NHC-catalyzed [3 + 4] annulation between 2-dromoenal and aryl 1,2-diamine: Insights into mechanisms, chemo and stereoselectivities

Abstract

We present a DFT study of the mechanisms, chemo- and stereoselectivities in the reaction of 2-bromoenal with aryl 1,2-diamine enabled by a chiral NHC. The catalytic reaction starts with NHC addition to 2-bromoenal, subsequent [1,2]-proton transfer results in the Breslow intermediate, which then undergoes sequential CBr bond breaking and [1,3]-proton transfer. The resulting acylazolium can transform to the [3 + 4] cycloadduct through subsequent CN bond formation, [1,3]-proton transfer and cyclization. Finally, elimination of catalyst provides 1,5-benzodiazepin-2-one. DFT results reveal that OAc− and HOAc play important roles respectively in the [1,2]- and [1,3]-proton transfer process. The CN bond formation step controls the enantioselectivity of the reaction, and preferably provides access to (R)-1,5-benzodiazepin-2-one. The computed enantioselectivity (97.5% ee) agrees well with experimental report (97% ee). Non-covalent NH···π, CH···N and CH···π interactions are the key factors for controlling the stereoselectivity. The NHC is demonstrated to play a role in CBr bond activation through reduce the electron density between the C and Br atoms, thus increases 2-bromoenal's electrophilicity and facilitates its subsequent reaction with diamines.