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

Abstract

Trifluoromethyl‐bearing 5‐membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp3)−H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium‐catalyzed α‐CF3‐α‐alkyl carbene insertion into C(sp3)−H bonds of a broad range of substrates 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 the synthesis of 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.