Ground-state intramolecular proton transfer inhibits the selective methylation on quinoline and pyridine derivatives

Methylation is one of the crucial steps for drug discovery, organic synthesis, and catalysis. Despite being a versatile and well-known chemical reaction, its chemoselectivity has not been well addressed. In this paper, we reported a thorough experimental and computational investigation of the selective N-methylation of N-heterocyclic compounds, mainly quinolines and pyridines. These reactions were conducted in a base-free manner under ambient conditions using iodomethane as the methylating reagent, exhibited good chemoselectivity, and were tolerant of other amine, carboxyl, or hydroxyl functional groups without needing protection. To this end, 13 compounds were synthesized as a proof-of-concept and 7 crystal structures were obtained. However, the chemoselectivity failed in the presence of a thiol group. Detailed quantum chemical calculations provided insights into the N-methylation mechanism and its selectivity and demonstrated that the isomerization induced by ground-state intramolecular proton transfer (GSIPT) in the presence of a thiol group inhibits the N-methylation.