Enantioconvergent Amination of Racemic Tertiary C–H Bonds

Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in traditional radical halogenation reactions of optically active tertiary C–H bonds. If the facile process of radical racemization could be effectively combined with an ensuing step of bond formation in an enantioselective fashion, then it would give rise to deracemizative functionalization of racemic tertiary C–H bonds for stereoselective construction of chiral molecules bearing quaternary stereocenters. As a demonstration of this unique potential in radical chemistry, we herein report that metalloradical catalysis can be successfully applied to devise Co­(II)-based catalytic system for enantioconvergent radical amination of racemic tertiary C­(sp³)–H bonds. The key to the success of the radical process is the development of Co­(II)-based metalloradical catalyst with fitting steric, electronic, and chiral environments of the D₂-symmetric chiral amidoporphyrin as the supporting ligand. The existence of optimal reaction temperature is recognized as an important factor in the realization of the enantioconvergent radical process. Supported by an optimized chiral ligand, the Co­(II)-based metalloradical system can effectively catalyze the enantioconvergent 1,6-amination of racemic tertiary C­(sp³)–H bonds at the optimal temperature, affording chiral α-tertiary amines in excellent yields with high enantiocontrol of the newly created quaternary stereocenters. Systematic studies, including experiments utilizing optically active deuterium-labeled C–H substrates as a model system, shed light on the underlying mechanistic details of this new catalytic process for enantioconvergent radical C–H amination. The remarkable power to create quaternary stereocenters bearing multiple functionalities from ubiquitous C–H bonds, as showcased with stereoselective construction of bicyclic N-heterocycles, opens the door for future synthetic applications of this new radical technology.