Computational study on NHC catalyzed [4+2] annulation between γ-chloroenals and pyrazolinones: mechanism and stereoselectivity

Abstract

We present a computational study on the mechanisms and stereoselectivities of the [4+2] annulation of an enal with a pyrazolinone catalyzed by N-heterocyclic carbene (NHC). The computational results show that the catalytic reaction proceeds via eight steps: nucleophilic addition of the NHC to the enal (step 1) followed by 1,2-proton transfer affords the Breslow intermediate (step 2). C–Cl bond cleavage generates the enolene intermediate (step 3). Successive 1,5-proton transfer (step 4) and γ-C–H deprotonation (step 5) afford the vinyl enolate intermediate, which undergoes nucleophilic addition to the pyrazolinone, forming a new carbon–carbon bond (step 6). Intramolecular cycloaddition (step 7) followed by dissociation of the catalyst from the product (step 8) completes the whole catalytic cycle. For step 2, in addition to the direct proton transfer pathway, water- and HOAc-mediated proton transfer mechanisms have been explored, and HOAc was found to play an important role as the proton shuttle in forming the Breslow intermediate. Step 6 determines the stereoselectivity of the reaction. A cumulative effect of a number of noncovalent interactions (π⋯π, CH⋯O, CH⋯π and repulsion interactions) between the vinyl enolate intermediate and the pyrazolinone creates a difference in the enantioselectivity. The computed enantioselectivity (99% ee) agrees well with the value reported by experiments (99% ee).