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

A mild and operationally simple C(sp(3))-H trifluoromethylation method was developed for unactivated alkanes by utilizing a bench-stable Cu-III 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(sp(3))-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.

Automated summary

A mild and operationally simple C(sp(3))-H trifluoromethylation method has been developed for unactivated alkanes using a bench-stable Cu-III complex as the initiator of the visible-light photoinduced reaction, as well as a source of trifluoromethyl radicals and trifluoromethyl anions for functionalization. The methylene-selective reaction mechanism involves radical-polar crossover and ionic coupling between the reactive carbocation intermediate and the anionic CF3 source, enabling efficient C-CF3 bond formation. This method can be applied for late-stage trifluoromethylation of natural products and bioactive molecules.