The quest for magic: recent advances in C(sp3)–H methylation

Abstract

Abstract Frequently referred to as the “magic methyl” effect, the introduction of a methyl group into a biologically active molecule has the potential to drastically alter its physical and biological properties and significantly increase potency. This effect is most pronounced when the methyl group is added at the α-position of an aliphatic heterocycle or ortho to a large rotatable group on an aromatic ring. Although seminal developments in C–H activation strategies offered solutions to the latter, until recent years there had been no selective and functional-group-tolerant method for C(sp3)–H methylation at late stages of synthesis. For many years, the lack of a generally applicable methylation strategy necessitated arduous de novo synthesis approaches to access methylated drug candidates, and discouraged further investigation and understandings of the magic methyl effect. This review will provide a summary of the most recent advances that enabled non-directed late-stage C(sp3)–H methylation, including through hydride transfer, chemical or anodic oxidation, and photocatalytic hydrogen atom transfer.