Catalytic Enantioselective Allenylation of Zincke Imine

Abstract

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