Mechanistic insights into the rhodium-copper cascade catalyzed dual C-H annulation of indoles

Density functional theory (DFT) calculations have been performed to provide mechanistic insight into the Rh/Cu co-catalyzed multicomponent annulation of indoles, diazo compounds, and alpha,beta-unsaturated esters. Indole can undergo electrophilic attack by a dirhodium-carbene complex to form a cyclopropane intermediate, which is transferred to an enolate by deprotonation. A dimetallic Michael-type addition reaction is proposed by DFT calculation, where the diastereoselectivity is controlled by the interaction energy between the incoming alpha,beta-unsaturated ester and enolate nucleophile. In copper catalysis, an intramolecular oxidation by copper enolate/copper ketonate resonance is revealed, by which copper enolate is partially oxidized to an alpha-carbonyl radical. Therefore, intramolecular radical addition with the indole moiety achieves annulation with the formation of a C3 radical in dearomatic indole. Oxidative hydrogen atom transfer then gives the aromatic annulation product by using excess copper chloride.