LAUSR

Abstract A systematic density functional theory (DFT) computation has been performed to understand the mechanism and stereoselectivity involved in the [3 + 4] annulation reaction between 2-bromoenal and 3-formylindol-2-methyl-malonate catalyzed by N-heterocyclic carbene (NHC). The optimal reaction path consists of nine steps: (1) nucleophilic addition of NHC to 2-bromoenal, (2) formation of the Breslow intermediate via Bronsted acid Et3N•H+-mediated proton transfer, (3) C–Br bond cleavage, (4) formation of acyl intermediate via a proton transfer promoted by Et3N, (5) C–C bond formation via Michael addition, (6) the base (Et3N) mediated proton transfer, (7) protonation of α-carbon atom, (8) intramolecular cyclization and (9) regeneration of NHC. Michael addition (Step 5) is found to be the stereocontrolling step. Non-covalent interactions (NCI) analysis suggests that the preference of S-configured azepino[1,2-a]indoles can be traced to the cumulative effects of C–H•••O, C–H•••N, C–H•••π and π•••π interactions. Notably, the NHC catalyst plays an important role in the C–Br bond activation, which is in contrast to other NHC-catalyzed cyclization reactions.