A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp 3 )-H Activation.

Trifluoromethyl-bearing 5-membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp 3 )-H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium-catalyzed α-CF 3 -α-alkyl carbene insertion into C(sp 3 )-H bonds of a broad range of substrates to access 7 types of CF 3 -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 CF 3 analogues of bioactive molecules. Ruthenium α-CF 3 -α-alkyl carbene complexes underwent stoichiometric reactions to give C-H insertion products, lending evidence for the involvement of metal α-CF 3 -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.