1997 2, 186-232 molecules - MDPIMolecules 1997, 2, 186-232 * To whom correspondence should be...

Molecules 1997, 2, 186-232

* To whom correspondence should be addressed.

© 1997 MDPI. All rights reserved

moleculesISSN 1420-3049

Preparation of αα,ββ-Unsaturated Ketones Bearing a TrifluoromethylGroup and Their Application in Organic Synthesis

Valentine G. Nenajdenko*, Andrei V. Sanin, Elizabeth S. Balenkova

Department of Chemistry, Moscow State University, 119899 Moscow, RussiaTel.: +7 (095) 939-43-94; Fax: +7 (095) 932-88-46; E-mail: [email protected]

Received: 9 December 1996 / Accepted: 28 March 1997 / Published: 1 December 1997

Abstract: The approaches to the synthesis of α,β-unsaturated CF3-containing ketones and their use in organicchemistry are reviewed. The synthetic applications of these ketones are discussed. The formation of 4-, 5-, 6-and 7-membered heterocycles bearing a CF3 group based on reactions of α,β-unsaturated CF3-containingketones with different nucleophiles are discussed.

Keywords: α,β-Unsaturated trifluoromethyl ketones, CF3-containing heterocycles, trifluoroacetylation,synthesis, review.

Introduction

Organofluorine compounds, particularly heterocyclicones, are very attractive targets both from a theoreticaland synthetic point of view. They have attracted muchattention especially in the last decade in biological andmedicinal chemistry [1]. This is due to the unique featuresof fluorine compounds and foremost their highphysiological activity [2, 3]. The introduction of fluorineinto organic compounds often permits dramaticmodification of their chemical and pharmaceuticalproperties.

The preparation of fluorine heterocycles is welldocumented. There are two general approaches:1) fluorination of an existing heterocyclic ring includingfunctional group transformations [4], for exampletransformation of a carboxy moiety to a trifluoromethylgroup [5] or the trifluoromethylation of heterocyclesusing CF3Cu [6, 7] or CF3 radicals [8, 9]. 2) constructionof heterocyclic rings using fluorinated synthons. Many

approaches to the synthesis of CF3-containingheterocycles are based on the use of β-dicarbonylcompounds [10, 11]. Cycloaddition reactions (usingtrifluoromethylalkenes [12], trifluoroacetonitrileoxide[13] or trifluoroacylketenes [14]) were also widely used inrecent years. However, the disadvantages of thesemethods, e.g. availability of starting compounds orutilization of aggressive and highly toxic reagents, havestimulated the development of new methods for synthesisof trifluoromethylated heterocyclic compounds. Manynew synthetic methods for the preparation oftrifluoromethylated heterocycles were first elaborated 30years ago, however the search for new reagents andapproaches to the synthesis of CF3-containing compoundsis still an actual goal of modern organic synthesis.

One simple and useful approach to the synthesis oftrifluoromethyl-containing heterocycles is the synthesisbased on the utilization of unsaturated ketones with atrifluoromethyl group (Scheme 1).

Molecules 1997, 2 187

CF3HET R

CF3O

COCF3R

Scheme 1.

In recent years a considerable effort has been devotedto find ways of preparation of unsaturated ketones with aCF3 group. Unsaturated ketones with a CF3 group arepotential important in organic synthesis. However, theseketones, especially ethylenic ones, are not readilyaccessible. Conventional procedures for the synthesis ofethylenic ketones have not been applicable to thepreparations of these ketones. Some approaches to thesynthesis of these ketones were summarized earlier byBégué and Bonnet-Delpon [15].

Preparation of αα,ββ-Unsaturated Ketones Bearing aTrifluoromethyl Group

Some trifluoromethyl-containing ketones are readilyavailable by acylation of electron reach alkenes with

trifluoroacetic anhydride (or other derivatives oftrifluoroacetic acid). Trifluoroacetylation of ketenedithioacetals [16], vinyl sulfides [16], vinyl amides [17],vinyl ethers [17, 18] (including cyclic vinyl ethers[18, 19]), enamines [20, 21] proceeds at room temperatureto give the corresponding β-trifluoroacetylatedcompounds in high yields (Scheme 2). Activated dienes,e.g. 1,1-bisalkylthio-1,3-alkadienes, react quite easily also(Scheme 3) [22]. The addition-elimination mechanism oftrifluoroacylation of electron-reach alkenes wasconfirmed by 1H NMR and kinetic study [23, 24]. Morereactive enamines such as 1-morpholino-1-cyclopenteneor 1-morpholino-1-cyclohexene give very complicatedreaction mixtures. In the case of1-morpholino-1-cyclohexene the product of bistrifluoroacylation was isolated (Scheme 2) [20].

RX

COCF3YCH2

RX

Y

(CF3CO)2O

54-100%1-6 7-12

1, 7 : Y = SAr2-6, 8-12 : Y = H, Alk, Ar1, 2, 7, 8 : X = S3, 9 : X = NSO2R

1

4, 10 : X = NCOR2

5, 11 : X = O6, 12 : X = NR3

1 36 f

(CF3CO) 2O

N

O

N

O

COC F3CF3CO

Scheme 2.

188 Molecules 1997, 2

43-100%

RS

RS

(CF3CO) 2ORS

RSCOC F3

14 15

Scheme 3.

Trifluoroacetylation of trithioorthoacetates results inthe acylated ketene thioacetals in high yield (Scheme 4)[25]. The products seem to result from trifluoroacylation

of ketene dithioacetals formed by elimination of thiolsfrom trithioorthoacetates.

58-100%

(ArS)2C=CHCOCFrt

(CF3CO)2O(ArS)3CCH3

16 7

3

Scheme 4.

Trifluoroacylation of triethylorthoacetate and thediethylacetal of some methyl ketones proceeds similarly(Scheme 5). It is very interesting that this reaction takes

place only in the case of trifluoro(trichloro)aceticanhydride. In the case of acetic anhydride this reactiondoes not proceed [26].

CH3

OE t

OE tOE t

(CF3CO) 2O/ Py

r.t. CF3CO

OE t

OE t

75%

CH3

R

OE tOE t

(CF3CO) 2O/ Py

r.t. CF3CO

R

OE t

R= Me, Ph 94-100%

17 18

19 11

Scheme 5.

Recently the trifluoroacylation of vinyl ethers wassuccessfully extended to the diacylation of alkyl vinyl

ethers with the use of excess trifluoroacetic anhydride (3equivalents) in the presence of pyridine (Scheme 6) [27].

RO

COC F3

COC F3

64-97%

(CF 3CO) 2O / PyRO

205

Scheme 6.

4-Ethoxy-1,1,1-trifluoro-3-buten-2-one 11a was firstlyprepared by the three step procedure fromnitropentafluoroacetone. Cycloaddition ofnitropentafluoroacetone 21 with ethylvinyl ether gives

rise to the formation of oxetane 22, subsequent cleavageof the four-membered ring in the presence of sulphuricacid leads to the formation of the corresponding carbinol23. The thermolysis of this carbinol in the presence of


K2CO3 gives rise to the target CF3 ketone. A similartransformation was also investigated for ketene

diethylacetal (Scheme 7) [28, 29].

-NO2F2CH

96%90%88%

64%

R = OEt70%R = H

OEt

RCF3CO

K2CO3OEt

RNO2F2COHF3C

H2SO4ONO2F2C

F3C

R

OEt+OEt

RO

F3C

NO2F2C

21 5 22 23 11a, 18a

Scheme 7.

The reaction of nitropentafluoroacetone 21 withisobutylene gives rise to the corresponding carbinol 23(Scheme 8). Subsequent elimination of

difluoronitromethane in the presence of K2CO3 leads totrifluoromethyl-β,β-dimethylvinyl ketone 24a [30].

24a2322a21

OF3C

NO2F2C CH3

CH3

+ CH3NO2F2COHF3C

K2CO3CH3

CH3CF3CO-NO2F2CH

96% 48%

Scheme 8.

The same ketone was previously prepared by Hennefrom trifluoroacetylacetone (Scheme 9). Addition of

methylmagnesium bromide with subsequent spontaneousdehydration of water gives this ketone in 55% yield [31].

55%

-H2OCF3

O

CH3

HO

CH3

MeMgBr

CF3

O

CH3

OCH3

CH3CF3CO

24a25 26

Scheme 9.

Perfluoroacylation of non-activated alkenes was notdescribed before 1992. Trifluoroacylating reagents arerestricted to trifluoroacetic anhydride and otherderivatives of trifluoroacetic acid. However, theelectrophilicity of these reagents is insufficient foracylation of alkenes. Attempts to improve their activitywith Lewis acids (as in the case of aromatic hydrocarbons'trifluoroacylation [32-34]) lead to cationic polymerizationof the unsaturated substrates. Perfluorinated acylium saltswhich can be used for the perfluoracylation of unsaturatedhydrocarbons are unstable and decompose readily withdecarbonylation (Eq.1) [35, 36].

RfCOCl + AgSbF6 [ RfCO+ SbF6

- ] RfF + SbF5 + CO

Eq.1

A novel method of direct electrophilicperfluoroacylation of alkenes was proposed, which isbased on the use of trifluoroacetic anhydride (or otheranhydrides of perfluorinated acids) in the presence of adimethyl sulphide-borontrifluoride complex (Scheme 10)[37].


+S(CH3)2

+

CH3R1

R2 S(CH3)2 CF3COOB F3-

R1

R2CHCOC F3

CF3COOB F3-

R1

R2 S(CH3)2

CH2COC F3

R1

R2CH2

H+, S(CH3)2

S(CH3)2, BF3

-H++CH2COC F3C

R1

R2

(CF3CO) 2O

+

19-49%24A22

2928

Scheme 10.

This method enables unsaturated ketones containingperfluoroalkyl groups without β-heteroalkyl substituentsto be obtained in moderate yields (Scheme 10) [37-42].Recently it was found that this complex is moreappropriate for the trifluoroacylation of various aromaticcompounds then other trifluoroacylating reagents [43].

The reaction takes place only for alkenes which givecations with stabilized groups - phenyl, allyl orcyclopropyl or tertiary cations. The electrophilicity of thisreagent exceeds the electrophilicity of trifluoroaceticanhydride, which reacts only with electron rich alkeneshaving heteroatoms at a double bond. In spite of aconsiderable raising of synthetic possibilities of thismethod compared with other perfluoroacylating reagentsthe reactivity of the new reagent is not sufficient to reactwith all alkenes. The essential disadvantage of thisreaction is also the low yields of ketones due to thespecific chemistry of the acylation which restricts yield to50%.

The trifluoroacylation of cyclopropyl containingalkenes such as isopropenylcyclopropane and

1,1-dicyclopropylethylene by trifluoroacetic anhydride inthe presence of the dimethyl sulphide-borontrifluoridecomplex proceeds in an unusual manner (Scheme 11).This reaction leads to the formation of the correspondingsulphonium salts in high yields [40], which are theproducts of the trapping of the homoallyl cation, formedin the process of cyclopropane ring opening. Since thesecompounds are β,γ-unsaturated ketones, they are prone tospontaneous transformation to the correspondingα,β-unsaturated ketones. The rearrangement of thecompounds proceeds over ca. two months at roomtemperature with no catalyst in quantitative yield.

The action of potassium fluoride, as a base, on thesesulfonium salts furnishes intramolecular nucleophilicsubstitution of the dimethyl sulphide group, which resultsin α,β-unsaturated ketones containing a perfluorinatedgroup (Scheme 11).

R = Me, cyclopropyl

100%

31-34%

R COC F3

KF, DMF

70-80o C, 6h

2 months, rt

CF3CO R

(CH2)3SMe2+

CF3COOB F3-

92-95% CF3COOB F3-

H

CH2CH2SMe2+

CF3COC H2

R

CF3COC H2

R:

+SMe2BF 3.Et2O

(CF 3CO) 2O

R

22 B 29

24

30

Scheme 11.

The trifluoroacylation of phenyl-substituted acetyleneshaving both terminal and internal triple bonds using thecomplex (CF3CO)2O-BF3-SMe2 was studied. This reactionleads to the formation of the corresponding sulfoniumsalts 32, which are the products of conjugate addition of

the CF3CO group and dimethyl sulfide to the acetylenemolecule (Scheme 12). Reaction of these sulfonium saltswith the excess of dimethyl sulphide yields thecorresponding trifluoroacetylated vinyl sulphides 33 inhigh yields. Oxidation of the sulphides by hydrogen


peroxide in acetic acid gives rise to the correspondingunsaturated sulfones 34 with the CF3CO moiety in the

β-position [42].

88-93%

Ph R

COC F3CH3SO2

H2O2

87-96%90-95%

Ph R

COC F3CH3S

CF3COOB F3-

S(CH3)2

+(CH3)2S

Ph R

COC F3S(CH3)2, BF3

(CF3CO) 2OPh R

3132 33 34

Scheme 12.

Some other existing methods for the preparation forunsaturated ketones with trifluoromethyl group are basedon the acylation of organoelement compounds. The firstsynthesis of 1,1,1-trifluoro-4-phenylbut-3-en-2-one by the

reaction of phenylvinylmagnesium bromide withtrifluoroacetic acid was described in 1959, but the yieldwas very low (Scheme 13) [44].

11%

PhCOCF3

1. Mg / Et 2O2. CF 3COOH

Ph

Br35 24b

Scheme 13.

It was found in subsequent investigations thatorganolithium compounds were more appropriate for the

synthesis of trifluoromethyl containing ketones and gavehigher yields of the target products (Scheme 14) [45].

36 24b

CF3CONPh

Li

Ph

COC F3

63%

Scheme 14.

A good route for the synthesis of fluorinated ketonesinvolves 1, 4-addition of an organocuprate to theacetylenic ketones, which are readily obtained byacylation of acetylides (Scheme 15). This method affordsethylenic ketones with high regioselectivity, howeverstereoselectivity is variable and yields are moderate[46-50].

It should be noted that in the case of some cupratesregioselectivity is low and the products of both 1,2- and1,4-additions are formed, but use of cyano and higherorder cuprates results in only unsaturated CF3 ketones[48]. In some cases the formation of cyanohydrins takesplace (Scheme 15).


15-64%64-83%

COC F3RR LiCF3COOE t R'2CuLi

R

R' COC F3

37 38 24

COC F3PhMe

Ph OH

NC CF3

LiMeCuCN+ Ph

CN

OH

CF3

38a 39 40

Scheme 15.

A novel method of the synthesis of trifluromethylcontaining unsaturated ketones was described recently[51]. The first step in this approach involvestrifluoroacylation of the corresponding vinyltellurideswith trifluoroacetic anhydride (Scheme 16) [52]. Thereaction proceeds stereospecifically to give only Zisomers of β-trifluoroacetylvinyltellurides in good yields.

The subsequent reaction ofβ−trifluoroacetylvinyltellurides with different zinccuprates via a conjugate addition-elimination processaffords the corresponding α,β-unsaturated trifluoromethylketones. In some cases competitive double addition ofzinc cuprates takes place [51].

56-90%X = (CN)(ZnCl2), ZnCl

R'2CuXiR'

COCF3RTe COCF3

(CF3CO)2O

RTe

41 42 24

Scheme 16.

Although the required ketones were obtained in goodyields, utilization of organotellurium compounds seems tobe a big disadvantage of this method.

Other described methods for the syntheses of theseketones include crotonic condensation of trifluoroacetone

with unsaturated or aryl aldehydes (Scheme 17) [53, 54].However, since competitive self-condensation oftrifluoroacetone takes place, it is necessary to use a 10fold excess of trifluoroacetone.

R 28-85%

R1CHO + MeCOCF3R1

O

CF3

R2 = Ar, Alk;R1 = Ph, 2CH=CH

42 43 24

Scheme 17.

The reaction of aryl aldehydes with1,1,1-trifluoroacetylacetone results in the corresponding

unsaturated CF3-containing ketones, but yields of thetarget ketones are very low [55].


18-24%

CF3

OH

Ar

O

Ar

COC F3

+

Ar COC H3

COC F3

+

N H

+ CF3COC H2COC H3ArCHO

42 252443 44

Scheme 18.

Quite recently a novel method for the synthesis ofα-alkoxycarbonyl-α,β-unsaturated trifluoromethylketones was found involving the Knoevenagelcondensation of aldehydes with trifluoroacetoacetates inthe presence of silica gel functionalized with amino

groups and p-toluenesulfonic acid (Scheme 19). It shouldbe noted that the use of such a catalyst aspiperidine/acetic acid gives raise to very low yields ofproducts [56].

464542

O

HR+

O

CF3CO2R1

1. Ap-s ilica gel

2. p-TsOH

O

CF3CO2R1

R

43-70%

Scheme 19.

Polyfluoroalkyl α,β-enones may be also preparedfrom β-iminophosphonates, accessible in four steps fromperfluoroalkanoyl chlorides. The β-iminophosphonate

anions condensed with an aldehyde lead to thecorresponding trifluoromethyl or perfluoroalkyl enonesafter acidic hydrolysis (Scheme 20) [57].

2451

5049

48C47

Rf CF2 COClP(OEt)3

Rf CF2 CO P(O)(OEt)2F

Rf OP(O)(OEt)2

P(O)(OEt)2

60-77%

F

Rf H

P(O)(OEt)2

1. BuLi-CuI / THF2. sat. aq. NH 4Cl MeNH2

Rf

NMe

P(O)(OEt)2rt, 2h

base

RCHO

NMe

RRf

H+ RfCO

R

70-95%Rf = CF3 , C 2F5, n-C6F13

R = Pr, i-Pr, n-hexyl, cyclohexyl, Ph, cinnamyl

excessof MeNH2

Scheme 20.

Quite recently a novel one pot procedure based on theHorner-Emmons olefination was elaborated.N-phenylrifluoroacetimidoyl chloride reacts with

diethoxyphosphorylmethyl (or ethyl) lithium, generated insitu from diethylmethylphosphonate and lithiumdiisopropylamide (Scheme 21). Subsequent addition of


the aldehyde gives rise to 1-aza-1,3-diene readilyconverted by HCl hydrolysis to the corresponding

unsaturated ketone bearing a CF3 group [58].

R

P

O

(EtO) 2LDA

NPhCl

CF3

R

P

O

(EtO) 2 CF3

NPhLi

R'CHO

R

P

O

(EtO) 2 CF3

NPhLi

NPhCF3

RR'

H

HCl

OCF3

RR'

H48-72%

52 53 D 54 24

Scheme 21.

Secondary carbinols, obtained by the addition of vinylorganometallics to trifluoroacetaldehyde [59] orperfluoroalkyl organometallics to unsaturated aldehydes(Scheme 22) [60-62] can be oxidized by Dess-Martin[63, 64] or Swern [65] reagents or using MnO2 [66] in

dichloromethane to the α,β-ethylenic trifluoromethylketones in good yields. [66, 67] It should be noted that thereduction of acetylenic CF3 ketones using LiAlH4 orNaBH4 does not give CF3 enones but the correspondingallyl alcohols [50, 64, 68].

24, 3858

4257

5655

RM + CF3 CHO

CF3M + RCHOR CF3

OH

IO

O

AcO OAcOAc

RCOCF3

R = Ph 90%

R = Ph(t-Bu)CH=CH 85%

Scheme 22.

The diastereoselective reduction of CF3 enones withbaker’s yeast was also investigated (Scheme 23).However, the main reaction product is a CF3 ketone rather

then an alcohol. The optical purity of alcohols preparedby this procedure is 81-85 % ee [69].

81-85% ee

5-7%46-74%R= Ph, Me

R

CF3OH

+CF3CO

RBaker's yeas t

CF3CO

R

24 59 58

Scheme 23.

Vinyl perfluoroalkyl ketones are formed in situ fromthe reactions of perfluoroalkyllithiums with ethylacrylate. They can be converted to

4-(perfluoroalkyl)tetrahydropyrimidines in moderate togood yields [70].


612460H

N

N R2

HO CF3R1

X-+

R1CF3

O

MeLi - LiBr

R1 COOM e

R1NH2

NH2CF3I

Scheme 24.

4-Ethoxy-1,1,1-trifluoro-3-buten-2-one 11a is readilyobtained by the trifluoroacylation of ethylvinyl ether withtrifluoroacetic anhydride [71]. The reactions of thisketone with electron-rich aromatics (Scheme 25) orphenyl magnesium bromide (Scheme 26) results in theformation of trifluoromethyl unsaturated ketones [72].

However, only very active aromatic compounds such asindole and dimethylaniline take part in the reaction.Reaction with anisole does not take place. The applicationof stronger Lewis acids such as BF3 or TiCl4 at roomtemperature or on heating was unsuccessful.

20%Me2N;61%

NH

Ar =

Ar

COC F3ZnCl2, CH2Cl2ArH+

EtO

COC F3

11a 62 24ab, 2 4ac

Scheme 25.

12b 24b

5824b

11a

EtO

COC F3Ph

COC F3

PhMgBr

+

Ph

CH(OH )CF3

Total y ield 40-60%Reaction time (h) Isomer ratio

2

201 : 11 : 7Et2NH

Et2N

COC F3 PhM gBr

Ph

COC F353%

Scheme 26.

β-Diethylamino-substituted trifluoromethyl-containingenones can be obtained by the reaction of triethylaminewith trifluoroacetyl chloride, trifluoroacetyl fluoride ortrifluoroacetic anhydride. Reaction of trifluoroacetylchloride with two equivalents of triethylamine results inthe 4-diethylamino-1,1,1-trifluoro-3-buten-2-one 12b. A

proposed reaction mechanism involves the oxidation oftriethylamine to diethylvinylamine by one equivalent oftrifluoroacetyl chloride which is itself reduced to floural(Scheme 27). Diethylvinylamine immediately reacts withanother equivalent of trifluoroacetyl chloride to give riseto the corresponding enone [73].


64

56 6b

12b6b63

63

18% based on CF3COCl

Et2NCOCF3-HNEt3

+ Cl-

NEt3CF3COCl + Et2NCH=CH2

CF3CHO + HCl + Et2NCH=CH2

+CF3CHCl-O

- Et 2N=CHMe

~H-

NEt3CF3COClCF3COCl + NEt3

Scheme 27.

In a subsequent investigation it was found that thereaction of triethylamine with an equimolar amount oftrifluoroacetic anhydride proceeds almost quantitatively

and leads to the product of double trifluoroacetylation ofdiethylvinylamine (Scheme 28) [74].

67

65 66

6665

96% based on recovered amine

NCH3

COCF3

+ (CF3CO)2O

NCH3

R = Et, i -Pr+ 3 R2EtNH+ CF3COO

-

+ CF 3)3CH(OCOCF 2R2NCOCF3

COCF34 R2NEt + 4 (CF 23CO) O

68

Scheme 28.

β-Alkyl- or dialkylamino substituted enones bearing aCF3 group are a very interesting type of unsaturatedketone. These compounds are readily available from thereaction of secondary or primary amines (includingaromatic ones) with4-ethoxy-1,1,1-trifluoro-3-buten-2-one or othertrifluoroacylated vinyl ethers. The alkoxy group in theseenones is easily substituted by ammonia and mono- ordialkylamines with the formation of β-aminosubstituted

CF3-bearing enones [75, 76]. 4-Ethoxy-1,1,1-trifluoro-

3-buten-2-one can be also used as a protecting reagent inpeptide synthesis [77]. The reaction with amino acidsproceeds readily at room temperature to give protectedamino acids without racemization. The amino acidsprotected by this procedure were used for dipeptidepreparation (Scheme 29). The removal of theN-4,4,4-trifluoro-3-oxo-butenyl protecting group occursunder mild conditions in the presence of 3N HCl.


R1, R 2 = Alk;R3 = H, Alk;

56-100%

R3R4N

R2

COC F3

R3R4NHR1OCOC F3

R2

11 12

92%

CO2t-Bu

i-PrN CON H

CF3 O

0°C, 1hDCC/NEt3/CH2Cl2

CO2tBui-Pr

NH2.HCl

88%

2. 6N HCl1. NaOH / H2O rt, 2h NHOOC

CF3O

+N COOH

H

CF3CO

OE t

11a 69

12al

12ai

Scheme 29.

It is also possible to undergo reaction with diamines.The reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-onewith ethylenediamine and o-phenylenediamine gives riseto the linking of two molecules of a ketone (Scheme 30)[75].

The same transformation proceeds readily also withunsaturated trifluoroacetyl ketones having a thioalkylgroup in the β-position (Scheme 31) [76].

80%97%

NH2

NH2

NHCH

NHCH CHCOC F3

CHCOC F3 NHCH

NHCH CHCOC F3

CHCOC F3

NH2NH2

COC F3EtO

11a

12ae 12af

Scheme 30.

7 12 56-100%

RNH COC F3

RNH2EtS

COC F3

Scheme 31.

A very interesting possibility is the transaminolisis ofβ-aminosubstituted ketones. N-N exchange proceeds

readily at room temperature without a large excess of thereagent amine. Usually a 1-3 times excess is enough.


However the reaction depends on the relative basicities ofthe leaving and entering amine. As a result the (CH3)2N

moiety can not be replaced by ammonia, but NH3 canreadily be replaced by dimethylamine (Scheme 32) [76].

12k12f

Me2NH

85%

Me2N

COC F3H2N COC F3

Scheme 32.

Another approach to the synthesis ofβ-aminosubstituted CF3 ketones was elaborated in the

reaction of amines with β-diketones having a CF3 group(Scheme 33) [78, 79].

25 12

CF3

O

R

O R1R2NH

CF3

O

R

NR1R2

61-76%

Scheme 33.

The structure and stereochemistry of these type ofenones were investigated by NMR and IR spectroscopy[75, 76, 80]. It was found that the configuration of theketone depends on the structure of the amine substituent.In the case of NH2 and AlkNH or ArNH only theZ configuration of ketones exists in low polar solvents or

in the pure form (Scheme 34). This stereochemistry is dueto the possibility of an intramolecular H-bond. More polarsolvents such as acetonitrile give rise to transformation tothe E-isomer. The 19F NMR spectroscopy shows thepresence of an equilibrium among three forms of theketone. IR spectra give similar data [75].

75- 80%20-25%

E- s-EE- s-ZZ- s-Z

OCF3

RNH

CF3O

RNH

CCl4

CD3CNNR

HCF3

O

Scheme 34.

β-Dialkylaminosubstituted ketones as shown by1H NMR spectra have hindered rotation around the N-C

bond due to the interaction of the nitrogen lone pair withthe carbonyl group (Scheme 35).

12j12j

-N

C2H5

C2H5O

CF3+

NC2H5

C2H5O

CF3

Scheme 35.

Acetylenic ketones with a CF3 group are gooddienophiles in the Diels-Alder reaction giving withcyclopentadiene the corresponding bicyclic CF3 enone.

Zefirov at al [81] investigated reversible photoinitiatedcycloaddition of this ketone to the quadricyclane skeleton(Scheme 36).


7124au7038a

∆ , CF 3CO OH

hν COC F3

Ph

COC F3

Ph

+Ph COC F3

Scheme 36.

Alkadienyl trifluoromethyl ketones werestereoselectively prepared by the reaction of4-ethoxy-1,1,1-trifluoro-3-buten-2-one with

alkenyldialkoxyboranes in the presence ofborontrifluoride etherate (Scheme 37) [82].

B(OR4)2R1

R2

R3

+ EtO COCF3

BF3.Et2O / CH2Cl20oC - rt, 1-120h

R1

R2

R3

COCF3

67-90%R1 - R4 = Alk

72

11a 24

71%

Bu B(OPr)2 BuCOCF3BF3.Et2O / CH2Cl2

0oC - rt, 1-120hEtO

COCF3+

24av11a73

Scheme 37.

Similar reactions proceed also with ketones withoutheteroatom substituents to give 3-alkynyl substituted

(Scheme 38) or γ,δ−unsaturated CF3 ketones (Scheme 39)[83, 84].

7424b

72

B(OR4)2R1

R2

R3

+ Ph COCF3


R1

R2

R3

COCF3

Ph

R1 - R4 = Alk , H, Br

82-99%

Scheme 38.

24b 75

73

+ Ph COCF3


R1 - R4 = Alk , H, Br

R B(OPr)2 RCOCF3

Ph 98-99%

Scheme 39.

The parent CF3 bearing enone - trifluoromethyl vinylketone 24o is not accessible with the procedures described

above. This ketone has been prepared by a five stageprocedure from trifluoracetoacetate (Scheme 40) [85].


CF3COCH=CH2NPhEt2

CF3COCH2CH2Cl

NaCr2O7H2SO4

CF3CHCH2CH2ClOH

KClCF3CHCH2CH2OTs

OHTsCl

CF3CHCH2CH2OHOH

1. NaBH42. LiAlH4

CF3COCH2COOEt

83% 62%

61% 36% 24o

45 76 77

78 79

Scheme 40.

This ketone is spontaneously dimerized to thecorresponding pyran (Scheme 41) [85].

8024o

CF3 O

CF3

OOCF3 COC F3

Scheme 41.


Table 1. Synthesis of α,β−unsaturated trifluoromethyl ketones.

N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.

7a (PhS) 2C=CHCOCF3A 100 25 7b

CH3 S 2C=CHCOCF3

AA

9398

1625

7c (CH3O S )2C=CHCOCF3 A 58 25 7d )2C=CHCOCF3(Cl S A 75 25

8a Cl S CH=CHCOCF3 A 97 16 8b Ph(PhS)C=CHCOCF3 A 79 16

8c CH3SCH=CHCOCF3AA

10067

1623

9aCOCF3

N

SO2

Ph

CH3 A 92 17

9bCOCF3

NSO2

Ph

CH3A 95 17 9c

CH3 SO2 N COCF3

O CH3

A 100 17

10aCOCF3

N

O

A 56 17 10b

COC F3

Ni-PrCOC H3

A 96 22

11aEtO

COCF3AAA

1007958

171823

11bCH3O

COCF3CH3

A 82 18

11c EtOCOCF3

CH3A 66 18 11d

O

COCF3

CH3

A 77 18

11eO

COCF3 AAA

848178

181923

11f

O

COCF3 AAA

7810067

181923

11gi- PrO

COCF3 A 72 23 11h COCF3OEt

O2N

A 100 17

11ht-BuO

COC F3 A 79 23 11ii-BuO

COC F3 A 63 23

12a N

O

COC F3A 83 20 12b

N

COC F3 A 53 20


Table 1. (continued)


12c

N

COC F3A 82 20 12d N

COC F3A - 20

12e NCOC F3

A - 20 12fH2N COCF3

FF

8693

7576

12gCOCF3M eHN

F 99 76 12hEtHN COCF3

FF

8996

7576

12i COCF3HN F 100 76 12j

COCF3

Et2NFF

86100

7576

12k

COCF3

M e2NF 96 76 12l

H2N COCF3F 93 76

12m

COCF3

N F 100 76 12n HN COCF3 F 99 76

12oM eHN COCF3

F 92 76 12p

COCF3

(P hCH2)2NF 98 76

12qHN COCF3

F 93 76 12r

H2N COCF3

PhF 88 76

12s

M eHN COCF3

PhF 100 76 12t

COCF3

Et2N

Ph

F 93 76

12u p- M eOC 6H 4NH COCF3 F 93 76 12v PhNH COCF3FFF

8288

100

877576

12w p- NO2C6H 4NH COCF3 F 88 76 12x

PhNH COCF3

C8H17F 89 87

12y

o-BrC 6H4NH COCF3

PhF 86 87 12z

p-BrC 6H4NH COCF3

C6H13F 87 87




12aam - ClC6H4NH COCF3

PhF 77 87 12ab

m -CH3OC6H4NH COCF3

PhF 96 87

12ac PhCH2HN COCF3 F 72 75 12ad COCF3NHN

F 97 75

12ae

NHCH

NHCH CHCOCF3

CHCOCF3

F 80 75 12af

NHCH

NHCH CHCOCF3

CHCOCF3

F 97 75

12ag3 ,5 - (C H 3O)2C 6H3NH COC F3

Ph

F 99 87 12ah COCF3NHiPr

HOOCF 89 77

12aiC O 2t- B u

i- Pr

N

CO N HCF3

O

F 92 77 12aj COCF3NHM eO2CCH2CH2

HOOC

F 70 77

12ak COCF3NHCH3

HOOCF 88 77 12al

COCF3

NHOOC

F 88 77

12am CO C F3NHtB uO 2CCH 2C H 2

HO O C

F 75 77 12anCOCF3NH

iPr

EtO2CCH2NHO

F 94 77

12aoCOCF3NH

PhCH2

HOOC

F 72 77 12apCO CF3NH

Ph CH 2

N H

OPhC H2

CO OM e

F 91 77

12aqC O C F3NH

C H 3

EtO 2C C H 2N H

O

F 80 77 12arCO CF3NH

tBu O 2CCH 2CH 2

NH

Ot- Bu O 2C

i- Pr

F 82 77

12as Me2N COC F3I 65 100 12at Et2N COC F3

I 71 100

12auN

COC F3

I 59 100 12av NCOC F3

I 78 100

13 N

O

COC F3CF3CO

A 57 20 15a

COC F3

n-PrS

n-PrS

A 43 22




15b

COC F3

EtS

EtSA 67 22 15c

COC F3

EtS

EtS

Et

A 43 22

15dCOC F3

S

S

A 100 22 18

EtO

EtO COCF3AI

7590

2629

20aEtO COCF3

COCF3

A 66 22 20bi-BuO COC F3

COC F3

A 97 22

24a

CH3

CH3 COCF3II

2829

2831

24b PhCOCF3

CDEEFG

905574595545

515357587237

24cCOCF3

G 28 37 24dCOCF3

G 19 41

24eCOCF3

CH3

G 11 41 24fCOCF3 G 49 41

24gCH3

CH3COCF3

CH3 G 26 41 24hCH3

COCF3G 30 41

24i

CH3

CH3 CH3

COCF3

G 11 41 24j

COCF3

G 32 40

24k COCF3

CH3

G 34 40 24l COCF3 G 31 40

24m

COCF3

OHPh

I 36 50 24n

COCF3

OTBDSPh

I 42 50

24oCOCF3

I - 85 24pn -C8H17

COCF3CH3

B 29 46

24qn -C10H21

COCF3CH3

B 44 46 24rn - C10H21

COCF3 C 65 51




24sn - C12H25

COCF3 C 71 51 24t CH3COCF3

CE

8463

5158

24u CH3OCOCF3

C 80 51 24v EtOOCCOCF3

C 70 51

24wPh

COCF3CH3

BG

5128

4441

24xn - C8H17

COCF3 C 58 51

24yn - C6H13

COCF3 E 68 51 24z

COCF3

CH3CH3 E 54 58

24aanC5H11

COCF3 E 52 58 24ab

NH

COCF3F 61 72

24acCOCF3

Me2N

F 20 72 24ad

COCF3

FE 72 58

24ae

COCF3

FCH3 E 58 53

24af

n-BuCOC F3

n-Bu B 66 46

24agPh

COC F3

n-Bu

B 56 46 24ahBu

COCF3 E 48 58

24ai

COCF3

O2NE 59 58 24aj COCF3 G 31 39

24ak COCF3 D 85 53 24al COCF3Ph C

EG

886039

515839

24am COCF3 D 80 53 24anPh

COC F3 D 67 53

24ao COCF3( )2

D 70 53 24ap COCF3CH3

CH3 CH3

G 27 39

24aq COCF3 G 21 39 24ar COCF3 D 28 53




24asCOCF3

Ph

CH3E 60 58 24at COCF3 D 40 53

24auCOC F3

Ph

H - 81 24avCOCF3

Bu F 71 83

24aw

S

N

CH3

O

CF3

F 75 90 24ax NCH3

O

CF3

F 76 90

24ayN

CH3

O

CF3CH3

CH3

F 78 90 24az

NCH3

O

CF3

F 70 90

24baCOC F3

Br

Bu

F 85 82 24bbCOC F3

Bu F 76 82

24bcCOC F3

Bu

Br

F 85 82 24bdCOC F3

Bu

MeF 70 82

24be COC F3Br

F 74 82 24bfCOC F3

F 74 82

24bgCOC F3

MeOOC

F 70 82 24bh COC F3P hC H 2O( C H 2)3

F 72 82

24biCOC F3

Bu

Br

Me

F 67 82 24bjCOC F3

Bu

Ph

Me

F 90 82

24bkCOC F3

Bu

Br

Ph

F 78 82 30a CF3CO

(C H 2)3SM e2+

CH3 CF3COOBF3- G 100 40

30bCF3CO

(C H2)3SM e2+

CF3COO BF3-

G 100 38 32aPh

COCF3

SM e2+ CF3COOBF3

-

G 95 42

32bPh

COCF3

SM e2+

CH3

CF3COOBF3-

G 90 42 32c

CF3COOBF3-

PhCOCF3

SM e2+

C2H5

G 94 42




33a

PhCOCF3

SCH3 G 96 42 33bPh

COCF3SCH3

CH3

G 94 42

33cPh

COCF3SCH3

C2H5

G 87 42 34aPh

COCF3SO2CH3

G 88 42

34bPh

COCF3SO2CH3

CH3

G 93 42 34cPh

COCF3SO2CH3

C2H5

G 88 42

38a COCF3Ph B 81 46 38b COCF3n - Bu BH

7135

4650

38c COCF3n - C6H13 BH

6946

4650

38d COCF3n - C8H17 BH

8145

4650

38e COCF3n - C10H21 BH

8373

4650

38f COCF3n - C12H25 BH

9165

4650

38g COCF3n - C14H29 H 79 50 38h COCF3n - C16H33 H 69 50

38i COCF3M e3SiO(C H2)3 B 71 46 38j COCF3O(C H2)3OB 72 46

42aCOCF3Te

A 84 52 42b COCF3PhTe A 69 52

42c COCF3EtO 2C(C H2)2Te A 75 52 42d COCF3NC(C H2)2Te A 70 52

42e COCF3TePh

A 50 52 42fCOCF3Te

O N A 55 52

46a PhCOCF3

COOEtD 58 56 46b

COCF3

COOEtCH3

D 61 56

46c

COCF3

COOEtCl

D 55 5646d

COCF3

COOEtCl

Cl

D 43 56

46e COCF3

COOEt

D 70 5646f

COCF3

COO i- PrCH3

D 58 56




42gCOCF3Te

A 81 52 103a M e2N COC F3

COC F3I 92 100

103b E t 2N COC F3

COC F3I 100 100 103c N

COC F3

COC F3I 83 100

103dN

COC F3

COC F3 I 77 100 103e NC OC F3

C OC F3

( Ph CH 2) 2 I 83 100

103fN

COC F3

COC F3Ph

CH 3I 98 100 111a

H2N H

CN

CF3CO

N I 71 103

111b

H2N H

CN

CF3CO

N

NCH 3

I 73 103 111c

H2N H

CN

CF3CO

N

O

I 68 103

111d

H2N H

CN

CF3CO

N

NE tO O C

I 76 103

- yield not givenMethods for the preparation of trifluoromethyl α,β-unsaturated ketones:(A) Trifluoroacetylation of electron-rich alkenes with trifluoroacetic anhydride(B) Condensation of acetylide anions with ethyl trifluoroacetate and addition of organocuprates to acetylenictrifluoromethyl ketones(C) Addition of organocuprates to β-trifluoroacetylvinyltellurides(D) Condensation of trifluoroacetone or ethyl trifluoroacetate with aromatic and ethylenic aldehydes(E) Condensation of aldehydes with β-iminophosphonates(F) Interaction of β-alkoxy-substituted CF3 enones with nucleophiles(G) Trifluoroacetylation of alkenes and alkynes with trifluoroacetic anhydride / BF3

./ Me2S complex(H) Alcohol oxidation(I) Multi-step procedures


Synthetic application of αα,ββ-unsaturated ketonesbearing a trifluoromethyl group

It seems to be very fruitful to use unsaturated ketoneswith a trifluoromethyl group for the synthesis oftrifluoromethyl-containing heterocycles. But the use ofthese enones in synthetic organic chemistry can beconsidered as unexploited. The first application ofunsaturated ketones with CF3 for the preparation of thecorresponding heterocycles was dated 1959 [44].However, really extensive utilization of trifluoroacetylketones in organic synthesis was started only quiterecently.

There are two general approaches: 1) syntheses basedon acetylenic CF3 ketones or enones having an heteroalkylsubstituent in the β−position to the CF3CO group, forexample, trifluoroacylated vinyl ethers; 2) synthesesbased on ketones without a heteroatom substituent. Thesetwo approaches differ in oxidation states of both reagents

and the resulting products. It is obvious that the first waygives rise to aromatic heterocycles and the second oneleads to the corresponding hydrogenated heterocycles.Investigation of the latter approach was started only quiterecently. The first publication is dated 1994 [50, 114].Possibly this is due to the fact that the ketones without aheteroatom substituent in the β-position to CF3CO groupare less available and their preparation is more complex.

Syntheses of trifluoromethyl-containing heterocyclesbased on the reactions of acetylenic ketones with somebifunctional nucleophiles were described by Linderman[86, 87]. The reaction with hydrazine results in theformation of the corresponding pyrazoles (Scheme 42). Inthe case of reactions with hydroxylamine under basic oracidic conditions isomeric, the 3-CF3 or 5-CF3 isoxazoles83 and 85 were formed [86]. It is very interesting that inthe case of the reaction of acetylenic ketones withhydroxylamine under basic conditions (MeONa / MeOH)the corresponding

76-92%

R = Ph, n -Bu, n-C 6H13

R COC F3H2NNH 2 NHN

R CF3

8138

80%n-C8H17 COCF3

NO

CF3n-C8H17

H2NOH,AcOH, 10% HCl C6H6,∆

n-C8H17 CCF3

NOH

38d 82 83

64%MeONa / MeOH

n-C8H17 CF3

N OOH

n-C8H17 CF3

N On-C8H17 COCF3

H2NOH,

C6H6,∆

84 8538d

Scheme 42.

4,5-dihydro-5-isoxazolol was isolated (Scheme 42).Subsequent elimination of water by reflux in benzenegave rise to the corresponding aromatic CF3 substitutedheterocycle.

The cyclization of adducts of acetylenic ketones 38 (or4-ethoxy-1,1,1-trifluoro-3-buten-2-one 11a) with aromaticamines under acidic conditions leads to 2-CF3 or 4-CF3substituted quinolines 87 and 88 in moderate yields(Scheme 43) [87-89].


+

N CF3

R

COC F3

NH

R

77-99%R = Alk, Ph 39-93%

R' N R

CF3

H+

R'MeOH, rt

ArNH 2or

R COC F3

EtO

COC F3

38

11a 86 87 88

Scheme 43.

It should be noted that in the case of the anilinederivative only the 2-CF3 substituted quinoline was

obtained probably via retro-1,4 addition (Scheme 44)[88, 89].

86a

87a

88a

or PPA

POC l3

N CF3

COC F3NH N

CF3

30% [87]

21% [88]

59% [89]

Scheme 44.

β-Dialkylamino substituted CF3 ketones react withphosphorous oxychloride to give Vilsmeier-like iminiumsalts (Scheme 45) [90]. These salts are less reactiveelectrophiles than the DMFA-POCl3 complex. They react

with dimethylaniline and some active methylene bases togive hemicyanines which are valuable for the synthesis ofcyanine dyes [90].

9493

9291

9089

C OC F3

E t2NPOC l3

Et2N

C F3

C l+

POC l2-A

A + NM e2 NM e2C F3

N Et2

NaC lO 4ClO 4

-

+

65%

12j

X-

A +S

N

CH 3

CH3+

NEt3

N aClO4

S

N

CH 3

CF3

NEt2+

ClO4-

68%

A +

N

CH3

CH3

NaC lO 4

NEt3

+NCH 3

C F3 NEt2

+ ClO4-

64%

X-

Scheme 45.


Under more rigorous conditions complex A reactswith two molecules of an ammonium salt to give

β-trifluoromethyldicarbocyanines (Scheme 46).

Z

N

CH3

CH3+ NaClO4

S

N

CH3

CF3

+

ClO4-

A, NEt3

Z

NCH3

ClO4-

Z= S, C(CH3)2, CH=CH42-60%

X-

9591

Scheme 46.

β-Alkoxy substituted CF3 ketones 11a and 11i alsoreact readily with heterocyclic ammonium salts to give

δ-trifluoromethylbutadienylmerocyanines in high yield(Scheme 47).

9211a, 1 1i 24az

X-

NCH3

OCF3

+N

CH3

CH3

+ or

BuOCOC F3

EtOCOC F3 NEt3 70%

+

or

BuOCOC F3

EtOCOC F3

NEt375-78%

X-

Z

N

CH3

O

CF3

Z= S, C(CH3)2, CH=CH

+

Z

N

CH3

CH3

91

11a, 1 1i24aw- 24ay

Scheme 47.

Trifluoromethyl containing cyanine dyes had not beendescribed previously. The same authors also investigatedspectroscopic data of these dyes [90].

Trifluoroacylated enol ethers are convenientprecursors for 5- and 6-membered heterocycles. Thereaction of β-alkoxy enones, having a CF3 group, withhydroxylamine proceeds analogously to the reaction of

acetylenic ketones to give a trifluoromethyl-containing4,5-dihydro-5-isoxazolol (applicable also to condensedrings) in good to excellent yield (Scheme 48) [18, 75].The dehydration of these dihydroisoxazolols withphosphorous pentoxide or sulphuric acid results in thecorresponding 5-CF3 substituted isoxazole [18, 75, 91].

H2NOH.HClH2O / Py

68-97%

ON

R2 R1

CF3HO

CF3COOR3

R1

R2

R1 = H, Me;R2 = H, Me, R3 = Me, Et;R2, R3 = (CH 2)n , n = 2, 3

P2O5

R1, R 2 = H 68%

ONCF3

11

92 85a

Scheme 48.


In the case of trifluoroacylated 2,3-dihydrofuran and3,4-dihydro-2H-pyran the reaction with hydroxylamineproceeds unexpectedly (Scheme 49). At a reactiontemperature of 0-20 °C the corresponding

dihydroisoxazolols which are the products of furan orpyran ring opening were isolated. However, raising of thereaction temperature gave rise to formation of rearrangedproducts [18].

( ( )n( )n

( )n

O

CF3CO H2NOH.HCl

H2O / Py NO CF3

OH

OH

0-20 °C65-85 °C

H2NOH.HClH2O / Py

OCF3HO

NC

n=1, 265-95%

20-90%

OCF3HO

NOH

93

)n

94a, 94b11e, 11f 92

Scheme 49.

It seems likely that this rearrangement proceeds viaelimination of water from the oximes of the aldehydesforming after recyclization of the ketones to furan orpyrans [18].

Hydrazine and alkylhydrazines react withtrifluoroacetylated vinyl ethers to afford thecorresponding pyrazoles in good yield [75, 92]. Reactionwith phenylhydrazine yields the correspondingpyrazoline [92].

95

81

11

R 4NHNH 2,EtOH, reflux

CF3COOR 3

R1

R2

59-98%

NN

R2 R1

CF3

R4

R4 = Ph

NN

R 2 R 1

CF3

R4HO

R4=H, Alk

Scheme 50.

Trifluoromethyl-containing pyrimidines were preparedby reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one 11a

with urea derivatives or formamide in the presence ofNH4Cl [93].

EtOCOCF3

HCONH2NH4ClN

N

CF3

23%

X=C(NH2)2 N

N

CF3

HX

X = O, S, NH, p-NSO2C6H4NHCOCH3

60-75%11a

96a 96

Scheme 51.

Alkylation of 4-CF3 pyrimidinone or 4-CF3pyrimidinethione with diazomethane gives rise to amixture of products of methylation at O (or S) and N

atoms (Scheme 52). The same authors also investigatedthe tautomeric equilibrium of 4-CF3 pyrimidines indifferent solvents [93].


73%

8%61%

X = S

+N

N

CF3

X

CH3

N

N

CF3

CH3X

X = O

N

N

CF3

HX

9 6 b

9 6 c

9 6 d

9 6 e

9 6 f

Scheme 52.

The synthesis of thiomethyl substituted CF3pyrimidines was studied by reaction of2-methyl-2-thiopseudourea sulphate withtrifluoroacetylated vinyl ethers. The target products wereprepared in 14-94% yield [94].

The reaction of tert-butylhydrazones withtrifluoroacetylated vinyl ether results in the corresponding

4-trifluoroacetylpyrazoles (Scheme 53) [95]. This reactionproceeds by a nucleophilic displacement of the ethoxygroup by hydrazone followed by cyclization, initiated byprotonation on the azomethine nitrogen. Air oxidation ofthe intermediate dihydropyrazoles gives thecorresponding 4-trifluoroacetylpyrazoles in good yield.

97

11a

34-66%t-Bu

COC F3R

NNEtO COC F3

t-BuNH

N R

AcOH / MeCNrt, 46-140 h

Scheme 53.

Ketones bearing a CF3 group enter into the reactionwith isonitriles to give the corresponding dihydrofurans,products of 1,4-cycloaddition (Scheme 54). This reactionproceeds readily both with ketones having a β-alkoxy

group and with ketones without a heteroatom substituent.This reaction proceeds below room temperature. Ketoneswithout a CF3 group do not enter into this reaction evenon prolonged heating [96, 97].

9824a

CH3

CH3CF3CO

C NR

O

CH3CH3

NRF3C

86-92%R = C(CH3)3, C6H11

Scheme 54.

Under the same conditions4-ethoxy-1,1,1-trifluoro-3-buten-2-one 11a gives the morestable 3-oxolene. When the trifluoroacetyl derivative of

ketenediethylacetal 18 was reacted with isonitriles nocycloaddition was observed. Only isomerisation of theketone to the ester 100 takes place (Scheme 55) [98].


54%R = C6H11

O NRF3C

OE tC NROE t

CF3CO

11a 99

70%

OE t

O

Et

F3CO

C NR

EtO

CF3 COOE t

18 100

Scheme 55.

Trifluoroacetylated vinyl ether 11 represents a1-oxa-1,3-butadiene system bearing anelectronwithdrawing CF3 substituent in the 2-position. Itwas found that this ketone behaves as an effective

heterodiene. Hetero-Diels-Alder reaction with vinyl ethersleads to the corresponding dihydro-2H-pyrans in goodyield (Scheme 56) [99].

101b

101a

11

80 oC, 30h

80 oC, 30h

OR 1CF3

O

OR 2

O

72-100%

68%

O OR 2

OR 1

CF3

O

OR 1

CF3 O

Scheme 56.

The same reaction proceeds readily withβ,β-bis(trifluoroacetyl)vinyl ethers and various electronrich alkenes under very mild conditions to providefunctionalized 5-trifluoroacetyl-6-trifluoromethyl-3,4-dihydro-2H-pyrans in excellent yields (Scheme 57) [25].β,β-Bis(trifluoroacetyl)vinyl alkyl ethers are much moreactive dienes than the correspondingβ-monotrifluoroacetylvinyl ethers for which vigorousreaction conditions (80 °C, 30h) are required forcycloaddition. The presence of the electron withdrawingCOCF3 group at the C-3 of the 1-oxa-1,3-butadienesystem, decreases the energy of the LUMO.

It was found by Hojo and coworkers [27] that thecorresponding β-aryloxy substituted enones with a CF3group, which are the products of double trifuoroacylationof aryl vinyl ethers decompose readily and could not beisolated in pure form. However, these authors found itpossible to generate the ketones in situ by diacylation ofaryl vinyl ethers with trifluoroacetic anhydride followedby a Hetero-Diels-Alder reaction with an excess ofsubstrate at 40 °C (Scheme 58). Thus, the corresponding2-trifluoromethyl substituted dihydropyrans wereprepared in a one-pot reaction from aryl vinyl ethers ingood yield.


102a- 102d

20a, 20b

R1O COCF3

COCF3

R2O

O( ) n

EtS

PhO

PhO

rt,15min-24h

rt,15min-48h

rt,1h

rt,15min

OR2O

OR1

COCF3

CF385-98%

O

OEtCOCF3

CF3O

( ) n

86-100%

OEtS

OR1

COCF3

CF3100%

O

OEtCOCF3

CF3PhO

PhO

77%

Scheme 57.

9-68%Ar = Ph, 4-MeC6H4, 4-MeC6H4, 4-BrC6H4

O

OA r

ArO CF3

COC F3

40 °C

ArO

ArO (CF 3CO) 2O / Py

COC F3

COC F3ArO

5 20 103

Scheme 58.

Cleavage of the corresponding dihydropyrans withdialkylamines opens up the route to 1-amino-4,4-bis(trifluoroacetyl)-1,3-butadienes (Scheme 59). These

ketones can be converted to the 1-amino-4-trifluoroacetyl-1,3-butadienes in the presence of HCl ingood yields [100].

59-78%

6N HCL / THF R1R2NCOC F3R

1R2NCOC F3

COC F3

77-100%

R1R2NH, MeCN

t-BuO

CF3

COC F3

EtO O

102a 103 12as- 12aw

Scheme 59.


A suggested reaction mechanism involves eliminationof i-butanol, electrocyclic ring opening and nucleophilicO-N exchange. This transformation takes place only for

CF3 containing pyrans (Scheme 60). It was found that thesame reaction for the corresponding non-fluorinatedcompound did not proceed.

R1R2NCOC F3

COC F3R 1R 2NH, MeCN

i-BuO

CF3

COC F3

EtO O CF3

COC F3

EtO O- i-BuOH

EtOCOC F3

COC F3

102a 104a 105a 103a

Scheme 60.

The same authors found it possible to prepare1-amino-4,4-bis(trifluoroacetyl)-1,3-butadiene bytrifluoroacylation of 1-amino-4-trifluoroacetyl-1,3-

butadiene. This reaction proceeds quantitatively at roomtemperature (Scheme 61).

100%(CF3CO) 2O/ PyEt2N COC F3

Et2N COC F3

COC F3

103b12at

Scheme 61.

Trifluromethyl-containing pyrroles were prepared inexcellent yields by reaction of trifluoroacetylated vinylethers with α-amino ketones or acetals of aminoaldehydes

with subsequent cyclization of the adducts by heating inmesitylene or trifluoroacetic acid (Scheme 62) [101, 102].

109108

10710611c

EtO

MeCOCF3

PhCOCH2NH2 NH

MeCOCF3

PhCOMesitylene, reflux 8h

71-100%

NH CH3PhCO

CF3

92%

(MeO)2CHCH2NH2,MeCN, rt, 4h NH

MeCOCF3

(MeO)2CH

100%

CF3COOH, rt, 4h

100%

NH CH3

COCF3

Scheme 62.

CF3-Substituted pyridines were prepared by thereaction of enaminonitriles with trifluoroacylated vinylethers. Acyclic intermediates were isolated in the case of

4-ethoxy-1,1,1-trifluoro-3-buten-2-one (Scheme 63)[103]. The raising of the reaction temperature leads toheterocyclization to the substituted CF3 pyridines.


112111110

68-95%68-76%

, NN COOE tNN CH3,ON,N=R1

CH3CN, ∆

0-5 °C

R =H, CH3

CF3CO

OE t

R N R1

CN

CF3

R

H2N R1

CN

CF3CO

RH2N R1

CNH

Scheme 63.

The reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-onewith α-sulfinyl carbanions was investigated (Scheme 64)[104].

115b115a

114b114a113

(3S) (3R)

OEt

OH

CF3OEt

CF3

OH

+

(3S, Rs)(3R, Rs)

Me

SO :

OEt

OH

CF3Me

SO :

OEt

CF3

OHCF3CO

OEtMe

S CH2Li

O :

38% 35%

Ni/Al Ni/Al

Scheme 64.

The reaction with the lithium salt of (R)-methylp-tolylsulfoxide proceeds in THF at -60 °C totallyregioselectively, affording only a tertiary alcohol, througha 1,2-addition (Scheme 64). Stereoselectivity of additionwas poor, diastereoisomeric alcohols were formed in a 1:1ratio. The diastereoisomers could be separated by columnchromatography. Subsequent desulphurization withRaney Ni resulted in enantiomerically pure CF3substituted alcohols [104].

These transformations proceed cleanly under mildconditions in contrast to non-fluorinated enones of similar

structure which give a complex mixture of products ofboth 1,2- and 1,4-addition [104].

Another type of trifluoromethyl containing ketoneused for the preparation of a CF3 substituted heterocyclesis a ketone without a heteroatom substituent at β-position.In contrast to the above mentioned reactions this ketonegives rise to hydrogenated heterocycles.

The thiol addition reaction to unsaturated CF3 ketoneswas investigated (Schemes 65 and 66). The reactionproceeds as a 1,4-addition to give the corresponding ketosulphides [50].


116a24x

COCF3

C8H17

COC F3

C8H17

PhS

82%

PhSH

Bu4NF

Scheme 65.

In the case of γ-silyloxy CF3 enone a diastereomericmixture of keto sulphides and enol sulphides in a 1/1 ratiowas formed. In the case of γ-hydroxy CF3 enone the

corresponding tetrahydrofuran was isolated which iseasily converted to the furan (Scheme 66). Also theaddition of glutathione was investigated [50].

+++

OTBDSPh

PhS CF3OH

OTBDSPh

PhS CF3OH

COCF3

OTBDSPh

PhSCOCF3

OTBDSPh

PhSPhSH

COCF3

OTBDSPh

24n 116b 116c 116d 116e

46%

Toluene

H2SO4 OCF3 PhOCF3HO

Ph

SPh

PhSHCOCF3

OHPh

24m 117 118

Scheme 66.

It was found that the reactions of some trifluoromethylketones of this type proceed easily with variousnucleophiles. The CF3 enones studied for the preparation

of heterocycles have other substituents at the double bondand their reactivity is rather different (Scheme 67).

24w24f24c24b

Ph

CH3 COCF3COCF3COCF3

Ph

COCF3

Scheme 67.

Heterocyclic derivatives of various structures,including one with a heterocyclic spiro fragment and asmall ring, are obtained.

These reactions open up the possibility of a one-stepsynthesis of CF3-containing derivatives of pyrazolidines,

pyrazolines, isoxazoles, thiazines, thiopyrans, thietane,pyrimidines, pyridines, pyrans and benzodiazepines(Scheme 68).


R1

R2 COC F3

CH 2(CN) 2NCCH 2CONH 2

O

Ph

R CF3

NH2

NCNH

CF3

OHR2

R1

O

NC

HN NR2

R1 CF3

HN NH

R2CF3

OH

R1H2NNH 2

NHHN

R1

R2

CF3

OH

X

(H2N)2CX

NHHN

R1

R2

X

CF3

SCF3

OHNH

N

R1

R2

CF3H2N NH2

NH4SH

S

COC F3OHCF3

R1

R2R1

R2

H2NSCR

NS

R1

R2CF3

OH

R

419

12

121

122

123

124125

126

127128

Scheme 68.

The reaction of these ketones with differenthydrazines proceeds readily under mild conditions(Scheme 69) [105]. In the case of the hydrazine thereaction results in the formation of the correspondingpyrazolidines, in contrast to non-fluorinated ketoneswhich react with hydrazine to give the correspondingpyrazolines. The pyrazolidines obtained contain a ratherstable aminoalcohol fragment due to a electronwithdrawing action of the CF3 group, however it wasfound possible to transform them to pyrazolines byheating a toluene solution with a catalytic amount ofp-toluenesulfonic acid. In some cases the elimination ofwater proceeds spontaneously, for example in the case ofthe pyrazolidine derivative of the ketone containing a

cyclobutane fragment. In the case of 1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b the pyrazolidines obtainedeliminated water spontaneously, but this transformationrequired ca. two months [105].

The reaction of 1,1,1-trifluoro-4-phenyl-3-buten-2-one24b with different substituted hydrazines was studied.The heterocyclization can proceed by two routes. Thefirst route is a primary Michael addition of a nucleophileto an enone with subsequent cyclization, and the secondroute is a primary addition of a nucleophile at thecarbonyl group with subsequent cyclization. However, itseems possible that both routes may take place dependingon the reaction conditions and the structure of thehydrazine [105].


TsOH

90%

_H2O HN N

R1CF 3R2

95%R1 = H, R2 = Ph

R1, R2 = 80%

95%

HN NH

CF3OH

R1

R2H2NNH2R

1 COCF3

R2

119a, 119b 120a, 120b24b, 24f

COCF3 H2NNH 2

HN NH

CF3OH HN N

CF3 79%

24c 119c 120c

Scheme 69.

In the case of methyl hydrazine two possibleregioisomers of the pyrazoline were isolated in a ~3:1ratio (Scheme 70). It is possible that this regiochemistryobserved is due to both the similar nucleophilicity of the

two nucleophilic centers of methylhydrazine and thepossibility of attack of the nucleophile at both the doublebond and the carbonyl group.

24b 120e120d

+N N

CF3Ph

Me

18%

MeNHNH2N N

Me

CF3Ph

59%

Ph

COCF3

Scheme 70.

In the case of phenyl hydrazine, reaction leads toformation of the corresponding pirazoline and here theprimary attack of the nucleophile takes place at the

carbonyl group of the ketone (Scheme71) [105]. In thecase of 1,2-dimethylhydrazine the correspondingpirazolidine was obtained in good yield.

24b 120fPh

COCF3

85%

N NPh

CF3PhPhNHNH2

119d24bPh

COC F3 MeNHNHMe

77%

N N

CF3Ph

OH

MeMe

Scheme 71.

The reaction with various urea derivatives results intetra- or dihydropyrimidines, bearing a CF3 substituent, inexcellent yields (Scheme 72) [106].


12124b, 24c

X=O X=SR1= H, R2 = Ph

R1+R2= -CH2CH2CH2-

NHHN

R1

R2CF3

OH

X

R1

R2COCF3 (H2N)2CX

85%77%

90%92%

X=O X=S

Scheme 72.

The reaction of 1,1,1-trifluoro-4-phenyl-3-buten-2-one24b with urea derivatives could result in a mixture of two

possible diastereoisomers of tetrahydropyrimidines withcis and tras arranged phenyl and CF3 groups (Scheme 73).

121a

121btrans

cis

HNHN

S

Ph

HOH

CF3

H

H

HNHN

S

Ph

HCF3

OH

H

H

NHHN

CF3

OH

S

Ph

H

NHHNCF3

S

Ph OH

H

Scheme 73.

However the reaction with urea and thiourea proceedsstereoselectively to give preferably isomers havingdiequatorially arranged Ph and CF3 moieties. Only traceamounts of other diastereoisomers are observed. Theconfiguration of the products was determined by NOEdata and X-ray crystallography.

It is possible that the transition state for the cyclizationof β-trifluoroacetylstyrene 24b to the correspondingpyrimidine has a chair conformation with the bulkygroups (Ph and CF3) equatorial. It is known that a

trifluoromethyl moiety is almost double the bulk of amethyl group and does not fall much behind that of atert-butyl group. The energy required for theconformational promotion from the equatorial to the axialposition for a trifluoromethyl group is more, than for anisopropyl group [107].

In the case of an adamantane containing CF3 ketone24f reaction with thiourea under the same conditionsgives rise to the corresponding dihydropyrimidinethione(Scheme 74).

122a24f

COCF3

81%

NH

NH

CF3

S

NH2CSNH2

Scheme 74.

The possibility of water elimination fromtetrahydropyrimidines to transform them to thecorresponding dihydroderivatives has been investigated

(Scheme 75). This reaction proceeds smoothly when thecompounds are heated in toluene with catalytic amountsof p-toluenesulfonic acid.


122121

Toluene

87%

95% 91%

R1+R2 = -CH2CH2CH2-

R1 = H, R2 = Ph

X=S

X=O

NHHN

R1

R2CF3OH

X

NHHN

R1

R2

X

CF3

X=S

TsOH

Scheme 75.

Reactions with guanidine proceed analogously to givethe corresponding CF3-containing aminopyrimidines(Scheme 76).

24f

24b

122b

121c

(H2N)2NH

(H2N)2NH

81%

NH

N

CF3

NH2

NHN

CF3

OH

NH2

Ph

77%

Ph

COC F3

COC F3

Scheme 76.

The reaction of 1,1,1-trifluoro-4-phenyl-3-buten-2-one24b with aminoguanidine proceeds unusually, to give theproduct having two heterocyclic fragments:tetrahydropyrimidine and pyrazoline (Scheme 77).

Tetrahydropyrimidines with a CF3 group are more stableto elimination of water than the correspondingCF3-containing pyrazolidines and this tendency is alsorealized in the case of this compound.

129

24b

NN

NH

N CF3

PhPh

CF3 OH

H2NCNHNH2

NH

61%

Ph

COC F3

Scheme 77.

The formation of CF3-containing dihydrothiazines[108] by reaction of these ketones with thiourea underacidic conditions was also investigated(Scheme 78). Thereaction proceeds regiospecifically to give only one

possible isomer of thiazine, the product of addition ofsulphur to the double bond and nitrogen to the carbonylgroup. We believe that this reactivity is according to thehard and soft acid and base principles [109].


123a, 1 23b

24b, 2 4c

(H2N)2CS

R1 = H, R2 = Ph

R1

R2COCF3

R1, R 2 = -CH2CH2CH2-75%68%

S N

R1

R2CF3

OH

NH2

HCl, EtOH

Scheme 78.

The reaction of ethylenic CF3 ketones withthioacetamide proceeds in the similar way. All CF3substituted thiazines have stable aminoalcohol fragments

and do not eliminate water under acidic conditions(Scheme 79).

24b, 24c, 2 4f123c- 123e

R1, R 2 =

R1= H, R2 = Ph

R1

R2COCF3

68%

78%

MeCNH2

S

S N

R1

R2CF3

OH

Me

R1, R2 = -CH2 CH2CH2-

65%

Scheme 79.

The reaction of CF3-containing ketones withmalononitrile under a variety of conditions wasinvestigated (Schemes 80-84) [110]. The reaction path isvery sensitive to the conditions of the reaction and thestructure of the starting ketone. 1,1,1-Trifluoro-4-phenyl-3-buten-2-one 24b reacts with malononitrile and a

catalytic amount of pyrrolidine or triethylamine to formthe corresponding pyran 124a (Scheme 80). The reactionof 1,1,1-trifluoro-4-methyl-4-phenyl-3-buten-2-one 24wwith malononitrile under the same conditions proceedsanalogously.

55 % 70 %

R = HR = CH3

O

PhR CF3

NH2

NC

CH2(CN)2

Ph

COCF3R

24b, 2 4w

124a, 124b

Scheme 80.

Ketones having an exocyclic double bond react verydifferently. Only the corresponding alkylidene dinitrileswere obtained under the same conditions (Scheme 81).


COCF

COCF3

COCF3-CH2-COCF3

CN

CNCH2(CN)2,

NH

/ C 6H6

CH2(CN)2, KF / i -PrOH

CN

CN

CN

CN47 %

83 %

_

24c

24f

130a

130b

3

Scheme 81.

When the reaction of 1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b with malononitrile was carried out withpotassium fluoride as a base the correspondingcyclohexanol - the product of Michael addition of

malononitrile to the double bond of two molecules of thisketone with subsequent aldol condensation was obtained(Scheme 82). The reaction proceeds stereospecifically togive only one isomer out of a possible eight.

Ph

COCF3 KF / i-PrOH

CH2(CN)2

Ph PhNC CN

HO CF3COCF3

77 %

PhCF3

O COCF3

PhCN

131

24b

CN

Scheme 82.

In the case of the reaction of malononitrile in thepresence of ammonium acetate only in the case of

1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b was thecorresponding pyridine isolated (Scheme 83).

Ph

COC F3CH 2(CN) 2,NH 4OAc, EtOH

NH

Ph CF3

NC

NH2

[O]N

Ph CF3

NC

NH2

28 %

24b

132 133

Scheme 83.

The reaction with malononitrile as a Knoevenagelcondensation was also investigated (Scheme 84). In thecase of the use of the TiCl4/2Py complex in

dichloromethane the corresponding 1,1-dicyano-2-trifluoromethyl-1,3-butadienes were prepared in 37-61%yield [110].


R1

R2 COCF3

CH2(CN)2,TiCl4·2C5H5N

R1

R2CN

CNCF3

R1 = Ph, R2 = HR1, R2 = -CH 2 CH2CH2-

R1, R 2 =

R1 = Ph, R2 = CH3

56%61%

55%

37%

24134a- d

Scheme 84.

In the case of the reaction with cyanoacetamide with acatalytic amount of KF the corresponding

tetrahydropyridines were isolated. This reaction proceedsstereospecifically (Scheme 85).

24b, 24c135a135b

R1

R2 COCF3

NCCH2CONH2KF / i-PrOH

NH

R1

R2CF3OH

NCO

92 %81 %

R1 = Ph, R2 = HR1, R2 = -CH 2 CH2CH2-

Scheme 85.

Reflux of a toluene solution of these piperidines with acatalytic amount of p-toluenesulfonic acid results inelimination of water to give the corresponding

dihydropyridines (Scheme 86). In the case of thederivative of 1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b amixture of two diastereoisomers is formed [110].

136c

136b136a

135b

135atoluene NH

Ph

NCO

CF3

NHNC

O

CF3

NH

Ph

NCO

CF3

+TsOH

90 %

2 : 1, general yield 87 %

toluene

TsOH

Scheme 86.

The reaction of CF3 bearing enones with NH4SH takesplace under very mild conditions [111]. The reaction of1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b proceedsstereospecifically, giving only one diastereoisomer out ofeight possible. The configuration of the obtainedtetrahydrothiopyran was established by 2D 1H-1H NOESY

experiments. This compound has Ph, Ph, CF3 and COCF3groups equatorially arranged, and an axial OH group(Scheme 87).

Formally the course of this reaction is the Michaeladdition of hydrosulphide anion to the double bonds oftwo molecules of 1,1,1-trifluoro-4-phenyl-3-buten-2-one


24b with subsequent aldol condensation. It was supposedthat the transition state of cyclization has a chair

conformation with all bulky groups (Ph, Ph, COCF3, CF3)equatorial (Scheme 88).

SPh

CF3

OH

HH

HH

Ph

H

CF3COSPh Ph

COCF3OHCF3

7,5 %

2.2 % 2,3 %

NH4SH

(92%)

EtOH, 20oC, 30 min

Ph

COCF3

24b126a

Scheme 87.

Ph

COCF3HSHS_

_

Ph

COCF3S_

SPhCF3

O COCF3

Ph SPh Ph

COCF3OHCF3

Ph

COCF3 PhCOCF3

Scheme 88.

Reaction of NH4SH with ketone derivative ofmethylenecyclobutane 24c leads to a 1/1 mixture of cis-and trans-diastereoisomers of the corresponding thiopyran(Scheme 89). Formation of two diastereoisomers in the

case of this ketone, as compared to one diastereoisomerwith the reaction of ketone 24b, is explainable by stericdifferences in the substituents in these ketones (H and Ph)compared with 24c (cyclobutane ring).

126b-c24c

+

S

COCF3OHCF3

S

COCF3OHCF3

EtOH, 20oC

(90%)

NH4SHCOCF3

Scheme 89.

A very unusual result was obtained in the reaction ofammonium hydrosulphide with a ketone containing anadamantane fragment 24f. The only product was thecorresponding 4-membered trifluoromethyl-containingheterocyclic ring 127 (Scheme 90). 2-Thietanols have notbeen described previously, apparently because thesemithioacetal fragment is unstable in the 4-memberedrings. We assume that this compound is stable due to boththe trifluoromethyl group stabilizing the geminal HO-C-S

fragments [112] and the adamantane structure, whichstabilizes spiro attached small rings [113]. Formation ofthe corresponding tetrahydrothiopyrans as in the cases ofother CF3 ketones does not take place for this ketone,apparently due to steric reasons. An attempt to make theanalogous thietanols from other CF3 ketones at lowtemperature with a 20-fold excess of ammoniumhydrosulphide was unsuccessful and only thecorresponding tetrahydrothiopyrans were isolated.


12724f

NH4SH

(86%)

EtOH, 20oC

SCF3

OHCOCF3

Scheme 90.

The reaction 1,1,1-trifluoro-4-methyl-4-phenyl-3-buten-2-one 24w with ammonium hydrosulphide undersimilar conditions results in the correspondingmercaptan 137 (Scheme 91). In spite of having a similarstructure to 1,1,1-trifluoro-4-phenyl-3-buten-2-one 24b,this enone is much less reactive. It seems likely that theformation of the corresponding tetrahydrothiopyran

does not take place due to 1,3-diaxial repulsions of themethyl groups. Apparently one of the reasons forcyclization in the case of adamantane containing ketones, isdue to stabilization of thietanol by adamantane. In the caseof ketone β-trifluoroacetyl methylstyrene this type ofreaction does not occur [111].

13724w

(70%)

EtOH, 20oC, 2hNH4SH, HCl Ph

CH3SH

COCF3

Ph

CH3 COCF3

Scheme 91.

The oxidation of obtained thiopyrans and thietane byhydrogen peroxide in acetic acid was also investigated.

The corresponding sulfones were obtained in good yield(Scheme 92).

S

COCF3OHCF3

O O

S

COCF3OHCF3

(93%)

(96%)

H2O2 CH3COOH/

/

5.5 : 1

70% aq.CH3COOH

S

COCF3OHCF3

O O

+S

COCF3OHCF3

O O

CH3COOHH2O2

(99%)

126b 138b

126c

138b

138c

SPh Ph

COCF3OHCF3

CH3COOHH2O2SPh Ph

COCF3OHCF3

O O

/

(97%)

126a138a

Scheme 92.

Oxidation of 2-thietanol proceeds unusually. Thecorresponding sultine 139 as a mixture ofdiastereoisomers (2.7/1) is formed (Scheme 93). This isprobably due to the labile semi-thioacetal fragment in

sultine which facilitates the cleavage of the thietane ring.The structure of the trans-diastereoisomer of sultine wasconfirmed by X-ray crystallography.


139127

92%61%

/H2O2 CH3COCH3

/H2O2 CH3COOH OSO

OH

CF3

SCF3

OH

Scheme 93.

An attempt to thermally extrude sulphur dioxide fromthis sultine to make the corresponding cyclopropane was

unsuccessful, only the starting ketone was obtained(Scheme 94) [111].

14013924f

COCF3 ∆∆∆∆

OH

CF3OS

O

OH

CF3

Scheme 94.

The reaction of CF3 ethylenic ketones witho-phenylenediamine was also investigated [114]. As aresult the corresponding 2,3-dihydro-1,5-benzodiazepines

128 were obtained (Scheme 95). In this case eliminationof water proceeds spontaneously to give conjugation ofthe aromatic ring and the CN double bond.

R1+R2 = -CH2CH2CH2-R1 = H, R2 = Ph

H2N NH2

NH

N

R1

R2

CF3

R1+ R2 =

R1

R2COCF3

86%81%

75%

24b,c,f

128a-c

Scheme 95.

In the case of β-alkoxy substituted CF3 ethylenicketones the reaction with o-phenylendiamines in refluxingxylene led to complex mixture of products. However, this

reaction proceeds readily using microwave irradiation togive a 4-CF3 and 2- CF3 substituted (1H,5)aryldiazepinesin 73-93% yield (Scheme 96) [115].


R2 = H, CH3, Cl, NO2, COPhR1 = H, CH3

130a-d129a-h

11i, 20b

irradiationMW

+

R1

R2

NH2

NH2

+

N

NR

R1

R2

CF3

R = H, COCF3

iBuO

COCF3

R

N

NCF3

RR1

R2

irradiationMW

Scheme 96.

The reaction of ketones 11i and 20b withethylendiamine proceeds analogiously (Scheme 97) [115].

131a,b

NH

NCF3

R

NH2

NH2

11i, 20b

irradiation

MW

+

R - H , COC F3

iBuO

COC F3

R

Scheme 97.

Conclusion

This study of the literature data shows that unsaturatedketones bearing CF3 groups are valuable synthons formany synthetic purposes. The particular features of theseketones include very high reactivity both of the doublebond and the carbonyl group, the formation of stablefragments CF3C(OH)N- or CF3C(OH)O-, and thestereoselectivity of addition of some of the nucleophiles.Many reactions of these ketones are uncharacteristic ofnon-fluorinated unsaturated ketones.

There are a lot of synthetic approaches to the synthesisof unsaturated ketones bearing a CF3 group. Some ketonesof this type are already readily available, however othersparticularly ethylenic ones without a heteroatomsubstituent at the β-position are less accessible andexisting procedures for their synthesis are limited.Therefore, the elaboration of new approaches for thepreparation of these ketones and their use in organicsynthesis are very important.

Acnowledgement

We thank Russian Fundamental InvestigationFoundation (Grants N97-03-33006a and N97-03-32959a)for financial support.

References and Notes

1. Hudlicky, M. Chemistry of Organic FluorineCompounds. Ellis Horwood Ltd., Chichester, 1992.

2. Filler, A.; Kobayashi, Y. Biomedical Aspects ofFluorine Chemistry. Kodansha Ltd., Tokyo, 1981.

3. Welch, J.T. Tetrahedron 1987, 43, 3123-31974. McClinton, M.A.; McClinton, D.A. Tetrahedron

1992, 48, 6555-6666.5. Mertes, M.P.; Saheb S.E. J. Heterocyclic. Chem.

1965, 2, 491-495.6. Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano,

M.; Kumadaki, I. J. Chem. Soc., Perkin Trans. I.1980, 2755-2761.

7. Leroy, J.; Rubinstein, M.; Wakselman, C. J.Fluorine Chem. 1985, 27, 291-298.

8. Kobayashi, Y.; Kumadaki, I.; Ohsawa, A.;Murakami, S.-I.; Nakano, T. Chem. Pharm. Bull.1978, 26, 1247-1251.


9. Girard, Y.; Atkinson, J.G.;Belanger, P.C.; Fuentes,J.J.; Rokach, J.; Rooney, C.S.; Remy, D.C.; Hunt,C.A. J. Org. Chem. 1983, 48, 3220-3234.

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Samples Availability: All the compounds published by thepresent authors in the cited literature [38-42, 105, 106,108, 110, 111, 114] are available from MDPI.

Preparation of alpha, beta-Unsaturated Ketones...AbstractKeywordsIntroductionPreparation of alpha, beta -Unsaturated Ketones...Synthetic application of alpha, beta-unsaturated ketones...ConclusionReferences and Notes

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