Russian Chemical Reviews 68 (6) 437 ± 458 (1999) Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis V G Nenaidenko, A V Sanin, E S Balenkova Contents I. Introduction II. Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones III. The use of a,b-unsaturated trifluoromethyl ketones in organic synthesis IV. Conclusion Abstract. Published data on the methods of synthesis and proper- ties of a,b-unsaturated trifluoromethyl-containing ketones are surveyed and described systematically. Primary attention is devoted to the use of these compounds in organic synthesis as useful building blocks for the preparation of various compounds bearing a trifluoromethyl group. The bibliography includes 133 references.I. Introduction Organofluorine chemistry has been vigorously developing during the last two decades. A large number of studies have been devoted to modification of natural products by introduction of a fluori- nated or perfluorinated substituent.1±3 These fluorinated deriva- tives often exhibit biological activities; some heterocyclic compounds containing a trifluoromethyl group have already found wide use as medicines (for example, triftazine, trifluorothy- midine).4 a,b-Unsaturated trifluoromethyl ketones (trifluoro- methyl a,b-enones) are fairly convenient building blocks for pre- paring heterocycles with a trifluoromethyl group. Most of the known approaches to the synthesis of these heterocycles suffer from serious drawbacks, associated either with the fact that the initial compounds are rather difficult to obtain or with the fact that they are fairly toxic and inconvenient to work with.1±3 Thus, development of methods for the synthesis and study of properties of trifluoromethyl a,b-enones present substantial interest and have been in the centre of attention of many researchers in recent years. In this review, we survey methods for the synthesis of a,b- enones with a trifluoromethyl (perfluoroalkyl) substituent at the carbonyl group, because these enones are used in organic synthesis much more often than those containing a CF3 group at other positions.5, 6 II.Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones Although the first a,b-unsaturated trifluoromethyl ketones were synthesised almost 40 years ago, the vigorous development of the methods for their synthesis has started only in the last decade.As a V G Nenaidenko, A V Sanin, E S Balenkova Department of Chemistry, Moscow State University, Leninskie Gory, 119899 Moscow, Russian Federation. Fax (7-095) 939 31 81. Tel. (7-095) 939 22 76 (Nenaidenko). E-mail: nen@acylium.chem.msu.ru Received 23 June, 1998 Uspekhi Khimii 68 (6) 483 ± 505 (1999); translated by Z P Bobkova #1999 Russian Academy of Sciences and Turpion Ltd UDC 547.384:547.321:547.7 437 437 445 456 rule, they cannot be prepared by the same procedures as non- fluorinated a,b-enones. Five possible approaches to the construction of the carbon skeleton of trifluoromethyl a,b-enones can formally be proposed.Four approaches are based on the formation of C(1) ± C(2), C(2) ± C(3), C(3)=C(4) and C(4) ±R3 bonds and one is based on transformations resulting in the appearance of a carbonyl group. R2 O 3 2 4 R3 F3C1 R1 Analysis of published data shows that the following principal methods for the synthesis of trifluoromethyl a,b-enones exist. �Trifluoroacetylation (for example, of alkenes, their organo- metallic derivatives or compounds generating alkenes in situ) to give a C(2) ± C(3) bond. � Condensation of 1,1,1-trifluoroacetone and its derivatives with aldehydes and the formation of the C(3) ± C(4) double bond in an elimination reaction. � Addition to alkynyl ketones (a,b-ynones) or to enones containing a b-substituent capable of being replaced (most often, an alkoxy group), and replacement of one carbonyl group in b- diketones containing a perfluoroalkyl substituent [formation of the C(4) ±R3 bond].In this case, examples described in the literature include formation of both C±C and C± heteroatom bonds. � Addition of perfluoroalkyl organolithium compounds to esters of acrylic acid to give the C(1) ± C(2) bond. This method is scarcely documented and has never been used for the preparation of trifluoromethyl a,b-enones. Apparently, this is due to the fact that synthesis of perfluorinated organolithium compounds requires the use of perfluoroalkyl iodides, which are toxic and difficult to work with (especially, trifluoromethyl iodide).3 � Oxidation of allyl alcohols, which are synthesised using perfluorinated or vinylic organometallic compounds, yielding a C=O group.This approach also has not found wide use. Below, we consider all the above methods for the synthesis of a,b-unsaturated trifluoromethyl ketones in the same order. 1. Trifluoroacetylation of alkenes a. Trifluoroacetylation of electron-rich alkenes by trifluoroacetic anhydride Trifluoromethyl a,b-enones are formed upon trifluoroacetylation of activated alkenes by trifluoroacetic anhydride (or other derivatives of trifluoroacetic acid) at room temperature or on438 cooling. The reaction is often carried out in the presence of pyridine, which increases the yield. R1X R1X (CF3CO)2O Y Y COCF3 (54% ± 100%) Y=H, Alk, Ar, SAr; X=O, S, Te, NSO2R2, NCOR3; R1, R2, R3=Alk, Ar.Activated alkenes can be represented by vinyl ethers 7 (including cyclic ones such as 1),8, 9 vinyl sulfides,10 ketene dithioacetals,10 vinyl tellurides,11 vinylamides,7 cyclic enam- ines 12, 13 and activated dienes such as 1,1-bis(alkylthio)alka-1,3- dienes 2 or N-acetyl-N-isopropyl-1-aminobuta-1,3-diene 3.14 R R (CF3CO)2O, Py COCF3 O O (CH2)n (77% ± 95%) (CH2)n 1 R=H, Me; n=1, 2. SR1 SR1 (CF3CO)2O, Py COCF3 R1S R1S R2 R2 (43% ± 100%) 2 R1=Alk; R2=H, Et. Pri Pri COCF3 N (CF3CO)2O, Py N COMe (96%) COMe 3 Trifluoroacetylation of vinyl ethers, vinylamides and 1,1- bis(alkylthio)alka-1,3-dienes 2 occurs stereospecifically yielding thermodynamically more favourable E-isomers of trifluoro- methyl a,b-enones.Trifluoroacetylation of vinyl tellurides gives rise to Z-isomers, because they are stabilised by an O± Te coordinate bond (X-ray diffraction data 11). Vinyl sulfides are trifluoroacetylated non-stereoselectively. According to the 1H NMR spectra and data on the reaction kinetics,15, 16 this process follows an addition ± elimination mechanism. Trifluoroacetyla- tion of vinyl ethyl ether gives polymers as side products.16 In the absence of pyridine, the highest yield (59%) was attained when the reaction was carried out in chloroform. Trifluoroacetylation of cyclic enamines, for example, 1-morpholinocyclopent-1-ene (or 1-morpholinocyclohex-1-ene), affords a complex mixture of products.In the case of less reactive 1-morpholinocyclohept-1-ene, doubly trifluoroacetylated prod- uct 4 was isolated.12 CF3CO (CF3CO)2O N O N O 15 ± 25 8C, 1.5 h CF3CO 4 (57%) Enamines 5, derived from indene, dihydronaphthalene and benzocycloheptene, react ambiguously with trifluoroacetic anhy- dride. Depending on the structure of the initial enamine, either trifluoromethyl enamino ketones 6 or products of their cyclisa- tion, oxazine derivatives 7, can be isolated. X X N N (CF3CO)2O COCF3 20 8C (CH2)n (CH2)n 6 (83%) 5 V G Nenaidenko, A V Sanin, E S Balenkova X N O CF3 (CH2)n 7 (30% ± 53%) X=CH2, (CH2)2, OCH2; n=1±3. The reactions of vinyl ethers with a threefold excess of trifluoroacetic anhydride in the presence of pyridine result in the formation of 3-(alkoxymethylidene)-1,1,1,5,5,5-hexafluoropen- tane-1,3-diones in high yields.17RO COCF3 RO (CF3CO)2O, Py COCF3 R=Et, Bui.Orthoacetates, acetals 18 and trithioorthoacetates 19 react with excess trifluoroacetic anhydride with elimination of alkyl or aryl trifluoroacetate (thioacetate) to give trifluoromethyl enones, i.e., they are precursors of the corresponding activated alkenes. It should be noted that only trifluoroacetic and trichloroacetic anhydrides enter into this reaction, whereas acetic anhydride does not. OEt OEt (CF3CO)2O, Py OEt Me 20 8C, 24 h CF3CO OEt OEtR1 (CF3CO)2O, Py OR2 Me 20 8C, 3 ± 48 h CF3CO OR2 OR2 (94% ± 100%) R1=Me, Ph; R2=Me, Et.SAr SAr (CF3CO)2O Me SAr 20 8C, 20 h CF3CO SAr SAr (58% ± 100%) b. Trifluoroacetylation of tertiary amines When trialkylamines are made to react with trifluoroacetic anhydride or trifluoroacetyl halides, b-dialkylamino-substituted trifluoromethyl enones are formed. The reaction of two equiv- alents of triethylamine with trifluoroacetyl chloride at 730 8C gives rise to 4-diethylamino-1,1,1-trifluorobut-3-en-2-one (in 18% yield based on the initial trifluoroacetyl chloride).20 The reaction mechanism proposed in the study cited 20 includes oxidation of triethylamine by one equivalent of trifluoroacetyl chloride to give diethyl(vinyl)amine. Trifluoroacetyl chloride is reduced simultaneously to fluoral. The subsequent interaction of diethyl(vinyl)-amine with a second equivalent of trifluoroacetyl chloride results in the formation of the corresponding enaminone. *H7 CF3COCl+NEt3 [CF3COCl/NEt3] + 7 CHMe] [CF3CHCl O Et2 N CF3CHO+HCl+Et2NCH CH2 NEt3 Et2N CF3COCl+Et2NCH CH2 + COCF3 7HNEt3Cl7 It has been found 21 that the reaction of triethylamine or ethyldiisopropylamine with an equimolar amount of trifluoro- acetic anhydride at 0 8C gives rise to doubly trifluoroacetylatedMethods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis products 8a,b (yield *25%), in conformity with the reaction stoichiometry 4R2NEt+4 (CF3CO)2O COCF3 + + CF3CH(OCOCF3)2+3R2EtNHCF3CO¡ R2N 2 COCF3 8a,b R=Et (a), Pri (b).Cyclic amines react in a similar way. For example, N-methylpiperidine is converted into the corresponding enami- none 9 in 96% yield (with allowance for the degree of conversion of the starting amine). (CF3CO)2O Me N Me N COCF3 9 Some alkaloids containing tertiary nitrogen atoms enter into similar reactions with trifluoroacetic anhydride. They are oxidised and the resulting enamine fragment is then trifluoroacetylated.22 c. Trifluoroacetylation of non-activated alkenes The electrophilicity of trifluoroacetic anhydride and other deriv- atives of trifluoroacetic acid is insufficient for trifluoroacetylation of non-activated alkenes. The attempts to increase the reactivity of these reagents by complex formation with Lewis acids prove successful only for acylation of aromatic compounds.Unsatu- rated substrates undergo cationic polymerisation under these conditions. The use of acylium salts for the acylation of unsaturated compounds would permit conducting the reaction at low temperatures and thus diminish the probability of polymer- isation and other side processes. Unfortunately, acylium salts with a perfluoroalkyl radical are unstable and decompose with decar- bonylation during their attempted synthesis.23, 24 RFCOF+AgSbF6 [RFCO+SbF ¡6] RFF+SbF5+CO A new method for direct electrophilic trifluoroacetylation of non-activated alkenes has been proposed.25 The method is based on the use of trifluoroacetic anhydride in the presence of a complex of dimethyl sulfide with boron trifluoride.This reagent is more electrophilic than trifluoroacetic anhydride, which reacts only with alkenes activated by a heteroatom at the double bond. However, the use of the complex BF3 . SMe2 has a drawback; acylation of an equivalent of an alkene results in the liberation of protonated dimethyl sulfide, which then reacts with at least one more equivalent of the alkene to give sulfonium salt 10. Con- sequently, the yield of vinyl trifluoromethyl ketones does not exceed 50%. This reaction proceeds with alkenes able to form benzylic, allylic or tertiary cations (of the type 11); however, in the last-mentioned case, mixtures of a,b- and b,g-enones are formed.26, 27 R1 Me + R1 + Me2SH SMe2 3 R2 R2 CF3CO2BF¡ 10 a R1 7H+ CHCOCF3 (19% ± 49%) R2 R1 + + 7Me2SH R2 3 R1 CH2COCF3 CH2COCF3 CF3CO2BF¡ 11 SMe2 + R2 SMe2 CF3CO2BF¡3 (a) (CF3CO)2O, BF3 .SMe2,760 to730 8C. 439 Cyclopropyl-substituted alkenes enter into a similar reac- tion.28, 29 The reaction of 2-cyclopropylpropene and 1,1-dicyclo- propylethene with trifluoroacetic anhydride in the presence of BF3 . SMe2 follows an unusual route and results in cyclopropane ring opening to give sulfonium salts 12.29 The salts 12, which are b,g-unsaturated ketones, rearrange spontaneously into a,b- enones 13 (2 months, *20 8C) in a quantitative yield. In the presence of a base (KF, DMF), the sulfonium salts 12 undergo cyclisation in which the dimethylsulfonium group is intramolecu- larly substituted to give a,b-enones with a cyclopropyl substituent 14.CF3COCH2 (CF3CO)2O, BF3 . SMe2 + SMe2 760 to740 8C R R H CF3COCH2 CF3CO2BF¡3 + R (CH2)2SMe2 12 (92% ± 95%) 20 8C, 2 months KF, DMF 70 ± 80 8C, 6 h R CF3CO CF3CO2BF ¡3 + COCF3 (CH2)3SMe2 13 (100%) R14 (31% ± 34%) R=Me, cyclo-C3H5. In the presence of the complex BF3 . SMe2 , trifluoroacetic anhydride trifluoroacylates alkynes with a phenyl substituent at the triple bond. The reactions afford sulfonium salts 15 as a result of conjugate addition of the CF3CO group and dimethyl sulfide to the alkyne molecule.30 The demethylation of these salts upon the reaction with dimethyl sulfide results in the formation of trifluoro- methyl a,b-enones 16.Oxidation of the enones 16 by hydrogen peroxide makes it possible to synthesise unsaturated compounds with two electron-withdrawing substituents at the double bond, namely, sulfonyl and CF3CO groups. Ph AlkCF3CO2BF ¡ SMe2 3 PhC CAlk + (CF3CO)2O, BF3 . SMe2 760 to740 8C COCF3 Me2S15 (90% ± 95%) Ph Ph Alk Alk H2O2 MeO2S COCF3 (88% ± 93%) MeS COCF3 16 (87% ± 96%) The reactions of pentafluoronitroacetone 17 with vinyl ethyl ether,31 ketene diethyl acetal 32 or isobutylene 33 give rise to products similar to those formed upon trifluoroacetylation of alkenes with trifluoroacetic anhydride. The reaction with acti- vated alkenes follows a cycloaddition pathway. Thus the com- pound 17 and vinyl ethyl ether react at 0 ± 5 8C to give oxetane 18.Opening of the oxetane ring and subsequent thermolysis of the resulting alcohols in the presence of catalytic amounts of K2CO3 affords 4-ethoxy-1,1,1-trifluorobut-3-en-2-one 19 (yield 96%). Ketene diethyl acetal enters into a similar reaction with the compound 17 (at 730 8C), 4,4-diethoxy-1,1,1-trifluorobut-3-en- 2-one being formed in 90% yield. NO2F2C OEt NO2F2C O F3C O+ 17 F3C 18 (90%) OEt440 OEt NO2F2C OEt K2CO3, 100 ± 140 8C F3C 7CHF2NO2 19 (64%) OH CF3CO The reaction of pentafluoronitroacetone 17 with isobutylene yields an alcohol, which eliminates difluoronitromethane to give 4-methyl-1,1,1-trifluoropent-3-en-2-one. NO2F2C Me 20 8C, 12 h K2CO3, 100 8C 17+ F3C 7CHF2NO2 Me OH Me (96%) Me Me CF3CO(48%) d.Trifluoroacetylation of vinylic and allylic organometallic compounds Trifluoroacetylated derivatives of non-activated alkenes can be prepared by acylation of vinylic organometallic compounds. The first trifluoromethyl-containing enone, 1,1,1-trifluoro-4-phenyl- but-3-en-2-one 20, was synthesised by the reaction of styrylmag- nesium bromide with trifluoroacetic acid in 1959; however, the yield of the product was relatively low.34 The subsequent studies showed that organolithium derivatives are better suited for the synthesis of trifluoromethyl enones; in this case, higher yields of the target products can be attained.35 However, only one example of this type of synthesis is known to date; apparently, this is due to the fact that the corresponding vinyllithium derivatives are difficult to obtain.a or b Br COCF3 Ph Ph 20 (a) Mg, Et2O; CF3COOH (yield 11%); (yield 63%). (b) Li, Et2O; CF3CON Trifluoromethyl a,b-enones can also be prepared from allylic organometallic compounds. For example, the reaction of allyl- magnesium bromide with sodium trifluoroacetate gives a mixture of the corresponding a,b- and b,g-enones (ratio *1 : 1) in an overall yield of 37%.36 CF3CO2Na CHCH2MgBr CH2 0± 15 8C, 5 ± 8 h CHCH2COCF3+MeCH CHCOCF3 CH2 When lithium diisopropylamide is made to react with N-ethylidene-tert-butylamine, a heteroallylic anion is formed; subsequent treatment of the anion with ethyl trifluoroacetate gives rise to 4-(tert-butylamino)-1,1,1-trifluorobut-3-en-2-one.37 7NCMe3 LiNPri2 MeCH NCMe3 H2C NCMe3 CF3CO2Et 7 F3C H2C 775 8C, 30 min NCMe3 O H (86%) Reactions of other vinylic or allylic organometallic com- pounds with trifluoroacetic acid or its derivatives have not been studied.Thus, trifluoroacetylation of alkenes is a convenient method for the synthesis of trifluoromethyl enones; however, it is applicable only to alkenes containing either an activating group (e.g., OR, SR, TeR, NR2) or, at least, a phenyl, vinyl or V G Nenaidenko, A V Sanin, E S Balenkova cyclopropyl substituent or two alkyl substituents (trifluoroacety- lation in the presence of Me2S . BF3). 2. Condensation of 1,1,1-trifluoroacetone and its derivatives; construction of a double bond upon an elimination reaction The condensation of 1,1,1-trifluoroacetone with aromatic or a,b- unsaturated aldehydes catalysed by the piperidine ± acetic acid system in THF makes it possible to prepare trifluoromethyl- containing conjugated enones, dienones and polyenones (reti- noids).38, 39 The reaction is stereospecific and gives E-isomers of enones.A drawback of this method is self-condensation of 1,1,1- trifluoroacetone during the reaction; therefore, it should be taken in more than 10-fold excess. NH, AcOH R RCHO +MeCOCF3 COCF3 20 8C, *4 h (28% ± 85%) a,b-Unsaturated ketones are often prepared by condensation of b-dicarbonyl compounds with aldehydes and ketones (Knoe- venagel condensation). However, b-dicarbonyl compounds con- taining a perfluoroalkyl substituent enter into this reaction with difficulty.Thus the reaction of aromatic aldehydes with 1,1,1- trifluoroacetylacetone yields a mixture of products resulting from condensation at the methyl and methylene groups in a relatively low yield.40 This fact was explained by assuming that the addition of amine, used as the catalyst, to the initial 1,1,1-trifluoroacetyl- acetone is the predominant reaction route. NH ArCHO+CF3COCH2COMe COMe Ar Ar Ar CF3+ COCF3 + O COCF3 H O(0% ± 14%) (0% ± 24%) (1% ± 6%) The reactions of b-diketones having one or two perfluoroalkyl groups with polyfluorinated aldehydes have also been studied.41 In the case of b-diketones with one perfluoroalkyl group, the carbonyl group adjacent to the perfluoroalkyl substituent, being more active, participates in the formation of the cyclic intermedi- ate.As a consequence, the elimination of a carboxylate anion gives rise to b-unsaturated ketones with a non-fluorinated substituent at the carbonyl group. K2CO3 or Et3N R1COCH2COR2+R3CHO 20 8C, 1 ± 2 h 7OCHR3 O CHR3 CHCOR2 R1C R1CCHCOR2 7R1CO¡2 O O7 R3 COR2 (20% ± 70%) R1=CF3, H(CF2)n; R2=Me, Ph, CF3, H(CF2)n; R3=H(CF2)n. When esters of trifluoroacetic acid are made to condense with aldehydes in the presence of traditional catalysts such as piper- idine ± AcOH, the target products are formed in fairly low yields.42 Recently, it has been proposed to use functionalised silica gel [silica gel treated with (3-aminopropyl)triethoxysilane] as the catalyst with toluene-p-sulfonic acid being added subsequently to the reaction mixture.A mixture of Z- and E-isomers of alkoxycarbonyl-substituted trifluoromethyl a,b-enones was obtained in this way in a good yield.42Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis COCF3 COCF3 R1 R1CHO+ 1. SiO2 2. p-TsOH PhH, D CO2R2 CO2R2 (43% ± 70%) R1=Alk, Ar; R2=Et, Pri. The Knoevenagel condensation of pefluoroalkyl-containing b-dicarbonyl compounds is often accompanied by side reactions (e.g., self-condensation, in the case of 1,1,1-trifluoroacetone), the yields of the target products being relatively low. This fact has stimulated the search for new methods for their synthesis.For example, the reaction of b-iminophosphonate anions with alde- hydes (the Horner ± Emmons reaction), which yields perfluoro- alkylated enones as the final products after acid hydrolysis, has been used for this purpose. Two approaches to the synthesis of b-iminophosphonates have been proposed. Perfluorocarboxylic acid chlorides can be converted via a four-stage procedure into compounds 21, which are then treated with a base (n-butyllithium, lithium diisopropylamide or sodium hydride) and with an alde- hyde.43 Ketones do not enter into this reaction. O P(OEt)3 P(OEt)3 RFCF2COCl 0720 8C, 2 h RFCF2CP(O)(OEt)2 OP(O)(OEt)2 RF 1. BuLi, CuI, THF 2. NH4Cl (sat.) 778 8C, 15 min F P(O)(OEt)2 H RF NMe MeNH2 1.B 2. RCHO P(O)(OEt)2 20 8C, 2 h F RF 21 (100%) P(O)(OEt)2 (60% ± 79%) NMe H3O+ RFCO R RF R (74% ± 95%) RF=CF3, C2F5, n-C6F13; R=Alk, Ph; B=BunLi, LiNPri2, NaH. b-Iminophosphonate anions can also be obtained from diethyl alkylphosphonates and trifluoroacetoimidoyl chloride. The synthesis is carried out as a one-pot procedure; first, diethyl alkylphosphonates are treated with two equivalents of lithium diisopropylamide and then with trifluoroacetoimidoyl chloride; after that, the required aldehyde is added to the resulting b-iminophosphonate anion.44 2 1. LiNPr i F3C R1 CF3 2. NPh Cl R1CH2P(O)(OEt)2 1. R2CHO 2. H3O+ 770 to 20 8C (EtO)2P NPh 770 8C O Li R1 R2 COCF3 (48% ± 72%) R1=H, Me; R2=Alk, Ar.A method for the synthesis of substituted trifluoromethyl dienyl ketones with a particular configuration at the double bond has been reported.45 Thus sulfoxides 22 were prepared from 1-trifluoromethyl-2-phenylthioacetylene via a four-stage proce- dure (Claisen rearrangement is the key stage of the process). Subsequent elimination of sulfinic acid from the sulfoxides 22 gave trifluoromethyl dienyl ketones 23 and 24 in high yields. 441 R2 R3 OH SPh F3C R1 [F3CC CSPh] NaH Br R2 F3C SPh CCl4, D R3 R3 O SPh O CF3 R1 R2 R1 (70% ± 98%) R3 m-ClC6H4CO3H COCF3 R1 CH2Cl2 SPh R2 (97% ± 100%) R3 CH2Cl2, D COCF3 R1 SOPh R2 22 COCF3 R3=H R1 R2 23 (83% ± 87%) R3 R1=H COCF3 24 (82% ± 87%) R2 R1, R2, R3=H, Alk, Ph.3. Addition to alkynyl ketones Alkynyl trifluoromethyl ketones are easily available compounds, readily formed upon acylation of lithium or magnesium acetylides (Iotsitch reagents) with trifluoroacetic acid or its derivatives.46 ± 50 The best yields were attained in the reaction of lithium acetylides with ethyl trifluoroacetate in the presence of boron trifluoride etherate.50 Et2O. BF3 RC CLi+CF3CO2Et 778 8C RC CCOCF3 (64% ± 83%) R=Alk, Ph. A method for the synthesis of trifluoromethyl a,b-enones is based on 1,4-addition of dialkylcuprates to acetylenic ketones. This reaction is highly regioselective but it is not stereoselective and gives products in moderate yields.50, 51 OH R1 R22 CuLi COCF3+ R1C C CF3 R1C CCOCF3 R2 R2 (0% ± 25%) (20% ± 64%) R1=Ph, Bun; R2=Me, Bun, But.The use of cyanocuprates results in higher yields and in a nearly 100% regioselectivity of the reaction. However, in some cases (for example, in the case of 1,1,1-trifluoro-4-phenylbut-3- yn-2-one), cyanohydrins are produced.51CF3 OH Ph NC LiMeCuCN OH C +PhC PhC CCOCF3 CF3 Me CN The reactions of alkynyl trifluoromethyl ketones with aro- matic amines afford b-amino-substituted trifluoromethyl enones in good yields.52442 ArHN COCF3 ArNH2 RC CCOCF3 MeOH, 20 8C R (77% ± 99%) R=Alk, Ar. Alkynyl trifluoromethyl ketones can act as dienophiles in the Diels ± Alder reaction. 1,1,1-Trifluoro-4-phenylbut-3-yn-2-one reacts with cyclopentadiene to give bicyclic trifluoromethyl enone 25, a norbornadiene derivative, which undergoes a rever- sible rearrangement to give compound 26 of the quadricyclane series.53 hn COCF3 PhC CCOCF3+ D, CF3CO2H Ph 25 COCF3 26 Ph 4.Addition to enones containing a replaceable group in the b-position A method for the synthesis of trifluoromethyl enones based on the reactions of various zinc dialkyl- and diaryl-cuprates with b-trifluoroacetylvinyl tellurides has been proposed.54 R22 CuX COCF3 R2 R1Te COCF3 778 to730 8C (56% ± 90%) R1=Bun, Bui, Ph; R2=Ar, Alk; X=(CN)(ZnCl)2, ZnCl. However, in the case of zinc dialkylcuprates, the reaction is accompanied by side formation of the double addition products, Alk2CHCH2COCF3, in 11%± 19% yields.The necessity of using organotellurium compounds is also an obvious drawback of this method. A new procedure for the synthesis of trifluoromethyl enones from b-trifluoroacetylvinyl sulfones 27 has been reported quite recently. The compounds 27 are formed as stable diols upon oxidation of trifluoroacetylated vinyl sulfides.55 Thus b-trifluoroacetylvinyl sulfone 27 (R=Ph) reacts with electron-rich aromatic compounds (furans, indoles and pyrroles) to liberate sulfinic acid and to give aryl- and hetaryl-substituted trifluoromethyl a,b-enones.55 The reaction is stereospecific yield- ing E-isomers of the enones. H2O2, CF3COOH RS COCF3 730 8C, 3 h HetH, CH2Cl2 Het RO2S COCF3 C(OH)2CF3 20 8C (64% ± 86%) 27 (94% ± 98%) R=Me, Ph. b-Alkoxy-substituted trifluoromethyl enones (most often, 4-ethoxy-1,1,1-trifluorobut-3-en-2-one) are used as the starting compounds in a large number of syntheses.These compounds can be readily prepared by trifluoroacetylation of vinyl ethers.56 Several studies consider the reactions of the enone 19 with diverse nucleophiles�electron-rich aromatic compounds, organometal- lic and organoboron compounds and amines. This reaction in the presence of zinc chloride can be carried out only for reactive aromatic compounds such as indoles, pyrroles 57, 58 and N,N- dimethylaniline.57 COCF3 COCF3 X EtO XH, ZnCl2, CH2Cl2 20722 8C, 3 ± 14 h 19 (20% ± 84%) X= R1 , NR2, 4-Me2NC6H4; R1=H, Me, Ph; NH R2=H, Me. V G Nenaidenko, A V Sanin, E S Balenkova Less reactive compounds such as anisole do not enter into this reaction, and the use of other Lewis acids (BF3 or TiCl4) results in resinification.57 The reactions of the enone 19 with other hetero- cyclic compounds such as furan, 2-methylfuran and thiophene under the same conditions do not lead to the desired result either.58 The reaction of 3-ethoxymethylidene-1,1,1,5,5,5-hexafluoro- pentane-1,3-dione with indoles and pyrroles occurs faster and gives products in higher yields.58 COCF3 COCF3 RH, ZnCl2, CH2Cl2 20 ± 22 8C, 3 ± 14 h EtO R COCF3 COCF3 (84% ± 88%) NMe.Me , R= NH The enone 19 reacts with quaternary salts derived from nitrogenous heterocycles to give dienones�d-trifluoromethylbu- tadienylmerocyanines 28 or 29.59 Z Z Me COCF3 19+ +NMe NMe 28 (75% ± 78%) X7 Z=S, Me2C, CH=CH.Me Et3N, EtOH 19+ 60 8C, 1 h MeN COCF3 N + Me X7 29 (70%) 4-Butoxy-1,1,1-trifluorobut-3-en-2-one enters into a similar reaction. The enone 19 reacts with the phenylmagnesium bromide to give a mixture of b-trifluoroacetylstyrene 20 and allylic alcohol 30, resulting from its reduction, in an overall yield of 40%± 60%, the proportion of the alcohol 30 increasing with an increase in the reaction time.57 The reaction of phenylmagnesium bromide with 4-diethylamino-1,1,1-trifluorobut-3-en-2-one, prepared from the enone 19, occurs more unambiguously;57 it gives only b-trifluoro- acetylstyrene 20 in 53% yield. PhMgBr, Et2O COCF3 EtO 710 to 20 8C 19 CH(OH)CF3 COCF3 + Ph Ph 30 2021 : 1 Reaction time /h The 20 : 30 ratio Et2NH PhMgBr, Et2O 20 1 : 7 COCF3 20 19 Et2N 0 to 20 8C, 20 h Recently, a new convenient and fairly versatile method for the synthesis of unsaturated trifluoromethyl ketones has been devel- oped; this method is based on the reactions of various organo- lithium compounds with 4-dimethylamino-1,1,1-trifluorobut-3- en-2-one 31 and 3-(N,N-dimethylaminomethylidene)-1,1,1,5,5,5- hexafluoropentane-2,4-dione 8c.The compound 8c can be easily prepared by acylation of the enaminone 31 with trifluoroacetic anhydride in the presence of pyridine.60 COCF3 (CF3CO)2O, Py, CH2Cl2 COCF3 Me2N 710 to 20 8C, 1 h COCF3 Me2N 31 8c (95%) The reactions of the trifluoromethyl enaminones 31 and 8c with organolithium compounds afford trifluoromethyl enones; inMethods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis the case of the enaminone 31, the reactions are stereospecific and give only E-isomers of the enones.60 COCF3 1.RLi, THF,770 to730 8C 31 (or 8c) 2. H3O+, 0 8C R1 R2 (30% ± 97%) R1=Ar, Het; R2=H, COCF3. The reaction of enaminodione 8c with 1-methyl-1H-2-indo- lyllithium 32 gives rise to the corresponding enedione 33 but does not stop at this stage; the subsequent cyclisation yields cyclo- penta[b]indole derivative 34.60 CF3CO 1. 8c COCF3 Li 2. H3O+, 0 8C NMe 32 NMe 33 CF3 HO COCF3 NMe 34 (63%) The same study 60 describes the reaction of the enaminone 31 with a mixture of lithiated ferrocenes, resulting in the formation of the corresponding mono- 35 and bis-enones 36.In the case of the enaminodione 8c, only the product of its interaction with mono- lithioferrocene, enedione 37, was isolated. Li Li 1. THF, 770 to760 8C 2. H3O+, 0 8C BuLi, THF Fe Fe Fe + 20 8C, 2 h Li COCF3 COCF3 31 Fe Fe + COCF3 36 (8%) 35 (38%) COCF3 COCF3 8c Fe 37 (35%) In order to synthesise conjugated trifluoromethyl enones containing an acetylenic fragment (enynones), which are promis- ing from the synthetic point of view, a method based on the reaction of lithium acetylides with the enone 31 has been developed.61 The reaction is stereospecific giving E-isomers of substituted trifluoromethyl enynones.1. 31 RC C RC CLi 2. H3O+, 0 8C COCF3 (26% ± 57%) R=Alk, Ar, Me3Si. The reactions of various trifluoroacetylated vinyl ethers with organoboron compounds, which occur with high stereoselectivity (92% ± 98%) to give the E-isomers of the corresponding dienones, have been studied.62, 63 Thus the reaction of alkenyldialkoxybor- anes with substituted vinylic ethers in the presence of boron trifluoride etherate affords the corresponding trifluoromethyl dienones.62 Similarly, 6-butyl-1,1,1-trifluorohex-3-en-5-yn-2-one is formed in the reaction of alkynyldialkoxyborane 38 with the enone 19.63 443 R4 R1 Et2O. BF3, CH2Cl2 B(OR3)2+EtO Alk COCF3 0 to 20 8C, 1 ± 120 h R2 R1 COCF3 Alk R2 R4 (67% ± 90%) R1=H, Me, Ph, Br; R2=H, Br; R3=Et, Pri; R4=H, Me, Ph.Et2O.BF3, CH2Cl2 BuC COCF3 20 8C,*140 h CB(OPri)2 + EtO 38 19 BuC C COCF3 (71%) b-(Thio)alkoxy-substituted trifluoromethyl enones react with ammonia and primary and secondary amines (including aromatic ones) at room temperature to give b-amino-substituted enones (enaminones) in high (sometimes quantitative) yields.64, 65 R1X R3R4N COCF3 COCF3 R3R4NH 0 ±20 8C R2 R2 (56% ± 100%) X=O, S; R1=Alk; R2=H, Me, Ph; R3=H, Alk; R4=H, Alk, Ar. Diamines enter into a similar reaction. Thus symmetrical enaminones have been synthesised by the reaction of ethylenedi- amine and o-phenylenediamine with two molecules of b-ethoxy trifluoromethyl enone 19.64 The route of transamination in the series of b-amino-substituted enones does not depend on the nature of the solvent, being determined by the ratio of the initial reactants and the basicities of both the entering and leaving amines.The highest yields are attained when the amine entering into the reaction is more basic than the leaving one (for example, an amino group can easily be replaced by a dimethylamino or methylamino group but not vice versa). The reactions occur at room temperature and do not require a large excess of the amine used.65, 66 R4R5N R1R2N R4R5NH COCF3 COCF3 7R1R2NH R3 R3 (75% ± 100%) R1=H, Alk; R2, R3=H, Alk, Ph; R4=H, Alk; R5=Alk. 5. Preparation of trifluoromethyl ketones from b-diketones Trifluoromethyl enaminones can be synthesised by the reaction of amines with b-diketones.When fluorinated b-diketones are made to react with ammonia,67 ammonium acetate, ammonium hydro- gen carbonate,68 alkylamines or dialkylamines, stable salts 39 are initially formed. Refluxing of the salts 39 obtained from b-diketones having one trifluoromethyl (or perfluoroalkyl) sub- stituent in benzene or toluene with azeotropic distillation of water affords b-amino-substituted enones in 12%± 76% yields.67 + R2R3NH2R1 RF b a 7 O O R1 RF R1 RF 39 (100%) NR2R3 O O O R1 RF c O H O RF=H(CF2)n (n=2, 4); R1=Alk, Ar; (a) R2R3NH (R2, R3=H, Alk), 20 8C; (b) PhH or PhMe, D; (c) R2R3NH (R2=Ph, R3=H), MeOH, 20 8C.444 In the case of low-basicity aromatic amines (e.g., aniline), salts are not formed and the correding enamines are obtained by prolonged keeping of the initial compounds in polar solvents such as methanol at room temperature (yields 70% ± 90%).67 As a rule (or always if R1=Alk), this reaction gives enami- nones in which the amino group is removed from the perfluoro- alkyl substituent.Apparently, the electron-withdrawing influence of this group stabilises the gem-amino-alcoholic fragment and hampers elimination of water in the case where the amine has added at the carbonyl group adjacent to the perfluoroalkyl substituent. b-Diketones having two perfluoroalkyl substituents react with amines, including aromatic ones, to give stable salts, which cannot be converted into the corresponding amino-substituted enones.69 However, these enones can be obtained by the reaction of ammonia or aliphatic amines with fluorine-containing b-chloro- vinyl ketones 40.70, 71 The compounds 40 are formed in the reaction of polyfluorinated b-diketones with SOCl2 in the pres- ence of DMF as a catalyst or with the Vilsmeier reagents [DMF± POCl3 orDMF± (COCl)2].71 ± 74 This approach has also been used to synthesise hexafluoromonothioacetylacetone 41, which exists in the enol form.72 RF RF RF RF SOCl2, DMF O 90 8C, 3 h O Cl H O 40 RF RF NH3 NH2 O (42% ± 65%) CF3 F3C NaSH SH O 41 (37%) RF=H(CF2)n.Similarly, treatment of hydroxytetrahydrofuranone 42 � the hemiketal form of a diketone�with ammonia is accompanied by opening of the furan ring and gives rise to the corresponding hydroxy enamino ketone 43.75 HO O O CF3 Me CF3CO2Et LiH OH OH O H2N COCF3 NH3 CF3 O OH OH 43 (45%) 42 The structure and the stereochemistry of b-amino-substituted trifluoromethyl enones were studied by NMR and IR spectro- scopy.64, 76 The configuration of their molecules was found to depend on the nature of the amino substituent. Trifluoromethyl enaminones with NH2, AlkNH or ArNH groups in non-polar solvents or neat exist entirely as Z-isomers, which is apparently due to the presence of an intramolecular hydrogen bond.In polar solvents such as acetonitrile, an equilibrium between the Z- and E- isomers is established. RNH RNH O CF3 CD3CN CF3 CCl4 E-s-E CF3 E-s-Z O RNH O Z-s-Z (20% ± 25%) b-Dialkylamino-substituted enones always exist as E-isomers.Their 1HNMR spectra exhibit two pairs of signals corresponding V G Nenaidenko, A V Sanin, E S Balenkova to the diethylamino group, which seems to be due to the hindrance of its rotation around the C(4) ±N bond caused by conjugation.64 + O O7 Et2N Et2N CF3 CF3 An attempt has been made 77 to prepare unsubstituted perfluoroalkyl enone � trifluoromethyl vinyl ketone � from ethyl trifluoroacetoacetate. The researchers found that this enone (like other unsubstituted perfluoroalkyl vinyl ketones) dimerises spontaneously at temperatures above 730 8C to give dihydro- pyran derivative 44. OH TsCl 1. NaBH4 2. LiAlH4 CF3COCH2CO2Et CF3CHCH2CH2OH (83%) OH OH KCl Na2Cr2O7, H2SO4 CF3CHCH2CH2Cl (61%) CF3CHCH2CH2OTs (62%) PhNEt2 [CF3COCH CH2] CF3COCH2CH2Cl (36%) CF3 O F3C COCF3 O F3C O 44 When two moles of methylmagnesium bromide are made to react with one mole of trifluoroacetylacetone, methylmagnesium bromide adds to the trifluoroacetylacetone anion formed initially (mostly at the carbonyl group further removed from the CF3 substituent). The resulting tertiary alcohol 45 is readily dehy- drated (to a large extent, during the hydrolysis) to give 1,1,1- trifluoro-4,4-dimethylbut-3-en-2-one.78 OH O O O H 1.MeMgBr 2. H3O+ Me F3C 7H2O Me F3C 45 Me Me CF3CO Me (55%) 6. Addition of perfluoroalkyl organolithium compounds to acrylic esters Perfluoroalkyl organolithium compounds, generated by the reaction of perfluoroalkyl iodides with methyllithium (trans- metallation reaction), react with methyl acrylate or methyl methacrylate to give perfluoroalkyl enones, which exist in the reaction medium as anions of the corresponding hemiacetals 46.Pefluoroalkyl a,b-enones having no substituents at the b-position are unstable and readily dimerise to give dihydropyran deriva- tives. Therefore, the hemiacetals 46 were introduced without isolation in reactions with isothiouronium salts or amidines, giving 4-perfluoroalkyltetrahydropyrimidines 47 in good yields.79 R1 CO2Me n-CnF2n+1I, MeLi, LiBr, Et2O 778 8C, 1 h NH2 CF3 HO + OLi R1 NH2 N MeO R1 CnF2n+1 R2 X7 MeOH, 20 8C R2 N 46 H 47 (61% ± 98%) R1=H, Me; R2=AlkS, Me, Ph; X=I, Cl; n=2, 4, 6, 8.Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis This method has not been used to prepare trifluoromethyl enones, probably, because trifluoromethyl iodide is a toxic gaseous compound, inconvenient to work with.3 7.Palladium-catalysed reactions Imino-derivatives of alkenyl (48) and alkynyl (49) trifluoromethyl ketones can be synthesised by condensation of trifluoroacetimi- doyl iodides 50 with various alkenes and alkynes in the presence of a palladium catalyst; no elimination of fluorine, typical of this type of reaction, occurs.80 The reaction is carried out under mild conditions, alkynes reacting much faster and at lower temper- atures than alkenes.R1 R1 F3C I NAr 48 (48% ± 95%) Pd NAr F3C F3C HC CR2 C CR2 50 ArN 49 (47% ± 92%) R1=CO2Me, Ph, CN, SO2Ph, C6H13; R2=Ph, CO2Me, CO2Et, C6H13, CH2OCOPh. 8. Oxidation of allyl alcohols Perfluoroalkyl-containing allyl alcohols can be synthesised in two ways, namely, by the addition of vinyl-containing organometallic reagents to fluoral 81 or to another perfluorinated aldehyde or by the addition of perfluoroalkyl organometallic compounds to a,b- unsaturated aldehydes.82, 83 In both cases, the corresponding halide and the metal are directly introduced in the reaction, because perfluoroalkyl organometallic compounds are unstable and vinyl organometallic compounds are usually formed in low yields. To increase the yield of perfluoroalkyl-containing allylic alcohols, ultrasonic treatment (yield 40% ± 70%) 82, 83 and catal- ysis by palladium or nickel complexes (yield 19%± 62%) 83 have been employed.a CHBr CF3CHO+Mg+RCH OH b RCH CHCHRF RFX +Zn+RCH CHCHO c RFI+Zn+PhCH CHCHO R=H, Me, Ph, Me3Si; RF=CF3, C2F5, C3F7; X=Br, I; (a) ultrasound, THF, 20 8C, 3 h; (b) ultrasound, DMF, 100 8C, 1 h; (c) (Ph3P)2PdCl2 or (Ph3P)2NiCl2, DMF, 20 8C, 3 ± 4 h. In addition, trifluoromethyl-containing allylic alcohols have been prepared by the reduction of alkynyl ketones with lithium tetrahydroaluminate.84 The reaction is stereospecific and gives the alcohols as E-isomers. OH LiAlH4 (2.1 equiv.) RC CCOCF3 THF, D, 8 h R CF3 (71% ± 97%) R=CnH2n+1 (n=4 ± 16), Ph(CH2)2CH(OSiMe2But).Trifluoromethyl-containing allylic alcohols can be oxidised into the corresponding enones on treatment with the Dess ± Martin reagent 84 ± 87 or Swern reagent 88 (DMSO± oxalyl chlor- ide ± triethylamine). Manganese dioxide in CH2Cl2 was also used for this purpose; however, in this case, the yield of the product was somewhat lower.89 (OAc)3 IO But But OH O COCF3 CH2Cl2, 20 8C, 3 h Ph Ph CF3 (85%) 445 OH COCF3 Ph 1. DMSO ± (COCl)2, CH2Cl2,760 8C 2. Et3N, 20 8C Ph CF3 (84%) OH COCF3 MnO2, CH2Cl2 CF3 20 8C (65%) Thus, despite the high yields of the target enones, this method is limited due to the poor accessibility of the initial allylic alcohols and has not found wide use. III. The use of a,b-unsaturated trifluoromethyl ketones in organic synthesis The first example of using a trifluoromethyl enone (b-trifluoro- acetylstyrene) for the synthesis of pyrazolines dates back to 1959;34 however, vigorous studies along this line started in the last decade.Trifluoromethyl a,b-enones are usually employed to prepare heterocyclic compounds. Attempts to use them for other purposes, for example, as protective reagents in peptide synthesis, have also been made (see below). All trifluoromethyl enones can be divided into two main types: (a) enones containing a group capable of being substituted (e.g., OR, SR, NR2) in the b-position and (b) enones without such group. b-Alkoxy- and b-amino- substituted trifluoromethyl enones as well as alkynyl trifluoro- methyl ketones (a,b-ynones) havthe widest application.Below we consider the use of these compounds in organic synthesis, except for their use to prepare trifluoromethyl-contain- ing enones from acetylenic ketones and enones of type (a), which is described in Section II.3. 1. Reactions of b-alkoxy-substituted enones and acetylenic ketones Enones containing a b-alkoxy group (trifluoroacetylated vinyl ethers) and alkynyl trifluoromethyl ketones are readily available reagents (see Sections II.1 and II.3). Their reactions with various nucleophiles are widely used to synthesise five-, six- and seven- membered heterocycles and other compounds containing a CF3 group. Hydrazine and methylhydrazine react with b-alkoxy-substi- tuted trifluoromethyl enones to give trifluoromethyl-containing pyrazoles 50.61, 90 The reaction of trifluoromethyl enones with phenylhydrazine affords pyrazolines 51.On treatment with sulfuric acid, the compounds 51 are not dehydrated.90 Appa- rently, the conjugation of the nitrogen lone electron pair with the benzene ring hampers aromatisation. In addition, the electron- withdrawing influence of the CF3 group stabilises the gem-amino- alcoholic fragment. R1 R2 R4=H,Me N F3C NR4 R1 OR2 R4NHNH2, EtOH, D 50 (59% ± 98%) R1 R3 R2 CF3CO R4=Ph F3C N HO NPh 51 (70% ± 82%) R1, R3=H, Me; R2=Me, Et. The reaction of alkynyl trifluoromethyl ketones with hydra- zine at room temperature gives rise to a mixture of pyrazoles 52 and pyrazolines 53.Subsequent refluxing of the reaction mixture in benzene with azeotropic distillation of water affords only pyrazoles 52 in good yields.91446 H2NNH2 RC CCOCF3 20 8C N NH N NH PhH, D OH 52 (76% ± 92%) 7H2O +R R CF3 CF3 52 53 tert-Butylhydrazones of aldehydes react with b-ethoxy enone 19 giving rise to 4-trifluoroacetylpyrazoles 54. A possible mecha- nism of this reaction includes replacement of the ethoxy group by the hydrazone. The subsequent cyclisation affords pyrazolines 55, which are oxidised to pyrazoles by atmospheric oxygen.92 R R COCF3 COCF3 [O] 19 N HN ButHN7N=CHR AcOH, MeCN, 20 8C, 48 ± 140 h NBut 55 NBut 54 (34% ± 66%) R= Et, Ar. It is noteworthy that the reactions of aldehyde methylhydra- zones do not give the corresponding pyrazoles.In all probability, the bulky tert-butyl group favours cyclisation resulting in the formation of intermediate 55. When the pyrazoles 54 are heated with 90% sulfuric acid, the tert-butyl group is removed, which gives N-unsubstituted 4-trifluoroacetylpyrazoles in high yields. The reactions of b-alkoxy-substituted enones with hydroxyl- amine follow different pathways, depending on the structure of the initial enone. Thus acyclic enones and enones containing no oxygen atom in the ring are converted into isoxazolines 56,9, 64, 93 which are dehydrated on treatment with P2O5 (followed by distillation of the reaction mixture) 64 or concentrated H2SO493 to give the corresponding isoxazoles 57 or 58.R2 R3 R3 COCF3 HO H2NOH. HCl, H2O, Py 35 ± 50 8C, 8 ± 16 h N R2 R1O F3C O 56 (68% ± 97%) P2O5 N R2=R3=H F3C O 57 (68%) F3C H2SO4, 35 8C, 5 h O R2±R3=(CH2)4 N 58 (90%) R1=Me, Et; R2, R3=H, Me; R2±R3=(CH2)4. Cyclic enones prepared by trifluoroacetylation of 2,3-dihyd- rofuran and 3,4-dihydro-2H-pyran are converted in a similar way at 0 ± 20 8C into isoxazolines 59, which result from opening of the furan or pyran ring. However, when the reaction is carried out at higher temperatures, it gives rise to tetrahydrofuran and tetra- hydropyran derivatives 60, formed apparently upon dehydration of aldehyde oximes 61, resulting from recyclisation of the starting enones.9 (CH2)n+1OH b OH N CF3CO CF3 O (CH2)n a 59 NC O HON (CH2)n (CH2)n c HO HO 7H2O F3C O F3C O 60 61 n=1, 2; (a) H2NOH.HCl, H2O, Py; (b) 0±20 8C, 5 ± 170 h; (c) 65±85 8C, 30 ± 170 h. V G Nenaidenko, A V Sanin, E S Balenkova Isoxazolines and isoxazoles were also obtained in good yields in the reaction of alkynyl ketones with hydroxylamine, the regiodirectivity of the reaction being dependent on the reaction conditions.91 Thus ketone 62 reacts with hydroxylamine in an alkaline medium to give isoxazoline 63; on refluxing in benzene with azeotropic distillation of water, this product undergoes dehydration to give the corresponding isoxazole 64. H2NOH, MeONa, MeOH 2 h, D n-H17C8C CCOCF3 62 O N O N PhH, D OH 7H2O CF3 n-H17C8 n-H17C8 CF3 63 64 (64%) This reaction performed in an acid medium gives initially oxime 65, which cyclises on refluxing in benzene giving rise to isoxazole 66, isomeric to the isoxazole 64. NOH PhH, D 62 H2NOH, AcOH, 10% HCl 20 8C, 15 h n-H17C8C CCCF3 65 O N CF3 n-H17C866 (80%) This reaction pathway may be due to the fact that in an acid medium, dehydration is possible, which shifts the equilibrium towards the oxime.In an alkaline medium, the formation of isoxazoline, which exists as the anion under these conditions, appears to be thermodynamically more favourable. The reactions of some b-alkoxy-substituted trifluoromethyl enones with isocyanides have been studied.94 b-Ethoxyvinyl trifluoromethyl ketone 19 reacts with cycohexyl isocyanide to give 2,5-dihydrofuran derivative 67, whereas b,b-diethoxyvinyl trifluoromethyl ketone isomerises under the same conditions to ester 68.OEt C=NC6H11-cyclo EtO COCF3 20 8C, 3 days F3C NC6H11-cyclo 19 O 67 (54%) OEt CO2Et F3C C=NC6H11-cyclo F3C 20 8C, 2 months EtO 68 (70%) O O Et When b-alkoxy-substituted enones are made to react with formamide in the presence ofNH4Cl, with compounds of the urea series 95 or with isothiouronium salts,96 trifluoromethylpyrimi- dines are formed. In the last-named case, the reaction is carried out in the presence of an acid or a base. N N CF3 HCONH2, NH4Cl 160 8C, 2 h (23%) EtO COCF3 HX 19 N X C(NH2 )2 N CF3 a or b, or c (60% ± 75%) (a) HCl, EtOH, 20 8C, 48 h (X=O, S); (b) PhH, D, 6 h (X=NH); (c) AcONa, AcOH, 100 8C, 2 h (X=p-NSO2C6H4NHCOMe).Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis R1 OR3 NH2 Py or HCl, MeOH, H2O + + MeS SO2¡¦ 4 D, 18 ¡À 79 h NH2 CF3CO R2 2 CF3 R1 N SMe R2 N (34% ¡À 94%) R1, R2=H, Me; R3=Me, Et; R1¡ÀR2=(CH2)2, (CH2)3.The reactions of b-alkoxy-substituted enones with enamino nitriles 69 result in the formation of pyridine derivatives contain- ing a CF3 group. Acyclic adducts 70 are formed as intermediates. For R1=H, they can be isolated in good yields on cooling. At room temperature, mixtures of the adducts 70 and cyanopyridines 71 are formed; refluxing of initial compounds in acetonitrile leads to pyridines 71 in high yields.97 CN X CHCl3 H2N 0¡À 5 8C, 24 h COCF3 NC COCF3 R1 70 (68% ¡À 76%) + MeCN, D, 1 h R1 OR2 X R2O 69 X N F3C MeCN D, 2 h CN R1 71 (68% ¡À 95%) Y (Y=O, NMe, NCOOEt).X= N , N Unlike reactions of enamino nitriles with alkoxyenones, which give 2-trifluoromethylpyridines, the reaction of 1,1,1-trifluoro-4- methoxypent-3-en-2-one with cyanothioacetamide results in the regioselective formation of 4-trifluoromethylpyridinethione 72, the structure of which was proved by X-ray diffraction analysis.98 The alkylation of the pyridinethiones 72 obtained by N-aryl- chloro(iodo)acetamides followed by cyclisation of the resulting compounds 73 in an alkaline medium affords 3-amino-4-trifluoro- methylthieno[2,3-b]pyridinecarboxamides 74.CF3 Me CN XCH2CONHAr NCCH2CSNH2 KOH MeO COCF3 S Me CF3 NH 72 (89%)CF3 NH2 CN KOH CONHAr DMF Me N S SCH2CONHAr Me N74 (68% ¡À 85%) 73 (73% ¡À 91%) X=Cl, I; Ar=Ph, 4-MeC6H4, 3-BuOC6H4. The reaction of the butoxy-substituted trifluoromethyl enone, prepared by trifluoroacetylation of vinyl isobutyl ether, with 1,2- diamines (o-phenylenediamine or 1,2-ethylenediamine) gives rise to 1,5-diazepine 75 or 76, while the reactions with o-aminophenols or o-aminothiophenol yield 1,5-oxazepines or 1,5-thiazepines 77, respectively. The bis(trifluoroacetyl) derivative was also intro- duced into this reaction. Good yields were attained by using microwave (MW) radiation, whereas conducting the reaction in boiling xylene resulted in a complex mixture of products (Scheme 1).99, 100 447 Scheme 1 COCF3 MW xylene, 8 ¡À 25 min X BuiO R1 NH2 HN R1(R2) R2 NH2 X R2(R1) N 75 (73% ¡À 93%) CF3 HN H2N NH2 X N CF3 76 (73% ¡À 77%) R3 NH2 HN R3 YH X CF3 YHO 77 (71% ¡À 89%) X=H, COCF3; R1=H, Me; R2=H, Me, Cl, NO2, COPh; R3=H, Cl; Y=O, S.3-Aminopyrazolo[3,4-b]pyridine derivatives 78 enter into a similar reaction as nucleophiles. On exposure to microwave radiation, trifluoromethyl-substituted derivatives of pyrido- [20,30:3,4]pyrazolo[1,5-a]pyrimidine 79 are formed in 62% ¡À78% yields (the yield in the thermal reaction is only 20%).101 R1 NH2 COCF3 MW or D + N X BuiO N R2 N78 R1 N X N CF3 N N R2 79 X=H, COCF3; R1=Me, CF3; R2=Me, Ar.4,4-Diethoxy-1,1,1-trifluorobut-3-en-2-one reacts with o-phe- nylenediamines, o-aminophenols and o-aminothiophenol to give five-membered heterocycles D benzoimidazoles, benzooxazoles and benzothiazoles D in high yields, the reaction occurring both on refluxing in toluene and on exposure to microwave radia- tion.100 R1 NH2 EtO COCF3 MW or + PhMe, D, 8 ¡À 15 min EtO R2 YH R1 N CH2COCF3 R2 Y (86% ¡À 96%) Y=O, S: R1=H, Cl; R2=H; Y=NH: R1, R2=H, Me. The reaction of b-ethoxy(phenoxy)-substituted enones with vinyl ethers affords 3,4-dihydro-2H-pyrans in good yields; thus, these enones are efficient heterodienes in the hetero-Diels ¡À Alder reaction.102448 OR2 O F3C OR2 CF3CO OR1 (72% ± 100%) 80 8C, 30 h OR1 O O F3C O R1=Et OEt (68%) R1=Et, Ph; R2=Alk, Ph.This reaction proceeds especially easily for b-alkoxy-substi- tuted bis(trifluoromethyl) enones. The presence of the second strong electron-withdrawing group, COCF3, increases the reac- tivity of trifluoromethyl enones as heterodienes. The reaction occurs at room temperature to give 5-trifluoroacetyl-3,4-dihydro- 2H-pyrans in high yields.17 OR1 OEt COCF3 COCF3 PhO EtS CF3 PhO CF3 O (100%) O (77%) SEt PhO OPh R1O COCF3 COCF3 (CH2)n OR2 O OEt OR1 COCF3 COCF3 (H2C)n R2O O CF3 CF3 O (86% ± 100%) O (85% ± 98%) R1=Et, Bui; R2=Et, Ph; n=1, 2. Aryl vinyl ethers react with trifluoroacetic anhydride to give the corresponding bis(trifluoroacetyl) derivatives.It was found 17 that these compounds are unstable and cannot be isolated in a pure state; however, they can be introduced without isolation in the reaction with a second equivalent of aryl vinyl ether. Aryloxy- substituted 5-trifluoroacetyl-3,4-dihydro-2H-pyrans 80 were obtained in this way in 50%± 68% yields. In some cases, these products are formed directly in trifluoroacetylation of aryl vinyl ethers.17 ArO ArO COCF3 (CF3CO)2O, Py ArO 40 8C, 24 h 40 8C, 5 h COCF3 OAr COCF3 ArO CF3 O 80 Ar=Ph, 4-MeC6H4, 4-BrC6H4. Ring opening in 5-trifluoroacetyl-3,4-dihydro-2H-pyrans 81 induced by secondary amines in acetonitrile gives rise to 1-amino- 4,4-bis(trifluoroacetyl)buta-1,3-dienes 82. The mechanism pro- V G Nenaidenko, A V Sanin, E S Balenkova posed for this reaction includes elimination of isobutanol, electro- cyclic ring opening and nucleophilic substitution of the amine for the ethoxy group.It is of interest that no reaction of this type occurs in the series of non-fluorinated analogues of pyrans 81.103 OBui COCF3 COCF3 7BuiOH CF3 EtO O EtO CF3 O 81 COCF3 R1R2NH EtO COCF3 COCF3 R1R2N COCF3 82 (77% ± 100%) R1=Alk, Ph; R2=Alk. One trifluoroacetyl group in bis(trifluoroacetyl)-substituted dienes 82 can be eliminated in an acid medium; this gives 1-amino- 4-trifluoroacetylbuta-1,3-dienes, which can be acylated by tri- fluoroacetic anhydride in the presence of pyridine to give the initial compounds 82.103 R1R2N 6MHCl, THF, 30 8C, 2 h 82 COCF3 (CF3CO)2O, Py, 20 8C, 4 h (59% ± 78%) 3,4-Dihydro-2H-pyran 83, prepared by hetero-Diels ± Alder reaction of b-ethoxy trifluoromethyl enone with vinyl ethyl ether, enters into a similar reaction.The dihydropyran ring opening induced by thiols in an acid medium is stereospecific and gives (E)- 1-alkylthio-4-trifluoroacetylbuta-1,3-dienes 84 in good yields.104 OEt RSH, TsOH, CH2Cl2 or PhH 40 ± 80 8C, 0.5 ± 5 h EtO CF3 O83 OEt RS CF3COOH, CHCl3 40 8C, 15 h COCF3 84 (70% ± 81%) O RS CF3 The reactions of b-ethoxy enone 19 with semicarbazide and thiosemicarbazide result in the formation of 2-pyrazoline-1- carboxamide 85 and 5-(1-thiosemicarbazido)-2-pyrazoline-1-thi- ocarboxamide 86, respectively.105 CF3 X=O OH N N a CONH2 85 (73%) COCF3 EtO CF3 H2NC(S)NHNH 19 OH X=S N N86 (22%) NH2CS (a) H2NCXNHNH2, EtONa, EtOH; NH4Cl, H2O.Apart from the synthesis of heterocycles, b-alkoxy-substituted enones have been used to prepare acyclic compounds. Thus the reaction of the lithium salt of (R)-methyl 4-tolyl sulfoxide 87 with the enone 19 (or some other perfluoroalkyl-containing enone) gives a mixture of two diastereoisomers of b-hydroxy sulfoxides 88a,b in a ratio of *1 : 1. These diastereoisomers were separated by chromatography; their configurations were determined by449 Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis 2. Reactions of b-amino-substituted trifluoromethyl enones X-ray diffraction analysis.The subsequent reduction of the sulfoxide group permits the preparation of two enantiomers of chiral allylic alcohols 89a,b with known absolute configurations in a pure state (overall yield 40% ± 94%).106 Me CF3 a OEt p-MeC6H4 S Me S + O 87 O OH 88a (26% ± 36%) CF3 OEt NaI, (CF3CO)2O, Me2O p-MeC6H4 S + 720 8C, 20 min O OH 88b (35% ± 58%) In addition to b-alkoxy-substituted trifluoromethyl enones, their b-dialkylamino-substituted analogues, readily prepared by treat- ment of b-alkoxy enones with dialkylamines, are also used for the synthesis of various trifluoromethyl-containing heterocyclic com- pounds. Since enaminones are less reactive in nucleophilic substitution than b-alkoxy enones, they are activated by virtue of POCl3 or trifluoromethanesulfonic anhydride.Thus the reac- tions of enaminones with POCl3 afford iminium salts 91a,b, vinylogues of the Vilsmeier complexes. Despite the fact that these salts are less reactive than the complex DMF. POCl3, they are still able to aminoformylate (*20 8C, 1 h), e.g., N,N-dime- thylaniline or quaternary salts of nitrogenous heterocycles 92 and 93. These reactions yield hemicyanines 94 ± 96, respectively, which are valuable intermediates in the synthesis of cyanine dyes.59 CF3 CF3 OEt OEt 77 CF3 OP(O)Cl2 p-MeC6H4S + p-MeC6H4S POCl3 R2N COCF3 + 20 8C Cl R2N OH S-89b OH R-89a 91a,b R=Me (a), Et (b). + (a) LiNPr i2,778 8C; EtOCH=CHCOCF3 (19). NEt2 91b Me2N 4 Me2N NaClO4 ClO¡ CF3 94 (65%) Trifluoroacetylated vinyl ethers (including cyclic ones) readily undergo haloform cleavage induced byKOHin boiling benzene in the presence of a small quantity of water to give a,b-unsaturated acids.8 KOH, H2O COCF3 CO2H Z Z CF3 RO RO 91b PhH, D, 1±8 h (60% ± 80%) NEt3, NaClO4 Me NEt2 X7 R=Et, Bun, Bui, Ph.N + Me N + Me ClO¡492 95 (68%) CF3CO HO2C Me KOH, H2O (CH2)n (CH2)n F3C NEt2 PhH, D, 5±7 h 91b O NEt3, NaClO4 + O (81% ± 100%) MeN n=1, 2. N + Me X7 96 (64%) 93 ClO¡4 When two equivalents of the quaternary salt 92 react with one equivalent of triethylamine and with the iminium salt 91, dicarbo- cyanines 97 are formed.59 Z Z Z CF3 a 2 Me X7 NMe N + Me N+Me ClO ¡492 97 (42% ± 60%) The replacement of the alkoxy group in b-alkoxy enones on treatment with amines occurs with high yields and the resulting enaminones are readily hydrolysed. Therefore, these enones can be used as protective reagents in peptide synthesis. Thus the b-ethoxy enone 19 reacts with amino acids in the presence of an equivalent of a base at room temperature to give the correspond- ing enaminones.The amino acids protected in this way were used to synthesise dipeptides 90. The protective group can be easily removed on treatment with 3 M HCl in dioxane at room temper- ature.107 Z=S, CMe2, CH=CH; (a) 91, NEt3, NaClO4, 20 8C, 30 min. R1 CO2H 1. NaOH, H2O, 22 8C, 1 ± 3 h COCF3 + EtO 2. 6 M HCl (pH 3) NH2 19HO2C CF3 R2(CO2R3)CHNH2 .HCl, DCC, Et3N, CH2Cl2 0 8C, 1 h R1 NH O (70% ± 89%) O The electrophilicity of iminium salts proves to be insufficient for them to react with aromatic compounds less reactive than N,N-dimethylaniline. Thus quenching with a solution of KHCO3 of the reaction mixture obtained upon the reaction between the complex of 4-dimethylamino-1,1,1-trifluorobut-3-en-2-one with POCl3 and 1,3-dimethoxybenzene gave a,b-unsaturated aldehyde 98 in 7%± 12% yield,108 more than 80% of the initial 1,3- dimethoxybenzene being recovered unchanged. HN 3 M HCl, dioxane CF3 R3O2C OMe 20 8C, 10 h 7 CF3 OPOCl2 R2 R1 KHCO3, H2O + + Cl NH O (80% ± 97%) O R2N R2 MeO R1 OMe CO2R3 NH CF3 HCl .H2N 90 (*90%) MeO CHO 98 (E:Z=7:1) R1=Me, Pri, (CH2)2CO2Me, (CH2)2CO2But, PhCH2; R2=H, Pri, PhCH2; R3=Et, But, Me; DCC is dicyclohexylcarbodiimide. Due to the low electrophilicity of the iminium salts obtained by the reaction of enaminones with POCl3 it has been proposed to450 use more reactive salt 99, formed from enaminone and trifluoro- methanesulfonic anhydride and containing a better leaving group (OSO2CF3).The reactions of this compound with electron- donating aromatic or heteroaromatic compounds under mild conditions give rise to a,b-unsaturated trifluoromethyl-contain- ing aldehydes.108 The reaction is stereoselective giving mainly E-isomers of the aldehydes; it occurs for relatively reactive compounds such as indoles, pyrroles, furans and 1,3-dimethoxy- benzene, whereas thiophene and anisole do not enter into this reaction, even when it is carried out under more rigorous conditions. (CF3SO2)2O COCF3 Me2N 75 to 0 8C CF3 ArH or HetH + OSO2CF3 Me2N 99 OSO2CF¡¦3 Ar(Het) Ar(Het) KHCO3, H2O +NMe2 F3C F3C OSO2CF¡¦3 CHO E:Z56 : 1 b-Arylamino-substituted trifluoromethyl enones cyclise on treatment with acids giving rise to 2-trifluoromethyl- (100) and 4-trifluoromethylquinolines (101).37, 52, 109, 110 As catalysts, POCl3, ZnCl2 and polyphosphoric acid (PPA) were used.Quino- lines 101 are the products of `normal' cyclisation, while the mechanism of formation of 2-trifluoromethylquinolines 100 needs to be further investigated. The ratio of the reaction products depends on the acidic catalyst used and the structure of the initial enone. Cyclisation of enones with R2=H gives only 2-trifluoromethylquinolines 100,37, 52 and when R2=Alk or Ph, 4-trifluoromethylquinolines 101 are formed predominantly.52 The presence of electron-donating substituents in the meta-positions of the aromatic amine substantially facilitates cyclisation and increases the total yield.NH COCF3 POCl3, 100 8C, 6 h or PPA, 165 8C, 3 h R2 R1 R2 CF3 and/or R2 N CF3 R1 R1 N 101 100 R1=Me, OMe, Hal; R2=H, Alk, Ph; PPA is polyphosphoric acid. R1 O Ph Ph CF3 CO2Et CO2Et N R1 N R1 B7 7 O R2 O R2 CF3 CF3 R1 O CF3 CO2Et S Ph S H CO2Et B7 Ph O CF3 CF3 V G Nenaidenko, A V Sanin, E S Balenkova The reactions of aniline derivatives with the iminium salt 99 afford 2-trifluoromethylquinolines and no 4-trifluoromethyl- derivatives.111 NH2 +99 R N CF3 R R=Me, OMe, SMe, OCF3, Cl, OH.Enaminone 102 cyclises on refluxing in a high-boiling solvent to give substituted 3-fluoromethylpyrrole 103.112 F3C COCF3 1,3,5-Me3C6H3 HNBz D, 8 h Me Bz Me NH102 103 (92%) A detailed study of the mechanism of cyclisation of such enamino ketones in the presence of a base demonstrated that the transformations of trifluoromethyl-containing ketones include not only 5-exo-trigonal cyclisation to give 3-trifluoromethylpyr- roles 104 but also previously unknown 3-exo-trigonal cyclisation, giving 2-trifluoromethylpyrroles 105. Similarly, in the case of sulfide derivatives of enones, 3-trifluoromethylthiophenes were isolated in addition to 2-trifluoromethylthiophenes (Scheme 2).113 Meanwhile, enaminones 106 cyclise in the presence of tri- fluoroacetic acid to yield 3-trifluoroacetylpyrroles.112, 114 COCF3 COCF3 CF3CO2H, H2O HN (MeO)2HC 20 ¡À 50 8C, 4 h R 106 R NH (87% ¡À 100%) R=H, Me, Ph.Reactions of 3-(diethylaminomethylidene)-1,1,1,5,5,5-hexa- fluoropenta-2,5-dione 8a (enaminodione, whose electrophilicity is enhanced by the presence of the second trifluoroacetyl group) with various nucleophiles have been studied.115 When the en- aminodione 8a reacts with aromatic amines in the presence of catalytic amounts of FeCl3, the diethylamino group is substituted to give N-aryl-substituted enaminodiones, which cyclise on treat- ment with PPA or TiCl4, the yields of the reaction products being substantially higher in the case of TiCl4.Scheme 2 R1 F3C R2 N R2 EtO2C N 7 Ph CO2Et Ph 104 (15% ¡À 64%) Ph CO2Et R2 R1 CO2Et R2 R1 N 7 N CO2Et F3 �º 7O N Ph R2 CF3 Ph 105 (26% ¡À 40%)Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis COCF3 Ar(Het)NH2 FeCl3 Et2N COCF3 8a COCF3 TiCl4, CH2Cl2, 20 8C Ar(Het)NH COCF3 (90% ± 100%) Cyclisation Ar(Het)NH product CF3 COCF3 NH N NH CF3CO F3C NH HO COCF3 N CF3 COCF3 F3C NH N N NH N N CF3 HN N COCF3 The reactions of the enaminodione 8a with bifunctional nucleophiles occur similarly to the reactions of b-alkoxy-substi- tuted enones.Thus the reaction of the compound 8a with hydrazine gives rise to trifluoromethyl-substituted pyrazole 107, while its reaction with phenylhydrazine yields a mixture of regioisomers 108 and 109 in 1 : 3 ratio.115 CF3CO H2NNH2 F3C MeCN 8a 20 8C, 4 h CF3CO PhNHNH2 F3C 108 (75%) The reactions of the enaminodione 8a with a-aminocarbonyl compounds (or their acetals)�2,2-dimethoxyethylamine or ethyl N-benzylglycinate�result in the corresponding pyrroles 110 and 111.115 In the reaction with 2,2-dimethoxyethylamine, for aroma- tisation to occur one molecule of CF3CO2H is eliminated; this is the pathway to 3-trifluoroacetylpyrrole 110.114 8a H2NCH2CH(OMe)2, CF3CO2H, H2O 20 8C, 4 h COCF3 PPA, D or COCF3 cyclisation products N Yield (%) BnNHCH2CO2Et, MeCN, 70 8C, 4 h PPA TiCl4 8a F3C 96 10 EtO2C NBn 0 15 The enaminodione 8a has also been introduced in reactions 0 90 with compounds of the urea series.The reaction of 8a with guanidine affords pyrimidine 112 in a good yield.115 The reaction with O-methylisourea affords two products � 1-methoxypyrimi- dine 113 and 1-diethylaminopyrimidine 114 � because diethyl- amine formed in the reaction reacts with methoxypyrimidine 113. Optimisation of the reaction conditions (MeCN, 65 8C, 4 h) makes it possible to prepare the target compound 113 in 65% yield. NH Me2NCNH2 100 7 8a MeCN, 20 8C, 4 h Me2N N 112 (85%) CF3 NH 60 25 N MeOCNH2 8a MeO N 113 (65%) 0 25 Thus, the enaminodione 8a is a readily available reagent, widely used for the synthesis of various heterocyclic compounds containing both trifluoromethyl and trifluoroacetyl groups.3. Reactions of trifluoromethyl enones containing no replaceable group N107 (96%) NH CF3CO + N NPh F3C N NPh 109 (25%) Trifluoromethyl enones containing no b-substituents able to be replaced are less available compounds than b-alkoxy- or b-amino- substituted enones; therefore, their reactions have not been studied so extensively. However, in the early 1990s, new methods for the synthesis of these compounds were developed (e.g., trifluoroacetylation of alkenes in the presence of the complex of dimethyl sulfide with boron trifluoride 25, 26).This stimulated vigorous studies of their synthetic potential. Trifluoromethyl enones containing no replaceable substitu- ents readily react with various bifunctional nucleophiles. Thus the reactions of phenyl-, cyclobutyl- or adamantyl-substituted enones with hydrazine result in the formation of pyrazolidines 115, which contain a gem-amino-alcoholic fragment, stabilised by the elec- tron-withdrawing influence of the CF3 group. Dehydration of the pyrazolidines 115, which occurs either during the reaction, or on prolonged storage, or on refluxing in benzene in the presence of a catalytic amount of toluene-p-sulfonic acid (depending on the nature of substituents R1 and R2) gives the corresponding pyrazo- lines.116 451 C(COCF3)2 (MeO)2CHNH COCF3 H2O 7CF3CO2H HN 110 (83%) CF3CO COCF3 Et2OC NBn COCF3 111 (96%) CF3 COCF3 N CF3 COCF3 COCF3 N + Et2N N114452 R1 COCF3 R1 CF3 H2NNH2 OH R2 7H2O EtOH, 20 8C R2 (80% ± 95%) CF3 R1 R2 HN N (90% ± 95%) R1=H, R2=Ph; R1±R2=(CH2)3, .b-Trifluoroacetylstyrene 20 reacts with substituted aryl- or alkyl-hydrazines. Thus the reaction with p-bromophenyl- and phenyl-hydrazine affords pyrazolines 116. Oxidation of the compound 116 with X=H by lead tetraacetate affords the corresponding pyrazole in a moderate yield.31 The reaction with p-nitrophenylhydrazine does not give pyrazoline; in this case, b-trifluoroacetylstyrene p-nitrophenylhydrazone 117 is formed in a low yield.p-XC6H4NHNH2 COCF3 Ph 20 Ph CF3 Ph CF3 X=H X=H, Br p-XC6H4N N CHCl3, Pb(OAc)4 N 116 (59% ± 67%) PhN(47%) Ph N NHC6H4NO2-p X=NO2 CF3 117 (14%) When b-trifluoroacetylstyrene 20 is made to react with methylhydrazine, a mixture of isomeric pyrazolines 118a,b (in *1 : 3 ratio) is formed, which is apparently due to the fact that the nucleophilicities of the nitrogen atoms in methyl hydrazine are close. The reaction with 1,2-dimethylhydrazine gives pyrazolidine 119, apparently due to the fact that elimination of water yielding a C=C bond is substantially hampered.116 Ph Ph CF3 CF3+ 2MeNHNH2 .H2SO4 AcONa, EtOH D, 5 h N NMe 118b (18%) MeN N 118a (59%) 20 Ph CF3 OH MeNHNHMe.2 HCl AcONa, THF D, 7 h MeN NMe 119 (77%) The enone 20 reacts with semicarbazide or thiosemicarbazide in an acid medium to afford semicarbazone 120a or thiosemicar- bazone 120b. These compounds are stable both in acid and alkaline media and do not tend to cyclise.105 Ph NNHC(X)NH2 20 H2NC(X)NHNH2 . HCl EtOH, D, 6 h 120a,b CF3 X=O(120a, 91%), S (120b, 93%). Conversely, the reaction with semicarbazide carried out in the presence of an equimolar amount of sodium ethoxide gives a cyclic compound, 5-trifluoromethylpyrazolidine-1-carboxamide 121.105 R1 OH R1 R2 CF3 1. H2NC(O)NHNH2, EtONa, EtOH 2. NH4Cl, H2O HN N R2 COCF3 CONH2 121 (46% ± 78%) R1=Ar, R2=H; R1±R2=(CH2)3, . V G Nenaidenko, A V Sanin, E S Balenkova The reaction occurs regio- and stereoselectively, yielding predominantly one diastereoisomer.The bulky substituents R1 and R2 occupy pseudo-equatorial positions, i.e. thermodynami- cally the most favourable isomers are produced.105 When trifluoromethyl-containing enones react with thiosemi- carbazide under the same conditions, either 3-trifluoromethyl-2- pyrazolinethiocarboxamides 122 or 5-trifluoromethyl-2-pyrazoli- nethiocarboxamides 123 are obtained, depending on the structure of the starting enone.105 CF3 R1 N N R1 NH2CS 122 (25% ± 54%) 1. H2NC(S)NHNH2, EtONa, EtOH 2. NH4Cl, H2O R2 COCF3 R1 OH R2 CF3 HN N 122: R1=Ar, R2=H; CSNH2 123 (61% ± 77%) 123: R1=Ph, R2=Me; R1±R2=(CH2)3, . Unlike pyrazolidines 115, pyrazolidine-1-carboxamides and -thiocarboxamides cannot be converted into the corresponding pyrazolines.105 The reaction of b-trifluoroacetylstyrene 20 with hydroxyl- amine in an acid medium gives rise to oxime 124, which does not tend to cyclise in either acid or alkaline medium.117 CF3 COCF3 Ph H2NOH.HCl, EtOH D, 6 h Ph 20 NOH 124 (94%) Meanwhile, the reactions of trifluoromethyl enones with hydroxylamine in the presence of an equimolar amount of sodium ethoxide give isoxazolidines 125 in good yields.117 R1 R1 OH 1. H2NOH, EtONa, EtOH 2. NH4Cl, H2O R2 CF3 R2 COCF3 HN O 125 (72% ± 93%) R1, R2=Ar, Het, Alk. The attempts to carry out dehydration of isoxazolidines 125 to isoxazolines were unsuccessful. Refluxing of these compounds in toluene with azeotropic distillation of water in the presence of toluene-p-sulfonic acid gives rise to the corresponding oxime, the initial enone being formed as a side product.At the same time, b-alkoxy enones or alkynyl ketones are converted into isoxazo- lines, which are dehydrated in an acid medium to give isox- azoles.63, 93 Thus, the possibility of aromatisation has the crucial influence on the reaction route. The isoxazolidines 125 are fairly interesting from the stereo- chemical viewpoint. They exist in solutions at room temperature as equilibrium mixtures (*1 : 1) of diastereoisomers. The energy barrier to nitrogen inversion in the compound 125 is almost a half that in the isoxazolidines described previously by Kostyanovsky et al.;118, 119 however, it is still high enough (51 ± 55 kJ mol71) 117 to retard nitrogen inversion.Therefore, the signals in the 1H and 13C NMR spectra recorded at room temperature are broadened, and when the temperature decreases, the conformation becomes `frozen' and signals for four diastereoisomers are observed (due to the chirality of the nitrogen atom). The reactions of trifluoromethyl enones with compounds of the urea series afford tetrahydropyrimidines 126 in high yields.120 The compounds 126 are easily dehydrated on refluxing in toluene in the presence of catalytic amounts of toluene-p-sulfonic acidMethods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis [unlike cyclohexane derivatives containing a C(OH)CF3 frag- ment]121 giving rise to dihydropyrimidines 127.120 R1 (H2N)2CX, EtOH D, 24 ± 120 h R2 COCF3 OH R1 CF3 R1 PhMe, TsOH R2 NH HN CF3 NH R2HN D, 6 h X 127 (87% ± 95%) X 126 (77% ± 92%) R1=H, R2=Ph; R1±R2=(CH2)3; X=O, S.In the case of b-trifluoroacetylstyrene 20, the reaction occurs stereoselectively, yielding predominantly (595%) one of the two possible diastereoisomers of 126. The configuration of the major diastereoisomer was established by X-ray diffraction analysis. This was found to be the thermodynamically more favourable trans-isomer (regarding the arrangement of the Ph and OH groups), in which the bulkiest substituents, Ph and CF3, occupy equatorial positions.Ph 4 5 HN CF3 3 1 NH H OH XIt should be noted that such stereochemistry has also been observed for cyclohexane derivatives with the same substituents at the 3- and 5-positions;121 this may be due to the relatively large effective size of the trifluoromethyl group { and to the high electron density on this group. The reaction of a sterically hindered trifluoromethyl enone having an adamantane fragment with thiourea gives dihydropyr- imidine 128.120 CF3NH COCF3 (NH2)2CS, EtOH D, 48 h S HN128 (81%) The reactions of phenyl- and adamantyl-substituted trifluoro- methyl enones with guanidine occur in a similar way giving rise to the corresponding aminopyrimidines 129 and 130. CF3 Ph (H2N)2C=NH. 12H2CO3 OH Ph N HN COCF3 EtOH, D, 9 h 20 NH2 129 (77%) CF3N (H2N)2C=NH.12H2CO3 COCF3 NH2 EtOH, D, 9 h NH 130 (81%) b-Trifluoroacetylstyrene 20 reacts with aminoguanidine to give compound 131, resulting from addition of two enone molecules to an aminoguanidine molecule and containing two heterocyclic moieties (tetrahydropyrimidine and pyrazoline).120 { The energy required for substituents to pass from an equatorial to an axial position (conformational energy) was reported 122 to increase in the sequence Me<Pri<CF3<But. 453 In this case, water is eliminated only from the five-membered ring, which is consistent with the general rule according to which trifluoro-substituted pyrazolidines are dehydrated more readily than tetrahydropyrimidines.116, 120 Ph Ph NH NH H2NCNHNH2 .H2CO3 20 N EtOH, D, 9 h N CF3 N F3C OH 131 (61%) The reactions of trifluoromethyl enones with thiourea and thioacetamide in an acid medium afford dihydrothiazines 132.123 Both reactions are regiospecific and give one isomer, formed upon the addition of sulfur at the double bond and nitrogen at the carbonyl group.This reaction route was interpreted 123 in terms of the principle of hard and soft acids and bases. OH R1 R1 COCF3 a or b CF3 R2 N S R2 R3 132 (65% ± 78%) R1=H, R2=Ph; R1±R2=(CH2)3, ; (a) (H2N)2CS, HCl, EtOH, D (R3=NH2); (b) MeC(S)NH2, EtOH, D (R3=Me). The reactions of some trifluoromethyl enones with thiols have been studied. Thus 1,1,1-trifluorodec-3-en-2-one reacts with benzenethiol to give b-oxo sulfide 133.86, 124 Bu4NF, THF n-C8H17 +PhSH COCF3 20 8C, 4 h PhS COCF3 133 (82%) n-C8H17 As opposed to this, the reaction of the enone 20 with 4-methylthiophenol gives rise to two products, b-oxo sulfide 134 and pyran 135.The compound 134 results from Michael addition, while the pyran 135 is formed upon interaction of two molecules of the ketone with one molecule of the thiol and one water molecule.124 4-MeC6H4SH, Et3N 20 EtOH, 20 8C7 Ph Ph H+ COCF3 COCF3 4-MeC6H4S 4-MeC6H4S134 Ph OH OH O COCF3 F3C CF3 H2O 4-MeC6H4S 4-MeC6H4S COCF3 Ph 135 Ph Ph The reaction is stereospecific, the compound 135 being formed as one diastereoisomer of the 16 possible isomers (the molecule has five asymmetric centres); the bulkiest phenyl, trifluoromethyl, and (4-methylphenylthio)phenylmethyl substituents occupy equa- torial positions.The relative configuration of the carbon atom located outside the ring and bearing the phenyl and 4-methylphe- nylthio substituents is also fixed. Thus, effective asymmetric 1,2- induction takes place.124 The reactions of trifluoromethyl enones with ammonium hydrogen sufide have been studied.125 The reaction pathway depends on the structure of the initial enone. For instance, the454 enone 20 reacts stereospecifically yielding tetrahydropyran 136 as one diastereoisomer of the eight possible isomers.125 H Ph S Ph Ph S CF3CO NH4SH, EtOH Ph 20 F3C 20 8C, 30 min COCF3 H H F3C HO OH 136 (92%) The reaction of ammonium hydrogen sulfide with cyclobutyl- substituted enone affords a mixture of cis- and trans-diastereo- isomers of tetrahydrothiopyran 137a,b (total yield 90%) in 1 : 1 ratio.125 S S a COCF3 + COCF3 COCF3 F3C F3C OH 137b OH 137a (a) NH4SH, EtOH, 20 8C, 3 min.The tetrahydrothiopyrans 136 and 137a are oxidised with retention of configuration, giving the corresponding sulfones 138 and 139 in almost quantitative yields. O O R1 R1 R1 R1 S S H2O2, AcOH R2 R2 R2 R2 D, 5 h COCF3 COCF3 F3C F3C OH 136, 137a OH 138, 139 R1=Ph, R2=H(136, 138); R1±R2=(CH2)3 (137a, 139). The reaction of ammonium hydrogen sulfide with adamanty- lidenemethyl ketone follows an unusual route and affords com- pound 140, containing a four-membered thietane ring, as the only product.On treatment with hydrogen peroxide in acetone or acetic acid, this product is oxidised to give 1,3-sultine 141 as a mixture of diastereoisomers.125 CF3 S COCF3 NH4SH, EtOH OH a or b 20 8C, 30 min 140 (86%) O O S OH CF3 141 (a) H2O2, Me2CO, D, 24 h (92%); (b) H2O2, AcOH, D, 1 min (61%). 1,1,1-Trifluoro-4-phenylpent-3-en-2-one with three substitu- ents at the double bond reacts with ammonium hydrogen sulfide to yield b-sulfanyl ketone 142.125 Ph Ph NH4SH, HCl, EtOH COCF3 Me 20 8C, 2 h Me COCF3 SH 142 (70%) Aryl-substituted trifluoromethyl enones were found to react with 2-sulfanylbenzaldehyde at room temperature in ethanol in the presence of a basic catalyst (triethylamine).This gives a mixture of two compounds, thiochromanes 143 and 2H-thiochro- menes 144, resulting from dehydration of 143. When the reaction mixture is refluxed for 1 h, the compounds 144 are formed in good yields. The intermediate thiochromane 143 (Ar=Ph) can be isolated in 65% yield only when the starting enone is b-trifluoro- acetylstyrene 20.124 V G Nenaidenko, A V Sanin, E S Balenkova Ar S COCF3 2-HSC6H4CHO D, 1 h Et3N, EtOH COCF3 Ar 143 OH Ar S COCF3 144 (64% ± 86%) The reactions of trifluoromethyl enones with malonodinitrile and cyanoacetamide in protic (ethanol, propan-2-ol) and aprotic (benzene) solvents in the presence of various basic catalysts (triethylamine, pyrrolidine, calcined potassium fluoride) have been studied.126 The reaction route depends on the reaction conditions and on the structure of the initial ketone.126 On refluxing in benzene with malonodinitrile in the presence of pyrrolidine as a catalyst, b-aryl-substituted enones are converted into pyrans 145.126 R CF3 R CH2(CN)2, HN COCF3 Ph O PhH, D, 4 h NC Ph 145 NH2 R=H, Me.Under the same conditions, cyclobutylidenemethyl trifluoro- methyl ketone is converted into cyclobutylidenemalonodinitrile, while adamantylidenemethyl trifluoromethyl ketone reacts in the presence of a stronger base (calcined potassium fluoride) to give adamantylidenemalonodinitrile. Apparently, in the case of ketones with an exocyclic double bond, the initial Michael addition of malononitrile is not followed by cyclisation to give pyran derivatives; instead, elimination of trifluoroacetone enolate occurs.The researchers cited suggest 126 that otherwise, cyclisa- tion products would contain a spiro-fused fragment and, as a consequence, the ring would be more strained. CH2(CN)2, HN COCF3 PhH, D, 4 h CN NC CN 7 7 CN 7CH2COCF3 COCF3 (83%) CN COCF3 CH2(CN)2, KF CN PriOH, D, 15 h (47%) The reaction of malonodinitrile with two equivalents of b-trifluoroacetylstyrene 20 in the presence of potassium fluoride in isopropanol affords substituted cyclohexanol 146, the product of addition of two molecules of the ketone to malonodinitrile and the subsequent intramolecular aldol condensation. The com- pound 146 is formed in a good yield as a single diastereoisomer of the eight possible isomers; the bulky substituents (Ph, CF3, COCF3) occupy energetically more favourable equatorial posi- tions.126 CN NC Ph Ph CH2(CN)2, KF 2 Ph COCF3 PriOH, D, 10 h 20 COCF3 CF3 HO146 (77%)Methods for the synthesis of a,b-unsaturated trifluoromethyl ketones and their use in organic synthesis The reactions of trifluoromethyl enones with malonodinitrile in the presence of ammonium acetate occur ambiguously.Only in the case of the enone 20, was pyridine derivative 147, resulting from oxidation of the corresponding dihydropyridine 148 with atmospheric oxygen, isolated in a low yield. Ph CF3 Ph CF3 [O] CH2(CN)2, NH4OAc N 20 NH NC EtOH, D, 72 h NC NH2 147 (28%) NH2 148 1,1-Dicyanobuta-1,3-dienes 149 126 were synthesised by Knoe- venagel condensation of trifluoromethyl enones with malonodini- trile in the presence of the complex TiCl4 .2Py in dichloromethane. R1 CH2(CN)2, TiCl4 .2Py CH2Cl2, 20 8C, 72 h R2 COCF3 Ph CF3 R1 CN R2 1. H2SO4, 20 8C, 6 h 2. KHCO3, H2O R1=Ph, R2=Me CN F3C CN 149 (37% ± 61%) NH2 150 (66%) R1=Ph; R2=H, Me; R1±R2=(CH2)3, . An attempt to carry out cyclisation of the compounds 149 in an acid medium was undertaken. When 1,1-dicyano-4-phenyl-2- trifluoromethylpenta-1,3-diene was treated with concentrated sulfuric acid, substituted benzonitrile 150 was obtained; in other cases, such cyclisation did not occur. It was found that on refluxing of benzylidene- and cyclo- butylidene-methyl trifluoromethyl ketones with cyanoacetamide in isopropanol in the presence of calcined KF, a stereospecific reaction occurs, giving piperidines 151a,b in high yields.126 R1 KF +NCCH2CONH2 PriOH, D, 6 h R2 COCF3 CF3 R1 OH R2 NH NC 151a,b O R1=Ph, R2=H(a); R1±R2=(CH2)3 (b).Dehydration of the piperidines 151a and 151b gives dihydro- pyridines 152a,b (a mixture of diastereoisomers in *2 : 1 ratio) and spiro compound 153, respectively. CF3 Ph Ph CF3 a 151a NH NH + NC 7H2O NC O 152b O 152a CF3 a 151b NH 7H2O NC O 153 (87%) (a) PhMe, TsOH, D, 48 h. Imino-derivatives of unsaturated trifluoromethyl-containing ketones 154 cyclise in the presence of palladium supported on carbon to give, depending on the reaction conditions, either 2-trifluoromethylquinoline derivative 155 or 5-trifluoromethyl- pyrrolidone derivatives 156.80 455 N CF3 Pd/C 200 8C CO2Me F3C CO2Me 155 (100%) O NC6H4Me 154 Pd/C, H2 NC6H4Me ButOK CF3 156 (91%) The reactions of trifluoromethyl enones with o-phenylenedi- amine afford 2,3-dihydro-1,5-benzodiazepines 157.127 The com- pounds 157 undergo spontaneous dehydration, apparently, due to the fact that this enables the energetically favourable conjugation of the resulting C=N bond with the benzene ring.R1 HN R1 COCF3 R2 o-(NH2)2C6H4 EtOH, D, 6±9 h R2 N F3C157 (75% ± 86%) R1=H, R2=Ph; R1±R2=(CH2)3, . g,d-Unsaturated trifluoromethyl-containing ketones 160 and 161 have been prepared by the reactions of b-trifluoromethylstyr- ene 20 with alk-1-enyl- (158) 128 and alk-1-ynyl-diisopropoxybor- anes (159) 62 in the presence of boron trifluoride etherate.R2 Et2O. BF3, CH2Cl2 Ph B(OPri)2 COCF3 + R1 20 ± 40 8C, 12 ± 144 h 20 158 R3 Ph R2 COCF3 R1 R3 160 (82% ± 99%) R1=Bun, Me; R2=H, Br; R3=H, Me. RC CCHPh Et2O.BF3, CH2Cl2 20+RC CB(OPri)2 40 8C, 2±12 h CH2COCF3 161 (94% ± 98%) 159 R=Bun, Ph. a-Alkoxycarbonyl-substituted trifluoromethyl a,b-enones, prepared by condensation of ethyl trifluoroacetoacetate with aldehydes, react with enamino esters 162 to afford fairly stable hydroxypyridines 163, whereas their non-fluorinated analogues are converted directly into 1,4-dihydropyridines.The hydroxy- pyridines 163 were dehydrated in the presence of a number of catalysts; the best yields were attained when the complex POCl3 . Py adsorbed on silica gel was used.129 CO2R2 Me R1 COCF3 (ClCH2)2 + D, 2±3 h H2N CO2R2 162 R1 R1 CO2R3 CO2R3 R2O2C R2O2C POCl3 . Py HO D, 3±6 h Me Me F3C F3C HN NH163 164 (76% ± 91%) The reaction of the enone 20 with b-aminocrotononitrile results in the formation of 6-trifluoromethylpyridine 165 in a low456 yield; oxidation of this product leads to the corresponding aromatic derivative 166.130 CN COCF3 + Ph Me H2N 20 Ph Ph CN CN Me F3C Me N F3C NH 166 165 The reactions of 1,1,1-trifluoro-4-methylpent-3-en-2-one with isocyanides occur at room temperature without catalysts to give stable 1,4-cycloaddition products, namely, substituted dihydro- furans 167.131 Me MeMe C NR 20 8C, 14 days Me CF3CO NR F3C O 167 (90% ± 92%) R=But, cyclo-C6H11. Treatment of perfluoroalkyl a,b-enones with reagents that are widely used for asymmetric reduction of non-fluorinated ketones (e.g., Binal-H, Darvon-red) 132 results in racemic alcohols.133 The microbial reduction of perfluoroalkyl enones by baker's yeast was studied; however, the corresponding saturated ketones rather than alcohols were formed as the major reaction products. The alcohols were formed with high enantioselectivities (ee 77%± 85%) but in very low yields.baker's yeast R R R + RF RFCO RFCO 35 ± 37 8C, 240 h (42% ± 77%) OH (3% ± 9%) RF=CF3, C2F5, n-C4F9; R=Me, Ph.The reaction of g-hydroxy enone 168, synthesised by oxida- tion of the corresponding protected allyl alcohol by the Dess ± Martin reagent, with benzenethiol affords a tetrahydrofuran derivative � hemiacetal 169. On refluxing in benzene in the presence of sulfuric acid with azeotropic distillation of water, the compound 169 eliminates water and benzenethiol being thus converted into the corresponding furan 170.84 CF3CO (CH2)2Ph PhSH, KOH, MeCN 20 8C, 2 h 168 OH F3C O O (CH2)2Ph (CH2)2Ph F3C p-TsOH HO PhH, D, 1 h 170 (46%) 169 SPh IV. Conclusion The data presented in this review can be summarised by stating that development of facile methods for the synthesis of trifluoro- methyl a,b-enones remains a topical task.Trifluoromethyl enones containing no RO, RS or R2N groups are not very easy to synthesise; nevertheless, they are highly reactive compounds possessing great synthetic potential. A remarkable feature of trifluoromethyl enones is their high reactivity towards nucleophiles combined with regio- and stereo- selectivity of the corresponding reactions. Similar reactions of their non-fluorinated analogues with nucleophiles occur non- selectively giving products in low yields or do not occur at all. 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