Catalytic Enantioselective Allenylation of Zincke Imine

Zincke imine, with rich history since its discovery more than a century ago, is a versatile intermediate in organic synthesis. In recent years, there has been renewed interest in temporary dearomatization of pyridines through their redox-neutral ring opening to Zincke imines as this strategy allows for site-selective pyridine functionalization. Despite their growing popularity, no catalytic asymmetric transformation involving Zincke imines has ever been realized. In this work, we have harnessed the intrinsic push-pull dienamine reactivity of Zincke imines to achieve an enantioselective Ir-catalyzed allenylation for the synthesis of highly enantioenriched (up to >99 : 1 e.r.) meta-allenylic pyridines with complete regiocontrol. This transformation proceeds in an enantioconvergent manner using racemic allenylic alcohol as the electrophile. Ammonium acetate-mediated cyclization of the resulting 3-allenylic Zincke imines restored the pyridine core. Notably, this approach provides previously inaccessible 2-substituted 3-allenylic pyridine regioisomer and complements our recently reported strategy using oxazinopyridine. Control experiments combined with computational studies reveal the exclusive dienamine selective nucleophilic attack originates from a lower distortion in the corresponding transition state.