N-Trifluoroethylation

DesMarteau, D. D. Montanari, V. Easy preparation of bioactive peptides from the novel N -trifluoroethyl amino adds. Chem. Lett. 

Scheme 2.152 Example of the synthesis of an aryl 1 H,lH-perfluoroalkyl iodonium triflimide (11) which is sufficiently hydrolytically stable to electrophilically trifluoroethylate amino acids in an aqueous medium [26]. The N-trifluoroethyl substructure element has recently gained importance in medicinal chemistry as a means of blocking the oxidative metabolism of pharmaceuticals via the nitrogen site.

The reaction leading to amine 3935 also affords some of the expected N-trifluoroethyl analog,12,43 and some reduction of the isoquinoline ring is observed with 40.36 The reduction of three benzophenone-type carbonyl groups in a tricalix[5]arene proceeded in 95% yield.44... 

N-Trifluoroethylation of amines. The usefulness of the reagent is shown by the selective mono-A-alkylation of amino alcohols at room temperature. 

I have been told of an analogue of MDE that has been synthesized, and explored by the researcher who synthesized it. It contains the N-trifluoroethyl group common to several pharmaceuticals such as Quazepam. The analogue is... 

At 320 °C, cesium tetrafluorocobaltate converts benzotrifluoride to /n-fluo-robenzotrifluoride, 2f/-heptafluorotoluene, octafluorotoluene, pertluoro-l -meth-ylcyclohexene, and perfluoromethylcyclohexane [29] l,3-Bis(trifluoromethyl)-benzene is convened at 420 °C to 4,5,6-trifluoro-l,3-bis(trifluoroethyl)bcnzene, perfluoro-l,3-dimethylbenzene, and perfluoro-l,3-dimethylcyclohexane [29], p-Xylene gives at 350 °C l,4-bis(difluoromethyl)tetrafluorobenzene, 1-di-fluoromethyl-3-trifluoromethyltetrafluorobenzene, perfluoro-1,3-dimethyl-benzene, and perfluoro-1,3-dimethyloyclohexane... 

Chlorodeoxy sugars by thermal decomposition of O-imino ester chlorides, synthesis of. .. 192 N-( 2-Chloro-l,l,2-trifluoroethyl) -... 

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]. 

Figure 6.16 Enantioselective transesterification of N-Cbz-amino acid 2,2,2-trifluoroethyl esters.

Other important derivatives for the preparation of (i-aminoacids are the corresponding P-aminonitriles. Lipase-catalyzed N-acylations of racemic cis-2-aminocyclopentane and cyclohexane carbonitriles with 2,2,2-trifluoroethyl butanoate have been successfully carried out in organic solvents and ionic liquids [53], PSL yielding better results than CALB (Scheme 7.29). 

Recently, a very interesting preparation of P-peptides has been carried out by Kanerva and coworkers through a two-step lipase-catalyzed reactions in which N-acetylated P-amino esters were first activated as 2,2,2-trifluoroethyl esters with CALB [55]. The activated esters were then used to react with a P-aminoester in the presence of CALA in dry diethylether or diisopropylether (Scheme 7.31). In this peptide synthesis, the aminoester was used in excess and the unreacted counterpart was easily separated and later recyded. 

N-alkylation of the amide NH group at a late stage in the synthesis with trifluoroethyl iodide and NaH went... 

The cyclization of N-(2,2,2-trifluoroethyl)-A-(3-methyl-4-fluorophe-nyl)aminomethylenemalonate (764) by heating in polyphosphoric acid at 105-115°C afforded a mixture of the 5- and 7-methyl isomers (765 and 766) (79USP4146625). 

Trifluoroethyl)-l,3-dioxino[5,4-/]quinoline-9-carboxylic acid (834) was obtained by the cyclization of N-(2,2,2-trifluoroethyl)-N-(l,3-benzodioxan-6-yl)aminomethylenemalonate (833) in boiling phosphoryl chloride [77JAP(K) 142098]. 

The ring closure of A-(2,2,2-trifluoroethyl)-N-[2-(l-piperazinyl)-4-pyrimidinyl]aminomethylenemalonate (1048) in polyphosphoric acid at 200-220°C for 10 min yielded 8-trifiuoroethylpyrido[2,3- /]pyrimidine-6-carboxylic acid (1049) [77JAP( K) 139094]. 

For the P-aminocarboxamides 134-137, CALA gave very low enantioselectivity. Because no ester function was present in the substrate, N-acylation proceeded satisfactory with CALB as the catalyst and trifluoroethyl butyrate as the acyl donor in t-butylmethyl ether/t-amylalcohol (TBME)/(TAME) mixtures at 45 °C (Scheme 4.40) [131]. 

Nakai, T. Tanaka, K. Ishikawa, N. The reaction of 2,2,2-trifluoroethyl iodide with sodium phenolate. A novel competition between substitution and elimination reactions. /. Fluorine Chem. 1977, 9, 89-93. 

Thymidine (85.4 g 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-l,l,2-trifluoroethyl)diethylamine (100.3 g 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70°C for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol 60.3%) of 2,3 -anhydrothymidine melting point 228°-230°C. 

Rarely is the substituent on nitrogen modified but there are occasional examples. The racemic bicyclic ft-lactams having medium to large rings have been resolved using enzymes. Lipase PS in the presence of vinyl butanoate converted (48%) racemic r-/3-lactams 210 (n = 3) in dry acetone into resolved CM-alcohol 211 (n = 3) and the rfr-ester 212 (n = 3) with ee 97% (Equation 24). A better result was obtained for racemic cis /3-lactam 210 (n = 5 and 8) when vinyl butanoate, was replaced by 2,2,2-trifluoroethyl butanoate, but the ee for 212 ( = 5) was 82% and the ee value for 212 (n = 8) could not be determined. A similar reaction with racemic rra j-/3-lactam ( = 8) required the use of CAL-B (a lipase from C. antarctica) and vinyl butanoate, and the ee value for the tram-alcohol 213 was 85% but the value for the ester 214 could not be determined <2003TA3805>. 

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