Mechanistic Insight into Palladium-Catalyzed Trifunctionalization of Terminal Alkynes: Origin of Enantio- and Regioselectivity

Abstract Density functional theory calculations were performed to investigate the mechanism and factors affecting the enantio- and regioselectivity in the palladium-catalyzed trifunctionalization of terminal alkynes. Our calculations uncover a novel mechanistic pathway, which differs from the catalytic cycle proposed by experimental authors. This improved mechanism highlights that CO2 elimination does not take place inside the catalytic cycle but proceeds as an off-cycle step. The reaction proceeds sequentially via C–O oxidative addition, direct deprotonation, C–B bond formation, 1,2-metalate shift, and inner-sphere C–C reductive elimination. Compared with inner-sphere C–C reductive elimination, the outer-sphere pathway is disfavored both thermodynamically and kinetically. The direct deprotonation process is characterized as the rate-determining step of the reaction. The excellent enantioselectivity is rationalized by the noncovalent interactions between the substrate and ligand. Regioselectivity is mainly controlled by steric effects.