A stereoselective nontraditional Heck reaction mechanism: Origins of enantioselectivity and diastereoselectivity

Nontraditional Heck-type reactions of C = heteroatomic variants have been a great challenge. Herein, we computationally investigate a nontraditional stereoselective Heck mechanism regarding hydrazone C = N-NH2 by using density functional theory (DFT) methods. Calculations indicate that the total potential barrier of the conversion is 25.6 kcal/mol, which is reasonable to be crossed under the current reaction conditions. Unlike C = C n-bonds, the coordination of C = N with transition metal palladium into a eta 1-complex is confirmed. A larger n-bond insertion barrier for C = N is required, which is rationalized by frontier molecular orbital (FMO) analysis with a wider LUMO-HOMO energy gap. n-bond insertion is the enantioselectivity determining step of the strategy and that the pathway toward the R-isomer exhibits a much lower energy barrier (24.2 vs 40.1 kcal/mol). n-bond insertion is also the diastereoselective control step with using DBBP ligands. Non-covalent interaction (NCI) analysis confirms that greater spatial hindrance is responsible for the stereoselectivity of the protocol. Meanwhile, calculations show that using an acid-promoted tactic can effectively improve the in situ production of hydrazone and significantly reduce the energy barrier.