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

Abstract

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(sp 3 )−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.

Controlling One- or Two-Electron Oxidation for Selective Amine Functionalization by Alternating Current Frequency

“…The drastically lowered potential for the second-electron oxidation of 1 in the presence of NaOAc is because iminium cations are generated via the low-potential α-amine radical route ( E 3 < E 2 , Figure ). As a result, the arylation product 1a is always accompanied by the cyanation product 1b under DC electrolysis, regardless of the applied voltage.…”

Electrosynthesis of 2-Substituted Benzoxazoles via Intramolecular Shono-Type Oxidative Coupling of Glycine Derivatives

“…This reaction via a sequence of direct electron–proton–electron transfer processes occurring on the anode surface generates an iminium ion intermediate that is trapped with nucleophiles, thus providing a variety of nitrogen-based products (Scheme a). Meanwhile, Shono-type oxidation has also become one of the most effective and direct methods to construct C–C, C–O, C–N, C–P bonds under much more mild conditions. However, the majority of the α-C­(sp 3 )–H functionalization protocols via Shono-type oxidation are limited to the use of multiple substituted cyclic amines as substrates, while unprotected secondary acyclic amines are rare.…”

Electrochemical C–H Functionalization of Cyclic Amines

“…In 2021, Lin and co-workers reported a modular, efficient, and selective route for the site-selective -methylation of protected amines using a combination of electrochemically driven formal C-H activation and organozincmediated methylation (Scheme 7). 13 Mechanistic analysis guided the development of an improved electrochemical protocol based on the classic Shono-type oxidation, which features broad substrate scope, high functional group compatibility, and operational simplicity. Besides, this protocol is amenable to the late-stage functionalization of bioactive molecules containing nitrogen groups that are prevalent in medicinally active agents.…”