Cu-Catalyzed Asymmetric Carbene Insertion into N-H, O-H, and S-H Bonds: Challenging the Existing Mechanistic Dogma

A comprehensive mechanistic study of asymmetric carbene insertion into N-H, O-H, and S-H bonds catalyzed by Cu-spiroBox is presented. We challenge the currently widely accepted mechanism involving Cu-enolate intermediates that has dominated carbene insertion reactions for more than a decade. Our DFT and DLPNO-CCSD-(T) calculations show that in all cases, the preferred route involves metal-associated enol intermediates. Our study demonstrates that the tautomerization process is dependent on the nature of the nucleophile: O-H and S-H insertion follow a stepwise route, whereas N-H insertion adopts a concerted pathway. This step is also found to control the stereochemical outcome in all three cases. Our study highlights the importance of enol intermediates in carbene chemistry, which might be more prevalent than what is currently believed.