Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C-H cyclization of imidazoles

The 3d transition metal-catalyzed enantioselective C-H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C-H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the pi-allyl nickel(II)-promoted sigma-complex-assisted metathesis (sigma-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional sigma-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P-H oxidative addition/migratory insertion, C(sp(2))-H activation via sigma-CAM, and C-C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the pi-allyl nickel(II) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C-H transformations.

Automated summary

The enantioselective C-H functionalization catalyzed by 3d transition metals provides a sustainable strategy for constructing chiral molecules. Investigation of the mechanism reveals multiple possible pathways, which can aid in the design of more efficient reaction systems.