Radical Enantioconvergent meta-Alkylation of Pyridines: Reaction Development and Mechanistic Insight

Enantioselective meta-C−H functionalization of pyridines represents a significant challenge and opportunity in synthetic chemistry and pharmaceutical development. While highly desirable, radical variants have remained elusive especially con-sidering the fundamental challenge of controlling the generation and stereochemical interception of short-lived, open-shell intermediates. Here we report the first successful realization of this transformation through radical enantioconvergent meta-C−H alkylation of pyridines enabled by temporary dearomatization. Our strategy involves dearomative cycloaddition, nickel-catalyzed enantioconvergent dehydrogenative cross-coupling of the resulting oxazino-pyridines with cyclic β-ketoamides, and acid-mediated rearomatization. Integrated experimental and computational mechanistic studies reveal the simultaneous generation of oxazino-pyridine radicals and nickel-bound α-carbonyl radicals, followed by their enantio-determining radical-radical cross-coupling. This protocol exhibits high regio- and enantioselectivity, remarkable functional group tolerance, scale-up potential and enables late-stage functionalization of pyridine-containing pharmaceuticals.