A theoretical study on the reaction mechanisms and stereoselectivities of NHC-catalyzed [2 + 2] cycloaddition of ketene with C=N double bond of isothiocyanate

In this work, three possible mechanisms, including mechanisms A and B associated with the stereoselective [2 + 2] cycloaddition product and mechanism C associated with the [2 + 2 + 2] cycloaddition product, have been investigated for N-heterocyclic carbenes (NHCs) catalyzed cycloadditions of ketenes with isothiocyanates by using density functional theory (DFT). Our calculated results suggest that the mechanism A is the most energy favorable pathway, which contains three steps, i.e. (1) the nucleophilic attack on the ketene by NHC catalyst for the formation of enolate intermediate, (2) regioselective [2 + 2] cycloaddition of the enolate intermediate with isothiocyanate, and (3) the dissociation of the NHC catalyst from the thioxo-β-lactam product. Notably, the [2 + 2] cycloaddition step is proved to be both the rateand stereoselectivity-determining step. Moreover, the reaction pathway associated with the R configuration is the most favorable pathway and leads to the major product, which is in good agreement with the experimental results. The mechanistic insights obtained in the present study should be valuable for the rational design of more efficient organocatalytic cycloadditons for the synthesis of heterocycle compounds with high selectivities. AMS subject classifications: 92E99