Mechanism and Origin of MAD-Induced Ni/N-Heterocyclic Carbene-Catalyzed Regio- and Enantioselective C−H Cyclization of Pyridines with Alkenes

This work presents a DFT-based computational study on the regio- and enantioselective C−H functionalization of pyridines with alkenes at the relatively unreactive C4-position, which was successfully achieved by Shi et al. J. Am. Chem. Soc. 2019 , 141, 5628–5634] using Ni⁰/N-heterocyclic carbene (NHC) catalysis under the assistance of an aluminum-based Lewis acid additive (2,6-tBu₂-4-Me-C₆H₂O)₂AlMe (MAD). The calculations indicate that the selective functionalization involves a three-step mechanism in which a unique H-migration assisted oxidation metalation (HMAOM) step is identified as the rate- and enantioselectivity-determining step. The newly proposed mechanism can well rationalize the experimental observation that the preferred product is the endo-type (vs. exo-type), R-configuration (vs. S-configuration) product at the C4 (vs. C2) position, and also unveil the reasons that the NHC ligand and the MAD additive can facilitate the reaction.