Theoretical study of nickel-catalyzed hydroalkylation of 3-pyrrolines: Origin of ligand-controlled regioselectivity

• Origin of ligand-controlled regioselectivity was clarified. • The reaction mechanisms do not proceed via the traditional route. • The two ligands undergo completely different mechanisms. Nickel catalysts have shown unique ligand control of regioselectivity in the hydroalkylation of 3-pyrrolines. The (2-(5-bromopyridin-2-yl)-3a,8a-dihydro-8 H -indeno[1,2- d ]oxazole) ligand ( L1 ) produces a C2-alkylated pyrrolidine, while the (4-benzyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole) ligand ( L2 ) delivers a C3-alkylated pyrrolidine. We have explored the mechanism and origin of the ligand-controlled regioselectivity with density functional theory (DFT) calculations. The calculation results show good agreement with the experimental results for the regioselectivity. The hydroalkylation reactions of 3-pyrrolines with the two different ligands occur via completely different mechanisms, neither of which is via the traditional route proposed by experimental research. These mechanistic rationales are supported by several related experimental observations in ref. 40. For the L1 ligand, the regioselectivity is determined by two competing transition states, a β-hydride elimination transition state and a C–C reductive elimination transition state. For the L2 ligand, radical coupling and β-H elimination steps are responsible for the regioselectivity. The bulky L1 ligand facilitates the β-hydride elimination step and thus leads to the C2-alkylated pyrrolidine product. The less bulky L2 ligand prefers radical coupling step and thus results in the C3-alkylated pyrrolidine product.