Iridium-catalyzed N-methylation of drug molecules†

N-Methyl amines play extremely important roles in numerous fields encompassing life science, drug discovery, and organic synthesis. Although numerous methylation strategies have been established, the methylation of densely functionalized drug molecules still remains a formidable challenge in terms of functionality tolerance and chemoselectivity control. Herein, we overcome the challenge by adopting a catalytically improved Eschweiler–Clarke methylation strategy. An array of drug molecules, as well as other amine molecules, can be late-stage edited in a highly selective manner via our iridium-catalyzed N-methylation protocol, exhibiting exceedingly high functionality compatibility and very high catalyst efficiency (S/C ratio as high as 50 000 and turnover frequency as high as 53 000 h⁻¹). This protocol is easy to scale up, as demonstrated by two decagram-scale reactions, and is orthogonal to previous methylation methods when different reactive sites are present in substrates. Mono- and dideuteromethylated drug molecules with exceedingly high deuterium incorporation ([D] = 97.4–99.9%) are also accessible by means of this protocol.