Mechanism and Origin of Regio- and Stereoselectivity in the Synthesis of Benzazocines via Palladium-Catalyzed [6+2] Annulation of Allenyl Benzoxazinanones with Terminal Allenes

Density functional theory calculations were carried out to elucidate the mechanism and the origin of regio- and stereoselectivity in the palladium-catalyzed [6+2] annulation of allenyl benzoxazinanones with terminal allenes. An unconventional oxidative addition–reductive elimination mechanism was revealed. The reaction starts with SN2-type oxidative addition of the substrate to Pd0, followed by decarboxylation to afford a π-allylpalladium intermediate. Pathway bifurcation leads to competing [6+2] and [4+2] annulations, and the more stable seven-membered palladacycle kinetically favors the [6+2] pathway and inhibits the [4+2] side reaction. Distortion/interaction analysis indicates that the exclusive Z-selectivity originates from the larger structural distortion of the E-configured transition state. Different from conventional three-center reductive elimination, the reaction proceeds via a zwitterionic-intermediate-mediated nucleophilic coupling pathway, which acts as the rate-limiting step with an overall barrier of 21.3 kcal/mol. This work rationalizes experimental selectivity and offers theoretical guidance for the design of related Pd-catalyzed annulation reactions.