Theoretical understanding mechanisms and stereoselectivities of [2+2] cycloaddition of ketenes with ketimines catalyzed by bifunctional N-heterocyclic carbene
Reaction mechanism of NHC-catalyzed asymmetric [2+2] cycloaddition reaction between ketenes and isatin-derived ketimines for the formation of spirocyclic indolo-β-lactams has been investigated using density functional theory (DFT). The catalytic cycle for the title reaction included three possible mechanisms: the “ketene preferential mechanism” (mechanism A) and the “imine preferential mechanism” (mechanisms B and C). They have three similar steps: the first step is the nucleophilic attack of the NHC catalyst, the second one is ring-closure proceed, and the last one is catalyst regeneration and product formation. This work adopted the two different N-heterocyclic carbene catalysts (named as NHC-I and NHC-II) involved in experiment. The calculated results indicate that the Gibbs free energy barriers of mechanism A are remarkably lower than those of mechanisms B and C, and the reaction pathway leading to the SS-configured product has the lowest Gibbs free energy barrier, which agrees with the experiments. It is worth noting that in mechanism A, NHC-I has a free-rotating hydroxyl group which can form a hydrogen bond and ketene, which greatly reduces the energy of the enolate intermediate and affects the cycloaddition process, improving the stereoselectivity of the reaction. Furthermore, the special role of the catalysts and origin of stereoselectivity of the title reaction were also identified by global reactivity index and frontier molecular orbital analyses. The new insights obtained in this study might provide clues for understanding the reaction mechanism of the high stereoselective reaction catalyzed by bifunctional N-heterocyclic carbene catalysts.
KeywordsN-Heterocyclic carbene (NHC) Density functional theory (DFT) [2+2] Cycloaddition Reaction mechanism
The authors received financial support from the National Natural Science Foundation of China (Grant Nos. 21001095 and J120062), China Scholarship Council (Grant Nos. 201807045019 and 201808230086), and the University Key Research Programs of Education Department in Henan Province (Grant No. 15A150082).
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Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with animals performed by any of the authors.
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