Theoretical study of the [3 + 4] annulation reaction of 2-bromoenals with malonates catalyzed by N-heterocyclic carbene

Abstract

• The detailed reaction mechanisms were examined. • Free energies were computed at the SMD(DCM)M06–2X/6–311++ G (2df,2pd) level. • The origins of stereoselectivity were identified. • The roles of the catalyst were determined. • The computed mechanism explains the proposed catalytic cycle. 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 Et 3 N• H + -mediated proton transfer, (3) C–Br bond cleavage, (4) formation of acyl intermediate via a proton transfer promoted by Et 3 N, (5) C–C bond formation via Michael addition, (6) the base (Et 3 N) 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.