Mechanism and regio- and stereoselectivity in NHC-catalyzed reaction of 2-bromoenals with β-ketoamides

Abstract

• The detailed reaction mechanisms were examined. • Free energies were computed at the SMD(CH 3 CN)M06-2X-D3/6-311++G(2df,2pd) level. • The origins of stereoselectivity were identified. • The roles of the catalyst were determined. • Substituent effects were explored. We have investigated an N-heterocyclic carbene (NHC)-catalyzed annulation reaction in order to determine the mechanisms and origins of stereoselectivity. DFT results show that the catalytic formation of spiro-glutarimides involves coordination of 2-bromoenal to NHC, followed by a bicarbonate aided proton transfer to form the Breslow intermediate. Subsequent debromination and proton transfer forms the α,β-unsaturated acylazolium intermediate. Then the reaction proceeds via Michael addition, proton transfer and intramolecular cyclization to deliver the cyclic intermediate, which finally releases NHC affording the spiro-glutarimide product. The Michael addition resulting in a new carbon−carbon bond is found to be the stereochemistry-controlling step and generates the SR-configurational product observed in experiment. The important role of noncovalent interactions (such as C−H•••O, C−H•••π, π•••π and lone pair (LP)•••π) in controlling stereoselectivity is elucidated by noncovalent interaction (NCI) analysis. Moreover, analysis of the global reactivity indexes (GRIs) and the computed C−Br bond lengths revealed that NHC plays an important role in activating C−Br bond. The detailed mechanism, regio- and stereoselectivity of NHC-catalyzed annulation between 2-bromoenals with β-ketoamides has been investigated using a DFT method.