Methylation and Alkylation of Pyridines at the <i>meta</i> Position Using Aldehydes or Aldehyde Surrogates

The installation of methyl groups can significantly enhance the drug potency, motivating the development of diverse methylation strategies. C-H methylation is particularly attractive, yet a broadly applicable method for <i>meta</i>-C-H methylation of pyridines─the most common <i>N</i>-heterocyclic pharmacophore─remains elusive. Herein, we report a method for <i>meta</i>-methylation of pyridines that utilizes dihydropyridines, generated in situ, in conjunction with benzotriazolylmethanol or paraformaldehyde as the methylating agent, enabling the construction of a diverse array of <i>meta</i>-methyl-substituted pyridines with excellent selectivity for monomethylation. Moreover, the method can be readily extended to <i>meta</i>-alkylation using aldehydes as alkyl sources. Density functional theory calculations, control experiments, and kinetic studies were performed to elucidate the reaction mechanisms, in which the cooperation of the borane catalyst with the base was crucial for the deoxygenation step. Given the impact of methyl groups on molecular potency and the prevalence of pyridine pharmacophores, we anticipate that this method may offer a powerful handle for accessing new drug candidates.