1997 2, 186-232 molecules · Molecules 1997, 2 187 C F 3 H E T R C F 3 O R C OC F 3 Scheme 1. In...
Transcript of 1997 2, 186-232 molecules · Molecules 1997, 2 187 C F 3 H E T R C F 3 O R C OC F 3 Scheme 1. In...
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
CF3
HET R
CF3
O
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
Molecules 1997, 2 189
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
K2CO3
OEt
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
K2CO3
CH3
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].
190 Molecules 1997, 2
+S(CH3)2
+
CH3R1
R2 S(CH3)2 CF3COOB F3-
R1
R2CHCOC F3
CF3COOB F3-
R1
R2 S(CH3)2
CH2COC F3
R1
R2
CH2
H+, S(CH3)2
S(CH3)2, BF3
-H++
CH2COC F3CR1
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
Molecules 1997, 2 191
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).
192 Molecules 1997, 2
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'2CuXi R'
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].
Molecules 1997, 2 193
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)2
F
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
194 Molecules 1997, 2
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
CF3
OH
+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].
Molecules 1997, 2 195
612460H
N
N R2
HO CF3
R1X-+
R1
CF3
O
MeLi - LiBr
R1 COOM e
R1
NH2
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 F3
53%
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].
196 Molecules 1997, 2
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
COCF3
4 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.
Molecules 1997, 2 197
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.
198 Molecules 1997, 2
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
CF3
O
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
C2H5
O
CF3
+
NC2H5
C2H5
O
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).
Molecules 1997, 2 199
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
+ EtOCOCF3
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
+ PhCOCF3
BF3.Et2O / CH2Cl20oC - rt, 1-120h
R1
R2
R3
COCF3
Ph
R1 - R4 = Alk , H, Br
82-99%
Scheme 38.
24b 75
73
+ PhCOCF3
BF3.Et2O / CH2Cl20oC - rt, 1-120h
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].
200 Molecules 1997, 2
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.
Molecules 1997, 2 201
Table 1. Synthesis of α,β−unsaturated trifluoromethyl ketones.
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
7a (PhS) 2C=CHCOCF3
A 100 25 7bCH3 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 NCOCF3
O CH3
A 100 17
10aCOCF3
N
O
A 56 17 10b
COC F3
Ni-PrCOC H3
A 96 22
11aEtO
COCF3
AAA
1007958
171823
11bCH3O
COCF3
CH3
A 82 18
11c EtOCOCF3
CH3A 66 18 11d
O
COCF3
CH3
A 77 18
11eO
COCF3AAA
848178
181923
11f
O
COCF3AAA
7810067
181923
11gi- PrO
COCF3 A 72 23 11h COCF3
OEt
O2N
A 100 17
11ht-BuO
COC F3 A 79 23 11ii-BuO
COC F3 A 63 23
12a N
O
COC F3
A 83 20 12b
N
COC F3 A 53 20
202 Molecules 1997, 2
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
12c
N
COC F3
A 82 20 12d N
COC F3
A - 20
12e N
COC 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 COCF3
F 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 COCF3
FFF
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
Molecules 1997, 2 203
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
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 COCF3NH
M eO2CCH2CH2
HOOC
F 70 77
12ak COCF3NHCH3
HOOCF 88 77 12al
COCF3
NHOOC
F 88 77
12am CO C F3NH
tB 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 Me2NCOC F3
I 65 100 12at Et2NCOC 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
204 Molecules 1997, 2
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
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
CH3
COCF3
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
COCF3
CH3
B 29 46
24qn -C10H21
COCF3
CH3
B 44 46 24rn - C10H21
COCF3 C 65 51
Molecules 1997, 2 205
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
24sn - C12H25
COCF3 C 71 51 24t CH3
COCF3CE
8463
5158
24u CH3OCOCF3
C 80 51 24v EtOOCCOCF3
C 70 51
24wPh
COCF3
CH3
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 COCF3
Ph CEG
886039
515839
24am COCF3 D 80 53 24anPh
COC F3 D 67 53
24ao COCF3( )2
D 70 53 24ap COCF3
CH3
CH3 CH3
G 27 39
24aq COCF3 G 21 39 24ar COCF3 D 28 53
206 Molecules 1997, 2
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
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 N
CH3
O
CF3
F 76 90
24ayN
CH3
O
CF3
CH3CH3
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 F3
BrF 74 82 24bf
COC F3F 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
Molecules 1997, 2 207
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
33a
PhCOCF3
SCH3 G 96 42 33bPh
COCF3
SCH3
CH3
G 94 42
33cPh
COCF3
SCH3
C2H5
G 87 42 34aPh
COCF3
SO2CH3
G 88 42
34bPh
COCF3
SO2CH3
CH3
G 93 42 34cPh
COCF3
SO2CH3
C2H5
G 88 42
38a COCF3Ph B 81 46 38b COCF3n - Bu BH
7135
4650
38c COCF3n - C6H13BH
6946
4650
38d COCF3n - C8H17BH
8145
4650
38e COCF3n - C10H21BH
8373
4650
38f COCF3n - C12H25BH
9165
4650
38g COCF3n - C14H29H 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
208 Molecules 1997, 2
Table 1. (continued)
N Ketone Meth. Yield Ref. N Ketone Meth. Yield Ref.
42gCOCF3Te
A 81 52 103a M e2NCOC F3
COC F3I 92 100
103b E t 2NCOC 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 F3
Ph
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
Molecules 1997, 2 209
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 F3
H2NNH 2 NHN
R CF3
8138
80%n-C8H17 COCF3
NO
CF3n-C8H17
H2NOH,AcOH, 10% HCl C6H6,∆
n-C8H17 CCF3
NOH
38d 8283
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-CF3
substituted quinolines 87 and 88 in moderate yields(Scheme 43) [87-89].
210 Molecules 1997, 2
+
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 t2N POC l3
Et2N
C F3
C l+
POC l2-A
A + NM e2 NM e2
C 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.
Molecules 1997, 2 211
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
NEt3
75-78%
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.
212 Molecules 1997, 2
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.HClH2O / Py N
O CF3OH
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
R4
HO
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-CF3
pyrimidinethione 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].
Molecules 1997, 2 213
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 CF3
pyrimidines 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
CH3
CH3
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].
214 Molecules 1997, 2
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 CF3
group, 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.
Molecules 1997, 2 215
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 F3
R1R2NCOC F3
COC F3
77-100%
R1R2NH, MeCN
t-BuO
CF3
COC F3
EtO O
102a 103 12as- 12aw
Scheme 59.
216 Molecules 1997, 2
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
Et2NCOC 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.
Molecules 1997, 2 217
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 CF3
substituted alcohols [104].These transformations proceed cleanly under mild
conditions 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].
218 Molecules 1997, 2
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 CF3
OH
OTBDSPh
PhS CF3
OHCOCF3
OTBDSPh
PhSCOCF3
OTBDSPh
PhSPhSH
COCF3
OTBDSPh
24n 116b 116c 116d 116e
46%
Toluene
H2SO4 OCF3 PhOCF3
HO
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).
Molecules 1997, 2 219
R1
R2 COC F3
CH 2(CN) 2
NCCH 2CONH 2
O
Ph
R CF3
NH2
NCNH
CF3
OHR2
R1
O
NC
HN NR2
R1CF3
HN NH
R2
CF3
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
R2
R1
R2
H2NSCR
NS
R1
R2
CF3
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].
220 Molecules 1997, 2
TsOH
90%
_H2O HN N
R1
CF 3R2
95%R1 = H, R2 = Ph
R1, R2 = 80%
95%
HN NH
CF3
OH
R1
R2H2NNH2R1 COCF3
R2
119a, 119b 120a, 120b24b, 24f
COCF3 H2NNH 2
HN NH
CF3
OH 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%
MeNHNH2
N NMe
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].
Molecules 1997, 2 221
12124b, 24c
X=O X=SR1= H, R2 = Ph
R1+R2= -CH2CH2CH2-
NHHN
R1
R2CF3
OH
X
R1
R2
COCF3 (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.
222 Molecules 1997, 2
122121
Toluene
87%
95% 91%
R1+R2 = -CH2CH2CH2-
R1 = H, R2 = Ph
X=S
X=O
NHHN
R1
R2
CF3
OH
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].
Molecules 1997, 2 223
123a, 1 23b
24b, 2 4c
(H2N)2CS
R1 = H, R2 = Ph
R1
R2
COCF3
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 CF3
substituted 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
R2
COCF3
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).
224 Molecules 1997, 2
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 F3
CH 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].
Molecules 1997, 2 225
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 COCF3
groups 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
226 Molecules 1997, 2
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.
Molecules 1997, 2 227
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.
228 Molecules 1997, 2
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
CF3
OSO
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
R2
COCF3
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].
Molecules 1997, 2 229
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.
230 Molecules 1997, 2
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.
10. Pashkevich, K.I.; Saloutin, V.I.; Postovskii, I.Ya.Uspekhi Khimii 1981, 50, 325-354.
11. Pashkevich, K.I.; Saloutin, V.I. Uspekhi Khimii1985, 54, 1997-2026.
12. Bonnet-Delpon, D.; Bégué, J.-P.; Lequeux, T.;Ourévitch, M. Tetrahedron 1996, 52, 59-70.
13. Tanaka, K.; Masuda, H.; Mitsuhashi, K. Bull. Chem.Soc. Jpn. 1984, 57, 2184-2187.
14. Boivin, J.; El Kaim, L.; Zard, S.Z. Tetrahedron1995, 51, 2585-2592.
15. Bégué, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991,47, 3207-3258.
16. Hojo, M.; Masuda, R.; Kamitori, Y. TetrahedronLett. 1976, 13, 1009-1012.
17. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.;Matsuo, S. Chem. Lett. 1976, 3, 499-502.
18. Colla, A.; Martins, M.A.P.; Clar, G.; Krimmer, S.;Fisher, P. Synthesis 1991, 483-486.
19. Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M.Synthesis 1986, 1016-1017.
20. Verboom, W.; Reinhoudt, D.N. J. Org. Chem. 1982,47, 3339-3342.
21. Trabelsi, H.; Cambon, A. Tetrahedron Lett. 1995,36, 3145-3148.
22. Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett.1986, 27, 353-356.
23. Moriguchi, T.; Endo, T.; Takata, T. J. Org. Chem.1995, 60, 3523-3528.
24. Hojo, M.; Masuda, R.; Kamitori, Y.; Okada, E. J.Org. Chem. 1991, 56, 1975-1976.
25. Hojo, M.; Masuda, R. J. Org. Chem. 1975, 40, 963-965.
26. Hojo, M.; Masuda, R.; Okada, E. Synthesis 1986,1013-1014.
27. Hojo, M.; Masuda, R.; Okada, E. Synthesis 1990,347-350.
28. Gambaryan, N.P.; Simonyan, L.A.; Petrovskij, P.V.Izv. Acad. Nauk SSSR, Ser. Khim. 1967, 918-921.
29. Avetisyan, E.A.; Simonyan, L.A.; Gambaryan, N.P.Izv. Acad. Nauk SSSR, Ser. Khim. 1972, 2742-2744.
30. Gambaryan, N.P.; Rokhlina, E.M.; Zeifman, Yu.V.Izv. Acad. Nauk SSSR, Ser. Khim. 1965, 1466-1469.
31. Henne, A.L.; Hinkamp, P.E. J. Am. Chem. Soc.1954, 70, 5147-5148.
32. Sheppard, W.A. J. Am. Chem. Soc. 1965, 87, 2410-2418.
33. Moskalev, N.V.; Sirotkina, E.E. Khim. Geterocycl.Soed. 1987, 1492-1495.
34. Gluhovcev, V.G.; Ilyin, Yu.V.; Ignatenko, A.V.;Brezhnev, A.Yu. Izv. Acad. Nauk SSSR, Ser. Khim.1987, 12, 2834-2837.
35. Olah, G.A.; German, A.; Lin, H.C. J. Am. Chem.
Soc. 1975, 97, 5481-5488.36. Olah, G.A.; Heliger, L.; Prakash, S. J. Am. Chem.
Soc. 1989, 111, 8020-8021.37. Nenajdenko, V.G.; Balenkova, E.S. Zh. Org. Khim.
1992, 28, 600-60238. Nenajdenko, V.G.; Balenkova, E.S. Zh. Org. Khim.
1993, 29, 687-688.39. Nenajdenko, V.G.; Sanin, A.V.; Balenkova, E.S. Zh.
Org. Khim. 1994, 30, 531-534.40. Nenajdenko, V.G.; Leshcheva, I.F.; Balenkova, E.S.
Tetrahedron 1994, 50, 775-782.41. Nenajdenko, V.G.; Gridnev, I.D.; Balenkova E.S.
Tetrahedron 1994, 50, 11023-11038.42. Nenajdenko, V.G.; Balenkova, E.S. Tetrahedron
1994, 50, 12407-12414.43. Kiselyov, A.S.; Harwey, R.G. Tetrahedron Lett.
1995, 36, 4005-4008.44. Neunhoeffer, O.; Alsdorf, G.; Ulrich, H. Chem. Ber.
1959, 92, 252-255.45. Shaub, B. Eur. Pat. Appl. EP 298478 (1988), C. A.,
111, 39005.46. Linderman, R.J.; Lohikar, M.S. Tetrahedron Lett.
1987, 28, 5271-5274.47. Linderman, R.J.; Lohikar, M.S. J. Org. Chem, 1988,
53, 6013-6022.48. Linderman, R.J.; Lohikar, M.S. Tetrahedron Lett.
1987, 28, 5271-5274.49. Margaretha, P.; Schroder, C.; Wolff, S.; Agosta,
W.C. J. Org. Chem. 1983, 48, 1925-1926.50. Linderman, R.J.; Jamois, E.A.; Tennyson, S.D. J.
Org. Chem. 1994, 59, 957-962.51. Mo, X.-S.; Huang, Y.-Z. Synlett 1995, 180-182.52. Mo, X.-S.; Huang, Y.-Z.; Zhao, Y.R. J. Chem. Soc.,
Chem. Commun. 1994, 2769-2770.53. Mead, D.; Loh, R.; Asato, A.E.; Liu, R.S.H.
Tetrahedron Lett. 1985, 26, 2873-2876.54. Mead, D.; Asato, A.E.; Denny, M.; Liu, R.S.H.;
Hanzawa Y.; Taguchi, T.; Yamada, A.; Kobayashi,N.; Hosoda, A.; Kobayashi, Y. Tetrahedron Lett.1987, 28, 259-262.
55. Gazit, A.; Rappoport, Z. J. Chem. Soc., PerkinTrans. I. 1984, 2863-2870.
56. Katsuyama, I.; Funabiki, K.; Matsui, N.;Muramatsu, H.; Shibata, K. Chem. Lett., 1996, 179.
57. Ishihara, T.; Maekawa, T.; Ando, T. TetrahedronLett. 1983, 24, 4229-4232.
58. Huang, W.S.; Yuan, C.Y. J. Chem. Soc., PerkinTrans. I. 1995, 741-742.
59. Ishikava, N.; Koh, M.G.; Kitazume, T.; Choi, S.T.J. Fluorine Chem. 1984, 24, 419-430.
60. Kitazume, T; Ishikava, N. J. Am. Chem. Soc. 1985,107, 5186-5191.
61. Kitazume, T.; Ishikawa, N. Chem. Lett. 1981, 1679-1680.
62. O’Reilly, N.J.; Maruta, M.; Ishikava, N. Chem.
Molecules 1997, 2 231
Lett., 1984, 517-520.63. Dess, D.B.; Martin J.C. J. Org. Chem. 1983, 48,
4155-4156.64. Linderman, R.J.; Graves, D.M. J. Org. Chem. 1989,
54, 661-668.65. Ratner, V.G.; Pashkevic, K.I. Izv. Acad. Nauk SSSR,
Ser. Khim. 1996, 3, 680-686.66. Hanzawa, Y.; Yamada, A.; Kobayashi, Y.
Tetrahedron Lett. 1985, 24, 2881-2884.67. Linderman, R.J.; Graves, D.M. Tetrahedron Lett.
1987, 28, 4259-4262.68. Hanzava, Y.; Kamagoe, K.; Kobayashi, N.
Tetrahedron Lett. 1985, 26, 2877-2880.69. Kitazume, T; Ishikava, N. Chem. Lett. 1984, 587-
590.70. Uno, H.; Matsushima, Y.; Tasaka, T.; Suzuki, H.
Bull. Chem. Soc. Jpn. 1990, 63, 293-295.71. 4-Ethoxy-1,1,1-trifluoro-3-buten-2-one, 1,1,1-
trifluoro-4-(3-indolyl)-3-buten-2-one and 1,1,1-trifluoro-4-phenyl-3-buten-2-one are commerciallyavailable from Aldrich since 1996.
72. Gorbunova, M.G.; Gerus, I.I.; Kukhar, V.P. J.Fluorine Chem. 1993, 65, 25-28.
73. Platoshkin, A.M.; Cheburkov, Yu.A.; Knunyants,I.L. Izv. Akad. Nauk USSR., Ser. Khim. 1969, 112-119.
74. Schreiber, S.L. Tetrahedron Lett. 1980, 21, 1027-1030.
75. Gerus, I.I.; Gorbunova, M.G.; Vdovenko, S.I.;Yagupol’skii, Yu.L.; Kukhar, V.P. Zh. Org. Chim.1990, 26, 1877-1883.
76. Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett.1989, 30, 6173-6176.
77. Gorbunova, M.G., Gerus, I.I.; Galushko, S.V.;Kukhar, V.P. Synthesis 1991, 207-209.
78. Pashkevich, K.I.; Filyakova, V.I. . Izv. Akad. NaukUSSR., Ser. Khim. 1986, 620-624.
79. Ratner, V.G.; Pashkevich, K.I. Zh. Org. Khim.,1990, 26, 1212-1215.
80. Vdovenko, S.I.; Gerus, I.I.; Gorbunova, M.G. J.Chem. Soc., Perkin Trans II, 1993, 559-562.
81. Proskurnina, M.V.; Kazmin, A.G.; Zenova, A.Y.;Lermontov, C.A.; Borisenko, A.A.; Zefirov, N.S.Zh. Org. Chim., 1996, 146-148.
82. Hara, S.; Kato, N.; Takada, E.; Suzuki, A. Synlett1994, 961-962.
83. Takada, E.; Hara, S.; Suzuki, A. Heteroatom Chem.,1992, 3, 483-486.
84. Takada, E.; Hara, S.; Suzuki, A. Tetrahedron Lett.1993, 34, 7067-7070.
85. Tordeux, M.; Wakselman, C. J. Fluorine Chem.1982, 20, 301-306.
86. Linderman, R.J.; Kirollos, K.S. Tetrahedron Lett.1989, 30, 2049-2052.
87. Linderman, R.J.; Kirollos, K.S. Tetrahedron Lett.1990, 31, 2689-2692.
88. Gerus, I.I.; Kropachev, L.V.; Gorbunova, M.G.;Ilchenko, A.Ya.; Kukhar, V.P. Ukr. Khim. Zh.(Russ. Ed.), 1993, 59, 408-411. See also a review ofthe authors: Gerus, I.I.; Gorbunova, M.G.; Kukhar,V.P. J. Fluorine Chem. 1994, 69, 195-198.
89. Keller, H.; Schlosser, M. Tetrahedron 1996, 52,4637-4644.
90. Pasenok, S.B.; Gerus, I.I.; Chajka, E.A.;Yagupol’skii, L.M. Zh. Org. Khim. 1989, 2, 379-384.
91. Martins, M.A.P.; Flores, A.F.C.; Freitag, R.;Zanatta, N. J. Heterocycl. Chem. 1995, 32, 731-733.
92. Braibante, M.E.F.; Clar, G.; Martins, M.A.P. J.Heterocycl. Chem. 1993, 30, 1159-1160.
93. Gerus, I.I.; Vdovenko, S.I.; Gorbunova, M.G.;Kukhar, V.P. Khim. Geterocycl. Soedin. 1991, 502-511.
94. Madruda, C.; Clerici, E.; Martins, M.; Zanatta, N. J.Heterocycl. Chem. 1995, 32, 735-738.
95. Kamitori, Y.; Hojo, M.; Masuda, R. J. Heterocycl.Chem. 1993, 30, 389-391.
96. Avetisyan, E.A.; Gambaryan, N.P. Izv. Akad. NaukUSSR., Ser. Khim. 1973, 2559-2562.
97. Simonyan, L.A.; Avetisyan, E.A.; Safronova, Z.V.;Gambaryan, N.P. Izv. Akad. Nauk USSR., Ser. Khim.1976, 2061-2065.
98. Abduganiev, E.G.; Avetisyan, E.A.; Rohlin, E.M.;Knunyants, I.L. Izv. Akad. Nauk USSR., Ser. Khim.1974, 392-397.
99. Hojo, M.; Masuda, R.; Okada, E. Synthesis 1989,215-217.
100. Hojo, M.; Masuda, R.; Okada, E. Synthesis 1990,425-427.
101. Okada, E.; Masuda, R.; Hojo, M.; Inoue, R.Synthesis 1992, 533-535.
102. Okada, E.; Masuda, R.; Hojo, M.; Yoshida, R.Heterocycles 1992, 7, 1435-1441.
103. Cocco, M.T.; Congiu, C.; Onnis, V. J. Heterocycl.Chem. 1995, 32, 543-545.
104. Bravo, P.; Bruche, L.; Farina, A.; Gerus, I.I.;Kolytcheva, M. T.; Kukhar, V.P.; Meille, S.V.;Viani, F. J. Chem. Soc., Perkin Trans. I, 1995,1667-1671.
105. Nenajdenko, V.G.; Sanin, A.V.; Balenkova, E.S. Zh.Org. Khim. 1995, 31, 786-791.
106. Nenajdenko, V.G.; Sanin, A.V.; Kuz’min, V.S.;Balenkova, E.S. Zh. Org. Khim. 1996, 32, 1579-1588.
107. Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99-108.
108. Nenajdenko, V.G.; Sanin, A.V.; Lebedev, M.V.;Balenkova, E.S. Zh. Org. Khim. 1995, 31, 783-785.
109. Ho, T.L. Chem. Rev., 1975, 75, 1-20.110. Sanin, A.V.; Nenajdenko, V.G.; Krasovskii, A.L.;
Churakov, A.V.; Howard, J.A.K.; Balenkova, E.S.Zh. Org. Khim. 1997, 33, 236-244.
232 Molecules 1997, 2
111. Sanin, A.V.; Nenajdenko, V.G.; Kuz’min, V.S.;Balenkova, E.S. J. Org. Chem. 1996, 61, 1986-1989.
112. Sheppard, W.A.; Sharts, C.M. Organic FluorineChemistry. Benjamin, New-York, 1969.
113. Lerman, B.M. Russ. Chem. Rev. (Engl. Transl.)1995, 64, 3-27.
114. Nenajdenko, V.G.; Sanin, A.V.; Balenkova, E.S.
Khim. Geterotsikl. Soedin. 1994, 10, 1429-1431.115. Reddy, A.C.S.; Rao, P.S.; Vekataratnam, R.V.
Tetrahedron Lett. 1996, 37, 2845-2848.
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.