Trifluoroethyl acetate

Kutsuna, S., Chen, L., Ohno, K., Tokuhashi, K., and Sekiya, A. Henry s law constants and hydrolysis rate constants of 2,2,2-trifluoroethyl acetate and methyl trifluoroacetate, Atmos. Environ., 38(5) 725-732, 2004. 

Racemization of (S)-l-phenylethanol in the presence of an Ru p-cymerie binu-clear complex and triethylamine was much faster in [BMIm][BF4] or [BMIm][PF,s] than in toluene [136]. A range of chiral alcohols (Figure 10.17) were resolved in the presence of this complex and immobilized PsL. The reactions were performed in [BM Im][PF6] with the activated ester 2,2,2-trifluoroethyl acetate as the acyl donor (Figure 10.17). A hydrogen donor was required to prevent the formation of partially oxidized byproducts. Enantiomerically pure acetates were isolated in high yield (>85%). 

Fig. 10. Rates of imidazole-catalyzed ester hydrolysis as a function of the rate of alkaline hydrolysis nucleophilic reactions of acetates, general base catalysis of acetates, a general base catalysis of methyl and ethyl esters, o (ionic strength 1-0 25°). Trifluoroethyl acetate measured with N-methylimidazole. From Kirsch and Jencks (1964a). Reproduced with permission of the American Chemical Society. (> = NOAc = acetoxime acetate).

Unlike the first step, the saponification is highly selective. The synthesis of the 2,2,2-trifluoroethyl acetate 5 requires high temperature (150-180°C) and pressure (15 bare). This reaction involves polar aprotic solvents such as NMP, DMSO and sulfolane. The major drawbacks of this process are corrosion and waste water disposal. 

A number of selective acylations and deacylations catalysed by enzymes, especially by lipases in organic solvents, have been reported. Methyl pentofuranosides could be selectively acetylated at 0-5 on a preparative scale by use of a lipase and 2,2,2-trifluoroethyl acetate as acyl donor in THF, while selective hydrolysis could be effected at the primary positions of peracetylated methyl pentofuranosides and hexopyranosides, and at the anomeric centres of peracetylated D-rilao- and D-xylo-furanoses and -pyranoses with lipases in aqueous DMF. ° Methyl -D-glucopyranoside, D-mannose, and 2-acetamido-2-deoxy-D-mannose were all substituted selectively at 0-6 by lipase-mediated... 

We found thaf fhe cymene-Ru complex 2b displayed good activity as the racemization catalyst in ionic liquids such as [EMImjBF ([EMIm]=l-ethyl-3-methylimidazolium) and [BMImjPFg ([BMIm]=l-butyl-3-methylimidazolium) at room temperature. Thus the first DKR in ionic liquid was achieved using lipase PS-C, 2b, and trifluoroethyl acetate as the acyl donor at room temperature (Scheme 5.14 and Chart 5.11) [20]. The products were readily removed by simple extraction with ether, and the remaining ionic liquid containing enzyme and Ru catalyst was reused without further treatment for the second run. This easy recovery and recycling of reaction medium and catalysts is a big advantage of DKR in ionic liquid. 

Nucleophilic Substitution of Hemiacetal Sulfonates. The resolved sulfonates were allowed to react with various organometallic reagents. In contrast to the corresponding acetaldehyde hemiacetal carboxylates, 1 -benzyloxy-2,2,2-trifluoroethyl acetate did not react with Bu2CuLi LiI/BF3 OEt2. However, we were pleased to find that the treatment of (R )-( )-mesylate of 61% ee with triethylaluminum in toluene at -20 °C gave (-)-2-benzyloxy-l,l,l-trifluorobutane in 66% yield with 46% ee. The absolute configuration of the product was determined by the synthesis of an authentic sample from (S)-l,l,l-trifluoro-1,2-epoxy propane. 

Condensation of sodium phenoxide witli 2,2,2-trifluoroethyl iodide gives a product of direct substitution in a low yield, several other ethers are formed by eliminatton-addition reactions [7] Use of mesylate as a leaving group and hex amethyl phosphoramide (HMPA) as a solvent increases the yield of the substitution [S] Even chlorine can be replaced when the condensation is performed with potassium fluoride and acetic acid at a high temperature [9] (equations 6-8)... 

In the preparation of the thiazides containing more highly functionalized side chains (183-185), an acetal of the aldehyde is usually used rather than the free carbonyl compound. Thus, trichlomethiazide (183) is prepared by reaction of 160 with the dimethyl acetal from dichloroacetaldehyde. In a similar vein, alkylation of the acetalthiol, 190, with allyl bromide affords 191. This yields altizide (184) on condensation with 160. Alkylation of 190 with 2,2,2-trifluoroethyl iodide gives 192. This leads to epithiazide (185) on condensation with 160. 

C) Preparation of 2-Methyl-3-(2,2,2-Trifluoroethyl)Thiomethyl-6-Chloro-7-Sulfamyl-3,4-Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide To 4.6 g (0.015 mol) of 4-amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide in 30 ml of the dimethyl ether of ethylene glycol is added 4.08 g (0.02 mol) of 2,2,2-trifluoroethylmercaptoacetaldehyde dimethylacetal followed by 1 ml of ethyl acetate saturated with hydrogen chloride gas. The resulting solution is refluxed for 1.5 hours, cooled and then slowly added to cold water dropwise with stirring. The crude product is filtered, dried and recrystallized from isopropanol (3.2 g), MP 202° to 202.5°C. A second recrystallization from isopropanol raised the MP to 202°... 

On heating with sodium borohydride in glacial acetic acid. 5//-dibenz[/t,/ azepine (5) undergoes sequential acylation and reduction to yield 5-ethyl-5/7-dibcnz[A,/ ]azepine (8, R = Et).192 Similarly, reduction in trifluoroacetic acid produces the trifluoroethyl derivative 8 (R = CF3CH2 61% mp 69-70 C).193... 

DKR of esters bearing an electron-withdrawing group at the ot-carbon can be performed easily under mild reaction conditions due to the low pKa of the oc-proton. Tsai et al. have reported an efficient DKR of rac-2,2,2-trifluoroethyl ot-chorophenyl acetate in water-saturated isooctane [40]. They used lipase MY from C. rugosa for the KR and trioctylamine as the base for racemization. (R)-chlorophenylacetic acid was obtained in 93% yield and 89.5% ee (Figure 4.15). 

Since these methoxylated and acetoxylated sulfides have an acetal structure, it is expected that Lewis acid catalyzed demethoxylation should generate a carbocation intermediate which is stabilized by the neighboring sulfur atom. In fact, nucleophilic substitution with arenes has been successfully achieved as shown in Scheme 6.7 [43], This procedure is useful for the preparation of trifluoroethyl aromatics. As already mentioned, generation of carbocations bearing an a-trifluoromethyl group is difficult due to the strong electron-withdrawing effect. Therefore, this carbon-carbon bond formation reaction is remarkable from both mechanistic and synthetic aspects. 

In a similar context, 6-18F-3,4-dihydroxyphenylalanine (6-18F-DOPA) was synthesized by direct fluorination of L-3-(3-hydroxy-4-pivaloxyphenyl)alanine (ra-P-DOPA) with Ac018F in acetic acid resulting in the 2- and 5-18F isomers. Hydrolysis of the reaction mixture in hydrochloric acid followed by HPLC separation gave 6-18F-DOPA (equation 23)44. Another application of Ac018F was reported in the synthesis of a trimethyl tin precursor of 2-oxoquazepam, 7-chloro-1 -(2,2,2-trifluoroethyl)-1,3--dihydro-5-(2-fluorophenyl)-2//-l,4-benzodiazepin-2-one, a benzodiazepine agonist, and its conversion to [18F]-2-oxoquazepam by reaction with AcQ18F (equation 24)45. 

BIS(TRIFLUOROETHYL) (CARBOETHOXYMETH YL)PHOSPHONATE (Acetic acid, [bls(2,2,2-trlfluoroethoxy)phosphlnyl]-, ethyl ester)... 

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