Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules

Abstract In pharmaceutical discovery, the “magic methyl” effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp 3 ) − H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp 3 ) − H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp 3 ) − H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C−H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C−H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the “magic methyl” effect in drug discovery.