Organic Chemistry

Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules



The “magic methyl” effect – a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group – provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)–H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthetic strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Version notes

Updated text and substrate scope


Thumbnail image of ChemRxiv - Manuscript (submitted 9-5).pdf

Supplementary material

Thumbnail image of SI - ChemRxiv.pdf
Supporting Information
Experimental and computational data
Thumbnail image of ChemRxiv - TOC.png
Table of content
Table of content image