A Computational Study on the 4-Dimethylaminopyridine (DMAP)-Catalyzed Regioselective [2+4] Cyclization of Allenic Ester with Cyclic Ketimine

The reaction mechanisms of [2+4] cyclization of allenic ester and cyclic ketimine catalyzed by 4-dimethylaminopyridine (DMAP) for forming highly functionalized hydropyridine derivatives were studied theoretically using density functional theory (DFT). Three possible reaction channels, including DMAP-catalyzed [beta,gamma]-/[alpha,beta]-[2+4] cyclization channel (i.e., channel A/B) and direct [beta,gamma]-[2+4] cyclization channel (i.e., channel C) were considered. According to the calculated results, channel A was concluded to be the most energetically favorable among the three channels, and the corresponding product is the main product, which is consistent with the experimental observation. The channel A consists of four steps, i.e., nucleophilic addition on the C atom of allenic ester by DMAP, the stepwise [beta,gamma]-[2+4] cyclization with ketimine, and the dissociation of DMAP with product. The analyses of global reactivity index (GRI) and frontier molecular orbital (FMO) suggested that DMAP not only enhances the nucleophilicity of allenic ester but also narrows the energy gap of the FMOs involved in the [2+4] cyclization, and thus makes the reaction more easily to occur. Moreover, the non-covalent interaction (NCI) analysis explored the origin of regioselectivity of the reaction.