Trifluoromethyl ketimines

An A-phosphinoylhemiaminal (3) has been used as a precursor to trifluoromethyl-ketimines (4) in situ alkylation with a dialkylzinc in the presence of a diphosphine monoxide auxiliary gives chiral , ,o -trifluoromc(.hyl amines (5) in high yield and ee up to 99%.16... 

Scheme 1.7 Preparation of trifluoromethyl substituted ketimines via the ethanolate adduct.

The only example of an N-sulfonyl ketimine participating in an ene reaction involves the tosyl imine of trifluoroacetone 266 [90] [Eq.(62)]. When heated with a terminal olefin such as allyl benzene (265) in refluxing xylene, imine 266 leads to ene product 267 in moderate yields. However, internal alkenes gave significantly lower yields of ene products. The inefficiency of the ene process with more highly substituted olefins was ascribed to unfavorable steric effects due to the bulky trifluoromethyl groups. Interestingly, with /J-methyl styrene and allyl thiophenyl ether, [2+2]-cycloadducts were detected rather than ene products. 

The trifluoromethyl-ketimine (90.4), on reaction with a strong base, is converted into a 2-phenylquinoIine in a novel type of cyclization in which the three fluorine atoms are displaced by nucleophiles. According to the base used, the quinoline may have either an oxygen or a nitrogen substituent at C-4. The t-butyl ether (R = tBu) is converted into the quinolinol (R = H) in high yield [3908]. 

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

Scheme 19.30 Enantioselective aza-Heniy reaction of cyclic trifluoromethyl ketimines catalysed by thiourea 23.

A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphi-noylimines has been developed for the synthesis of chiral a,a,a-trifluoromethyl-amides (249). Ketimines (250), generated in situ from the corresponding hemiaminals, led to the chiral amides in high yields and excellent enantiocontrol (Scheme 101). ... 

Vovk et al. have described the first synthesis of chiral p-aryl-p-trifluoromethyl-p-aminoketones based on an L-proline-catalysed Mannich reaction between aryl trifluoromethyl ketimines and acetone. As shown in Scheme 3.4, the desired fluorinated aminoketones were isolated in high yields and enantioselectivities of up to 92% ee. 

PrqKiration by reaction of m-(trifluOTCMnethyl) benzoyl chloride with resorcinol dimethyl ether in the presence of aluminium chloride or titanium tetrachloride in refluxing n-hexane for 8 h [239]. - Preparation by reaction of m-(trifluoromethyl)benzonitrile with m-methoxyphe-nol in the presence of aluminium chloride for 8 h at 190°, followed by hydrolysis of the ketimine so formed [77]. 

Strekowski L, Janda L, Lee H (1997) Synthesis of Bis(2-arylquinolin-4-yl)amines by lithium Bis(trimethylsilyl)amide-mediated cyclization of ketimines derived from 2-(trifluoromethyl) anilines and aryl methyl ketones. J Org Chem 62 4193 197... 

Zhang F-G, Ma H, Nie J, Zheng Y, Gao Q, Ma J-A (2012) Enantioselective diynylation of cycUc JV-acyl ketimines access to chiral trifluoromethylated tertiary ceubinamines. Adv Synth Catal 354 1422-1428... 

Scheme 29.15 Enantioselective aza-Henry reaction of cyclic trifluoromethyl ketimines, and the anti-HIV drug candidate DPC 083 synthesized by this method. PMB p-methoxybenzyl.

The C6 thiourea 24 has been shown recently to be well suited for the enanti-oselective aza-Henry reaction of rritromethane with ketimines, yielding the products in high yields and ee s (Scheme 6.29) [71]. The reaction was also performed with a nitro-cyclopropane alkane and a trifluoromethyl substituted ketamine, thus forming a precursor for the synthesis of possible anti-HIV drug candidates. 

---