A-trifluoromethylated amines

The reaction ot tormamides with sulfur tetrafluoride in the presence of potassium fluoride leads to replacement of both carbonyl oxygen and hydrogen with fluorine. The formyl group is directly converted into the trifluoromethyl group A-(trifluoromethyl)amines are formed in near quantitative yields [233] (equation 121)... 

Nucleophilic Perfluoroalkylation of Nitrones The reaction of a,N-diaryl nitrones with (trifluoromethyl)trimethylsilane (TMSCF3) gives O-trimethylsilyl ethers of a-(trifluoromethyl)-hydroxylamines. This reaction is initiated by potassium ten -butoxide. Removal of the trimethylsilyl group on acid treatment leads to a-(trifluoromethyl)hydroxylamines, whereas catalytic hydrogenation gives a-(trifluoromethyl)amines (Scheme 2.194). 

Conversion of tertiary formamides into A-(trifluoromethyl)amines involves a reduction-oxidation process in which sulfur tetrafluoride is reduced to elemental sulfur.175 Both /V,/V-dial-kyldifluoro(phenyl)methy la mines and A -(trifluoromethyl)amines are mild fluorinating reagents for the replacement of hydroxy groups by fluorine.176... 

Katagiri, T. Takahashi, M. Fujiwara, Y. Diara, H. Uneyama, K. General syntheses of optically active a-trifluoromethylated amines via ring-opening reactions of A-benzyl-2-trifluoromethylaziridine. J. Org. Chem. 1999, 64, 7323. 

Scheme 8.76 Enzymatic DKRs of a-trifluoromethylated amines with Pd/AlaOa.

In 2013, Lin and co-workers reported enzymatic resolution of a-trifluoromethylated amines via DKR employing a combination of CALB with palladium on a support of Al203. As shown in Scheme 8.76, aromatic a-trifluoromethylated amines as well as aliphatic amines were achieved in up to 62 to 82% yields, respectively, and enantioselectivities of up to >99% ee. Moreover, the catalyst system could be recycled for at least five times retaining 70% conversion and 99% ee value in the case of 2,2,2-trifluoro-l-phenylethanamine as substrate, for example. Interestingly, stereoselectivity... 

The asymmetric, phosphoric acid (348) catalysed synthesis of aromatic and heteroaromatic a-trifluoromethylated amines (356) from trifluoro-methyl imines (355), has been achieved by Akiyama in good to excellent yields (72-99%) with overall excellent enantioselectivities (96-98%) (Scheme 94). 

The numerous preparations of mono-, di-, tri-, and hexafluoro derivatives of valine, norvaline, leucine, norleucine, and isoleucine, using classical methods of amino acid chemistry (e.g., amination of an a-bromoacid, " azalactone, Strecker reaction, amidocarbonylation of a trifluoromethyl aldehyde, alkylation of a glycinate anion are not considered here. Pure enantiomers are generally obtained by enzymatic resolution of the racemate, chemical resolution, or asymmetric Strecker reaction. ... 

Indium-mediated diastereoselective allylation of L-glyceraldimines with4-bromo-1,1,1-trifluoro-2-butene provided stereoselectively, after further steps, enantiopure 4,4,4-trifluorovaline or 4,4,4-trifluoroisoleucine." ° Enantiopure hexafluorovahnes have been prepared by separation of the diastereomeric mixture resulting from the Michael addition of a chiral amine onto an ester of bis(trifluoromethyl) acryhc acid. Presence of the two CF3 groups reverses the orientation of the Michael addition (Figure 5.7)." ... 

Aliphatic amino acids are converted into (trifluoromethyl)amines 12 by treatment with sulfur tetrafluoride in hydrogen fluoride. Hydrogen fluoride simultaneously protects the amino group by protonation and serves as a catalyst.113 The reactions proceed with retention of configuration. Yields of (trifluoromethyl)amines from a-amino acids vary from very low to approximately 40% and are limited by the formation of dioxopiperazines.113... 

Secondary a-amino acids in which formation of dioxopiperazines is hindered, c.g. A-dodec-ylalanine (13), give better yields of the corresponding (trifluoromethyl)amines.113... 

Similarly, A -alkyl-A -arylthiocarbamoyl chlorides react with sulfur tetrafluoride to give the corresponding (trifluoromethyl)amines, e.g. 3.206... 

In a similar way, dimethyl(trifluoromethyl)amine (55% yield, bp 20 C) and diethyl(tri-fluoromethyl)amine (63% yield, bp 70-71 C) can be obtained by fluorination of dimethyl-and diethyl(trichloromethyl)amine with antimony(III) fluoride.27... 

Diethyl(trifluoromethyl)amine (19 14.1 g, 0.1 mol) was added dropwise to i-PrOH (22 6g, 0.1 mol) at 40CC with stirring, an exothermic reaction occurred and the mixture was brought to reflux. Once the addition was complete the mixture was stirred for a further 15 min. The volatile 2-fluoropropane (23) which evolved during the course of the reaction was condensed into a cold trap at — 78°C yield 4.6 g (74%). An identical yield was obtained when the same procedure was performed with [difluoro(phenyl)-methyl](dimethyl)amine (21) instead of 19. 

With primary and secondary amines, the aminolysis of a trifluoromethyl group to a carbonitrile group is not possible nevertheless, under these reaction conditions, analogs of carboxylic acids, c.g. amidines,51,52 amides29,53 - 55 or thioamides,56 are formed. 

A catalytic asymmetric in situ reduction of N-H imines has been achieved in a sequence in which trifluoroacetophenones, ArCOCF3, are first converted to silylimines [using LiN(SiMe3)2], and then on to give trifluoromethylated amine salts, Ar-C(CF3)-NH2.HC1, in good to excellent yield and ee.5s The intermediate N-H imines can be isolated via methanolysis of the N-Si bond, while the enantioselective reduction can be carried out using a chiral borane auxiliary. 

Addition of lithium bis(trimethylsilyl)amide to perfhiorinated ketones and solvolysis of the N-Si bond in methanol resulted the formation of stable, isolable N-H imine Z-E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures with oxazaborolidine catalysts and catecholborane provided trifluoromethylated amines in 72-95% yields and 75-98% ee 267... 

Since Kagan s first report of N-N bond reduction using Sml2,39 the reagent is now routinely used for the transformation. The reaction has been used widely in asymmetric synthesis to reduce the products of asymmetric additions to, or reductions of,47 hydrazone derivatives. For example, Enders reported the nucleophilic addition of alkyllithiums to trifluoroacetaldehyde SAMP and RAMP hydrazones in an asymmetric approach to a-trifluoromethyl-sub-stituted amines.48 After activation of the adducts by benzoylation, Sml2-mediated N-N bond cleavage proceeded in high yield (Scheme 4.41). 

A-[l-Chloro-2,2,2-trifluoro-l-(trifluoromethy)ethyl]-A-(dimethylaminomethylene) amine (291) gave 2,3-bisdhnethylamino-5,5,6,6-tetrakis (trifluoromethyl)-5,6-dihydropyrazine (292) (I i3N, MeCN, 20°C, 3 h 50% structure confirmed by X-ray analysis).1323... 

Reactions of the mercurial with halogens or interhalogens lead to the formation of a series of pentafluorosulfanyl AMialo(trifluoromethyl) amines, SF5N(X)CF3 (X = F, Br, Cl, I) (210). 

Depending on the fluorinating reagent used, the reaction of imines leads to different fluorination products. Treatment of Schiff bases with trifluoromethyl hypofluorite gives A,A-difluoro amines under mild reaction conditions however, if the reaction is carried out using A-fluoro-bis(trifluoromethanesulfonyl)amine (TfjNF), a-monofluoro 2 and/or a,a-difluoro ketones 3 are obtained (Table 11). ... 

Both the radical (photochemically promoted)36 and ionic addition (in the dark), via NeX dissociation37, of jV-halo-bis(trifluoromethyl)amines to (Z)- and ( )-2-butene in the gaseous phase (sealed Pyrex tube) afforded /6-halo amines (93-99% yield). A 100% anti addition was observed in the ionic process37. In the radical process, better selectivity (antijsyn addition 90 10) was obtained from (Z)-2-butene and the A-chloro amine36. The determination of the configuration of the adducts is based on H NMR evidence. 

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