Direct C(sp3)−H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes

Abstract

AbstractA mild and operationally simple C(sp3)−H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench‐stable CuIII complex, bpyCu(CF3)3, as the initiator of the visible‐light photoinduced reaction, the source of a trifluoromethyl radical as a hydrogen atom transfer reagent, and the source of a trifluoromethyl anion for functionalization. The reaction was initiated by the generation of reactive electrophilic carbon‐centered CF3 radical through photoinduced homolytic cleavage of bpyCu(CF3)3, followed by hydrogen abstraction from an unactivated C(sp3)−H bond. Comprehensive mechanistic investigations based on a combination of experimental and computational methods suggested that C−CF3 bond formation was enabled by radical–polar crossover and ionic coupling between the resulting carbocation intermediate and the anionic CF3 source. The methylene‐selective reaction can be applied to the direct, late‐stage trifluoromethylation of natural products and bioactive molecules.