Understanding the mechanism of the N-heterocyclic carbene-catalyzed ring-expansion of 4-formyl-β-lactams to succinimide derivatives

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed ring-expansion of 4-formyl-beta-lactams to succinimides has been studied using DFT methods at the B3LYP/6-31G** level. The first step is the nucleophilic attack of NHC to the aldehyde to yield the zwitterionic intermediate, which by a proton-transfer process affords the Breslow intermediate. The lactam N-C breaking bond in this intermediate yields an enol-amidate, which by a keto-enol type equilibrium becomes the ketone form. The subsequent ring-closure achieved by the nucleophilic attack of the amidate to carbonyl carbon allows the formation of the five-membered ring. Finally, elimination of NHC affords the succinimide. Analysis of the nucleophilicity index correctly explains the behaviors of the NHCs and the Breslow intermediates in the umpolung reactivity of aldehydes. (C) 2009 Elsevier Ltd. All rights reserved.