JCR"S#005Ł[ The thermal dissociation of hydroximoyl chlorides in an inert solvent at 099Ð029>Calso generates the nitrile oxide at low concentration ð52BSB608\ 79JPS"A#524Ł[ The analogous elim!ination of nitrous acid from nitrolic acids "O1NCR1NOH# takes place at or near room temperatureð80JCS"P1#138Ł[

N O–R+

NOH

X

R

–2H

NOH

R

X+ –HX

baseor heat

Scheme 9

As some hydroximoyl halides are di.cult to isolate in pure form and others are toxic\ for example\as skin irritants\ it is common practice to generate them in situ using NCS or NBS\ and then to carryout the dehydrochlorination:cycloaddition in one pot using triethylamine as the base[ Treatment ofaldoximes with t!butyl hypochlorite followed by bis"tributyltin# oxide also a}ords nitrile oxides\presumably via the O!stannyl oxime "RCH1NOSnBu2# ð83JCS"P0#302Ł[ Other reagents which allowone!pot halogenation:dehydrohalogenation include sodium hypochlorite ð71S4497Ł\ sodium hypo!bromite ð56JOC1292Ł and Chloramine!T ð78S46Ł[ Oxidations of aldoximes to nitrile oxides have alsobeen accomplished using lead tetraacetate ð57T4140Ł\ mercuric acetate ð81OPP80Ł and dimethyl!dioxirane ð81NKK319Ł[

2[19[0[3[1 From nitromethyl compounds

The dehydration of nitromethyl compounds\ which was _rst reported by Mukaiyama and Hoshinoin 0859 ð59JA4228Ł\ continues to provide a versatile approach to nitrile oxides which complementsthe oxime oxidation method[ Mono! and difunctional diisocyanates are the most common dehy!drating agents ðB!77MI 219!91\ 77CC0228Ł[ The reaction pathway "Scheme 09# is believed to involveaddition of the nitronate anion to the isocyanate and decarboxylation of the resulting adduct "15#to the nitrile oxide and arylamine^ the latter then react with further isocyanate to a}ord aninsoluble and readily separable diarylurea as the coproduct[ Alternative dehydrating agents includephosphorus oxychloride ð62OS"42#48Ł\ acid chlorides ð75BCJ1716Ł and anhydrides ð67CPB2143Ł\methyl chloroformate ð73CC0402Ł\ p!toluenesulfonic acid with ð83JCR"S#005Ł or without microwaveradiation ð73BCJ1420Ł\ and tosyl chloride:potassium carbonate:07!crown!5 ð75M0980Ł[ Nitrile oxidescan also be formed from nitromethyl compounds via nitronate esters ð73JOC3484Ł[

N O–R+ArNCO

NO2–

R –CO2

–ArNH2

R NO2 HN

ON

Ar

R

O–

O

+

–

Scheme 10(26)

2[19[0[3[2 From a!nitroalkanoate esters

Thermolysis in an inert solvent of alkyl esters of a!nitroalkanoic acids results in expulsion ofcarbon dioxide and the alkanol\ and formation of a nitrile oxide which can be trapped in the


presence of a suitable dipolarophile ð76BCJ0837Ł[ The reaction pathway\ which is believed to proceedvia initial cyclisation to an intermediate oxazetidinone N!oxide "16# followed by decarboxylation\is illustrated in Scheme 00 for the generation of ethoxycarbonylformonitrile oxide from diethylnitromalonate[ The method is suitable for aliphatic nitrile oxides as well as amide! and ester!substituted analogues[ A similar mechanism involving decarboxylation of an intermediate0\1!oxazetidine N!oxide has been invoked to explain the formation of arenenitrile oxides on photo!lysis of a!nitrostilbenes ð73AJC0120Ł[

N O–EtO2C+–EtOH –CO2

NO2

EtO2C

EtO2C

N

EtO2COEt

O

–O OH+

N O

EtO2C

–O

O

+

(27)

Scheme 11

2[19[0[3[3 From furazan N!oxides

Dimerisation to furazan N!oxides "14#\ which is the normal decay pathway for nitrile oxides atambient temperature\ is a reversible process[ Thermolysis results in cleavage of the O"0#0N"1# andC"2#0C"3# bonds to generate two nitrile oxide fragments\ the temperature required being criticallydependent on the steric and electronic properties of the substituents "Scheme 01#[ If the only accessto furazan N!oxides was by dimerisation of nitrile oxides then this approach would be of limitedsynthetic value[ They can\ however\ be prepared by several other routes including oxidation ofglyoximes ð73CHEC680Ł and dehydration of a!nitroketoximes[ The latter can be prepared by a!nitrosation and oximation of ketones and via the tautomeric vicinal nitronitroso compounds"pseudonitrosites# by addition of dinitrogen trioxide to the corresponding alkene[ This approach isgenerally of synthetic value for mononitrile oxides only when the furazan N!oxide is symmetricallysubstituted[ Bicyclic furazan N!oxides\ formed\ for example\ from cycloalkenes and dinitrogentrioxide\ are ideally suited for the generation of bis"nitrile oxides# "Equation "4## ð72JCS"P0#182Ł[Nitrile oxides are also formed together with an equivalent amount of nitrile on thermal or photo!chemical cleavage of furazans ð73CHEC"4#282Ł^ bicyclic furazans a}ord v!cyanonitrile oxides[

50–250 °C

< 50 °C

heat

–RCNNO

N

R R

O NO

N

R R

+ NR O–+

(25)Scheme 12

heat

NO

N O–+

NO–

N–O ++

( )n

(CH2)n

(5)

2[19[0[3[4 Generation of fulminic acid and heteroatom!substituted analogues

The parent nitrile oxide fulminic acid "formonitrile oxide\ HC2N¦0O−#\ which was the _rst

member of the series to be discovered ð0799MI 219!90Ł\ is somewhat of an exception in terms of itsreactivity and methods of formation ðB!60MI 219!90Ł[ For example\ although it can be generated bythe hydroximoyl halide route from formohydroximoyl iodide ð62CB2180Ł\ the MukaiyamaÐHoshinoprocedure fails^ treatment of nitromethane with phenyl isocyanate:triethylamine instead a}ordsa!nitroacetanilide ð52BSF039Ł[ The original route of Howard via mercury fulminate is still utilised^it involves reaction of nitric acid with ethanol\ acetaldehyde or glyoxylic acid oxime in the presenceof mercury or mercuric nitrate[ Alternative approaches include elimination of nitrous acid fromformonitrolic acid "O1NCH1NOH#\ hydrolysis of fulmidotrimethylsilane "TMSC2N¦

0O−#


formed by treatment of mercury fulminate with trimethylsilyl bromide ð71S608Ł\ hydrolysis ofbromo"hydroxyimino#acetic acid ð02CB3990Ł\ and ~ash vacuum pyrolysis of isoxazol!4!onesð68AG"E#356Ł[ Although it can be isolated\ formonitrile oxide is explosive and for synthetic applica!tions it is best generated in situ[

The formation of various derivatives have been reportedðB!60MI219!90Ł inwhich the acidic hydrogenof formonitrile oxide is replaced by\ for example\ halide\ cyano or sulfonyl groups[ For example\bromoformonitrile oxide ð82JCS"P0#1040Ł\ cyanogen oxide "N2CC2N¦

0O−#\ cyanogen dioxide"−O0¦N2CC2N¦

0O−# ð76AG"E#044Ł and benzenesulfonylformonitrile oxide ð73JOC3484Ł haveall been generated by dehydrochlorination of the appropriate hydroximoyl halides[

2[19[0[4 Nitrile Sul_des

The nitrile sul_des "RC2N¦0S−# are ideally suited for the synthesis of _ve!membered het!

erocycles incorporating the C1N0S unit\ many of which are accessible only with di.culty byother means[ Although nitrile sul_des are of very limited lifetime and\ unless matrix isolatedð80TL0376Ł\ decompose rapidly at temperatures above 49K to sulfur and the corresponding nitrile\they undergo preparatively useful cycloaddition reactions with various reactive dipolarophiles[Electron!poor alkynes and nitriles add readily a}ording\ respectively\ isothiazoles and 0\1\3!thia!diazoles^ unactivated alkynes and nitriles do not react[ Other applications include the formation of1!isothiazolines from alkenes\ 0\2\3!oxathiazoles from aldehydes and ketones\ 0\3\1!dithiazolesfrom thiones and thioesters ð80JCS"P0#072Ł\ 3\4!dihydro!0\1\3!thiadiazoles from imines and 0\1\3!thiazaphospholes from phosphaalkynes[ The synthetic aspects of their chemistry have been reviewedð78CSR22Ł\ and they have also been discussed as part of a broader account of N!sul_des ð80CRV252Ł[

The principal method of generation of nitrile sul_des "Scheme 02# involves thermal decar!boxylation at 099Ð039>C of 0\2\3!oxathiazol!1!ones "17#\ which are readily prepared by treatmentof the corresponding carboxamide with chlorocarbonylsulfenyl chloride ð67JOC2625Ł[ Photolysis of"17# also a}ords nitrile sul_de!derived products\ but the yields are invariably lower[ Nitrile sul_descan be trapped as their 0\2!dipolar cycloadducts on thermolysis of the closely related 0\3\1!dithiazol!4!ones "18#\ which are accessible from the thiocarboxamide and trichloromethanesulfenyl chloridefollowed by hydrolysis of the resulting 0\3\1!dithiazole!4!thiones ð71TL4342Ł[ 0\2\3!Oxathiazoles"29#\ the adducts resulting from cycloaddition to the carbonyl group of aldehydes and ketones\undergo thermal cycloreversion at 029Ð069>C regenerating the nitrile sul_de ð74JCS"P0#0406Ł[ The3\4!dihydro!0\1\3!thiadiazoles formed by additions to imines also undergo cycloreversion and theresulting nitrile sul_de can be trapped\ but the yields of adducts are low ð75JCR"S#045Ł[

heat

–R2CONR S–+

heat

–COXN S

XO

R

N S

OR

R

R

(30)(28) X = O(29) X = S

Scheme 13

Two other preparatively useful approaches to nitrile sul_des have been reported[ Heating "ben!zylimino#sulfur di~uoride\ prepared from benzylamine and SF3\ with sodium ~uoride and 07!crown!5!polyether at 029>C generates benzonitrile sul_de which can be trapped by reactive dipolarophilessuch as dimethyl acetylenedicarboxylate ð68JOC409Ł[ The reaction is believed to involve 0\2!elim!ination of two moles of HF\ as illustrated in Scheme 03^ acetonitrile sul_de and tri~uoroacetonitrilesul_de have also been generated by this route ð79JOC2642Ł[

N S–Ar

N

Ar

S FSN

F

FAr

H

N

H

Ar

S

F –

N

S

ArN

Ar

S

SPh2

N

Ar

S–

SPh2

+

–Ph2S

:

F –

+

Scheme 14(31)

+

576Nitriles Bearin` a Heteroatom Other Than Nitro`en

Thermolysis "49Ð69>C# of N!thioaroyl diphenylsul_mides\ which can be synthesised from diphenylsul_mide and methyl dithiobenzoates\ in the absence of a dipolarophile a}ords the correspondingnitriles together with diphenyl sul_de and sulfur[ However\ when the reaction is repeated in thepresence of electron!poor alkynes isothiazoles are formed ð65BCJ2013Ł\ presumably via the unstableantiaromatic thiazirine "20# and the arenenitrile sul_de as intermediates "Scheme 03#[

Benzonitrile sul_de has been invoked as a transient intermediate in the photofragmentationreactions of various phenyl!substituted _ve!membered heterocycles incorporating C\ N and S[ Ineach case the process is believed to involve extrusion of a stable fragment such as CO1\ COS\CS1\ N1 or N1O forming the thiazirene "20#\ followed by rearrangement to benzonitrile sul_de[Representative examples include dithiazolethiones "21# and "22#\ thiatriazole "23# and mesoionicoxathiazolone "24# ð67JCS"P0#0334\ 70LA0914Ł[ Although the intermediates have been detectedspectroscopically\ the yields of cycloadducts in the presence of a dipolarophile are generally low"4Ð18)#[

N S

SS

Ph

(32)

S S

NS

Ph

(33)

S NN

NPh

(34)

S NO

Ph

(35)

O–

+

2[19[0[5 Nitrilium Ions

Nitrilium ions "25#\ which are isoelectronic and isostructural with acetylenes\ have been invokedas intermediates in various well!known processes including the Beckmann and Curtius rearrange!ments\ and the Ritter\ Gattermann and BischlerÐNapieralski reactions[ The _rst stable salts wereisolated in the 0849s by Klager and Grill ð44LA"483#10Ł and by Meerwein et al[ ð45CB198Ł[ Theyare reactive electrophiles well suited for the synthesis of C!substituted imines\ imidates andO!acylisoamides[ Reactions with a carboxylate followed by addition of a primary amine a}ord thecorresponding secondary amide and the procedure has been used as a mild method for peptidesynthesis ð79JA3426Ł[ Although they can be isolated\ for example\ as their ~uoroborate or hexa!chloroantimonate salts\ for synthetic purposes further reactions with nucleophiles are often carriedout in situ[ The chemistry of nitrilium salts has been the subject of several reviews ð55AHC"5#84\79ACR337\ 74HOU"E4#0461Ł[

A convenient source of nitrilium ions is provided by imidoyl halides "26# which are readilyaccessible by direct halogenation of the imine ðB!68MI 219!90Ł or treatment of the correspondingcarboxamide with SOX1\ PX4 or Ph2P:CX3 ð64AG"E#790\ 64CJC0222Ł[ In aqueous organic solventmixtures\ ionisation takes place to the nitrilium salt "Scheme 04#\ the rate of the process beingdependent on the electronic nature of both carbon and nitrogen substituents and on the ionisingpower of the solvent[ Beckmann rearrangement with SbCl4 of ketoxime O!chloroformates "27\X�Cl# and O!chlorooxalates "27\ X�COCl# a}ords the hexachloroantimonate salts ð89S0017Ł[An alternative and increasingly used approach involves N!alkylation of nitriles with\ for example\trialkyloxonium tetra~uoroborate ð74TL3538Ł[ Tri~ate ð72JCS"P0#0956Ł\ hexachloroantimonateð73CB0899Ł and tetrachloroferrate salts ð79BCB322Ł have also been isolated[ Nitriles react withalkyl chloroformates and SbCl4 to give nitrilium hexachloroantimonates in high yield ð82S315Ł[N!Arylation occurs on heating a nitrile with a diazonium salt ð45CB198Ł[ Alternative precursorsinclude isonitriles which are su.ciently basic to undergo 0\0!addition at carbon\ and addition ofelectrophiles to the C1C unit of ketenimines[

2[19[1 N!SUBSTITUTED ANALOGUES OF NITRILES BEARING A HETEROATOMOTHER THAN NITROGEN�

2[19[1[0 Phosphaalkyne Synthesis

In comparison with nitriles the corresponding trivalent monocoordinated l2s0!phosphorus com!pounds\ the phosphaalkynes "RC2P#\ have a relatively brief history[ Although the parent member

� Some phosphaalkynes with heteroatom substituents attached to carbon are included here for convenience[ See also 2[19 and4[22[


N R2R1

N

R2

X

R1

+

(36)

–X– R1X

SbCl5

NR1 N

OCOX

R2

R1

N–C R2+

–CO2

R2X

(38)

Scheme 15

(37)

of the series\ the unstable and highly reactive methylidynephosphane "phosphaacetylene\ HC2P#\was characterised in 0850 ð50JA0658Ł it was not until 0870 that the preparation of a kinetically stableanalogue "tert!butylphosphaalkyne\ ButC2P# was _rst reported ð70ZN"B#05Ł[ Since this time a richand varied chemistry has emerged[ Despite in many cases substantial steric hindrance\ they undergoa wide range of reactions including ð1¦0Ł!cycloadditions\ ð0\2Ł!dipolar cycloadditions and DielsÐAlder reactions^ ð1¦1Ł!cycloadditions\ HOMO!DielsÐAlder additions and ene reactions involvingC2P have also been described[ The synthesis and reactions of phosphaalkynes has been thesubject of several reviews by Regitz ð77AG"E#0373\ 89CRV080\ 81BSB248\ 83JHC552Ł\ and their impact onorganometallic chemistry has also been surveyed by Nixon ð77CRV0216\ 82CI"L#393Ł[

b!Elimination from suitably substituted phosphanes is the most generally applicable approach tophosphaalkynes "Scheme 05#[ Flash pyrolysis of the dichlorophosphane "28# results in extrusion ofHCl which is removed by added base to avoid side and retro!reactions[ This method is suitable forthe generation of the short!lived parent phosphaacetylene and derivatives including RC2P\ whereR�H\ Me\ F\ Cl[ Analogues with conjugating substituents such as HC2C0 and N2CC2C0 are formed on co!pyrolysis of phosphorus trichloride with the propargyl halide[ The phosphino!substituted compound "Me1N#2P¦

0C2P[Ph3B− has been prepared by base!induced dehydro!chlorination of the corresponding dichlorophosphane ð80CC291Ł[ Various transient phosphaalkynescan be generated by dehydrochlorination of a\a!dichlorophosphanes "39# ð80AG"E#085Ł[ Flash vac!uum pyrolysis "FVP#!induced b!elimination of trimethylsilyl chloride from chlorophosphaalkene"30# proceeds similarly and has been used to form the phenyl and trimethylsilyl compounds[ Lithiumtrimethylsilanoate is readily eliminated from the lithiated alkenes RC"OTMS#1PLi[

heat

–TMS-Cl

PR

P-TMS

R

TMS-O–2 HCl

PCl

R

TMS

(39)

(42)(40)

R PCl2

R

Cl

Cl

PH2

heat

–TMS-O-TMS

heat

–2 HCl

K2CO3heat

(41)

Scheme 16

The most well!developed method for the synthesis of kinetically stable phosphaalkynes involvesNaOH!catalysed elimination of hexamethyldisiloxane from phosphaalkenes "31#[ The startingmaterials can be prepared by acylation of tris"trimethylsilyl#phosphane\ a process which is believedto involve initial formation of the acylphosphane RCOP"TMS#1 followed by a rapid 0\2!shift of atrimethylsilyl group[

The 0 ] 0 adduct "32# between tris"trimethylsilyl#phosphane and isopropyl isocyanate provides asource of the donor!substituted phosphaalkyne "33# ð78AG"E#42Ł which then undergoes NaOH!catalysed elimination of hexamethyldisiloxane\ the _nal product being formed "Scheme 06# by a0\2!silyl shift in the intermediate 0!aza!2!phosphaallene "34#[ The corresponding tert!butyl precursor


"35# reacts similarly and\ with replacement of the TMS group by hydrogen\ generates tert!butylaminophosphaacetylene "ButNHC2P# ð80HAC466Ł[ The diisopropylamino compoundPri

1NC2P is prepared by the reaction of tri~uoromethylphosphane with excess diisopropylamine\presumably via the phosphaalkene Pri

1NCF1PH ð89CB1206Ł[

–TMS-O-TMSN

TMS

Pri

PPriN C P-TMSP(TMS)2

TMS-O

RN

(45) (44)(43) R = Pri

(46) R = But

Scheme 17

Alternative sources include primary alkynylphosphines which undergo Lewis base!inducedrearrangement via an intermediate phosphallene ð81CC304Ł "Scheme 07#\ and di!tert!butyl!sub!stituted phosphinodiazo compounds "36# derived from lithiated diazo compounds and di!tert!butylchlorophosphane ð89CRV080Ł^ on FVP at 249>C:09−3 mbar "36# is converted into the phos!phaalkyne with elimination of 1!methylpropene "Scheme 07#[ Under more forcing FVP conditions"849>C:4×09−3 mbar# tert!butylphosphaacetylene itself also eliminates 1!methylpropene thusproviding an alternative\ albeit low yielding\ route to methylidynephosphane ð76JOM"227#218Ł[Palladium! or platinum!promoted dechlorination of 1\1!dichlorophosphaalkenes has been reportedð81TL1870\ 82OM3151Ł^ the process is believed to involve a highly reactive isocyaphide ligand[ Iso!cyaphides have also been invoked as transient intermediates in the conversion of chloro!lithiophosphaalkenes to phosphaalkynes ð80CB1566\ 81CL0942Ł "Scheme 08#[

R

P• PHR PH2

R

N2

R

PButR PBut

2 R P–N2

RC PBut

: :

(47)Scheme 18

– CH2=CMe2

P

Li

ClR P

–LiClR

RPCP:C

R– +

Scheme 19

The generation of stabilised quinquevalent "l4s2# phosphaalkynes has been the subject of inves!tigation since the late 0879s[ These compounds show an interesting pattern of reactivity and can actboth as a phosphaalkyne "RC2PR1# in addition and cycloaddition reactions\ and as a nucleophilicphosphanylcarbene "RC0PR1# capable of C0H insertion[ Two examples have been studied inparticular detail[ Bertrand and co!workers have shown that the trimethylsilyl derivative "37# bearingdiisopropylamino!stabilising substituents can be generated by photolysis of phosphiniodiazo com!pound "38#\ which is readily prepared from the chlorophosphine and the lithiated diazo compound"49# "Scheme 19# ð77JA5352\ 89PS"38#290Ł[ Under FVP conditions the product can be isolated[ Asimilar procedure has been adopted by Regitz and co!workers to form phosphino analogue "40#starting from the silver diazo compound "41# ð75TL0892Ł[ A few isolated examples of the relatedl5s3!thiaalkynes have also been described ð74JA879\ 77AG"E#0423Ł^ the methylidynesulfur tri~uoridederivatives RC2SF2 "R�CF2\ SF2# were prepared by KOH!induced dehydro~uorination ofCF2CH1SF4 "or CF2CH1SF3# and SF2CH1SF4\ respectively[

Arsaalkynes have so far received much less attention[ Following the technique successfully

R P(NPri2)2

heat or hν

–N2

N2

R

X

+ (Pri2N)2PCl N2

R

P(NPri2)2

(50) R = TMS, X = Li(52) R = Ph2P(O), X = Ag

(49) R = TMS (48) R = TMS(51) R = Ph2P(O)

Scheme 20


developed for phosphaalkynes the kinetically stabilised l2s0!derivatives of the form RC2As\ whereR�But and 1\3\5!But

2C5H1\ have been generated by ~uoride!ion induced elimination of hexa!methyldisiloxane from the arsaalkene RC"OTMS#1AsTMS ð75AG"E#153\ 82AG"E#092Ł[

2[19[1[1 Methods for the Synthesis of AlkylidyneÐTransition Metal Compounds

Since the discovery of the _rst alkylidyne "carbyne# complexes of chromium\ molybdenum andtungsten by Fischer et al[ in 0862 ð62AG"E#453Ł\ the chemistry of the carbonÐmetal triple bond hasdeveloped rapidly\ and there is widespread current interest in their properties\ their potential inorganic synthesis\ their relationship to the better known alkylidene "carbene# complexes "see Chap!ters 2[98 and 4[13#\ and particularly in their role as catalysts for metathesis and polymerisation ofalkenes and alkynes[ Although many of the known alkylidyne compounds are of Group 5 to 7metals in low oxidation states "Fischer!type complexes#\ the corresponding complexes of {early|transition metals and Group 5 metals in higher oxidation states "Schrock!type complexes# are alsowell documented[ The chemistry of alkylidyne complexes "LnM2CR\ where M�Cr\ Mn\ Fe\ Nb\Mo\ Ta\ W\ Re\ Os# has been the subject of several reviews and a multiauthor monograph publishedin 0877 ðB!77MI 219!92Ł[ The literature up to 0875 ð76AOC"16#40Ł and from 0875 to 0889 ð80AOC"21#111Łhas been surveyed in detail[ Carbyne complexes of ruthenium and osmium ð75AOC"14#010Ł\ highoxidation!state molybdenum and tungsten complexes ð75ACR231Ł\ and the interplay between alkyl!idyne and carborane ligands at metal centres ð82AOC"24#024Ł have also been reviewed[

The various synthetic strategies employed for the preparation of alkylidyneÐmetal complexes canbe divided into two broad categories] those that use non!alkylidyne precursors and those thatinvolve modi_cation of an existing alkylidyne compound[ These are summarised with representativeexamples for illustration in the following sections\ in which the terms {alkylidyne| and {carbyne| areused interchangeably for compounds containing a carbonÐmetal triple bond[ For detailed coveragethe reader is referred to the reviews cited above[

2[19[1[1[0 Synthesis from nonalkylidyne precursors

The conversion of existing groups into alkylidyne ligands is a common mode of entry to the series[Alkylidene "carbene# complexes are useful starting materials as their chemistry is well established andthey undergo a variety of abstraction\ substitution and rearrangement reactions[ Lewis acid!mediated abstraction of an alkoxy group has proved to be a versatile synthetic route[ When thetrans ligand is a strong p!acceptor\ e[g[ CO\ it is readily replaced by a halide from the Lewis acid toa}ord a neutral trans!halocarbyne complex "Equation "5##^ a wide range of groups attached to thecarbyne carbon can be accommodated including alkyl\ aryl\ alkenyl\ alkynyl\ dialkylamino\ iminoand silyl[ The _rst ironÐcarbyne complex ð"CO#2"PPh2#Fe2CNPri

1ŁBCl3 was prepared similarly[The potential of dihalocarbene ligands to act as precursors of carbynes is demonstrated by theconversion of the osmium complex Cl1"CO#"PPh2#1Os1CCl1 into Cl"CO#"PPh2#1Os2CCPh ontreatment with phenyllithium in a process which formally involves both elimination and substitutionof chlorine[ Rearrangement of carbene complexes can also lead to carbynes^ C : Cr migration ofthe nucleophilic group "Nu�halogen\ SeR\ TePh\ SnPh2\ PbPh2# in "CO#4Cr1C"Nu#NR1 occursthermally with concomitant loss of CO a}ording trans!"Nu#"CO#3Cr2CNR1[

2 BX3M

R

OMe

MeOBX2+OC

CO

COOC

CO+ CO +

M = Cr, Mo, W; X = Cl, Br, I

MX

CO

COOC

CO(6)R

Abstraction with base of an a!hydrogen atom from a carbene ligand LnM1CHR has beenutilised for the preparation of various anionic carbyne complexes ðLnM2CRŁ−^ the conversion ofa neopentylidene into a neopentylidyne ligand involving abstraction of a proton by butyllithium isillustrated by the formation of ð"CH1But#2Ta2CButŁLi"dmp#1 from "CH1But#2Ta1CHBut in thepresence of N\N?!dimethylpiperazine "dmp#[ Removal of two a!protons from "h4!C4Me4#"CH1But#ReO using Ti"h4!C4H4#Cl2 a}ords the Re"VI# complex Cl1"h4!C4Me4#Re2CBut[ Depro!tonation of h1!carbene complexes can also lead to carbynes[ Migration of an a!hydrogen promotedby the addition of phosphines has also been observed^ trimethylphosphine with Cl"Cp#"CH1But#


Ta1CHBut a}ords Cl"Cp#"PMe2#1Ta2CBut and Cl"Cp#"CH1Ph#2Ta yields the correspondingbenzylidyne complex\ presumably via a carbene intermediate[ Alkenyl ligands in LnM0CR1CR1

are capable of rearrangement into carbynes LnM2CR2^ for example\ an H!shift in molybdenum\the complex CpðP"OMe#2Ł2Mo0CH1CHBut leads to CpðP"OMe#2Ł2Mo2CCH1But[

The formal abstraction of oxide\ O1−\ from acyl or carbamoyl ligands is another direct route tocarbyne complexes[ The approach is illustrated by the formation of the alkylidyne"halo#tetra!carbonyl complexes\ trans!X"CO#3M2CR where M�Cr\ Mo and W\ from the reaction of oxaloylhalides with the anionic pentacarbonylmetal acyl complexes NMe3ð"CO#4MCORŁ[ The amino!carbyne complex trans!Cl"CO#3W2CNEt1 is formed similarly by treatment of Lið"CO#4WCORŁwith thionyl chloride[

b!Addition\ particularly of electrophiles\ to unsaturated ligands is another general approachto carbynes "Scheme 10#[ Protonation of acetylide and alkylidene has proved useful for thesynthesis of high oxidation state molybdenumÐalkylidyne complexes^ for example\ Br"Cp#ðP"OMe#2Ł1Mo1C1CHPh is converted into Br"Cp#ðP"OMe#2Ł1Mo2CCH1Ph in the presence ofHBF3\ and the manganese complex ðCp"CO#1Mn2CCPh1ŁBF3 is formed similarly fromCp"CO#1Mn1C1CPh1[ b!Addition of hydride to alkylidene ligands is also possible[ Other ligandswhich have been successfully converted into carbynes by b!addition of electrophiles include isocy!anide\ carbonyl and thiocarbonyl "Scheme 10#[

•LnM

EE+

R

E+

LnM

E

E

RLnM R

LnM N RN•LnM

RLnM N

R

EE+

X•LnME+

LnM X E

+

X = O, S

Scheme 21

By analogy with the generation of l4s2!phosphaalkynes from phosphiniodiazo compounds"Scheme 19# the corresponding a!metallodiazoalkanes of the form LnM0CR1N1 are potentialprecursors of metallocarbynes "LnM0CÝRtLnM2CR# by thermal or photochemical extrusion ofnitrogen[

Metathesis of metalÐmetal triple bonds with alkynes achieves direct introduction of a new carbyneligand in a single step and has been used successfully for the preparation of complexes of tungstenand molybdenum[ The process is promoted by the presence of bulky ligands such as tert!butoxide^for example\ the reaction of hexakis"tert!butoxy#ditungsten "42# with symmetrically!substitutedalkynes is reported to a}ord the corresponding carbynes "43# quantitatively "Scheme 11#[ Nitrilesreact similarly producing both carbyne and nitrido compounds[ Cycloalkenes yield bisalkylidynecomplexes of the form "ButO#2W2C"CH1#nC2W"OBut#2 ð78MM1458Ł[

(ButO)3W W(OBut)3

RR

R N

(ButO)3W

(ButO)3W N

(53)

R

(ButO)3W R

2(54)

(54)+

Scheme 22

2[19[1[1[1 Modi_cations of alkylidyneÐmetal complexes

Alkylidyne complexes can undergo a range of reactions while retaining intact the carbonÐmetaltriple bond\ and these have been widely exploited for the synthesis of new analogues[ This approachcan involve modi_cation of the metalÐligand framework\ modi_cation of the alkylidyne ligand oroxidation:reduction of the metal centre[ Of these the former has been the most investigated[


Ligand!substitution reactions have been used to prepare numerous derivatives[ Although thedonor molecule\ depending on its nucleophilicity\ can also attack the carbyne carbon\ displacementof leaving groups such as CO can be accomplished[ The successful application of this approach isillustrated in Equation "6# using trans!"halide#"CO#3M2R as the substrate and phosphines:phosphites as the nucleophile\ a system which has been studied in particular detail from both amechanistic and synthetic viewpoint ð75JOM"206#076Ł^ disubstituted products are obtained whennitrogen!donor ligands such as pyridine\ 1\1?!bipyridine and 0\09!phenanthroline are used[ Althoughdirect replacement of more than two carbonyl ligands by simple donor ligands does not occurso readily the amino complexes are susceptible to substitution reactions^ the pyridine inCl"CO#1"py#1W2CPh can be replaced by PMe2 to a}ord Cl"CO#1"PMe2#1W2CPh which itself isnot readily accessible by direct substitution of CO by PMe2[ Treatment of the bromo analogueBr"CO#1"py#1W2CPh with trimethylphosphite gives ClðP"OMe#2Ł3W2CPh and the tetra!kisisocyanide analogue has also been made by the same approach ð89JOM"262#068Ł[ The weaklycoordinated BF3 ligand is labile and readily substituted by neutral or anionic nucleophiles includingPPh2\ AsPh2\ CN−\ SCN− and ButNC[ Carbyne complexes with a metalÐmetal\ e[`[\ "CO#4M!n0W"2CPh#"CO#3\ have been prepared via substitution of the halide in the complex "44# bycarbonyl metallates[ Photochemically induced cis!to!trans isomerisation and photosubstitution reac!tions of alkylidyne complexes have also been reported[

+ L + COMX

CO

COOC

COR

(55)M = Cr, W; L = PPh3, P(OPh)3; X = Cl, Br, I; R = Ph, Me

(7)MX

L

COOC

COR

Several novel alkylidyne complexes have been synthesised by modi_cation of the substituentattached to the carbyne carbon[ This can involve manipulations within the group or its completereplacement[ Examples in the former category include the addition of dimethylamine to ethynyl!carbyne ditungsten compounds L"CO#3W2C0C2CPh yielding L"CO#3W2C0CH1C"NMe1#Ph\ and desilylation of LðP"OMe#2Ł1Mo2CCH1TMS by NaF:aq[ MeCN to form LðP"OMe#2Ł1Mo2CCH2[ Nucleophiles can displace leaving groups such as chloride from the carbyne^for example\ treatment of trans!L"CO#1Mo2CCl with phenyllithium a}ords the benzylidyne deriva!tive L"CO#1MoC2CPh[

Metal alkylidyne complexes undergo various oxidation and reduction reactions[ Thus\ bromineoxidation of trans!Br"CO#3M2CR "M�Mo\ W^ R�Me\ Ph\ CH1But# in the presence of 0\1!dimethoxyethane "DME# a}ords the DME!stabilised complexes Br2"DME#M2CR and representsconversion of a Fischer!type into a Schrock!type complex ð75JA437Ł[ Reductions of these products"Zn:MeCN:PMe2# then provide access to carbonyl!free Fischer complexes of the formBr"PMe2#3M2CR[


3.21Isocyanides and theirHeteroanalogues (RZC)IAN A. O’NEILUniversity of Liverpool, UK

2[10[0 ISOCYANIDES 582

2[10[0[0 General Methods for Isocyanide Synthesis 5822[10[0[0[0 The alkylation and alkynation of cyanides 5832[10[0[0[1 The reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction# 5842[10[0[0[2 a!Eliminations from formic acid derivatives of primary amines 5842[10[0[0[3 Deprotonation and further elaboration of isocyanides 5862[10[0[0[4 Use of orànometallic isocyanides 5872[10[0[0[5 Reduction of isocyanates\ isothiocyanates and isocyanide dihalides 5872[10[0[0[6 Miscellanous methods 588

2[10[0[1 Aliphatic Isocyanide Synthesis 5882[10[0[1[0 Saturated isocyanide synthesis 5882[10[0[1[1 b and more remotely unsaturated isocyanides 6992[10[0[1[2 Halo!substituted isocyanides 6912[10[0[1[3 Aliphatic isocyanides bearin` an oxyèn!based functional `roup 6922[10[0[1[4 Aliphatic isocyanides bearin` a sulfur!based functional `roup 6972[10[0[1[5 Aliphatic isocyanides bearin` a Se! or Te!based functional `roup 6982[10[0[1[6 Aliphatic isocyanides bearin` a nitroèn!based functional `roup 6982[10[0[1[7 Aliphatic isocyanides bearin` other substituents 600

2[10[0[2 a\b!Unsaturated Isocyanides 6012[10[0[2[0 General methods 6012[10[0[2[1 Isocyanides bearin` an a\b!double bond 6042[10[0[2[2 Isocyanides bearin` an a\b!aryl or hetaryl substituent 610

2[10[1 ISOCYANIDE ANALOGUES WITH A HETEROATOM OTHER THAN NITROGEN 615

2[10[0 ISOCYANIDES

2[10[0[0 General Methods for Isocyanide Synthesis

Caution] low molecular wei`ht isocyanides have a vile and penetratin` odor[ All preparative pro!cedures should be performed in a well!ventilated fume hood[

The _rst isocyanide was prepared accidently by Lieke in 0748 when he treated allyl iodide withsilver cyanide in an attempt to prepare allyl cyanide ð0748LA"001#205Ł[ The product he obtained hada {{penetrating and vile odor^|| indeed\ the odor was so unpleasant that many of his subsequentexperiments were performed outdoors[ Several years later\ Meyer reported the preparation of methyland ethyl isocyanide by the alkylation of silver cyanide ð0755JPR036Ł[ In 0756\ Hofmann describedthe synthesis of isocyanides from primary amines by treating them with KOH and chloroformð0756LA"033#003Ł[ This synthesis subsequently became known as the Hofmann carbylamine reaction\and was used for many years as a diagnostic test for primary amines[ The _rst truly general synthesisof isocyanides\ the dehydration of N!monosubstituted formamides\ was developed in the 0859s[ The

582

583 Isocyanides and their Heteroanalo`ues

pioneering work of Ugi in this area led to the introduction of phosgene as the reagent of choice forthis transformation ð54AG"E#361Ł[ These developments allowed the general synthetic applications ofisocyanides to be explored[

In the nineteenth century\ the structure of isocyanides presented something of a dilemma[ Gautiersaw isocyanides as {{true homologs of hydrocyanic acid\|| since like the acid\ {{they have the greatestdeleterious e}ect on an organism[|| On the basis of his hydrolysis results\ Gautier proposed the _rststructural formula for ethyl isocyanide "0# ð0758LA"035#008Ł[ He later went on to suggest structures"1# and "2#[ Some years later\ Nef proposed structure "3# because of the large number of a!additionreactions of the isocyanide carbon ð0781LA"169#156Ł[ In 0829\ a polar structure "4# was proposed byLindemann and Wiegrebe in analogy with the structure of carbon monoxide ð29CB0549Ł[

Et N C Et N C

CC2H5 Et N

N

(1)

•

(2)

R N

(3) (4)

C

(5)

+ –

Hammick found the partial dipole moment of the isocyano group to be opposite to that of thecyano group ð29JCS0765Ł[ Shortly after\ Brockway ð25JA1405Ł and then Gordy and Paulingð31JA1841Ł\ presented electron di}raction data which supported a predominantly triple!bondedstructure[ The infrared data of isocyanides indicated an almost triple!bonded structure\ althoughthis did not rule out a double!bond structure entirely[ Finally\ two decades after the proposal ofLindemann and Wiegrebe\ extensive microwave studies provided perhaps the most conclusiveevidence for structure "4# ð49MI 210!90Ł[ These results proved the linearity of the C0N0C bondsystem beyond doubt[

The almost unique property of isocyanides in bearing a formally divalent carbon allows them toengage in a range of unique reactions\ and they are endowed with a rich and versatile chemistry[a!Addition reactions are particularly common\ and this has been exploited in the elegant work ofPasserini and Ugi ð80COS"3#0972Ł[ Ugi has shown that isocyanides participate in four!componentcondensations "3CC# and this work has been extended to _ve! ð50CB1791\ 67M638Ł and even seven!component condensations ð82AG"E#452Ł[ Scho� llkopf pioneered the use of a!metallated isocyanidesin synthesis ð66AG"E#228\ 68PAC0236Ł\ and the tosylmethyl isocyanide "TosMIC# reagent of vanLeusen has found widespread use in the synthetic community ð61SC170\ 63LA33\ 66TL3118\ 79S214\74RTC49\ B!76MI 210!90\ 81S30\ 81TA176Ł[ Ito has contributed extensively to the synthetic chemistry ofisocyanides ð77JOC3047\ 77PAC472\ 89JA1326Ł[ Isocyanides have also found use in the synthesis ofnovel polymers ð61CRV0909\ 81AG"E#0498\ 82JA8090Ł[ Finally\ the recent terrestrial synthesis of ethynylisocyanide ð80AG"E#0533Ł\ and its subsequent detection in interstellar space\ has implications for therole of isocyanides in prebiotic chemistry ð60T2958Ł[

Until relatively recently\ very few naturally occurring isocyanides were known^ however\ thereare currently more than 199 isocyanide containing natural products[ This area has been reviewedrecently ð77MI 210!90\ 78PAC498\ 81ACR322Ł[ This review does not cover the extensive coordinationchemistry which isocyanides participate in ð79CCR082\ 72AOC"11#198\ 83AG"E#0204Ł\ but deals with thesynthetic organic methods for their preparation[ The chemistry of isocyanides was last reviewedcomprehensively by Ugi ðB!60MI 210!90Ł\ and several more general reviews of isocyanide chemistryhave been published ðB!72MI 210!90\ 74HOU"E4#500Ł[ Subsequent to this\ several updated and morespecialized reviews on isocyanides have been published[ These include the Ugi and Passerinireactions ð71AG"E#709\ 80COS"3#0972Ł\ ~uorinated isocyanides ð83AG"E#0204Ł\ functionalized iso!cyanide metal complexes ð82CRV0132Ł\ and multidentate isocyanides ð82AG"E#549Ł[

In this introductory section\ the various general methods for the synthesis of isocyanides arediscussed[ More speci_c examples are given in the appropriate section[

There are seven methods for isocyanide synthesis^ these are shown below]"i# the alkylation and alkynation of cyanides\"ii# the reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction#\"iii# a!eliminations from formic acid derivatives of primary amines\"iv# deprotonation and further elaboration of isocyanides\"v# use of organometallic isocyanides\"vi# reduction of isocyanates\ isothiocyanates and isocyanide dihalides\ and"vii# miscellaneous methods[

2[10[0[0[0 The alkylation and alkynation of cyanides

The treatment of alkyl iodides with silver cyanide was the _rst preparative procedure for thesynthesis of isocyanides[ Treatment of ethyl iodide with silver cyanide yields the silver complex of

584Isocyanides

ethyl isocyanide[ This is not routinely isolated\ but treated with potassium cyanide to liberate thefree isocyanide "Scheme 0# ð52OSC"3#327\ 68TL052Ł[ The mechanism of this reaction has been studiedin some detail ð74TL2270Ł[ In general\ the yields are modest and the use of expensive silver saltslimits the scale on which this reaction can be performed[

EtI + AgCN EtNC•AgI Et NCKCN

Scheme 1

So�ngstad and co!workers have reported improved yields by the use of onium dicyanoargenatesin the preparation of di! and triphenyl isocyanides ð63ACS"A#144Ł[ Silver cyanide has also been usedin the synthesis of more highly functionalized isocyanides[ For example\ treatment of the glycosylbromide of 1!deoxy tri!O!benzyl!D!glucose gives the anomeric isocyanide in 79) as a single "a#anomer "Equation "0## ð65TL2316Ł[

AgCN, 15 minO

OBn

Br

BnOBnO

O

OBn

NC

BnOBnO (1)

Alkyl isocyanides can also be obtained by treating the alkylation products of silver hexa!cyanoferrates or hexacyanocobaltates with the hydroxides ð16M60Ł\ or cyanides ð17JCS679Ł of thegroup 0 metals\ or even simply by heating ð48AG275Ł[ When ethanolic solutions of hydrogenhexacyanoferrate and HCN are heated to 019>C\ up to 39) of ethyl isocyanide is formedð50JOC2115Ł[

2[10[0[0[1 The reaction of primary amines with dichlorocarbene "the Hofmann carbylamine reaction#

The carbylamine reaction\ _rst described by Hofmann\ was one of the earliest general methodsfor isocyanide synthesis[ In its simplest form\ the reaction involves the treatment of a primary amineand chloroform with an aqueous solution of KOH[ The reaction is thought to involve the generationof dichlorocarbene\ its addition to the primary amine\ and a sequential b! and a!elimination"Scheme 1#[

R NH2

CHCl3, KOH

[:CCl2]

RNH2

CCl2R

N

Cl

+– proton transfer

β-elimination

α-eliminationR NC

Scheme 2

Several problems\ particularly with respect to yield were apparent in the earlier procedures[Mainly due to the e}orts of Ugi ð61"AG"E#429Ł\ Weber ð61TL0526Ł and Gokel ð77OSC"5#121Ł whointroduced the use of phase transfer catalysts\ good yields of isocyanides can now be obtained usingthis approach[ An interesting variation involves the use of aliphatic hydrazones as substrates[ Ontreatment with chloroform:KOH under phase transfer conditions the isocyanoimines are isolatedð65ACS"B#884Ł[ Mayer and co!workers have reported the conversion of N!sul_nylamines into iso!cyanides by reaction with CHCl2 and solid KOH in the presence of a phase transfer catalyst ð66S164Ł[Finally\ dichlorocarbene has been found to cleave carbodiimides to form isocyanides and isocyanidedichlorides ð55TL078Ł[

2[10[0[0[2 a!Eliminations from formic acid derivatives of primary amines

Undoubtedly the most common preparative method for the synthesis of isocyanides involves thedehydration of N!monosubstituted formamides "Equation "1##[


R NC

O

NH

R–H2O

(2)

A large number of di}erent reagents are available to e}ect this transformation[ Currently\ themost widely used dehydrating reagents used are based on phosgene[ Ugi was the _rst to describethe use of phosgene in the presence of a tertiary amine ð50CB1703Ł[ A number of tertiary amineshave been used\ including trimethylamine\ triethylamine\ tri!n!butylamine\ N\N!dimethyl!cyclohexylamine\ N\N!dimethylaniline\ pyridine\ quinoline\ and 0\3!diazabicycloð1[1[1Łoctane"dabco# ð54AG"E#361Ł[ The base of choice does appear to be triethylamine\ owing to a combinationof cost and volatility[ The high toxicity and handling properties associated with phosgene have ledto the use of diphosgene and triphosgene in the preparation of isocyanides[ Diphosgene "trichloro!methyl chloroformate# ð69OS"49#084Ł is a stable liquid which has been reported to give higher yieldsthan phosgene in the dehydration of formamides to isocyanides ð66AG"E#148Ł[ More recently\triphosgene "bis"trichloromethyl#carbonate# in the presence of a tertiary amine base has been usedto e}ect the dehydration ð76AG"E#783Ł[ Triphosgene has the advantage that it is a crystalline materialof low volatility\ which can be readily weighed out under anhydrous conditions[

The use of POCl2 in the presence of a tertiary amine has also found widespread use in thedehydration of formamides to isocyanides[ The bases that have been used include pyridineð62OSC"4#299\ 78TL0704\ 89T5240Ł\ triethylamine ð77OSC"5#876\ 77OSC"5#519Ł\ 1\5!lutidine ð73TL4964\77OSC"5#121Ł\ diisopropylamine ð74S399\ 75SC754\ 77LA654\ 89CB524Ł\ and potassium t!butoxideð75ZN"B#021Ł[

Several other phosphorus!based dehydrating systems have been reported[ For example\ Appel etal[ have shown that a combination of PPh2:CCl3:NEt2 will convert formamides into isocyanidesð60AG"E#021\ 63JOC0128\ 65LA072\ 77TL0342Ł[ This system has also been used in the preparation of N!isocyanoiminotriphenylphosphane ð79AG"E#379Ł[ Recently\ this dehydrating system has been modi!_ed by Ichikawa who used CBr3:PPh2:Pri

1NEt ð81JCS"P0#1024Ł[ Ugi and co!workers have reportedMitsunobu!type conditions "PPh2:dead "diethyl azodicarboxylate## for the dehydration reactionð61AG"E#818Ł[ Triphenylphosphine dibromide has been utilized in the dehydration of formamidesto isocyanides ð57LA"607#13Ł\ as have phosphorus trichloride\ phosphorus tribromide\ phosphoruspentachloride\ and phosphorus pentoxide ð59CB128Ł[

p!Toluenesulfonyl chloride or benzenesulfonyl chloride in conjunction with a base is still a widelyused method for the dehydration of formamides[ A variety of bases have been employed\ includingpyridine ð47JOC0110\ 75CJC1364\ 78S607\ 81JOC1907Ł and quinoline ð52JCS3179\ 62OSC"4#662Ł[ A par!ticularly interesting use of the TsCl:pyridine dehydrating system was reported by Ugi and co!workers who described the preparation of a variety of macromolecular isocyanides from polymer!bound formamides ð71AG"E#263Ł[ The use of methanesulfonyl chloride:pyridine has also been dis!closed ð68JA0597\ 68TL1634Ł[

The application of Vilsmeier!type dehydrating systems is also well documented in the synthesisof isocyanides from formamides[ The classical SOCl1:DMF mixture\ generating chloro!dimethylformiminium chloride at low temperature\ followed by addition of the formamide and thenNa1CO2 was used by Walborsky ð59CB128\ 61JOC076\ 66LA39\ 77OSC"5#640Ł[ A more recent variationon this method utilizes 1!chloro!2!ethylbenzoxazolium tetra~uoroborate in the presence of tri!ethylamine ð66CL586Ł[

A particularly mild dehydrating reagent oxomethylenebis!"2H¦!imidazolium# bis"methane!sulfonate# was recently described byUgi et al[ ð71JCR"S#68Ł[ This reagent\ which is prepared in situ bythe addition ofmethanesulfonic acid to oxomethylenebis"imidazole#\ is reported to be particularly ef!fective in the preparation of homochiral isocyanoesters\ which are prone to racemization "Equation "2##[

CO2Me

NHCHOPh

+ +CO2Me

NCPh

N N

O

NHHN+ +

2 Ms–

2NH

NH

+

Ms– + CO2

(3)

Very recently\ Baldwin et al[ have reported the use of tri~uoromethanesulfonic anhydride inconjunction with diisopropylethylamine at −67>C as a highly e}ective method for the dehydrationof functionalized formamides to isocyanides ð89SL592Ł[ Several other examples of this dehydratingsystem have subsequently been reported "Equation "3## ð89TL1936\ 80SL604\ 81JCS"P0#1024\ 82TL468\83CC74Ł[

586Isocyanides

(CF3SO2)2O, Pri2NH

CH2Cl2, –78 °C

86%O

H

O

NHCHOSTol

O

H

O

NCSTol

(4)

In addition to the reagents cited above\ a number of less commonly encountered dehydratingreagents have been employed[ For example\ cyanuric chloride in the presence of K1CO2 has beenused on several occasions ð50AG108\ 60OS"40#20\ 66AG"E#151Ł[ Other reagents in this category includeBF2:HgO ð50JOC1191Ł\ and di!1!pyridyl sul_te:NEt2 ð75TL0814Ł[

2[10[0[0[3 Deprotonation and further elaboration of isocyanides

Isocyanides that do not bear an a!hydrogen atom add Grignard reagents and organolithiumcompounds\ generating metallated aldimines intermediates ð58JA6667\ 60TL3854\ 63JOC500Ł[ The lith!ium derivatives have then been used as acyl anion equivalents ð69JA5564\ 63JOC599\ 63JOC593\ 67JOC623Ł[

In 0857\ Scho� llkopf was the _rst to report that isocyanides bearing an a!hydrogen atom can bemetallated at the a!position ð57AG"E#794Ł[ Metallation can be accomplished with a variety of bases\including n!butyllithium\ potassium t!butoxide\ sodium methoxide\ 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu#\ NEt2\ and NaH ð63AG"E#678\ 66AG"E#228Ł[ The choice of base depends on the substituentsR0 and R1\ with acidifying substituents allowing the use of weaker bases in the metallation step"Equation "4##[ The a!metallated isocyanides are not isolated but subjected to further reaction inthe same vessel[ A wide range of electrophiles has been used and these are discussed in more detailin the appropriate section[

NC

R2

R1

R2

R1

CN – M++ base– M+ + base-H (5)

A particularly useful example involves the condensation of a!metallated isocyanides with com!pounds containing polar multiple bonds[ The initial addition adduct to aldehydes and ketonescontains an electrophilic isocyanide carbon atom which can then be attacked intramolecularly bythe alkoxide[ The resulting heterocycle anion is in equilibrium with the precursor\ the equilibriumlying on the side of noncyclized anion[ By careful choice of proton source\ either the heterocycle orthe substituted isocyanide can be obtained "Scheme 2#[ Thus\ certain heterocyclic ring systems canbe used as precursors to substituted isocyanides by a deprotonation:reprotonation protocol[

R2

CN

R1 – M+ +R3 R4

O

R2

CN

R1

O– M+

R3

R4

R2

CN

R1

OH

R3

R4

ON

R1

R2 R3R4

M

ON

R1

R2 R3R4

AcOH

MeOH

Scheme 3

a!Metallated isocyanides have also found extensive use as a!amino anion equivalents ð63AG"E#678\66AG"E#228\ 68PAC0236Ł[

There are however\ limitations to this approach^ notably sec!alkyl isocyanides without activatingsubstituents cannot be metallated[ Cyclopropyl and cyclobutyl isocyanides are exceptions to thisrule[ The use of a!metallated isocyanides in synthesis has been reviewed several times ð63AG"E#678\66AG"E#228\ B!68MI 210!90\ 68PAC0236Ł[


2[10[0[0[4 Use of organometallic isocyanides

The use of TMS!CN in the presence of a catalytic Lewis acid promotes the ring opening ofoxiranes to give either the b!"trimethylsilyl#oxy cyanide or isocyanide[ In general\ harder Lewisacids "those containing Al# favor the formation of cyanides\ while softer ones "containing zinc\ tin\gallium and palladium# favour isocyanide formation ð76JOC0902\ 89JOC1905Ł[ This behaviour is aconsequence of the well!known equilibrium between TMS!CN and its isocyanide ð65IC490Ł[

Gassman and co!workers have carried out extensive studies on the ring opening of epoxides withTMS!CN and ZnI1 to give b!hydroxy isocyanides ð71JA4738\ 72TL544\ 73TL2148Ł[ This methodologyhas also been applied by Gassman to the ring opening of oxetanes to yield g!hydroxyisocyanidesð74TL3860Ł[

Tertiary alkyl halides can also be utilized in transformations of this type[ For example\ Reetz etal[ have shown that 0!chloroadamantane is converted into 0!isocyanoadamantane by treatmentwith TMS!CN and TiCl3 "Equation "5## ð70JOC4334\ 72T850Ł[

TMS-CN, TiCl4

CH2Cl2, 0 °C78%

Cl NC(6)

A particularly interesting preparation of isocyanides involves the treatment of alkenes "fromwhich tertiary carbocations can be generated# with HCN in the presence of cuprous halides at 099>Cð55JOC3069Ł[ The initial product is the cuprous halideÐisocyanide product\ which on treatment withNaCN\ yields the free isocyanide[

2[10[0[0[5 Reduction of isocyanates\ isothiocyanates and isocyanide dihalides

The reduction of isocyanates to isocyanides has been e}ected by a number of di}erent reagents[The earliest reagents used were phosphines and phosphites[ However\ they su}er from the drawbackof requiring high temperature ð51JOC2540\ 55JOC2362Ł[ Mukaiyama|s reagent\ 1!phenyl!2!methyl!0\2\1!oxazaphospholidine\ has proved an e}ective reducing agent for both isocyanates and iso!thiocyanates at room temperature\ but it is di.cult to prepare and store ð54BCJ747Ł[

Baldwin and co!workers reported two silicon!based reagents\ namely\ diphenyl!t!butylsilyllithiumand trichlorosilane:triethylamine for the e.cient conversion of isocyanates into isocyanides "Scheme3# ð71CC831Ł[ The latter reagent was preferred owing to its less basic nature and cost and easeof product puri_cation[ A subsequent NMR study on the mechanistic pathway of diphenyl!t!butylsilyllithium deoxygenation showed the presence of intermediates "5# and "6# "Scheme 3#ð72T1878Ł[

R NCO R NC

R NCO R NC

O– Li+

N SiButPh2R

(6)

OSiButPh2

N LiR

+ Ph2ButSiO– Li+

Cl3SiH, NEt3

Ph2ButSiLi

(7)

Scheme 4

Collman|s reagent\ Na1Fe"CO#3\ has been shown to reduce both isocyanates and isothiocyanatesto the iron carbonyl complex of the isocyanide ð78OM0427Ł[

The reduction of isothiocyanates to isocyanides is more easily achieved than the correspondingisocyanate reductions\ and can be carried out using a range of di}erent reagents[ These includetriethylphosphine ð0769CB655Ł\ copper ð0762CB109Ł\ triphenyltin hydride ð52JOC0696Ł\ tri!n!butyltin

588Isocyanides

hydride ð75TL044Ł\ phenylacetyl chloroformamidine ð55CB2052Ł\ and photolysis ð53AG"E#530Ł[ Theuse of SmI1 for the reduction of isothiocyanates to isocyanides has also been reported ð81CL0032Ł[

Isocyanide dihalides ð58AG"E#19Ł have proved to be valuable precursors to isocyanides[ They canbe prepared by the addition of the halogen "chlorine and bromine# to the parent isocyanide[ Theyare frequently used as a {{protecting group\|| masking the reactivity of the isocyanide[ Isocyanidedichlorides are the most commonly used dihalides[ Several methods exist for their conversion intothe parent isocyanide[ Aliphatic isocyanide dichlorides are reduced by iodide ion[ The intermediateisocyanide diiodide is unstable and dissociates spontaneously into the isocyanide and iodineð53CA5684Ł[ Triethylphosphine also e}ects the reduction of isocyanide dichlorides ð0769CB655\51AG737\ 53CA5684Ł as does LiAlH3 ð66JA6256Ł[

The electrochemical reduction of isocyanide dichlorides to give isocyanides has also been disclosedð81TL3668Ł[

The reaction of isocyanide dichlorides with certain transition metal complexes yields the cor!responding isocyanide metal complex ð64AG"E#258\ 67JA3201\ 67TL2916\ 68AG"E#64Ł[ Magnesium metalwas used as the reducing agent by Lentz in the preparation of tri~uoromethyl isocyanideð73JFC"13#412Ł[

2[10[0[0[6 Miscellanous methods

Ho�~e and Lange have reported a novel {{reagent!free|| isocyanide synthesis[ The starting materialsare 4!alkyl"aryl#aminotetrazoles\ which are prepared from 4!aminotetrazole or monosubstitutedthioureas[ Oxidation with sodium hypobromite or lead tetraacetate leads to liberation of theisocyanide and nitrogen "Equation "6## ð65AG"E#002Ł[

NN

NH

NNH

PhNaOBr, 0 °C

H2O, CH2Cl2

Ph NC + 2 N2 + NaBr + H2O (7)

Photochemical methods for the synthesis of isocyanides are rare but they are known[ Boyerand co!workers have described the photodissociation of formimidoyl cyanides to produce thecorresponding N!alkylisocyanides ð64JCS"P0#0632Ł[ The irradiation of N!n!propyl!0\7!di!t!butyl!4\5!di!oxo!1\2!benzobicycloocta!1\6!diene gives n!propyl isocyanide in good yields "Equation "7##ð62CC588Ł[

O

N Pr

But

But

But

But

+ COPrNC +hν

(8)

The photolysis of dihydropyrazine derivatives in the presence of rose bengal and oxygen has beenreported to give isocyanides ð77TL0016\ 81JOC1138Ł[

2[10[0[1 Aliphatic Isocyanide Synthesis

2[10[0[1[0 Saturated isocyanide synthesis

The most common method for the synthesis of saturated isocyanide synthesis involves thedehydration of the corresponding N!formamide[ The phosgene!based reagents are the most e}ective\and this area has been covered in a number of review articles ð54AG"E#361\ B!60MI 210!90\ 66AG"E#148\76AG"E#783Ł[ The combination of SOCl1:DMF in the presence of Na1CO2 or K1CO2 has also beenreported to be particularly e}ective in saturated aliphatic isocyanide synthesis ð61JOC076\ 77OS"5#519Ł[Luning and co!workers have reported the use of POCl2:Pri

1NH in the synthesis of the highlyhindered 1\1\4\4!tetramethyl cyclopentylisocyanide "Equation "8## ð74S399\ 80CB1444Ł[


NHCHO NCPOCl3, HNPri

2

80–85%(9)

The phase transfer modi_cation of the carbylamine reaction has also been widely used in saturatedaliphatic isocyanide preparation ð77OSC"5#121Ł as have the methods of Ho�~e and Lange ð65AG"E#002Łand Appel ð60AG"E#021Ł[

In their approach to the natural product 8!isocyanopupukeanane\ a fully saturated isocyanide\Yamamoto and co!workers used TsCl:pyridine in the dehydration of the N!formamide to theisocyanide "Equation "09## ð68JA0598Ł[

NHCHO NC

TsCl (1.5 equiv.)

pyridine, 1.5 h89%

(10)

Scho�llkopf and co!workers have reported the synthesis of 0\1!ethylene diisocyanide\ 0\2!propylenediisocyanide\ and 0\3!butylene diisocyanide ð79LA17\ 70LA092Ł[ All three diisocyanides were preparedby the dehydration of the precursor diformamides with phosgene[ The simultaneous preparation ofthree isocyano groups by dehydration of the precursor triformamide using diphosgene gives noveltridentate isocyano ligands "Equation "00## ð80JOM"309#C8\ 80JOM"392#C04\ 81AG"E#0101\ 82AG"E#549Ł[

NHCHOR

3NC

R

3

O

O ClCl3C

(11)

R = H, Me

The synthesis of both cis! and trans!1\1\3\3!tetramethylcyclobutane!0\2!diisocyanide has beenreported ð51CJC752Ł as has cis\ cis!0\2\4!cyclohexanetriisocyanide ð79IC2742\ 82AG"E#549Ł[

An unusual preparation of alkyl isocyanides\ reported by Bartoli et al[\ involves the sequentialreaction of iron"II# tetraphenylporphyrin "TPP# with dichlorocarbene and two equivalents of aprimary amine[ The initial product is the isocyanide iron"II# TPP complex[ Heating to 069>C underreduced pressure then allows isolation of the free isocyanide ð67TL2916Ł[

Detailed experimental procedures for the preparation of the following aliphatic isocyanideshave been published] methyl isocyanide ð62OSC"4#662Ł\ ethyl isocyanide ð52OS"4#327Ł\ t!butyl iso!cyanide ð77OS"5#121Ł\ 0\0\2\2!tetramethylbutyl isocyanide ð77OS"5#640Ł 0\3!diisocyanocyclohexaneð54AG"E#361Ł\ and cyclohexyl isocyanide ð62OSC"4#299Ł[

2[10[0[1[1 b and more remotely unsaturated isocyanides

The most widely used approach to this class of isocyanide is very similar to the saturatedanalogues\ namely the dehydration of the parent N!formamide[ A range of unsaturated isocyanideshave been prepared by Ruchardt and co!workers\ who used POCl2:Pri

1NH to dehydrate the pre!cursor formamides[ Examples include isocyanides with both allylic and propargylic substituents"Table 0# ð81CB414Ł[

A number of naturally occurring compounds contain remote unsaturation[ For example\ thenatural product theonellin isocyanide was prepared by dehydration of the N!formamide withtri~uoromethanesulfonic anhydride:Pri

1NEt at −67>C in high yield "Equation "01## ð80SL604Ł[

OHCHN CNTf2O, EtNPri

2

–78 °C89%

(12)

690Isocyanides

Table 0 Examples of allylic and propargylic isocyanates[

NC

NC

NC

NC

NC

NC

NC

Isocyanide Yield(%)

77

67

RNH

O

69

48

39

POCl3, Pri2NH, CH2Cl2

R NC

83

67

In the synthesis of the natural product hapalindole J\ Natsume et al[ chose to use the POCl2:pyridine dehydrating protocol to convert the precursor formamide into the isocyanide ð78TL0704Ł[In their synthesis of the natural product 7\04!diisocyano!00"19#!amphilectene ð78JOC0372Ł\ Piers etal[ utilized the PPh2:CCl3:NEt2 methodology of Appel for the simultaneous dehydration of two N!formamido groups "Equation "02##[

OHCHN

HH

OHCHN

H

CN

HH

CN

HPPh3, CCl4, NEt3

CH2Cl2, 55 °C, 6.5 h(13)

Corey et al[ have reported the total synthesis of 6\19!diisocyanoadociane[ The introduction ofboth isocyano groups was achieved by treatment of the bistri~uoroacetate "7# with TMS!CN in thepresence of TiCl3\ giving a mixture of four diastereoisomeric products "Equation "03## ð76JA176Ł[

CF3OCO

CF3OCO H

H

H

(8)

CN

CN H

H

HTMS-CN (15 equiv.)

TiCl4 (20 equiv.)CH2Cl2, 2.5 h

70%

(14)

Many naturally occurring isocyanides contain remote unsaturation[ Recent examples of thesecan be found in the references ð81TL0482\ 81TL5712Ł[


Scho�llkopf and co!workers have prepared E!3!phenyl!2!butenyl!isocyanide by treatment of cin!namyl bromide with the lithio anion of methyl isocyanide ð66LA39Ł[ The preparation of b!ionylisocyanide and all trans!retinyl isocyanide using the dehydration of the parent formamides withSOCl1:DMF:Na1CO2 has also been reported "Equation "04## ð62HCA0560Ł[

NHCHO NC i, SOCl2/DMF –40 °C

ii, Na2CO3 88%

(15)

Makosza et al[ have shown that nitroarenes react with phenylthiomethyl isocyanide in the presenceof KOBut resulting in the introduction of an isocyanomethyl substituent into positions ortho orpara to the nitro group ð82S0104Ł[ Both chloro and cyano substituents were also present on the arylring "Equation "05##[ Further examples of the synthesis of this class of compounds has been reportedð89H"20#0744Ł[

NO2

Z

+ PhS NC

NO2

Z

NC

i, ButOK/DMF 0 °C, 15–30 min

ii, CO2, AcOEt 47–72%

(16)

Z = H, Cl, NO2, CN

The electrochemical reduction of a!mono and dialkyl derivatives of p!toluenesulfonyl methylisocyanides gives the parent primary and secondary alkyl and aralkyl isocyanides ð80TL4428Ł[

A detailed experimental procedure for the preparation of benzyl isocyanide has been reportedð89OSC"6#16Ł[ Van Leusen has described the preparation of b\g!unsaturated isocyanides by thecondensation of TosMIC with hindered ketones\ followed by dehydration of the product formamidewith POCl2:NEt2 ð80RTC391Ł[

An unusual family of polyisocyanide compounds has been prepared by Mann and co!workersð89JOC3849Ł[ Treatment of diphenyl methyl isocyanide with BunLi followed by the addition of 9[4equiv[ of 0\2!dibromopropane yielded 0\0\2\2!tetraphenyl!0\2!diisocyanopropane[ By varying theamount of 0\2!dibromopropane\ a range of novel polyisocyanides was prepared "Scheme 4#[

CN

PhPh CN Ph CN Ph

Ph

NCPh

Ph

CN Ph

Ph

NCPh

NCPh

CN

PhPh

Ph

NC

CNBr

PhPhNC

Ph

Ph

Br Br

Ph

CN

CNBr

PhPh

CNBr

PhPh

– Li+

i, BunLi

ii,

i, BunLi

ii,

i, BunLi

ii,

Scheme 5

2[10[0[1[2 Halo!substituted isocyanides

The synthesis of a!halogenated isocyanide chromium pentacarbonyl complexes has been reportedð77CB350Ł^ examples of F\ Cl and Br substituents were described[

The preparation of a number of simple ~uorinated isocyanides has been disclosed[ Treatment ofdi~uoromethanimines with PPh2 yielded the poly~uorinated isocyanides shown in Equation "06#

692Isocyanides

ð83AG"E#0204Ł[ The dehydration protocol of Ugi has also been applied to the preparation of 1\1\1!tri~uoroethyl isocyanide and 1!~uoroethyl isocyanide ð81ICA62Ł[

NCRN

F

F

RPPh3

(17)

R = CF3, Et, C3F7

Lentz has reported the synthesis of tri~uoromethylisocyanide by the reduction of the tri~uoro!methylisocyanide dibromide with magnesium metal ð73JFC"13#412\ 77CB0334\ 78AG"E#0145Ł[ The use ofzinc in DMF has also been reported to e}ect this transformation ð83AG"E#0204Ł[ The preparationof trichloromethyl isocyanide as its chromium pentacarbonyl complex was described by Degelð68AG"E#64Ł[ The intriguing sulfur penta~uoride isocyanide has recently been prepared by a similarreductive process "Equation "07## ð78AG"E#0145Ł[

N

Br

BrF5S

F5S NCMg, THF

(18)

Hagedorn et al[ noted that N!1!hydroxy!1!phenylethyl formamide gave 1!chloro!1!phenylethylisocyanide on treatment with POCl2:pyridine in modest yield ð50AG15Ł[ The synthesis of 2\2!diphenyl!2!isocyano!0!bromopropane has been described ð89JOC3849Ł[

Baldwin and Yamaguchi have reported the preparation of b!iodo isocyanides by the initial trans!addition of iodine isocyanate across alkenes\ to give the intermediate b!iodo isocyanate[ Reductionof the isocyanate with trichlorosilane:NEt2 then gives the b!iodo isocyanide in good yield ð78TL2224Ł^examples of both cyclic and acyclic alkenes were given "Scheme 5#[

The synthesis of a number of remotely halogenated isocyanides has been reported ð50AG15\74HOU"E4#500Ł[

I

NCO

I

NC

AgOCN

I2

Cl3SiH

HNPri2, CH2Cl2

Scheme 6

2[10[0[1[3 Aliphatic isocyanides bearing an oxygen!based functional group

A number of di}erent approaches have been utilized in the synthesis of this class of compounds[Examples of oxygen bound directly to the isocyano nitrogen are known[ Thus\ ~ash vacuumpyrolysis of 2!methyl!4!oxo!3!phenyloximino!3\4!dihydro!4!oxazole gives phenoxy isocyanidewhich was isolated at low temperature ð70JOC0935Ł[ More recently the matrix isolation of isofulminicacid "CN0OH# has been described ð77AG"E#827Ł[ The preparation of a!oxygenated isocyanides hasrecently been disclosed by Yoshida et al[ ð83CC438Ł[ Thus\ anodic oxidation of a!oxygenatedorganotin compounds in the presence of Bu3NBF3 and TMS!CN gives good yields of the a!oxygenated isocyanides "Equation "08##[

OMe

R SnBu3

OMe

R NC

Bu4NBF4, THF

TMS-CN, e–(19)

a!Acyloxy isocyanides were _rst reported by Ho�~e\ who treated benzoyl bromide with silvercyanide in acetone[ The free isocyanide is liberated by treatment with KCN[ In most cases theproducts could be isolated\ although they became {{dark and resinous at room temperature and inthe presence of air|| "Equation "19## ð63AG"E#565\ 66AG"E#616Ł[

O

Ph Br

O O

O Ph

Br O

O Ph

NC i, AgCN

ii, KCN(20)+


Acyl isocyanides were synthesized only relatively recently[ Ho�~e and Lange have reported thattreatment of acyl iodides with silver cyanide yielded the corresponding acyl isocyanides ð66AG"E#151Ł[These are highly unstable compounds that are best stored and used in solution "Equation "10##[

(21)O

R I

AgCN O

R NC

The a!epoxy isocyano group is a highly unusual functional group[ There are only three naturalproducts\ isonitrin C "trichoviridin# ð65CPB721\ 79T404\ 71ABC0792Ł\ aerocyanidin ð77JAN343Ł andcavernoisonitrile ð81TL5712Ł\ known to contain this moiety[ Scho� llkopf et al[ have reported thatester!substituted a!epoxy isocyanides can be prepared by the conjugate addition of basic peroxideto a!isocyano acrylates "Equation "11## ð73LA597Ł[

O

CO2Me

NCR1

R2R2

R1 NC

CO2Me

30% H2O2

NaOH, MeOH(22)

Recently\ Baldwin and O|Neil have developed a more general route to this class of compoundsð89TL1936Ł[ Epoxidation of a\b!unsaturated formamides with dimethyldioxirane at −67>C\ followedby in situ dehydration of the intermediate epoxy formamide with tri~uoromethanesulfonic an!hydride:Hu�nig|s base gave the epoxy isocyanides in modest yield "Scheme 6#[

OOHCN

OCNNHCHO OO

CH2Cl2, –40 °C

(CF3SO2)2O

EtNPri2, –78 °C

Scheme 7

H

The pioneering work of Scho� llkopf et al[ has led to methodology for the preparation of a widerange of isocyanides bearing oxygen functionality[ In 0857\ these authors reported that treatmentof simple alkyl isocyanides with BunLi at −67>C generated the corresponding a!lithio isocyanide[Addition of an aldehyde or ketone then gave either the alkene "on warming# or with protonationthe oxazoline[ The source of proton was subsequently found to be important[ Addition of glacialacetic acid immediately after addition of the carbonyl compound "kinetic protonation# leads to theb!hydroxy isocyanide[ Protonation in alkaline medium is reversible and gives the oxazoline as thethermodynamic product "Scheme 7# ð69AG"E#347\ 60AG"E#380Ł[ The crystal structure of an a!lithiated!isocyanide has been reported ð81AG"E#68Ł[

The a!lithio isocyanide can be alkylated with alkyl bromides or iodides ð66LA39Ł[ The reactionof a!lithio isocyanides with epoxides and oxetanes\ followed by protonation\ yields the b! and g!hydroxy isocyanides\ respectively\ with attack occurring at the least hindered carbon "Scheme 8#ð65LA1094Ł[

With an acidifying substituent on the a!position\ deprotonation can be achieved with weakerbases ð63AG"E#678Ł[ a!Isocyanoalkanoic esters can be metallated with KOBut in THF[ With ethyl a!isocyanopropionate\ alkylation leads to 1!isocyano!1!methylalkanoic esters[ From ethylisocyano!acetate the major product is the dialkylated compound along with starting material ð60AG"E#220\63AG"E#678\ 74SC156Ł[ When 0\2!dibromopropane is the alkylating agent\ ethyl isocyanoacetate gives0!isocyanocyclopropanecarboxylate[ The use of other bis!electrophiles has also been describedð60AG"E#220\ 64CB0479Ł[ The preparation of substituted 0!isocyanocyclopropane carboxylates hasalso been achieved by the addition of dimethylsulfoxonium methylide to b!substituted ethyl a!isocyanoacrylates "Scheme 09# ð62LA500Ł[ A detailed procedure for the preparation of ethylisocyanoacetate has been described ð77OSC"5#519Ł[ t!Butyl isocyanoacetate has also been preparedand utilized in similar transformations ð75AG"E#643Ł[ The preparation of "¦#!7!phenylmenthylisocyanoacetate has been described ð81TA28Ł[

Ethyl 1!isocyano!1!lithiopropionate adds to epoxides to give\ after protonation with glacial aceticacid\ g!isocyanoalcohols[ If no proton source is added and the solution allowed to warm to roomtemperature\ cyclization of the alkoxide on to the ester occurs to give the unusual isocyano lactone"Scheme 00# ð62AG"E#212Ł[

694Isocyanides

R1 NC R1 NC

R2 O– Li+R3

R1 NC

O

R2 R3

R2 OHR3

R1 NC

–Li+

N

OR3

R2

R1

– Li+–78 °C to RT

+ LiOCN

–78 °C

BunLi

THF, –78 °C

R2 O– Li+R3

R1 NC N

OR3

R2

R1

R2

R3

R1

AcOH–70 °C

MeOH

Scheme 8

R1OH

NC

R2 R4

NCR1

R3

OHR5

R2

R1

CN– Li+NC

R2

R1BunLi

THF, –78 °C

O

O

R6

R5

R3

ii, AcOH

i,

i,

ii, AcOH

–30 °C

Scheme 9

O

–

R2

R1 NC

CO2Et CO2Et

NCR1

R1

Me2S NC

O R1 R2

CO2Et

+Me2S

CH2–

+

Scheme 10

EtO2C O– Li+

NC

CN

EtO2C

O

EtO2C OH

NC

OCN

O

–70 °C to 0 °C– Li+

∆

AcOH

Scheme 11


The reaction of potassium ethyl isocyanoacetate with ethyl chloroformate gives potassium diethylisocyanomalonate\ which can be alkylated in situ by alkyl halides to give the diethyl a!alkyl!a!isocyanomalonates ð64LA422Ł[

The conjugate addition of the sodium anion of both ethyl isocyanoacetate and ethyl isocyano!propionate to both a\b!unsaturated esters and nitriles has been described by Scho�llkopf and co!workers ð62LA0460\ 62CB2271Ł[ The reaction proceeds in both cases with a catalytic amount of sodiumethoxide "Scheme 01#[

EtO2C

CN

R1– Na+CO2Et

R1

CN

EtO2C

NCR1

R2

NC

R3R3

NC

R2

Scheme 12

i,

ii, AcOH

NaOEt

EtOH

The conjugate addition of carbanions to 1!isocyanoacrylic esters provides a useful route for thepreparation of a range of oxygenated isocyanides ð66LA0063Ł[ The carbanions used include Grignardreagents and diethyl sodium malonate "Scheme 02#[

EtO2C NC

EtO2C

R1 R2

CO2Et

NC

CO2EtR3

R1

R2

NC

CO2EtR2

R1 CO2Et

CO2Et

i, R3MgHal Et2O, 0 °C

ii, AcOH

i,

NaOEt, EtOH

ii, AcOH

Scheme 13

It has been reported that naturally occurring isocyanide acids can be converted into the cor!responding esters by reaction with alcohols:phenols in the presence of dicyclohexylcarbodiimide"dcc# and a catalytic amount of 3!dimethylaminopyridine "dmap# ð89JCS"P0#1004Ł[

Van Leusen and co!workers have reported an unusual approach to the preparation of steroidalisocyanides\ whereby the reduction of the parent a\b!unsaturated isocyanide with NaBH3 gives thesaturated isocyanide in excellent yield ð80S420Ł[

N!Alkylisocyanoacetamides can be readily prepared by the treatment of ethyl isocyanoacetatewith primary amines "Equation "12## ð78S530Ł[

CN CO2Et CNNHR1

O

R1NH2

EtOH(23)

The preparation of 1!aryl!1!isocyanoacetamides has also been reported\ by an initial Ugi con!densation between aromatic aldehydes\ isocyanides and ammonium formate\ followed by dehy!dration of the N!formamide with POCl2:NEt2 ð89LA824Ł[ This work has been extended to thepreparation of N!substituted 0!isocyano!0!cycloalkanecarboxamides ð80LA732Ł[ The condensationof chiral amines with methyl isocyanoacetate has also been reported ð74ABC0650Ł[

The synthesis of dialkyl!0!isocyanomethylphosphonates has been reported by Scho�llkopf and co!workers ð63LA33\ 70LA698\ 70LA0582\ 73LA599\ 73S0922\ 82LA316Ł[ Scho� llkopf and co!workers have shownthat the lithium anion of diethyl isocyanomethylphosphonate opens epoxides in the presence ofBF2OEt1 to give diethyl 2!hydroxy!0!isocyanoalkylphosphonates[ Mesylation of the hydroxy groupand base!promoted cyclization then leads to diethyl 0!isocyanocyclopropylphosphonates "Scheme03# ð82CB316\ 75AG"E#643Ł[

HO P(OEt)2

O

NC

R2

R1 P(OEt)2

NCR1

H

HR2

O

CN P(OEt)2

O

O

H

R2R1

H

i, BunLi

ii,

iii, H2O

BF3•OEt2

i, MsCl, NEt3

ii, C5H11tOK

Scheme 14

696Isocyanides

A number of other routes to oxygenated isocyanides have been employed[ The ring opening ofboth oxiranes and oxetanes in the presence of TMS!CN and a soft Lewis acid gives access to b! andg!hydroxy isocyanides\ respectively ð71JA4738\ 72TL544\ 73TL2148\ 74TL3860\ 89OSC"6#183Ł[ A particularlyinteresting variation of this reaction involves treatment of the ketone "8# with TMS!CN and TiCl3to give the oxygenated adamantane "09# "Equation "13## ð89S535Ł[

O-TMS

NC

O

(9) (10)

TMS-CN, ZnI2 (15 mol%)

CH2Cl2, ∆, 16 h(24)

The base!promoted ring opening of heterocycles has also found extensive use in the synthesis ofaliphatic isocyanides bearing oxygen functionality[ Meyers et al[ have shown that treatment ofdihydro!0\2!oxazines with BunLi at −67>C\ gives after hydrolytic workup\ g!hydroxy isocyanidesin good yield "Scheme 04# ð58TL4040Ł[

N

O

N

O

NC

O– Li+

NC

OH

– Li+

H2O H2O

80%

i, BunLi

ii, THF, –78 °C

Scheme 15

1!Oxazolines also participate in this reaction ð66AG"E#228\ 76S582Ł[ A particularly elegant exampleof this involves the in situ trapping of the anionic intermediate to generate the product isocyanide"Scheme 05# ð68JOC1931Ł[

N

O

R1

EtO

N

O

R1

EtO

R2 NCR1

EtO O

R1 NC

EtO O– Li+– Li+

R2XBunLi

–78 °C

Scheme 16

The direct base!promoted condensations of isocyanides have also been employed\ particularlywith a!isocyanoesters[ Ito has reported the ~uoride!catalyzed Michael addition of a!isocyanoestersto enones ð78TL0146Ł and Pirrung has used the condensation of a!isocyanoesters with 0\1!dibromo!propane\ in the synthesis of ethyl 1!methyl!0!isocyanocyclopropanecarboxylate ð75JOC1092Ł[ Theuse of palladium!catalyzed allylation of a!isocyanoesters has also been disclosed "Equation "14##ð76TL3738\ 77TL4040Ł[ Other examples of a!isocyanoester condensations have been reportedð62LA0460\ 64CB0479\ 75AG"E#643\ 77TL5210Ł[

R1 CO2EtNC

OAcCO2Et

CN

R1

+Pd(PPh3)4

base, THF(25)

Seebach et al[ have reported the synthesis of a number of nonracemic oxygenated isocyanidesusing the diphosgene dehydration protocol ð77CB496Ł[ Examples are given in Scheme 06[ Furtherexamples of homochiral isocyanides bearing oxygen functionality have been reported ð89CB524\80JCS"P0#1384Ł[

The preparation of remotely hydroxylated isocyanides has been described[ Treatment of g! andd!hydroxy formamides with phosgene:NEt2 yields the corresponding hydroxyisocyanides in goodyield ð63AG"E#488Ł[ The syntheses of 1!vinyloxyethyl isocyanide ð78ZOR0462Ł and methoxy!isobutylisocyanide ð78OPP400Ł have also been reported[

Livinghouse et al[ have reported that the conjugate addition of the lithio anion of methylisocyanide to cyclohexenone proceeds smoothly\ and that the intermediate enolate anion can be O!silylated to give the silyl enol ether isocyanide "Equation "15## ð76JA489\ 81JA3978\ 81T1198Ł[ In a


NH

NC

O

NC

CO2Me

NNC

O NC

OCHO NC

OAc

NH

O

NC

O

ONH

NCH

OH

Scheme 17

further study\ Livinghouse and co!workers examined the factors which a}ect the ratio of 0\1! to0\3!addition in the reaction of a!metalomethyl isocyanides with a\b!unsaturated ketones ð76S280Ł[The synthesis of g!isocyano silyl enol ethers has also been described ð78TL0146\ 80JOC6245Ł[

O TMS-O NCO-TMS

NC

+Li NC + i, THF, –78 °C

ii, TMS-Cl(26)

The preparations of a number of sugars bearing isocyanides have been disclosed[ These include2!isocyano!2!deoxythymidine ð78S607Ł\ 1\2\3\5!tetra!O!benzoyl!D!glucopyranosyl isocyanide "as amixture of anomers# ð65TL2316\ 67JOC0861\ 68TL052\ 74MI 210!90Ł\ 1\2 ] 4\5!di!O!isopropylidene!b!D!mannofuranosyl isocyanide ð80JOC498Ł\ 1\2\3!tri!O!acetyl!b!D!xylopyranose isocyanide ð75TL044Ł\and 4!O!tert!butyldimethylsilyl!1\2!O!isopropylidene!a!D!ribofuranosyl isocyanide ð77LA654Ł[ Thepreparation of b!lactams bearing an isocyanide group has also been described ð63CC167\ 73TL4964Ł[

2[10[0[1[4 Aliphatic isocyanides bearing a sulfur!based functional group

Van Leusen and Scho�llkopf have described the preparation of thiomethyl isocyanides[ In bothcases the precursor formamides were dehydrated[ Van Leusen chose the use of POCl2:Et2N\ whereasScho� llkopf used PPh2:CCl3:NEt2 "Scheme 07# ð62TL516\ 62TL518Ł[ The synthesis of thionaphthyl!methyl isocyanides has also been reported ð77TL0324Ł[

A potentially versatile route to a!thioisocyanides has been reported by Isoe and co!workers[ The

RS NHCHO RS NCPPh3, CCl4

NEt3, CHCl360 °C

POCl3

(MeOCH2)2, Et3N

Scheme 18

698Isocyanides

aniodic oxidation of a!substituted organotin compounds in THF:Bu3NBF3 in the presence of TMS!CN yields the requisite a!thioisocyanides in good yield "Equation "16## ð83CC438Ł[

SPh

C8H17 SnBu3

SPh

C8H17 NC

Bu4NBF4

TMS-CN, THF, e–

53%

(27)

Katritzky et al[ have described a ~exible route to a!alkylthio isocyanides ð82S34Ł[ Reaction ofbenzotriazole with formamide and an aldehyde gave the intermediate formamides in good yield[These compounds next react with the sodium salts of both aromatic and aliphatic thiols to generatethe N!"a!alkylthioalkyl#formamides[ Dehydration with POCl2:Na1CO2 then gave the a!alkylthioisocyanides "Scheme 08#[

NN

N

R1NHCHO

SR2

R1 NCNN

N

H

SR2

R1 NHCHO

R1CHO

H2NCHO

R2SH, EtOHNa, RT

i, POCl3, CH2Cl2 0 °C, 4 h

ii, Na2CO3 20 °C, 12 h

Scheme 19

In a study of the stereochemistry of the reactions of b!halothioethers with NaCN and AgCN\Ruano et al[ have prepared a number of b!methylthioether isocyanides ð74TL2270Ł[

Arenesulfonylmethyl isocyanides have been used extensively in synthesis[ They can be preparedeither by the addition of a!lithiomethyl isocyanide to arenesulfonyl ~uorides ð61LA"655#029\ 61TL1258Ł\or by the dehydration of the precursor formamide ð61LA"655#029\ 61TL1258\ 74RTC49Ł[ The most widelyused arenesulfonylisocyanide is tosylmethyl isocyanide "TosMIC# "for a detailed procedure for thepreparation of TosMIC\ see ð77OSC"5#876Ł#[ Treatment of TosMIC with a suitable base generatesthe a!anion\ which can be quenched with electrophiles[ The most convenient procedure for thealkylation of TosMIC involves the use of phase transfer catalysis ð64TL2376Ł[ Both mono! anddialkylation of TosMIC is possible\ and many examples of these reactions exist in the literature"Scheme 19# ð66TL3118\ 66TL3122\ 79S214\ 70JOC4048\ 71TL4224\ 72SC220\ 72SC268\ 77T6132\ 89TL5106\ 80SL76Ł[

NC

R2

R1

TosNC

Tos

R1

Tos NCNaH

DMSOR1X

NaH

DMSOR2X

Scheme 20

Monoalkylated TosMIC derivatives can also be alkynated by treatment with base and an acidchloride ð66TL3122Ł[ The use of silicon electrophiles has also been reported ð74RTC066Ł[ The chem!istry of TosMIC has been reviewed ðB!76MI 210!90Ł[

2[10[0[1[5 Aliphatic isocyanides bearing a Se! or Te!based functional group

No examples of this functionality could be found in the primary literature[

2[10[0[1[6 Aliphatic isocyanides bearing a nitrogen!based functional group

A number of isocyanides bearing a nitrogen centre directly attached to the isocyanide nitrogenatom have been reported[ Husigen et al[ have shown that thermolysis of arylhydrazono!2!methyl!4!oxo!3\4!dihydro!0\1!oxazoles gives aryl amino isocyanides ð72CB2916Ł[ Simple dialkylamino iso!cyanides have been prepared by the dehydration of formyl hydrazones using POCl2:NEt2 "Equation"17## ð51AG"E#223\ 53AG"E#536\ 54LA"575#81Ł[ The chemistry of dialkylamino isocyanides has beenstudied ð47JA3040\ 59JOC798Ł\ and the preparation of isodiazomethane metal complexes has beenreported ð66AG"E#696Ł[


NCR2NH

NR2N CHO

COCl2

NEt3(28)

Hegarty et al[ have shown that treatment of hydrazides with PCl4 gives N!"arylalkyl# aminoisocyanides\ and whose chemistry was then studied in solution ð75CC0085Ł[ The preparation of theunstable secondary isocyanoamines has been reported "Equation "18## ð70JOC0934Ł[ The pyrolysisof 3!hydrazonoisoxazol!4"3H#!ones yields the secondary isocyanoamines^ in all cases the substituenton nitrogen was an aryl or heteroaryl group[

NO O

N NHR

RHN NC + CO2 + MeCN∆

(29)

The synthesis of imino isocyanides has been disclosed[ They are prepared by the dehydration ofthe precursor formyl hydrazone ð51AG388\ 52AG294Ł[ This class of compounds has also been preparedand isolated "as the dibromo addition adduct# via the bromination of arylidene hydrazinotetrazolesð69TL3968Ł[ The preparation of N!isocyanoiminotriphenylphosphane "CN0N1PPh2# has beenreported via the dehydration of formyl hydrazine with PPh2:NEt2:CCl3 ð79AG"E#379Ł[

Ignasiak and co!workers have studied the preparation and chemistry of aryl diazoisocyanides[These compounds are prepared by the dehydration of formyl triazenes[ It was found that SOCl1:pyridine was the only dehydrating system that yielded the desired isocyanide "Equation "29##ð64JCS"P0#1011Ł[

N N

NHCHO

Ar

N N

NC

Ar

SOCl2

N

(30)

The matrix isolation and characterization of the extremely reactive diisocyanogen "CN0NC# hasbeen described ð77AG"E#825Ł^ however\ subsequent studies showed that the authors had preparedthe isomeric isocyanogen "CN0CN# ð80JA5093Ł[ The _rst preparation of diisocyanogen was laterreported ð81AG"E#0107Ł\ by the thermolysis of norbornadienoneazine[

N!Imidoyl isocyanides have been prepared by the treatment of N!phenylimidoyl bromides withsilver cyanide in chloroform ð66AG"E#616Ł[ Compared to the N!acyl isocyanides\ they are con!siderably more stable in solution[ However\ attempts to isolate them led to isomerization to thecorresponding imidoyl cyanides[

A number of a!amino isocyanides have been prepared\ including N!"isocyanomethyl#!N!nitro!propylamine ð70AP"203#348Ł and 0!"isocyanomethyl#!azoles ð72CPB612Ł[ Katritzky et al[ havereported the synthesis of a!"benzotriazolyl#alkyl isocyanides "Scheme 10# ð89JCS"P0#0736Ł\ and in anextension of this chemistry\ developed a general route to a!amino isocyanides[ Thus\ treatment ofbenzatriazole with formamide and the appropriate aldehyde gives the 0!substituted!N!for!mylaminobenzatriazole[ On reaction with a secondary amine\ the corresponding 0!substituted N!"a!amino#formamide is obtained[ These formamides are then dehydrated to the corresponding a!amino isocyanides using POCl2:Na1CO2 ð82S34Ł[

NN

N

RNHCHO

NN

N

H

N

O

R NHCHO

N

O

R NC

NH

O

K2 CO3MeOH62%

RCHO

H2NCHO

i, POCl3, CH2Cl2

ii, Na2CO3 96%

R = Ph

Scheme 21

Katritzky has also described the preparation and use of 0H!benzotriazol!0!yl!methyl isocyanide"BetMIC# "00# ð78TL5546\ 89JCS"P0#0736\ 80JOC3328\ 80S757Ł[

Scho� llkopf et al[ have prepared a!isocyanonitriles by the dehydration of a!formylamino nitriles

600Isocyanides

NN

N

NC

BetMIC(11)

using POCl2:NEt2[ The deprotonation and subsequent chemistry of the a!anion has also beeninvestigated "Equation "20## ð64LA0420Ł[

(31)R

NHCHO

CN

R

NC

CN

POCl3, NEt3, CH2Cl2

The unusual triisocyanide ligand shown in Equation "21# was prepared by dehydration of theprecursor triformamide with diphosgene ð80AG"E#192Ł[

(32)

N

NHCHOOHCHNNHCHO

N

CNNCNC

diphosgene

The preparation of isocyanides bearing remote nitrogen functionality has been reportedð47JOC0488Ł[ Thus treatment of primary amines bearing a remote tertiary amine group withCHCl2:KOH gave the isocyanide in modest yield "Equation "22##[

(33)R2N NH2( )nR2N NC

( )n

KOH, CHCl3

R = Me, Et; n = 2,3

2[10[0[1[7 Aliphatic isocyanides bearing other substituents

The syntheses of aliphatic isocyanides bearing silicon\ germanium and tin substituents have beenreported[ Treatment of trimethyliodosilane with silver cyanide gave trimethylisocyanosilane in 79)"Equation "23## ð41JA4136Ł^ the paper also reported the preparation of dimethyldiisocyanosilane[

(34)TMS-I TMS-NC + AgIAgCN

Van Leusen and co!workers have published an improved procedure for the preparation oftrimethylsilylmethyl isocyanide ð75SC754Ł[ This useful compound was previously prepared by thesilylation of a!lithio methyl isocyanide ð73SC528Ł[ It was reported that treatment of chloro!methyltrimethylsilane with formamide gave N!""trimethylsilyl#methyl# formamide in 62)[ De!hydration using POCl2:Pri

1NH then gave the desired product in 64)[ Bis! and tris"trimethyl!silyl#methyl isocyanide have also been prepared ð69JOM"14#274Ł[

Trialkyl and triaryl isocyanosilanes have been prepared by a number of methods ð41JA4136\47JA3040Ł^ the unusual disilanyl isocyanide has also been reported ð51JCS437Ł[

Trimethylisocyanogermane and trimethyltinisocyanide have been prepared ð59JOC798Ł by thetreatment of trimethyliodo metal derivative with silver cyanide[ They are both considered to be anequilibrium mixture of the cyano and isocyano forms[ The synthesis of tetraisocyanogermane hasalso been disclosed ð40JA4328\ 47AG545Ł[


Van Leusen and co!workers have prepared a number of boron substituted methyl isocyanidesð84TL1098Ł[ The synthesis of phosphine functionalized isocyanides as metal ligands has been reported"Equation "24## ð74JOM"183#C10\ 89JOC3849Ł[

Li+ Ph2P–CNBr

PhPh

CNPPh2

PhPh (35)

2[10[0[2 a\b!Unsaturated Isocyanides

2[10[0[2[0 General methods

The synthesis of a\b!unsaturated isocyanides has received somewhat less attention compared totheir saturated analogues[ The _rst synthesis of vinyl isocyanide appeared only in 0857 ð57JA2650Ł[As a consequence\ they have been utilized far less in synthetic methodology[ A number of naturallyoccurring a\b!unsaturated isocyanides have been isolated and synthesized including xanthocillinð51AG104Ł\ isonitrins A ð80SL440Ł and B ð78SL8Ł\ and dermadin ð70TL2648Ł "Scheme 11#[ Furtherexamples have also been reported ð74T0820\ 77MI 210!90\ 81ACR322Ł[

NC

NCHO

OH

CN

O

CO2H

NC

O

H

O

NC

O

H OH

OH

xanthocillin X dermadin

isonitrin A isonitrin B

Scheme 22

As with saturated isocyanides\ a number of general methods have been developed for theirsynthesis^ these are given below]

"i# the dehydration of a\b!unsaturated formamides\"ii# deprotonation and further elaboration of isocyanides and a\b!unsaturated isocyanides\"iii# b!elimination from functionalized isocyanides\"iv# base promoted ring opening of heterocycles\"v# isomerization of allyl isocyanides[

"i# The dehydration of a\b!unsaturated formamides

The dehydration of a\b!unsaturated formamides has proved to be a popular method for thesynthesis of a\b!unsaturated isocyanides[ The synthesis of the acid labile precursor a\b!unsaturatedformamides has proved to be troublesome\ although several methods now exist for their preparation[Their subsequent dehydration to a\b!unsaturated isocyanides has been e}ected using a number ofreagents\ all of which have been used in the synthesis of saturated isocyanides[

Barton et al[ have reported that the treatment of oximes with formicÐacetic anhydride andimidazole followed by TiCl2 leads to a\b!unsaturated formamides in good yield[ Their dehydration

602Isocyanides

to a\b!unsaturated isocyanides was then carried out using phosgene in the presence of 0\3!diazabicycloð1[1[1Łoctane "dabco# "Scheme 12# ð77TL2232Ł[

NOH

HNCHO NC

i, AcOCHO, imidazole, DMF, 0 °C

ii, Ti(OAc)3

COCl2, dabco

66% overall

Scheme 23

Baldwin and co!workers have reported that sulfenimines on treatment with formicÐacetic anhy!dride in the presence of PPh2 and propylene oxide give a\b!unsaturated formamides in good yieldð89TL1940Ł[ The precursor sulfenimines are accessible from either the parent ketone ð74CC0473Ł oramine ð68JOC0107Ł[ The subsequent dehydration to give the a\b!unsaturated isocyanide was carriedout using tri~uoromethanesulfonic anhydride in the presence of Hu�nig|s base "Scheme 13#ð89SL592Ł[

NH2

HNCHO NC

O

NSTol

PPh3, AcOCHO

, CH2Cl2O

Scheme 24

(CF3SO2)2O, Pri2NEt

CH2Cl2, –78 °Cor

Barrett and co!workers have recently reported a mild method for the preparation of a\b!unsatu!rated formamides based upon the Bu2SnH reduction of selenocarbamates ð82CC0659Ł[ The dehy!dration was e}ected using the methodology of Baldwin ð89SL592Ł or TsCl:pyridine "Scheme 14#[

Ph Cl

O

Ph N3

OPh

HN SePh

O

Ph

HN H

O

NaN3

DMF

PhNC

i, PhMe, ∆

ii, PhSeH, ButOK (cat.)

Bu3SnH, AIBN

PhH, ∆

(CF3SO2)2O, Pri2NEt

CH2Cl2, –78 °C

Scheme 25

Scho�llkopf et al[ have developed a general procedure for the synthesis of functionalized a\b!unsaturated formamides^ these compounds can be readily dehydrated to give the a\b!unsaturatedisocyanides[ The process is known as formylaminomethylenation\ and involves the reaction of a!metallated isocyanides bearing an acidifying substituent such as CO1R ð61LA"655#005\ 63MI 210!90\65CB2853Ł\ SO1Ar ð61LA"655#029\ 80RTC391Ł\ P"O#"OR#1 ð81JOC1138Ł\ or 2! or 3!pyridyl ð65LA858Ł\with aldehydes or ketones in aprotic media "Equation "25##[ Such compounds allow access to a widerange of highly functionalized a\b!unsaturated isocyanides[ This area has been reviewed ð66AG"E#228\63AG"E#678Ł[

R1

R2

OX

NC R1

R2 X

NHCHO+

i, base

ii, H+(36)

X = CO2Et, SO2Ar, P(O)(OEt)2, 3,4-pyridyl


"ii# Deprotonation and further elaboration of isocyanides and a\b!unsaturated isocyanides

A number of di}erent reagents which can be deprotonated and condensed with an appropriateelectrophile have been developed for the synthesis of a\b!unsaturated isocyanides[ Van Leusen andco!workers were the _rst to report the use of lithio!a!"trimethylsilyl#tosylmethyl isocyanide"TosMIC# in the synthesis of a\b!unsaturated isocyanides[ Reaction of lithio!a!"trimethyl!silyl#tosylmethyl isocyanide with an appropriate aldehyde or ketone yields the a\b!unsaturatedisocyanide in good yield ð71RTC191Ł[ In a related approach based on WadsworthÐEmmons!typechemistry\ Scho� llkopf et al[ have described the condensation of the lithio anion of diethyl"isocyano!methyl#phosphonate with aldehydes to give the a\b!unsaturated isocyanide product ð63LA33\66LA0056\ 73LA599Ł[

A Peterson!type alkeneation has been used in the synthesis of a\b!unsaturated isocyanides[ Thedeprotonation of trimethylsilylmethyl isocyanide with BunLi at −67>C for 0 hour\ followed byaddition of 1\4!dimethoxybenzaldehyde has been reported to give the a\b!unsaturated isocyanide in59) as a 0 ] 0 mixture of "E#:"Z# isomers ð89S457Ł[

The direct deprotonation of a\b!unsaturated isocyanides bearing an a!hydrogen has beendescribed by Scho�llkopf ð66LA0056Ł[ Thus\ treatment of the a\b!unsaturated isocyanide with BunLiat low temperature\ followed by quenching with an electrophile gives the a!functionalized a\b!unsaturated isocyanide "Scheme 15# ð66LA0056Ł[

R1

R2

NC R1

R2 Li

NC R1

R2 E

NCBunLi, THF/Et2O

–110 °C to –70 °C

E+

E+ = TMS-Cl, MeI, ClCO2R, CO2

Scheme 26

"iii# a and b!Elimination from functionalized isocyanides

"a# a!Eliminations[ Ugi and co!workers have reported the preparation of cyclohexenyl isocyanideby the sequential dehydration:elimination "of HCN# from N!"0!cyanocyclohexyl# formamide onreaction with POCl2:KOBut ð52LA"555#54Ł[

"b# b!Eliminations[ The b!elimination of a nucleofuge from a suitably functionalized isocyanideis a particularly useful method for the synthesis of a\b!unsaturated isocyanides[ The _rst reportedsynthesis of vinyl isocyanide involved the treatment of N!formylethanolamine with benzenesulfonylchloride followed by treatment with ethanolic KOH ð57JA2650Ł[ Other leaving groups that havebeen reported include halogens ð50AG15\ 78TL2224Ł\ methanesulfonate ð70TL2648Ł\ p!toluenesulfonateð73CC022\ 66LA0056Ł\ and epoxide ð74CC705Ł[ For a general discussion of this reaction\ see ð75JA2042\78CC0120Ł[

"iv# Base!promoted rin` openin` of heterocycles

Dondoni et al[ have used this approach in the synthesis of substituted a\b!unsaturated isocyanides"Scheme 16# ð73CC147\ 76S582Ł[ Treatment of 3\4!substituted oxazoles with BunLi at low temperaturegives the 1!lithiated oxazole\ which is in equilibrium with the ring open isocyano tautomer[ Additionof an electrophile\ such as acetyl chloride or trimethylsilyl chloride yields the substituted a\b!unsaturated isocyanide in modest yield[ Further examples have been reported ð64LA422\ 68JOC1931Ł[

"v# Isomerization of allyl isocyanides

Several examples of this protocol have been reported[ Ito has reported that copper"I# oxidecatalyses the isomerization of allyl isocyanides to the corresponding a\b!isocyanides at room tem!perature ð60T2684Ł[ In his synthesis of the isonitrile 169\ Baldwin et al[ utilized a 0\4!diazabicyclo!ð4[3[9Łundec!4!ene "dbu# and iodine!catalyzed isomerization of the dienyl ester "00# to the dienylisocyanide "Scheme 17# ð73CC022Ł[

604Isocyanides

R2 O

NCR1

OR2 OLi

NCR1

R2 O-TMS

NCR1

MeCOCl TMS-Cl

N

OR2

R1 N

OR2

R1

LiBunLi, Et2O, –78 °C

Scheme 27

CO2Et

NC

CO2Et

NC NC

CO2Et

dbu I2

Scheme 28

2[10[0[2[1 Isocyanides bearing an a\b!double bond

"i# With no further substituents

The _rst synthesis of an a\b!unsaturated isocyanide was of simple vinyl isocyanide ð57JA2650Ł[Sequential treatment of N!formylethanolamine with benzenesulfonyl chloride and KOH gives vinylisocyanide\ which was described as having an {{atrocious odor\ followed by a bitter aftertaste[||King and Borodinsky ð74T2124Ł published the synthesis of a number of unfunctionalized a\b!unsaturated isocyanides using the methodology of Scho� llkopf ð66LA0056Ł "addition of a!lithiomethylisocyanide to the appropriate aldehyde:ketone\ followed by addition of TsCl and thenKOH:MeOH#\ and the allyl isocyanide:a\b!unsaturated isocyanide isomerization methodology ofIto ð60T2684Ł "Scheme 18#[

R1 R2

O

THF, –78 °CLi NCR2

NC

O– Li+R1 TsCl, THF, –70 °C

R2NC

OTsR1

R2NC

R1KOH

MeOH

Scheme 29

Scheme 29 shows examples of some of the a\b!unsaturated isocyanides that King and Borodinskyprepared[

In the total synthesis of the antibiotic O?\O?!dimethylxanthocillin\ Hagedorn et al[ treated the

But

NC NCNC

Pri

NCNC

Scheme 30


precursor dihydroxy formamide with POCl2:pyridine to give the bisb!chloro isocyanide[ Treatmentwith KOH:pyridine resulted in elimination of HCl to give the a\b!unsaturated isocyanide "Scheme20# ð51AG104\ 52AG294\ 54CB082Ł[

MeO

OH

OHNH

HNOMeCHO

OHC MeO

Cl

ClNC

NCOMe

MeONC

NCOMe

KOH

pyridine

POCl3

pyridine

Scheme 31

The total synthesis of axisonitrile!3 by Hart et al[\ utilizes an unusual route to the precursor a\b!unsaturated isocyanide[ Conversion of the a\b!unsaturated carboxylic acid to the correspondinga\b!unsaturated acyl azide\ followed by Schmidt rearrangement and reduction of the a\b!unsaturatedisocyanate _rst gives the a\b!unsaturated formamide[ Dehydration with TsCl:pyridine then yieldedthe natural product "Scheme 21#[

HCO2H

HNHCHO

HNC i, NaH

ii, (PhO)2PON3, ∆

iii, LiEt3BH, THF, –78 °C

TsCl

pyridine

Scheme 32

In their synthesis of erbstatin\ van Leusen et al[ prepared the a\b!unsaturated isocyanide "01#using the condensation of lithio diethyl "isocyanomethyl#phosphonate with 1\4!dimethoxy!benzaldehyde[ The product was obtained in 64) yield as a 09 ] 0 mixture of "E#:"Z# isomers"Equation "26## ð89S457Ł^ for related studies\ see ð76JAN0196Ł[

OMe

CHO

OMe

OMe

OMe

NC

+(EtO)2P NC

O BunLi, THF, –78 °C(37)

(12)

The preparation of alkynyl and cyclobutenyl isocyanide complexes have recently been reportedð83AG"E#229Ł\ and the matrix isolation of ethynyl isocyanide has also been disclosed ð80AG"E#0533Ł[

"ii# With halo!substituents

The synthesis of the highly ~uorinated a\b!unsaturated isocyanide "02# has been reported byvacuum thermolysis of the precursor chromium pentacarbonyl complex at 139>C "Scheme 22#ð81CC0412\ 82AG"E#0345Ł\ and the preparation of a number of chlorovinyl isocyanide chromiumpentacarbonyl complexes has been published ð78JOM"268#86Ł[

Matsumoto and co!workers have reported the preparation of b!bromo!a!isocyanoacrylic acidesters[ Condensation of methyl isocyanoacetate with the appropriate aldehydes followed by brom!ination with NBS _rst gave the b!bromo!a!formylaminoacrylic acid esters[ Dehydration withPOCl2:NEt2 then gave the a\b!unsaturated isocyanides in good yield "Scheme 23#[ These compounds

606Isocyanides

(CO)5CrCN

F

F

F

CN

F

F

F

70 °C

(CO)5 CrCN

F

F

F

FF F

F

FNN

FC(CO)5Cr C Cr(CO)5

FF F

F

FNN

FC(CO)5Cr C Cr(CO)5

(13)

FVP, 240 °C

+

Scheme 33

are particularly useful\ because the b!bromine can be substituted with a variety of heteroatomsusing a conjugate addition:elimination procedure[ A variety of other substituents on the b!positionwere also reported ð77T4356\ 89S670Ł[

R NHCHO

CO2Me

R NHCHO

CO2MeBr

R NC

CO2MeBr

NBS

CCl4

POCl3

Et3N, CH2Cl2

Scheme 34

The synthesis of 0!chloro a\b!unsaturated isocyanides has been achieved by the condensation ofthe lithio anion of a!chloro!a!isocyanomethylphosphonates with aldehydes and ketonesð76JAN0088Ł\ and a synthesis of the natural product indsocin which contains an a\b!unsaturatedisocyanide bearing a chloro substituent\ has been reported ð76JAN0191Ł[

"iii# With oxy`en!based substituents

A large number of a\b!unsaturated isocyanides bearing oxygen!based substituents have beenreported[ The condensation of a!metallated ethyl isocyanoacetate with aldehydes or ketones leadsto the corresponding ethyl a!"formyl!amino#acrylates and a large range of aldehydes and ketoneshave been shown to participate in this reaction ð58AG"E#561\ 61LA"655#005\ 63MI 210!90Ł[ Dehydrationto the isocyanide is then carried out using phosgene:NEt2 and yields the b!substituted ethyl a!isocyanoacrylates "Scheme 24# ð62LA500Ł[ Scho� llkopf has examined the synthetic uses of thesecompounds extensively ð66AG"E#228Ł[

i, base

ii,

iii, H+

R1 R2

O

R1 NHCHO

CO2EtR2

R1 NC

CO2EtR2CN CO2Et

COCl2, NEt3

Scheme 35

An unusual approach to the synthesis of a\b!unsaturated isocyanides bearing an ester substituentinvolves the condensation between t!butyl isocyanoacetate and amide diethyl acetals ð75AP"208#362Ł[

The use of a!isocyanomethylphosphonates in the synthesis of a\b!unsaturated isocyanides hasalso received much attention ð63LA33\ 70LA88\ 76JAN0196\ 80TL2796Ł[ Condensation of the a!lithioanion of isocyanomethylphosphonatediethylester with aldehydes or ketones gives the a\b!unsatu!rated isocyanide via elimination of lithium diethylphosphate[ Both aryl and alkyl ketones were usedand the condensation with glyoxal was also described ð63LA33Ł[ This methodology was applied tothe total synthesis of antibiotic B 260 "Scheme 25# ð73LA599Ł[ A wide range of aldehydes and ketonesparticipate in this condensation reaction[


(EtO)2P Li

O

R1NC R2 R3

O

R3

R2 NC

R1

(EtO)2P NC

O+

NH

CHO

NH

+

NC

THF, –70 °C

i, NaHMDS (2 equiv.), THF, –78 °C

ii, AcOH

B 371

Scheme 36

Van Leusen and co!workers have prepared a number of steroid derivatives that contain an a\b!unsaturated isocyanide by the condensation of isocyanomethylphosphonate!diethyl esters with theparent steroidal ketone in the presence of KOBut\ followed by dehydration with POCl2:Pri

1NHð80RTC282\ 81JOC1138Ł[ The reaction has been developed further by the use of t!butyl "diphenyl!phosphinyl#isocyanoacetate[ Again\ deprotonation followed by union with an aldehyde or ketoneand subsequent elimination of lithium diphenylphosphinate gives a\b!unsaturated isocyanidesð70LA88Ł[

Baldwin et al[ have published a number of total syntheses of highly oxygenated a\b!unsaturatedisocyanide containing natural products[ In their total synthesis of isonitrile 169\ the initial elim!ination of a b!tosyl isocyanide gives an allyl isocyanide\ which is isomerized to the dienyl isocyanideusing dbu and iodine ð73CC022Ł[ The unusual isocyanide spirolactone "05# was prepared via aninitial ring opening of the b!epoxy isocyanide "03#\ followed by an oxidation with pyridiniumchlorochromate "pcc#[ The 0\1 addition of lithium "Z#!b!lithioacrylate to the ketoisocyanide "04#furnished the spirolactone natural product in low yield "Scheme 26# ð74CC705Ł[

(14)

KOBut, THF

O

NC NC NC

HO O

OO

NC(15) (16)

Li

CO2Li

PCC

CH2Cl2

i,

ii, H3O+

Scheme 37

The three related natural products] isonitrin A\ isonitrin B "deoxytrichoviridin#\ and isonitrin C"trichoviridin#\ have all been synthesized by the Baldwin research group ð78SL8\ 80SL440Ł[ IsonitrinsA and B contain an a\b!unsaturated isocyanide in a _ve!membered ring along with a high degreeof oxygenation[ The a\b!unsaturated isocyanide in isonitrin B was prepared by treatment of thesulfenimine "06# with aceticÐformic anhydride:PPh2:propylene oxide to give the a\b!unsaturatedformamide[ Dehydration to the a\b!unsaturated formamide was e}ected with tri~uoro!methanesulfonic anhydride in the presence of Hu�nig|s base at −67>C "Scheme 27# ð78SL8\ 80SL440Ł[

N

O

H O-TBDMS

OH

STol NHCHO

O

H O-TBDMS

OH

NC

O

H O-TBDMS

OH

(17)

O

PPh3, HCO2Ac

CH2Cl2

(CF3SO2)2O, Pri2NEt

CH2Cl2, –78 °C

Scheme 38

Fukuyama et al[ have reported the total synthesis of the isocyanide ester "08# whereby the a\b!unsaturated isocyanide moiety was introduced by treatment of the b!mesyl isocyanide "07# withbase "Equation "27## ð70TL2648Ł[

608Isocyanides

OMs

NC

O

MeO2C

NC

O

MeO2C

(18) (19)

KOBut, THF, PhMe, –78 °C(38)

The synthesis of the antibiotic A!21289A was reported by Scho�llkopf and co!workers using aprocedure where the a\b!unsaturated isocyanide was prepared by the dehydration of the precursora\b!unsaturated formamide utilizing POCl2:NEt2 "Equation "28## ð64CB0479\ 74LA0714Ł[

HCO2 H

HCO2 H

H O2CH

H O2CH

O

ONHCHO

O

OOHCHN

HO H

HO H

H OH

H OH

O

ONC

O

OCN

i, POCl3 (2.2 equiv.), NEt3 (2.2 equiv.)

ii, phosphate buffer (pH 7.3)

ANTIBIOTIC A 32390 A

(39)

More recently\ Baldwin and co!workers have applied their sulfenimine!based methodology in thesynthesis of analogues of antibiotic A!21289A[ The a\b!unsaturated formamide "10# was preparedfrom the sulfenimine "19# as described earlier ð78SL8\ 80SL440Ł[ Dehydration to the a\b!unsaturatedisocyanide was then achieved using tri~uoromethanesulfonic anhydride:Hu�nig|s base at −67>C"Scheme 28# ð83CC74Ł[

OO

NTolS

O

O-TBDMS

O-TBDMS

O

NSTol

O

OO

NHCHO

O

O-TBDMS

O-TBDMS

O

NHCHO

OO

NC

O

O-TBDMS

O-TBDMS

O

NC(CF3SO2)2O, Pri

2NEt

CH2Cl2, –78 °C

(21)

, CH2Cl2 i, HCO2Ac, PPh3,

ii, Hg(OAc)2iii, dbu

(20)

Scheme 39

Kende has prepared the a\b!unsaturated isocyanide "11# by the dehydration of the precursorformamide with tri~uoromethanesulfonic anhydride:Hu�nig|s base at −67>C "Equation "39##ð82TL468Ł[

(CF3SO2)2O, Pri2NEt

CH2Cl2, –78 °C

99%

OMe

O

NHCHOBn2N

OMe

O

NCBn2N

(22)

(40)


"iv# With sulfur!based substituents

The group of van Leusen has also reported the synthesis of 0!"arylthio#alkenyl isocyanides by thecondensation of the lithio anion of "arylthio#methyl isocyanides with TMS!Cl\ followed by additionof another equivalent of BunLi and the requisite aldehyde at −67>C[ A mixture of "E# and "Z#isomers was produced "Scheme 39# ð74RTC066Ł[ The paper also discusses the synthesis and use ofdiethyl "isocyano"arylthio#methyl#!phosphonate in the preparation of 0!"arylthio#alkenylisocyanides[

SR1

NC

SR1

NC

SR1

NC

TMSR2

i, BunLi

ii, TMS-Cl

i, BunLi

ii, R2CHO

Scheme 40

a\b!Unsaturated isocyanides bearing an a!tosyl group are conveniently prepared from the con!densation of the lithio anion of a!"trimethylsilyl#tosylmethyl isocyanide "TosMIC# with aldehydesð71RTC191Ł[ In all the examples given\ an aromatic aldehyde was used "Equation "30##[

R CHO + Li

NC

TMS

TosTHF

–78 °C to – 30 °C

R NC

Tos

+ TMS-OLi (41)

"v# With nitro`en!based substituents

Meerwein and co!workers have reported that ethyl isocyanoacetate reacts with N\N!dimethyl!formamide acetal at room temperature to give ethyl 2!dimethylamino!1!isocyanoacrylate in 67)yield "Equation "31## ð50LA"530#0\ 68LA0333Ł[

(42)Me2N+NC

CO2Et

Me2N NC

CO2Et

OEt

OEt

The unusual a\b!unsaturated isocyanide "12# was prepared by the mono deprotonation of 0\2!diisocyanopropane with BunLi at −67>C\ followed by intramolecular cyclization of the resultinganion and in situ trapping with TMS!Cl "Scheme 30# ð79LA17Ł[

TMS-Cl

CN NC

Li

N

Li

NC N NCLi+

–

N NCTMS

(23)

Scheme 41

The addition:elimination of benzylamine to "Z#!methyl!b!bromo!a!isocyanocinnamate gives "E#!methyl!b!benzylamino!a!isocyanocinnamate "Equation "32## ð77T4356Ł[

Br

Ph CO2Me

NCN

Ph CO2Me

NC

HPh

PhCH2NH2, Et3N

50%(43)

610Isocyanides

2[10[0[2[2 Isocyanides bearing an a\b!aryl or hetaryl substituent

"i# General methods

Although several other methods exist\ the most common method for the preparation of arylisocyanides is the dehydration of the appropriate precursor formamide[ The presence of the arylring does not allow for displacement!type reactions commonly found in the preparation of aliphaticisocyanides[ The general methods of preparation are listed below]

"i# dehydration of formamides\"ii# the Hofmann carbylamine reaction\"iii# reduction of isocyanates\ isothiocyanates and isocyanide dihalides\"iv# deprotonation of aryl imidates and aryl heterocycles\"v# abnormal Beckmann rearrangements\"vi# ring cleavage reactions of heterocyclic compounds[

These general methods are discussed in more detail below["a# The dehydration of aryl formamides[ The dehydration of aryl formamides is the most widely

used procedure for the synthesis of aryl isocyanides "Equation "33##\ and a large range of dehydratingreagents have been used[

N CHO

H

Ar

Ar NC–H2O

(44)

The reagents of choice are phosgene ð54AG"E#361Ł and diphosgene ð66AG"E#148Ł in the presenceof a tertiary amine[ In a review article by Ugi\ the preparation of over 149 isocyanides is describedby the phosgene method\ many of which are aryl isocyanides ð54AG"E#361\ B!60MI 210!90Ł[ Otherdehydrating reagents that have been used include POCl2 in the presence of a tertiary amine ð52CJC752\47AG691\ 50OS"30#02\ 55TL770\ 59CB128Ł or secondary amine ð74S399Ł\ PCl4\ P1O4\ ð59CB128Ł\ PPh2Br1

ð57LA"607#13Ł\ PPh2:diethyl azodicarboxylate "dead# ð61AG"E#818Ł\ and PPh2:CCl3:NEt2ð60AG"E#021Ł[ The use of SOCl1:DMF:Na1CO2 has also found widespread application ð61JOC076Ł[Miscellaneous dehydrating systems include di!1!pyridyl sul_te:NEt2 ð75TL0814Ł and cyanuricchloride:K1CO2 ð50AG108Ł[

The treatment of N!aryl thioformamides with cyanogen bromide:NEt2\ has been reported to yieldaryl isocyanides ð53CA"59#4527Ł[

"b# The Hofmann carbylamine reaction[ The treatment of a primary aromatic amine with aque!ous KOH:CHCl2 under phase transfer conditions leads to the corresponding aryl isocyanide inreasonable yields ð61AG"E#429\ 61TL0526Ł[ The mechanism of this transformation was discussed inSection 2[10[0[0[ Other variations have been reported[ Krapcho has described the generation ofdichlorocarbene by thermolysis of sodium trichloroacetate\ followed by its reaction with primaryarylamines to give the isocyanide ð51JOC0978Ł[ Thus\ the reaction is performed under anhydrousconditions[

The conversion of N!sul_nylarylamines to aryl isocyanides in good yield using CHCl2:KOH:C5H5

has been reported ð66S164Ł["c# The reduction of isocyanates\ isothiocyanates and isocyanide dihalides[ Triethylphosphite has

been used in the conversion of aryl isocyanates into aryl isocyanides ð51JOC2540Ł as has 1!phenyl!2!methyl!0\2\1!oxaphospholidine "Mukaiyama|s reagent# ð54BCJ747Ł[

Baldwin et al[ have reported the preparation of aryl isocyanides by the reduction of the precursorisocyanate using either diphenyl!t!butylsilyllithium or Cl2SiH:NEt2 ð71CC831Ł[

Aryl isothiocyanates can be converted into aryl isocyanides using a variety of reagents\ including\triethylphosphine ð0769CB655Ł\ triethylphosphite ð51JOC2540Ł\ triphenyltin hydride ð52JOC0696Ł\phenylacetyl chloroformamidine ð55CB2052Ł\ and samarium diiodide ð81CL0032Ł[

The transformation of arylisocyanide dihalides into aryl isocyanides has been e}ected with anumber of di}erent reagents\ including phosphines ð51AG737\ 53CA"59#5684Ł\ and potassium iodideð53CA"59#5684Ł[ More recently\ the electrochemical reduction of N!aryl isocyanide dichlorides hasbeen reported to give aryl isocyanides in excellent yields ð81TL3668Ł[

"d# Deprotonation of aryl imidates and aryl heterocycles[ Pornet et al[ have reported that treatmentof aryl imidate ethers with magnesium diisopropylamides yields the corresponding aryl isocyanideð54AG"E#691\ 69TL2298\ 60TL856Ł[ In a recent extension of this approach\ it has been disclosed that thereaction of disubstituted aryl imidate ethers with lithium dialkylamides gives very high yields ofdisubstituted aryl isocyanides "Equation "34## ð89CA"001#007364Ł[


R2

R1

N OR4

R3R2

R1

NC

R3

LDA, –78 °C

hexane

R1, R2 = H, alkyl; R3 = H, alkyl, alkoxy, aryl, aryloxy

(45)

LDA = Lithium diisopropylamide

The treatment of benzoxazoles with BunLi at low temperature followed by addition of TMS!Cl\gives high yields of 1!siloxyaryl isocyanides ð72JOM"135#048Ł[

"e# Abnormal Beckmann rearran`ements[ A number of oxime derivatives have been reported togive mixtures of cyanides and isocyanides under Beckmann!type conditions[ For example\ treatmentof syn!oximes of aromatic aldehydes with 0\0!diethoxy!0!propene in the presence of BF2 andHgO gives mixtures of the corresponding aromatic isocyanide "49Ð62) and the cyanides "9Ð12)#"Equation "35## ð50JOC1191Ł[

Ph NO Et

OEtOEt Ph NC Ph CN+

BF3, HgO

Et2O(46)

Other examples include 2\4!disubstituted!3!hydroxy!benzaldehyde oxime tosylates ð50ZN"B#734Łand the transformation of aryl aldoximes to isocyanides using aryl cyanates ð55CB1250Ł[ Wernerand Piquet attempted a Beckmann rearrangement on g!benzil monoxime with benzenesulfonylchloride under basic conditions and obtained phenyl isocyanide ð93CB3184Ł[

"f# Rin` cleava`e reactions of heterocyclic compounds[ An interesting thermolytic method hasbeen described by Wentrup and co!workers whereby simply heating 3!iminoisoxazalones "preparedfrom nitroso compounds# gives good yields of heteroaryl isocyanides ð67AG"E#577Ł[ The reactionsof indole with nitroso compounds have also been reported to give isocyanides ð04CB842Ł[

Treatment of quinazoline!2!oxide with Ac1O leads to 1!isocyanobenzonitrile ð50CPB524Ł\ and aninteresting ring cleavage reaction occurs when 1!methylpyridine reacts with dichlorocarbene\ leadingto phenyl isocyanide ð36BSF890Ł[ Several other examples of similar ring cleavage reactions are givenð47CB0279\ 53JA0245Ł[

"ii# Aryl isocyanides

Ugi has reported the synthesis of a wide range of aryl isocyanides utilizing his phosgene:NEt2procedure[ Comprehensive details can be found in the references ð54AG"E#361\ B!60MI 210!90Ł[ Morerecently\ diphosgene ð66AG"E#148Ł has been utilized in the preparation of benzoisocyanides[ Otherdehydrating reagents that have been employed in the synthesis of aryl isocyanides include\POCl2:pyridine ð59CB128Ł\ PPh2:CCl3:NEt2 ð60AG"E#021Ł\ PPh2:diethyl azodicarboxylate "dead#ð61AG"E#818Ł\ POCl2\ P1O4 ð59CB128Ł\ and triphenylphosphine dibromide ð57LA"607#13Ł[ The de!hydration of the parent formamide with POCl2:Pri

1NH has also proved a popular reagent systemð74S399Ł\ and a practical synthesis of azidophenylisocyanide has been disclosed ð75ZN"B#021Ł[

The Vilsmeier approach developed by Walborsky and co!workers has also been used in thesynthesis of aryl isocyanides ð61JOC076Ł\ and the synthesis of penta~uorophenyl isocyanide has beenreported[ Thus\ dehalogenation of dibromo!N!"penta~uorophenyl#methanimine with magnesiumgave the product in analytically pure form "Equation "36## ð77CB0334Ł[

FF

F

F F

N

Br

Br FF

F

F F

NC (47)Mg

The deprotonation of ethyl N!phenylformimidate with BunLi yields phenyl isocyanide "Equation"37## ð69TL2298Ł[ A further development in this area describes the reaction of substituted aryl imidateethers with lithium dialkylamides at low temperature to give substituted aryl isocyanides in excellentyields ð89CA"001#007364Ł[

612Isocyanides

BunLi, hexanePhN OEt Ph NC (48)

Although not a widely used method\ Farrar has described the preparation of 3!chlorophenylisocyanide by treatment of the sodium salt of N!"3!chlorophenyl#dichloromethylsulfonamide withNa1CO2 at 099>C ð59JCS2947Ł[

N\N?!Diaryl!N!hydroxyformamidines give aryl isocyanides on heating to 069>C ð13JCS"014#76\13JCS"014#1432Ł\ and Ho�~e has reported that 4!aryl aminotetrazoles give high yields of aryl isocyanidesupon oxidation with sodium hypobromite or lead tetraacetate ð65AG"E#002Ł[

A number of aryl isocyanides bearing a functionalized ortho!methyl substituent have beenprepared[ Substituents include Cl and I ð73IC850Ł\ CN and CO1Me ð63BCJ0075Ł\ ketone ð68JOC1929Ł\and amide ð68TL0928Ł[ All these compounds were prepared by deprotonation of o!methyl phenylisocyanide with BunLi at low temperature and quenching the anion with the appropriate electrophile"Scheme 31#[

LDA, DIGLYME, –78 °C E+

NC NC

Li

NC

E

Scheme 42

Ito and co!workers have described the preparation of o!diisocyanoarenes by dehydration of theprecursor o!di"formamido#arenes using diphosgene ð77S603Ł[ He has also published the synthesis ofthe highly hindered 3!"t!butyldimethylsiloxy#!1\5!xylyl isocyanide by dehydration of the precursorformamide with POCl2:KOBut\ ð59CB128\ 82JOC5655Ł[

Recent interest in the coordination chemistry of multidentate aryl isocyanides has resulted in thesynthesis of a number of novel aryl isocyanides ð82AG"E#549\ 79IC2749Ł[ Thus\ dehydration of thebisformamide "13# with PPh2:CCl3:Et2N gave the bidentate isocyanide ligand "14# "Equation "38##ð71IC1067Ł[

O O

N N

OHC

HCHO

H

O O

NC CN

(24) (25)

PPh3, CCl4

NEt3

(49)

The trimethylsilyloxy substituted aryl isocyanide "16# has been prepared by treatment of theprecursor benzoxazole "15# with BunLi followed by trapping with TMS!Cl "Scheme 32#ð73JOM"159#236Ł[

O O( )n

ON N

O

O O( )n

OLi

NC CN

OLi

O O( )n

O-TMS

NC CN

O-TMS(26) (27)

BunLi TMS-Cl

Scheme 43

A number of tridentate aryl isocyanide ligands have been synthesized by the dehydration of theprecursor triformamides with diphosgene ð80AG"E#192\ 80CB0572\ 81OM73Ł^ some examples are shownin "17# and "18#[

N

O O

CN

O

CN

NC

O O

CN

O

CN

NC

(28) (29)


An interesting class of bi! and tetradentate benzoisocyanides has been disclosed by Ito et al[ð75JOM"292#290Ł[ On treatment of 0\1!dibromoethane with o!lithiomethylphenyl isocyanides\ oxi!dative dimerization was found to occur\ leading to 0\1!bis"isocyanophenyl#ethanes in good yields[These intermediates could then be further deprotonated\ and on treatment with one equivalent of0\1!dibromoethane the cyclic tetra!isocyanide product "29# was isolated "Scheme 33#[

i, LDA, –78 °C

ii, BrBrNC

NCNC

i, LDA (4 equiv.), –78 °C

ii, BrBr

NC

NC

CN

NC

(30)

Scheme 44

"iii# Polycyclic aromatic isocyanides

Ugi and co!workers have reported the preparation of a number of polycyclic aromatic isocyanidesutilizing the dehydration of the precursor formamides with phosgene\ which appears to be themethod of choice "Equation "49##[

N CHO

H

Ar

Ar NCCOCl2

R3N(50)

Some examples are given in "20#\ "21# and "22#\ and further examples can be found ð54AG"E#361\B!60MI 210!90Ł[

NCNC NC

(31) (97%) (32) (97%) (33) (93%)

"iv# Heterocyclic aromatic isocyanides

Wollweber et al[ have reported the preparation of a number of heterocyclic isocyanides bythe thermolysis of iminoisoxazolones[ The latter compounds are conveniently prepared by thecondensation of nitroso compounds with 2!phenylisoxazol!4"3H#!one[ Heating in toluene at 89>C\followed by removal of the solvent and sublimation then leads to product isocyanides in excellentyields ð67AG"E#577Ł[ Examples are shown in Scheme 34[

614Isocyanides

NO

Ph N R

O

R NC

NC

Me2N NH

N

CN

NPh

N

CN

NH

N

CN

Ph NPh

NMe

CN

ONMe

NC

Ph

∆

–PhCN, –CO2

Scheme 45

Ugi and co!workers have reported the preparation of a large number of heterocyclic aromaticisocyanides using his phosgene dehydration protocol\ which again appears to be the method ofchoice ð54AG"E#361\ B!60MI 210!90Ł[ The heterocyclic systems include\ furans\ pyridines\ tetrazoles\quinolines\ benzotriazoles\ benzothiophene and benzothiazoles^ examples are given in Scheme 35[

N CHO

H

Ar

Ar NC

ONC

O

NC

N

CN

N

NC

SO2 O

Ph

CN O

N

SNC

O

ONC

NCNN

NN

NC

COCl2

R3N

(77%) (93%) (71%)

(50%) (60%) (41%)

(64%) (46%)

Scheme 46

NC

Kozikowski et al[ have disclosed the preparation of the thiophene isocyanide "23# ð80SL543Ł fromthe corresponding thiophene amine using the Hofmann carbylamine approach "Equation "40##[

CHCl3, 50% NaOH

TEBA, CH2Cl2

NHEt

S

NH2

NHEt

S

NC

(34)

(51)

TEBA = Triethylbenzylammonium chloride


The unusual 1\3\5!triisocyanotriazinetris"pentacarbonylchromium# has been reported as a stablecompound "24# ð71CC073Ł[

N

N

N

N

CCr(CO)5

NCCr(CO)5

N(OC)5CrC

(35)

2[10[1 ISOCYANIDE ANALOGUES WITH A HETEROATOM OTHER THAN NITROGEN

There are no known examples of isocyanide analogues RX1C\ where X�phosphorus\ arsenic\antimony or bismuth[ The intermediacy of a {phosphaisocyanide| has been implicated when C!halophosphaalkenes are treated with base at low temperature "Scheme 36# ð80CB1566\ 83CR0302Ł[The product of the reaction is a phosphaalkyne\ which was suggested to have been formed byrearrangement of the highly unstable phosphaisocyanide at −74>C[

R P

Li

X

R P C R P

Scheme 47


References to Volume 3

EXPLANATION OF THE REFERENCE SYSTEM

Throughout this work\ references are designated by a numberÐlettering coding of which the _rsttwo numbers denote tens and units of the year of publication\ the next one to three letters denotethe journal\ and the _nal numbers denote the page[ This code appears in the text each time areference is quoted^ the advantages of this system are outlined in the Introduction[ The system hasbeen used previously in {{Comprehensive Heterocyclic Chemistry\|| eds A[ R[ Katritzky and C[ W[Rees\ Pergamon\ Oxford\ 0873 and is based on that used in the following two monographs] "a# A[ R[Katritzky and J[ M[ Lagowski\ {{Chemistry of the Heterocyclic N!Oxides\|| Academic Press\New York\ 0860^ "b# J[ Elguero\ C[ Marzin\ A[ R[ Katritzky and P[ Linda\ {{The Tautomerism ofHeterocycles\|| in {{Advances in Heterocyclic Chemistry\|| Supplement 0\ Academic Press\ NewYork\ 0865[

The following additional notes apply]

0[ A list of journal codes in alphabetical order\ together with the journals to which they refer\ isgiven immediately following these notes[ Journal names are abbreviated throughout using theCASSI "Chemical Abstracts Service Source Index# system[

1[ Each volume contains all the references cited in that volume^ no separate lists are given forindividual chapters[

2[ The list of references is arranged in order of "a# year\ "b# journal in alphabetical order ofjournal code\ "c# part letter or number if relevant\ "d# volume number if relevant\ "e# page number[

3[ In the reference list the code is followed by "a# the complete literature citation in the con!ventional manner and "b# the number"s# of the page"s# on which the reference appears\ whether inthe text or in tables\ schemes\ etc[

4[ For nontwentieth!century references the year is given in full in the code[5[ For journals which are published in separate parts\ the part letter or number is given "when

necessary# in parentheses immediately after the journal code letters[6[ Journal volume numbers are not included in the code numbers unless more than one volume

was published in the year in question\ in which case the volume number is included in parenthesesimmediately after the journal code letters[

7[ Patents are assigned appropriate three!letter codes[8[ Frequently cited books are assigned codes[09[ Less common journals and books are given the code {{MI|| for miscellaneous with the whole

code for books pre_xed by the letter {{B!||[00[ Where journals have changed names\ the same code is used throughout\ e[g[ CB refers to

both Chem[ Ber[ and to Ber[ Dtsch[ Chem[ Ges[

Journal Codes

AAC Antimicrob[ Agents Chemother[ABC Agric[ Biol[ Chem[AC Appl[ Catal[AC"P# Ann[ Chim[ "Paris#AC"R# Ann[ Chim[ "Rome#ACH Acta Chim[ Acad[ Sci[ Hung[

616

617 References

ACR Acc[ Chem[ Res[ACS Acta Chem[ Scand[ACS"A# Acta Chem[ Scand[\ Ser[ AACS"B# Acta Chem[ Scand[\ Ser[ BAF Arzneim[!Forsch[AFC Adv[ Fluorine Chem[AG Angew[ Chem[AG"E# Angew[ Chem[\ Int[ Ed[ Engl[AHC Adv[ Heterocycl[ Chem[AHCS Adv[ Heterocycl[ Chem[ SupplementAI Anal[ Instrum[AJC Aust[ J[ Chem[AK Ark[ KemiAKZ Arm[ Khim[ Zh[AM Adv[ Mater[ "Weinheim\ Ger[#AMLS Adv[ Mol[ Spectrosc[AMS Adv[ Mass[ Spectrom[ANC Anal[ Chem[ANL Acad[ Naz[ LnceiANY Ann[ N[ Y[ Acad[ Sci[AOC Adv[ Organomet[ Chem[AP Arch[ Pharm[ "Weinheim\ Ger[#APO Adv[ Phys[ Org[ Chem[AQ An[ Quim[AR Annu[ Rep[ Prog[ Chem[AR"A# Annu[ Rep[ Prog[ Chem[\ Sect[ AAR"B# Annu[ Rep[ Prog[ Chem[\ Sect[ BARP Annu[ Rev[ Phys[ Chem[ASI Acta Chim[ Sin[ Engl[ Ed[ASIN Acta Chim[ Sin[AX Acta Crystallogr[AX"A# Acta Crystallogr[\ Part AAX"B# Acta Crystallogr[\ Part BB BiochemistryBAP Bull[ Acad[ Pol[ Sci[\ Ser[ Sci[ Chim[BAU Bull[ Acad[ Sci[ USSR\ Div[ Chim[ Sci[BBA Biochim[ Biophys[ ActaBBR Biochim[ Biophys[ Res[ Commun[BCJ Bull[ Chem[ Soc[ Jpn[BEP Belg[ Pat[BJ Biochem[ J[BJP Br[ J[ Pharmacol[BMC Bioorg[ Med[ Chem[ Lett[BP Biochem[ Biopharmacol[BPJ Br[ Polym[ J[BRP Br[ Pat[BSB Bull[ Soc[ Chim[ Belg[BSF Bull[ Soc[ Chim[ Fr[BSF"1# Bull[ Soc[ Chim[ Fr[\ Part 1C ChimiaCA Chem[ Abstr[CAN CancerCAR Carbohydr[ Res[CAT Chim[ Acta Turc[CB Chem[ Ber[

618References

CBR Chem[ Br[CC J[ Chem[ Soc[\ Chem[ Commun[CCA Croat[ Chem[ ActaCCC Collect[ Czech[ Chem[ Commun[CCR Coord[ Chem[ Rev[CE Chem[ ExpressCEN Chem[ Eng[ NewsCHE Chem[ Heterocycl[ Compd[ "Engl[ Transl[#CHEC Comp[ Heterocycl[ Chem[CI"L# Chem[ Ind[ "London#CI"M# Chem[ Ind[ "Milan#CJC Can[ J[ Chem[CJS Can[ J[ Spectrosc[CL Chem[ Lett[CLY Chem[ ListyCM Chem[ Mater[CMC Comp[ Med[ Chem[COC Comp[ Org[ Chem[COMC!I Comp[ Organomet[ Chem[\ 0st edn[COS Comp[ Org[ Synth[CP Can[ Pat[CPB Chem[ Pharm[ Bull[CPH Chem[ Phys[CPL Chem[ Phys[ Lett[CR C[ R[ Hebd[ Seances Acad[ Sci[CR"A# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ ACR"B# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ BCR"C# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ CCRAC Crit[ Rev[ Anal[ Chem[CRV Chem[ Rev[CS Chem[ Scr[CSC Cryst[ Struct[ Commun[CSR Chem[ Soc[ Rev[CT Chem[ Tech[CZ Chem[!Ztg[CZP Czech[ Pat[DIS Diss[ Abstr[DIS"B# Diss[ Abstr[ Int[ B[DOK Dokl[ Akad[ Nauk SSSRDP Dyes Pigm[E ExperientiaEC Educ[ Chem[EF Energy FuelsEGP Ger[ "East# Pat[EJM Eur[ J[ Med[ Chem[EUP Eur[ Pat[FCF Forschr[ Chem[ Forsch[FCR Fluorine Chem[ Rev[FES Farmaco Ed[ Sci[FOR Forschr[ Chem[ Org[ Naturst[FRP Fr[ Pat[G Gazz[ Chim[ Ital[GAK Gummi Asbest Kunstst[GEP Ger[ Pat[GEP"O# Ger[ Pat[ O}en[

629 References

GSM Gen[ Synth[ MethodsH HeterocyclesHAC Heteroatom Chem[HC Chem[ Heterocycl[ Compd[HCA Helv[ Chim[ ActaHOU Methoden Org[ Chem[ "Houben!Weyl#HP Hydrocarbon ProcessIC Inorg[ Chem[ICA Inorg[ Chim[ ActaIEC Ind[ Eng[ Chem[ Res[IJ Isr[ J[ Chem[IJC Indian J[ Chem[IJC"A# Indian J[ Chem[\ Sect[ AIJC"B# Indian J[ Chem[\ Sect[ BIJM Int[ J[ Mass Spectrom[ Ion Phys[IJQ Int[ J[ Quantum Chem[IJS Int[ J[ Sulfur Chem[IJS"A# Int[ J[ Sulfur Chem[\ Part AIJS"B# Int[ J[ Sulfur Chem[\ Part BIS Inorg[ SynthIZV Izv[ Akad[ Nauk SSSR Ser[ Khim[JA J[ Am[ Chem[ Soc[JAN J[ Antibiot[JAP Jpn[ Pat[JAP"K# Jpn[ KokaiJBC J[ Biol[ Chem[JC J[ Chromatogr[JCC J[ Coord[ Chem[JCE J[ Chem[ Ed[JCED J[ Chem[ Eng[ DataJCI J[ Chem[ Inf[ Comput[ Sci[JCP J[ Chem[ Phys[JCPB J[ Chim[ Phys[ Physico!Chim[ Biol[JCR"M# J[ Chem[ Res[ "M#JCR"S# J[ Chem[ Res[ "S#JCS J[ Chem[ Soc[JCS"A# J[ Chem[ Soc[ "A#JCS"B# J[ Chem[ Soc[ "B#JCS"C# J[ Chem[ Soc[ "C#JCS"D# J[ Chem[ Soc[\ Dalton Trans[JCS"F0# J[ Chem[ Soc[\ Faraday Trans[ 0JCS"F1# J[ Chem[ Soc[\ Faraday Trans[ 1JCS"P0# J[ Chem[ Soc[\ Perkin Trans[ 0JCS"P1# J[ Chem[ Soc[\ Perkin Trans[ 1JCS"S1# J[ Chem[ Soc[ "Suppl[ 1#JEC J[ Electroanal[ Chem[ Interfacial Electrochem[JEM J[ Energy Mater[JES J[ Electron[ Spectrosc[JFA J[ Sci[ Food[ Agri[JFC J[ Fluorine Chem[JGU J[ Gen[ Chem[ USSR "Engl[ Transl[#JHC J[ Heterocycl[ Chem[JIC J[ Indian Chem[ Soc[JINC J[ Inorg[ Nucl[ Chem[JLC J[ Liq[ Chromatogr[

620References

JMAS J[ Mat[ Sci[JMC J[ Med[ Chem[JMOC J[ Mol[ Catal[JMR J[ Magn[ Reson[JMS J[ Mol[ Sci[JOC J[ Org[ Chem[JOM J[ Organomet[ Chem[JOU J[ Org[ Chem[ USSR "Engl[ Transl[#JPC J[ Phys[ Chem[JPJ J[ Pharm[ Soc[ Jpn[JPO J[ Phys[ Org[ Chem[JPP J[ Pharm[ Pharmacol[JPR J[ Prakt[ Chem[JPS J[ Pharm[ Sci[JPS"A# J[ Polym[ Sci[\ Polym[ Chem[\ Part AJPU J[ Phys[ Chem[ USSR "Engl[ Transl[#JSC J[ Serbochem[ Soc[JSP J[ Mol[ Spectrosc[JST J[ Mol[ Struct[K Kristallogra_yaKFZ Khim[ Farm[ Zh[KGS Khim[ Geterotsikl[ Soedin[KO Kirk!Othmer Encyc[KPS Khim[ Prir[ Soedin[L LangmuirLA Liebigs Ann[ Chem[LC Liq[ Cryst[LS Life Sci[M Monatsh[ Chem[MAC Macromol[ Chem[MC Mendeleev Chem[ J[ "Engl[ Transl[#MCLC Mol[ Cryst[ Liq[ Cryst[MI Miscellaneous ðbook:journalŁMIP Miscellaneous Pat[MM MacromoleculesMP Mol[ Phys[MRC Magn[ Reson[ Chem[N NaturwissenschaftenNAT Nat[NEP Neth[ Pat[NJC Nouv[ J[ Chim[NKK Nippon Kagaku Kaishi "J[ Chem[ Soc[ Jpn[#NKZ Nippon Kagaku ZasshiNZJ N[ Z[ J[ Sci[ Technol[OCS Organomet[ Synth[OM OrganometallicsOMR Org[ Magn[ Reson[OMS Org[ Mass Spectrom[OPP Org[ Prep[ Proced[ Int[OR Org[ React[OS Org[ Synth[OSC Org[ Synth[\ Coll[ Vol[P PhytochemistryPA Polym[ AgePAC Pure Appl[ Chem[

621 References

PAS Pol[ Acad[ Sci[PB Polym[ Bull[PC Personal CommunicationPCS Proc[ Chem[ Soc[PHA PharmaziPHC Prog[ Heterocycl[ Chem[PIA Proc[ Indian Acad[ Sci[PIA"A# Proc[ Indian Acad[ Sci[\ Sect[ APJC Pol[ J[ Chem[PJS Pak[ J[ Sci[ Ind[ Res[PMH Phys[ Methods Heterocycl[ Chem[PNA Proc[ Natl[ Acad[ Sci[ USAPOL PolyhedronPP Polym[ Prepr[PRS Proceed[ Roy[ Soc[PS Phosphorus SulfurQR Q[ Rev[\ Chem[ Soc[QRS Quart[ Rep[ Sulfur[ Chem[QSAR Quant[ Struct[ Act[ Relat[ Pharmacol[ Chem[ Biol[RC Rubber Chem[ Technol[RCM Rapid Commun[ Mass Spectrom[RCP Rec[ Chem[ Prog[RCR Russ[ Chem[ Rev[ "Engl[ Transl[#RHA Rev[ Heteroatom Chem[RJ Rubber J[RP Rev[ Polarogr[RRC Rev[ Roum[ Chim[RS Ric[ Sci[RTC Recl[ Trav[ Chim[ Pays!BasRZC Rocz[ Chem[S SynthesisSA Spectrochim[ ActaSA"A# Spectrochim[ Acta\ Part ASAP S[ Afr[ Pat[SC Synth[ Commun[SCI ScienceSL SynlettSM Synth[ Met[SR Sulfur ReportsSRI Synth[ React[ Inorg[ Metal!Org[ Chem[SS Sch[ Sci[ Rev[SST Org[ Compd[ Sulphur\ Selenium\ Tellurium ðR[ Soc[ Chem[ seriesŁSUL Sulfur LettersSZP Swiss Pat[T TetrahedronT"S# Tetrahedron\ Suppl[TA Tetrahedron AsymmetryTAL TalantaTCA Theor[ Chim[ ActaTCC Top[ Curr[ Chem[TCM Tetrahedron\ Comp[ MethodTFS Trans[ Faraday Soc[TH ThesisTL Tetrahedron Lett[TS Top[ Stereochem[

622References

UK Usp[ Khim[UKZ Ukr[ Khim[ Zh[ "Russ[ Ed[#UP Unpublished ResultsURP USSR Pat[USP US Pat[WCH Wiadom[ Chem[YGK Yuki Gosei Kagaku KyokaishiYZ Yakugaku Zasshi "J[ Pharm[ Soc[ Jpn[#ZAAC Z[ Anorg[ Allg[ Chem[ZAK Zh[ Anal[ Khim[ZC Z[ Chem[ZN Z[ Naturforsch[ZN"A# Z[ Naturforsch[\ Teil AZN"B# Z[ Naturforsch[\ Teil BZOB Zh[ Obshch[ Khim[ZOR Zh[ Org[ Khim[ZPC HoppeÐSeyler|s Z[ Physiol[ Chem[ZPK Zh[ Prikl[ Khim[

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94CB0624 H[ Staudinger^ Ber[ Dtsch[ Chem[ Ges[\ 0894\ 27\ 0624[ 429\ 420

95CB0959 P[ Friedlander^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0959[ 14095CB0070 W[ Gulewitsch and T[ Wasmus^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0070[ 50595CB0262 T[ Curtius and A[ Darapsky^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0262[ 35795CB0268 T[ Curtius and J[ Thompson^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0268[ 35795CB0272 T[ Curtius and J[ Thompson^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0272[ 36595CB0745 A[ J[ Ultee^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 0745[ 50495CB2951 H[ Staudinger^ Ber[ Dtsch[ Chem[ Ges[\ 0895\ 28\ 2951[ 420

96CB1698 A[ Braun and J[ Tcherniac^ Ber[ Dtsch[ Chem[ Ges[\ 0896\ 39\ 1698[ 50896JCS0827 N[ T[ M[ Wilsmore^ J[ Chem[ Soc[\ 0896\ 80\ 0827[ 423\ 42496LA"240#243 C[ Pomeranz^ Justus Liebi`s Ann[ Chem[\ 0896\ 240\ 243[ 50196LA"245#44 H[ Staudinger^ Justus Liebi`s Ann[ Chem[\ 0896\ 245\ 44[ 45096NAT409 N[ T[ M[ Wilsmore and A[ W[ Stewart^ Nature\ 0896\ 64\ 409[ 424

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10HCA776 H[ Staudinger and E[ Hauser^ Helv[ Chim[ Acta\ 0810\ 3\ 776[ 47310HCA786 H[ Staudinger and W[ Braunholtz^ Helv[ Chim[ Acta\ 0810\ 3\ 786[ 475

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12CB0025 D[ Vorla�nder\ J[ Osterburg and O[ Meye^ Ber[ Dtsch[ Chem[ Ges[\ 0812\ 45\ 0025[ 34112CB0061 K[ van Auwers^ Ber[ Dtsch[ Chem[ Ges[\ 0812\ 45\ 0061[ 50112HCA180 H[ Staudinger\ H[ Schneider\ P[ Schotz and P[ M[ Strong^ Helv[ Chim[ Acta\ 0812\ 5\ 180[ 42312JA1056 C[ D[ Hurd and C[ Kocour^ J[ Am[ Chem[ Soc[\ 0812\ 34\ 1056[ 42412JA2984 C[ D[ Hurd^ J[ Am[ Chem[ Soc[\ 0812\ 34\ 2984[ 424

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22CB126 A[ Schonberg\ A[ Stephenson\ H[ Kaltschmitt\ E[ Peterson and H[ Schulten^ Ber[ Dtsch[Chem[ Ges[\ 0822\ 55\ 126[ 436

22CB300 H[ Meerwein^ Ber[ Dtsch[ Chem[ Ges[\ 0822\ 55\ 300[ 17922CB0901 F[ Arndt and H[ Scholz^ Ber[ Dtsch[ Chem[ Ges[\ 0822\ 55\ 0901[ 36822JA3050 F[ C[ Whitmore and G[!H[ Fleming^ J[ Am[ Chem[ Soc[\ 0822\ 44\ 3050[ 50122JA3188 E[ P[ Kohler and F[ W[ Brown^ J[ Am[ Chem[ Soc[\ 0822\ 44\ 3188[ 50122JCS252 E[ C[ S[ Jones and J[ Kenner^ J[ Chem[ Soc[\ 0822\ 252[ 354

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24CB749 N[ A[ Preobrashenski\ A[ M[ Poljakowa and W[ A[ Preobrashenski^ Ber[ Dtsch[ Chem[ Ges[\0824\ 57\ 749[ 420\ 421

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Comprehensive Organic Functional Group Transformations, Volume 3 (Synthesis:Carbon with One...

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