Ortho-Methylation of Pyridine via Intramolecular N-methyl Migration

Abstract

Pyridine is a privileged scaffold in pharmaceuticals, and selective C2-alkylation, particularly methylation, represents a valu-able strategy to fine-tune drug-like properties such as metabolic stability and solubility. However, achieving highly site-selective methylation at the C2 position remains challenging. Herein, we report a ruthenium-catalyzed, copper-mediated protocol that enables direct C2-methylation of pyridines. The transformation proceeds through a formal N-to-C methyl migration in N-methylpyridinium salts, which serve dually as activated substrates and internal methyl donors, thereby ensuring excellent atom economy. This operationally simple and scalable approach is compatible with the late-stage modification of complex bioactive molecules. Furthermore, the migratable groups can be extended to longer alkyl and benzyl substituents, highlighting the broad synthetic utility of this strategy.