Trifluoropyruvates

C-alkylation of secondary and tertiary aromatic amines by hexafluoroacetone or methyl trifluoropyruvate is performed under mild conditions [172] (equation 147) The reaction of phenylhydrazme with hexafluoroacetone leads selectively to the product of the C-hydroxyalkylation at the ortho position of the aromatic ring The change from the para orientation characteristic for anilines is apparently a consequence of a cyclic transition state arising from the initial N hydroxy alky lation at the primary amino group [173] (equation 148)... 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

On reaction of methyl trifluoropyruvate with phosphorus pentachlonde 1,1,2,2 tetrachloro-3,3,3-trifluoro-l-methoxypropane IS obtained [273] Hexafluo-roacetone hydrazone is oxidized to bis(tnfluoromethyl)diazomethane upon tieat-ment with phosphorus pentachlonde [274]... 

Burger2 has shown that alkynes undergo both Lewis acid-catalyzed and thermal carbonyl-yne reactions with 3,3,3-trifluoropyruvates to give allenes. Reaction of 1 (Equation (2)) occurs to give a 1 1 mixture of diastereomeric allenyl carbinols 2. Alternatively, reaction of hexyne 1 and methyl trifluoropyruvate with MgBr2-OEt2 at low temperature afforded 2 as an 8 1 mixture of diastereomers. The thermal reaction does not suffer from allylic alcohol byproducts arising from reaction of the substrate with the Lewis acid.3... 

An asymmetric intermolecular carbonyl-ene reaction catalyzed by 1 mol% of chiral A-triflyl phosphoramide (/ )-4t (1 mol%, R = 4-MeO-CgH ) was developed by Rueping and coworkers (Scheme 69) [88], Various a-methyl styrene derivatives 163 underwent the desired reaction with ethyl a,a,a-trifluoropyruvate 164 to afford the corresponding a-hydroxy-a-trifluoromethyl esters 165 in good yields along with high enantioselectivities (55-96%, 92-97% ee). The presence of the trifluoromethyl group was crucial and the use of methyl pyruvate or glyoxylate instead of 164 resulted in lower reactivities or selectivities. 

Scheme 69 Carbonyl-ene reaction of a-methyl styrenes and ethyl a,a,a-trifluoropyruvate...

Trifluoroalanine has also been prepared by reducing trifluoropyruvate imines (ethyl trifluoropyruvate is available commercially it is prepared either from per-fluoropropene oxide or by trifluoromethylation of ethyl or f-butyl oxalate). These imines are obtained by dehydration of the corresponding aminals or by Staudinger reaction. They can also be obtained by palladium-catalyzed carbonylation of trifluoroacetamidoyl iodide, an easily accessible compound (cf. Chapter 3) (Figure 5.4). Reduction of the imines affords protected trifluoroalanines. When the imine is derived from a-phenyl ethyl amine, an intramolecular hydride transfer affords the regioisomer imine, which can further be hydrolyzed into trifluoroalanine. ... 

Asymmetric hydrogenation of imines derived from trifluoropyruvate, in the presence of a chiral complex of palladium (ligand = (R)-BINAP), affords ethyl (/f)-trifluoroalaninate with ca. 90% The ee values strongly depend on the solvent,... 

Good stereoselectivities have been obtained with the addition of organometallics onto homochiral cyclic acylimines (Figure 5.27), or onto sulfmylimines derived from trifluoropyruvate (Figure 5.28). " Asymmetric Strecker reaction of jS-sulfmyl... 

The acyl imines of methyl trifluoropyruvate react as heterodienes with electron-rich olefins in [4 + 2] cycloadditions, as exemplified by the synthesis of trifluoro-methyl aspartic acid (Figure 5.29). ... 

A slight modihcation of this procedure using A-acyl-a-amino acids obtained from trifluoropyruvic acid and the corresponding nitrile has been described. In... 

Trifluorovinylstannane has been successfully employed in the Stille crosscoupling reaction with aryl or vinyl halides in the presence of a palladium catalyst [190, 191] (Scheme 68). Recently, ethyl 3-(tributylstannyl)-2-methoxyacrylate was prepared from ethyl trifluoropyruvate in several steps and used in the Stille reaction for the synthesis of a-fluoro-keto acid derivatives [192] (Scheme 69). 

Uneyama has described some interesting reactions of the N-aryl imines of ethyl trifluoropyruvate. Tandem alkylation/defluorination occurred (Eq. 97) upon exposure to diethylzinc, via attack at nitrogen and SN2 displacement of fluoride anion [279]. Interestingly, an alkylzinc halide reagent attacked regioselec-tively at carbon, perhaps the more expected outcome. 

Trifluoropyruvic acid hydrate reacts with /V-benzylurea to give 3-ben zyl-5-hydroxy-5-tnfluoromethyl-2,4 imidazoledione [/07] (equation 93). 

Semicarbazide hydrochloride [705] and amidrazones [106] react with trifluoropyruvates to give six-membered heterocycles A variety of trifluoromethyl substituted heterocyclic systems is available, starting from the hydrate of trifluoropy-ruvicacid, a versatile 1,2-bielectrophilic building block (reaction type 2, equation 10) [107] (equation 24). 

Prakash, Olah, and co-workers256 have prepared Mosher s acid analogs by the hydroxyalkylation of substituted benzenes with ethyl trifluoropyruvate [Eq. (5.95)]. Deactivated aromatics (fluorobenzene, chlorobenzene) required the use of excess triflic acid indicative of superelectrophilic activation.3 5 In contrast to these observations, Shudo and co-workers257 reported the formation gem-diphenyl-substituted ketones in the alkylation of benzene with 1,2-dicarbonyl compounds [Eq. (5.96)]. In weak acidic medium (6% trifluoroacetic acid-94% triflic acid), practically no reaction takes place. With increasing acidity the reaction accelerates and complete conversion is achieved in pure triflic acid, indicating the involvement of diprotonated intermediates. 

Condensation of 2-aminobenzylamine with methyl 3,3,3-trifluoropyruvate gave a mono-adduct C11H13F3N2O2 in almost quantitative yield which reacted smoothly with cyclohexanone in diethyl ether at room temperature to give a mixture of 1 and 2 in 38 and 28% yield respectively. 

Methyl trifluoropyruvate alkylates a series of substituted indoles catalysed by the chiral non-racemic 2,2/-bipyridylcopper(II) triflate complex (32) to form methyl 3,3,3- trifluoro-2-hydroxy-2-indole-3-yl propanoates [e.g. (33)] in high enantiomeric excess and good yield.37... 

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