Comprehensive theoretical study of nickel-NHC-catalyzed enantioselective intramolecular indole C-H cyclization: Reaction mechanism, reactivity, regioselectivity, and electronic processes

Density functional theory was used to illuminate the reaction mechanism of Ni(0)-NHC-catalyzed enantioselective intramolecular C-H cyclization of indoles. The omega B97XD functional with 6-31G(d,p) basis set (SDD for nickel) was employed to optimize all intermediates and transition states. The computations revealed that the reactivity of C1-H bond was the best among all C-H bonds of indole catalyzed by the Ni-NHC complex, and in the C1-H bond activation, the concerted oxidative addition was more dominant than the ligand-to-ligand H transfer reaction, due to the lower free energy barrier. The most favorable channels predicted theoretically went through the ligand-to-ligand H transfer reaction and reductive elimination, and two chiral products ((R)- and (S)-tetrahydroindolizines) were coexisted as a result of similar transition states and little difference in free energy barrier. Hence, the model ligand L1 was not good for the regioselectivity. Nevertheless, another ligand L2, a chiral N-heterocyclic carbene ligand, gave good regioselectivity, and it changed the rate-determining step and generally decreased the free energies of transition states and intermediates.

Automated summary

Density functional theory was used to investigate the reaction mechanism of Ni(0)-NHC-catalyzed enantioselective intramolecular C-H cyclization of indoles. The computations revealed that the C1-H bond showed the highest reactivity, and the concerted oxidative addition played a major role in the activation process. Two chiral products coexisted due to similar transition states and little difference in free energy barrier.