A Computational Study of NHC-Catalyzed [3 + 3] Annulation of Enals with Pyrazol-5-amines: Mechanism, Regio-and Stereoselectivities

Abstract

The reaction between enals and pyrazol-5-amines catalyzed by a chiral NHC was theoretically investigated to understand the mechanisms and origins of regio-and stereoselectivity. The catalytic reaction proceeds via eight steps: (1) nucleophilic attack of the NHC on enal, (2) intramolecular proton transfer, (3) oxidative reaction, (4) addition to pyrazol-5-amine, (5) deprotonation, (6) protonation, (7) cyclization and (8) catalyst liberation. CsHCO₃ serves as a proton shuttle in accelerating proton transfer. For the fourth step, both 1,2-and 1,4-addition modes were investigated and the 1,4-addition pathway is more favored. The stereoselectivity of the reaction is determined by the 1,4-addition step, in which attack of the si-face of the acyl azolium intermediate on the re-face of pyrazol-5-amine is identified as the most favorable addition mode, affording the S-pyrazolo [3,4-b]pyridin-6-one. The computed enantioselectivity (98% ee) correlates well with experimental findings (99% ee).Noncovalent interaction (NCI) and atoms in molecules (AIM) analyses revealed that the enantioselectivity originates from the interactions between the acyl azolium and pyrazol-5-amine. Global reactivity index analysis was also conducted to reveal the role of the NHC catalyst. These results will facilitate understanding of the reaction mechanism and guide the future design of novel catalytic reactions.