Umpolung at the meta ‐Positions of Oxazino‐Pyridines Enabling Nucleophilic Pyridine Functionalization

ABSTRACT Selective C─H functionalization of azines is of paramount importance to synthetic and medicinal chemistry. However, nucleophilic functionalization at meta‐ position of pyridines has remained elusive because of the intrinsic polarity mismatch. In this study, we report a mild and practical protocol for meta ‐selective nucleophilic alkoxylation of azines using alcohols through a dearomatization–rearomatization sequence. Taking advantage of oxazino‐pyridines as redox‐active intermediates, single‐electron oxidation generates the corresponding radical cations, which undergo nucleophilic addition to afford allylic radicals. Distinct from the established radical–radical cross‐coupling pathway, these nucleophilic allylic radicals undergo further oxidation to form electrophilic allylic cations, thereby enabling capture by alcohols prior to rearomatization. This umpolung mechanism is supported by both experimental and computational studies. This catalyst‐free method features precise regiocontrol, remarkable functional group tolerance, scale‐up potential, and applicability to late‐stage functionalization of pharmaceuticals. Furthermore, this strategy was extended to nucleophilic meta ‐hydroxylation of pyridines using water, as well as chlorination, bromination, and iodination using halide salts.