Mechanistic study of the Ni‐catalyzed hydroalkylation of 1,3‐dienes: The origins of regio‐ and enantioselectivities and a further rational design

Abstract The development of the catalytic regio‐ and enantioselective hydrofunctionalization of 1,3‐dienes remains a challenge and requires deep insight into the reaction mechanisms. We herein thoroughly studied the reaction mechanism of the Ni‐catalyzed hydroalkylation of 1,3‐dienes with ketones by density functional theory (DFT) calculations. It reveals that the reaction is initiated by stepwise oxidative addition of EtO‐H followed by 1,3‐diene migratory insertion to generate the alkylnickel(II) intermediate, rather than the experimentally proposed ligand‐to‐ligand hydrogen transfer (LLHT) mechanism. In addition, we rationalized the role of t BuOK in the subsequent addition of enolate of ketone and transmetalation process. Based on the whole catalysis, the CC reductive elimination step, turns out to be the rate‐ and enantioselectivity‐determining step. Furthermore, we disclosed the origins of the regio‐ and enantioselectivity of the product, and found that the 1,2‐selectivity lies in the combination effects of the ligand‐substrate electrostatic interactions, orbital interactions and Pauli repulsions, while the enantioselectivity mainly arises from substrate‐ligand steric repulsions. Based on mechanistic study, new biaryl bisphosphine ligands affording higher enantioselectivity were designed, which will help to improve current catalytic systems and develop new transition‐metal‐catalyzed hydroalkylations.