Mechanisms and Stereoselectivities in the NHC-Catalyzed [4 + 2] Annulation of 2-Bromoenal and 6-Methyluracil-5-carbaldehyde

To disclose the reaction mechanism and selectivity in the NHC-catalyzed reaction of 2-bromoenal and 6-methyluracil-5-carbaldehyde, a systematic computational study has been performed. According to DFT computations, the catalytic cycle is divided into eight elementary steps: nucleophilic attack of the NHC on 2-bromoenal, 1,2-proton transfer, C-Br bond dissociation, 1,3-proton transfer, addition to 6-methyluracil-5-carbaldehyde, [2 + 2] cycloaddition, NHC dissociation, and decarboxylation. The Bronsted acid DABCO·H⁺ plays a crucial role in proton transfer and decarboxylation steps. The addition to 6-methyluracil-5-carbaldehyde determines both chemoselectivity and stereoselectivity, leading to R-configured carbocycle-fused uracil, in agreement with experimental results. NCI analysis indicates that the CH···N, CH···π, and LP···π interactions should be the key factor for determining the stereoselectivity. ELF analysis shows the main role of the NHC in promoting C-Br bond dissociation. The mechanistic insights obtained in the present work may guide the rational design of potential NHC catalysts.