Mechanisms and origins of stereoselectivity in the NHC-catalyzed oxidative reaction of enals and pyrroles: a density functional theory study

Abstract

The mechanism, chemoselectivity and stereoselectivity in the NHC-catalyzed reaction between enals and pyrroles for the synthesis of 5,6-dihydroindolizine were studied using DFT calculations. The cycle for catalytic generation of 5,6-dihydroindolizine proceeds via seven steps: (1) addition of the NHC to enal, (2) formation of a Breslow intermediate through [1,2]-proton transfer, (3) oxidation, (4) Michael addition, (5) [2+2] cycloaddition, (6) liberation of NHCs and (7) decarboxylation. Our results show that the presence of DMAP·H⁺ lowers the barrier for [1,2]-proton transfer. In addition, NHC·H⁺ plays a key role in decarboxylation. Michael addition which involves the formation of a new C–C bond was identified to be the chemo- and stereoselectivity-determining step, leading to the experimentally observed 5S,6R-dihydroindolizine. Analysis of the noncovalent interactions revealed that the observed stereoselectivity is attributed to the differential weak interactions (CH⋯π, LP⋯π and CH⋯CH) involved in the transition states during the Michael addition step. The computational results not only rationalize experimental observations but also provide some useful information for the future design of new catalytic processes.