Mechanistic Study on Palladium-Catalyzed Regioselective Oxidative Amination: Roles of Ammonium Salts.

Anti-Markovnikov selective oxidative amination reaction with simple alkenes is particularly promising but challenging because of the inherent electronic effect of the alkene substrate which is in favor of the Markovnikov product. In a recently reported Pd-catalyzed anti-Markovnikov oxidative amination reaction, the addition of quaternary ammonium salts is shown to be critical. We performed a comprehensive DFT study to elucidate the reaction mechanism and the origin of the regioselectivity, as well as the roles of the ammonium salts. Our results show that without and with the ammonium salts the reaction mechanisms are different. Detailed analyses indicate that the steric effects account for the switch of regioselectivity. The roles of the quaternary ammonium salts have been elucidated: (1) MeNOAc plays the role of base in deprotonating the phthalimide and allows the reaction to proceed through a trans-aminopalladation mechanism; (2) MeNCl facilitates the thermodynamically favorable transformation of Pd(OAc) to the palladate ([Pd(AcO)Cl]), which lessens the polarity of the carbon-carbon double bond, minimizes the inherent electronic effects, and leads to a steric-effect-controlled reaction; (3) MeNCl is essential in decreasing the activation barrier in the rate-determining ligand exchange step by Cl acting as a better leaving group (compared to AcO).