Mechanistic Approach Toward the C4‐Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

The development of site‐selective functionalization of N‐heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4‐aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4‐selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4‐pyridyl pyridinium salt intermediates, 4‐aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C–H pyridination of additional N‐heteroarenes, presenting a strategic avenue for installation of diverse functional groups.