Radical enantioconvergent meta-C─H alkylation of pyridines.

Enantioselective meta-C─H functionalization of pyridines represents a long-standing challenge that, if resolved, would open transformative avenues in synthesis and drug discovery. Radical-based approaches are particularly attractive yet have remained elusive. We here report a radical enantioconvergent meta-C─H alkylation of pyridines enabled by temporary dearomatization. Our strategy comprises dearomative cycloaddition, nickel-catalyzed enantioselective dehydrogenative coupling of oxazino-pyridines with cyclic β-ketoamides, and acid-mediated rearomatization. Integrated experimental and computational studies support a mechanism based on enantio-determining cross-coupling of simultaneously generated oxazino-pyridine-derived allyl and nickel-bound α-carbonyl radicals. This protocol exhibits high regio- and enantioselectivity, remarkable functional group tolerance, scale-up potential and enables late-stage functionalization of pyridine-containing pharmaceuticals.