posted on 2022-01-11, 21:32authored byLuiz F.
T. Novaes, Justin S. K. Ho, Kaining Mao, Kaida Liu, Mayank Tanwar, Matthew Neurock, Elisia Villemure, Jack A. Terrett, Song Lin
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 synthesis strategy
thus circumvents multistep de novo synthesis that
is currently necessary to access such compounds and has the potential
to accelerate drug discovery efforts.