Formal [4+3] Bridged Cyclization of Pyridines/Isoquinolines with Vinylcarbenes via Dearomatized Oxazinopyridine Intermediates

Abstract The direct dearomative cycloaddition of pyridines provides a powerful tool to construct medicinally important azabicyclic scaffolds. However, existing methods are limited to accessing isoquinuclidine (2‐azabicyclo[2.2.2]octane) cores. Here, we present a formal [4+3] bridged cyclization of pyridines/isoquinolines with vinylcarbenes, enabled by a dearomatization‐cycloaddition strategy through a traceless oxazino azaarene intermediate. This method facilitates the efficient construction of previously unexplored bridged azabicyclo[3.2.2]nonatrienes and their benzofused derivatives with high efficiency and excellent chemo‐, regio‐, and stereoselective control. Furthermore, downstream conversions of the bridgehead imino group enable the synthesis of diverse bridged azabicyclic and heterotricyclic frameworks. Integrated mechanistic studies and computational analyses revealed two distinct cyclization mechanisms for the reaction of oxazino pyridine/isoquinoline intermediates with vinylcarbenes, providing insights into the origins of observed regioselectivity.