A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3)-H Activation.

Abstract

Trifluoromethyl-bearing 5-membered ring structures are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust sp3 hybridized C-H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium-catalyzed α-CF3-α-alkyl carbene insertion into a broad range of C(sp3)-H bonds to access 7 types of CF3-bearing saturated 5-membered carbo- and heterocycles. The reaction is particularly effective for benzylic C-H insertion exerting good site-, diastereo- and enantiocontrol, and applicable to access chiral CF3 analogues of bioactive molecules. Ruthenium-α-CF3-α-alkyl carbene complexes underwent stoichiometric reactions to give C-H insertion products, lending evidence for the involvement of metal-α-CF3-α-alkyl carbene species in the catalytic cycle. DFT calculations revealed that the π…π attraction and intra-carbene C-H…F hydrogen bond elucidate the origin of selectivity of the benzylic C-H insertion reactions.