A combined experimental and computational study reveals a crossover between conventional cross-coupling and carbene insertion pathways in a Pd catalyzed C(sp2)–H insertion†

Computational (DFT and DLPNO-CCSD(T)) calculations along with experimental tools (deuterium labelling, kinetic studies using VTNA, ESI-HRMS and UV) are used to probe the mechanism of a Pd(II)-catalyzed enantioselective carbene insertion into C(sp²)–H of indole. Using deuterium labelling studies, we demonstrate the intermediacy of a metal-hydride species, which contrasts with mechanistic routes for other transition metals (Rh, Fe, Au, Cu, etc.). Our VTNA study reveals the order to be one in both diazo and indole, which along with microkinetic modelling aligns well with the computationally predicted mechanism. The mechanism is further supported by the detection of the most stable intermediate in the catalytic cycle using ESI-HRMS. An investigation into the origin of stereoselectivity using DLPNO-CCSD(T) presents a new paradigm, wherein stereocontrol arises during the formation of the Pd carbene itself as opposed to proton transfer steps found for all other metal catalysts.