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

Abstract

A 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.