Mechanisms and stereoselectivities of NHC-catalyzed [4 + 2] cycloaddition reaction between phenylacetic acid and o-quinone methide: A computational investigation

Abstract

The mechanisms and stereoselectivities in N-heterocyclic carbene-catalyzed [4+2] cycloadditions of phenylacetic acid and o-quinone methide have been studied by the use of density functional theory (DFT) calculations. Various possible reaction pathways were located and compared. The most energy favorable pathway can be characterized by four stages: the formation of intermediate IM2 via the nucleophilic attack of catalyst to phenylacetic acid (stage I); deprotonation of IM2 to generate the NHC-bounded enolate intermediate IM4 (stage II); addition of IM4 to R2 to form the six-membered ring intermediate IM5 (stage III) and elimination of catalyst leading to the RS-configuration product P(RS) (stage IV). For stage II, both direct deprotonation and base-mediated deprotonation were examined, DFT calculations indicate that traces of base are essential for the deprotonation process. The [4+2] cycloaddition step (stage III) is found to be the rate- and stereoselectivity-determining step with an overall free energy barrier of 16.6kcal/mol. The predicted high cis-diastereoselectivities and enantioselectivities for the [4+2] annulation reaction are in good agreement with the experimental observations. The present study should be useful to the development of this kind reactions in the future.