A-Trifluoromethyl esters

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. 

Andreev and co-workers have undertaken extensive studies on the reactions of allyl, crotyl, and propargyl alcohols with 2-substituted pentafluoropropenes 14.11 Allyl and crotyl alcohol react at 5-20 C with various 2-substituted pentafluoropropenes 14 in the presence of potassium fluoride in dimethylformamide to give -substituted a-(trifluoromethyl) esters 16. Saponification yields the corresponding acids. 

Keywords a-Trifluoromethylated esters, vinyl ketones, XPhos (I), organocatalyst, N,N-dimethyformamide, room temperature, Michael reaction, Michael adducts... 

To a solution of XPhos (I 0.01 mmol) in DMF (0.4 mL) were added a-trifluoromethylated ester (1 0.2 mmol) and a,p-unsaturated ketone (2 0.6 or 0.8 mmol), and the mixture was then stirred at room temperature for 1 h (monitored by F NMR spectroscopy). Upon completion of the reaction, it was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine, dried over sodium sulfate, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ EtOAc) to yield the desired product 3. All the products were characterized with the help of detailed spectral measurements. 

The enantiomeric excesses of the cyanohydrins obtained are determined via the diastereomcric Mosher esters with (/ )-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride16 by GC. 

The enantiomeric excess values of the (S)-cyanohydrins are obtained from the ( + )-(R)-Mosher ester derivatives [a-methoxy-a-(trifluoromethyl)phenylacetates], whereas the corresponding benzeneacetic acids are first converted into their isopropyl carboxylates which then yield the ( + )-(ft)-Mosher ester derivatives. 

Lipase-catalyzed methanolysis of racemic N-benzyloxycarbonyl (Cbz) amino acid trifluoroethyl esters carrying aliphatic side chains afforded the L-methyl esters and the D-trifluoromethyl esters (Figure 6.16). The released alcohol (CF3CH2OH) is a weak nucleophile that cannot attack the ester product. The nucleophilidty of the leaving group is depleted by the presence of an electron-withdrawing group [63]. 

The enantiomeric excess (ee) of the hydrogenated products was determined either by polarimetry, GLC equipped with a chiral column or H-NMR with a chiral shift reagent. Methyl lactate and methyl 3-hydroxybutanoate, obtained from 1 and 2, respectively, were analized polarimetry using a Perkin-Elmer 243B instrument. The reference values of [a]o(neat) were +8.4° for (R)-methyl pyruvate and -22.95° for methyl 3-hydroxybutcinoate. Before GLC analysis, i-butyl 5-hydroxyhexanoate, methyl 5-hydroxyhexanoate, and n-butyl 5-hydroxyhexanoate, obtained from 1, 5, and 6, respectively, were converted to the pentanoyl esters, methyl 3-hydroxybutanoate was converted to the acetyl ester, and methyl 4-methyl-3-hydroxybutanoate obtained from 2 was converted the ester of (+)-a-methyl-a-(trifluoromethyl)phenyl acetic acid (MTPA). 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

H and13C NMR Data. Some typical proton and carbon NMR data for trifluoromethyl ethers, sulfides, and esters are given in Scheme 5.11. Continuing the trend observed going from CH2F to CF2H to CF3 carbons, the 13C chemical shift of a trifluoromethyl ether is actually more shielded (by about 5 ppm) than that of a trifluoromethyl hydrocarbon. Scheme 5.12 summarizes the relative impact of an ether substituent upon the chemical shifts of various fluorinated carbons. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Trifluoromethyl)trimethylsilane has been prepared by a modification5 of the procedure originally published by Ruppert.4 The optimized yield is 75%. Other less convenient methods are also available for its preparation. (Trifluoromethyl)trimethylsilane acts as an in situ trifluoromethide equivalent under nucleophilic initiation and reacts with a variety of electrophilic functional groups. Carbonyl compounds such as aldehydes, ketones and lactones react rather readily5 7 with (trifluoromethyl)trimethylsilane under fluoride initiation. The reagent also reacts with oxalic esters,8 sulfonyl fluorides,9 a-keto esters,10 fluorinated ketones,11 and... 

Smooth conversion of ( )-(—)-neocarazostatin B (268) to carquinostatin A (278) was achieved by oxidation using ceiium(IV) ammonium nitrate (CAN). The identity of the absolute configuration of both alkaloids, and also the enantiopurity of neocarazostatin B (>99% ee), has been additionally confirmed by the transformation of carquinostatin A (278) to the (l ,l )-]VIosher ester 822 by reaction with (S)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl (MTPA) chloride (613) (Scheme 5.97). 

A somewhat different approach is used for the preparation of the analogue that contains a trifluoromethyl group. The scheme involves first the conversion of ort/zo-trifluoromethyl aniline (27-1) to a quinolol. The compound is thus condensed with EMME and cyclized thermally (27-2). That intermediate is then saponified the resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (27-3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (27-4) then affords the coupled intermediate (27-5). An ester interchange of that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID flocatfenine (27-6) [31]. 

Recently, Ishihara and coworkers demonstrated that zinc-mediated reaction of 2-bromo-2,3,3,3-tetrafluoropropanoate with chiral imines afforded three- and erythro-i omscs, of a-fluoro-a-(trifluoromethyl)-/3-amino esters in good yields with high diastereomeric excess (equation 121)178. 

Barbier conditions have been utilized by Wakselman et al. to carry out reactions of trifluoromethyl bromide with aldehydes, a-keto esters, activated esters and anhydrides in the presence of pyridine to give trifluoromethylated compounds [51,52] (Scheme 18). 

Decarboxylation of (bromodifluoromethyl)malonates (9) reminiscent of Krapcho s deal-koxycarbonylation process, is observed on treatment with potassium fluoride in dimethyl sulfoxide at 170 °C to give 2-(trifluoromethyl)-substituted esters 10.43 The precursors are prepared by reacting diethyl malonates 8 with dibromodifluoromethane in the presence of sodium hydride. The exchange of bromine for fluorine in 9 followed by decarboxylation is an excellent method of introducing a trifluoromethyl group a- to an ester group. 

The conversion of the bromodifluoromethyl group to a trifluoromethyl group is only possible after cleavage of one ester group. The direct SN2 displacement of bromide ion by fluoride ion is prevented by electronic and steric factors. 

Aldrich Chemical Company, Inc., and were used without further purification. Dichloromethane used in the preparation of the Mosher ester was obtained from EM Science and was distilled from calcium hydride under a nitrogen atmosphere. (R)-(-)-a-Methoxy-a-(trifluoromethyl)phenyfacetyl chloride was prepared from (S)-(-)-a-methoxy-a-(trifluoromethyl)phenylacetic acid, as described in Note 21. 

The esters of As(SeH)3 are more difficult to prepare than the oxygen or sulfur analogues. They are all either solids or high boiling oils, and their structures are almost certainly pyramidal. Darmadi et al.AS prepared the trifluoromethyl ester using Hg(SeCF3)2, which is a yellow oil (m.p. -31 °C) (equation 11). 

Table 8. Stereoselective Ester Enolate [2,3] Wittig Rearrangement of Substituted Methyl (Z)-2-[(4,4,4-Trifluorobut-2-enyl)oxy]acetates (Z)-25 to y.ti-U nsaturated anti-( )-a-Hydroxy-/3-(trifluoromethyl) Esters (E)-2617...

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