General and Modular Access to Enantioenriched α-Trifluoromethyl Ketones via Nickel-Catalyzed Reductive Trifluoroalkylation

The development of new catalytic enantioselective access to stereogenic CF3-containing molecules is of great interest for expediting the discovery of lead compounds that remain challenging. Specifically, enantioselective synthesis of valuable ketones featuring stereogenic alpha-CF3 has rarely been reported. We devise a general and modular approach to facilely access enantioenriched alpha-CF3 ketones via nickel-catalyzed reductive cross-coupling of readily available acid chlorides and racemic alpha-CF3 alkyl bromides in an enantioconvergent fashion under mild conditions. This protocol features neighboring directing group-free, high chemoselectivity, excellent functional group tolerance, facile scale-up, and notable amenability to straightforward downstream elaboration toward pharmaceutically useful enantioenriched beta-trifluoromethylated secondary and tertiary alcohols, thus constituting a reliable, direct, practical, and efficient synthetic alternative to furnish enantiopure alpha-CF3 carbonyls. Interestingly, an appropriate choice of the phosphine ligand as coligand plays an important role in high efficiency and asymmetric induction. Mechanistic studies suggest a radical chain pathway. [GRAPHICS]