Theoretical Insights into Enantioselective [3 + 2] Cycloaddition between Cinnamaldehyde and Cyclic N-Sulfonyl Trifluoromethylated Ketimine Catalyzed by N-Heterocyclic Carbene

Abstract

The density functional theory (DFT) method was used to investigate the mechanism and the origin of stereoselectivity of N-heterocyclic carbene (NHC)-catalyzed [3 + 2] cycloaddition between enals and cyclic imine N-sulfonyl trifluoromethyl ketimines at the M06-2X/SMD/6-311+G­(d,p)//M06-2X/SMD/6-31G (d,p) level. The results show that the favorable reaction path consists of five steps: nucleophilic attack, proton transfer, the formation of the C–C bond, the tautomerism of the enol intermediate, the formation of the five-membered ring, and the regeneration of the catalyst. For the process of proton transfer, the base-assisted reaction can reduce the activation free energy and make the reaction easier to occur compared with the direct proton transfer process. The formation of the C–C bond is the crucial step of stereoselectivity, in which two chiral centers and four configurations of intermediates (RR/RS/SR/SS) were generated. The free energy barriers obtained and the noncovalent interaction analysis confirm that the dominant configuration is SS, becoming the final trans-type product observed in experiment. Furthermore, through the analyses of the conceptual DFT and natural atomic charges, it is revealed that NHC acts as a double catalyst, which can not only increase the nucleophilicity of reactants by Lewis base but also activate the C–H bond and promote the proton transfer process. The understanding of the mechanism obtained in this study should be helpful to the other organic catalytic reactions with high stereoselectivity.

Elucidating the Mechanism and Selectivity of [3+2] Cycloaddition: A DFT and Molecular Docking Investigation of the Reaction of 6-Butoxy-5,6- Dihydro-4H-1,2-Oxazine 2-Oxide with Dimethyl Maleate

“…Employed for this purpose was the M06-2X [28] functional in tandem with D3 dispersion correction [29] and the 6-311G(d,p) basis set [30]. The M06-2X functional has been endorsed as a suitable computational approach for investigating 32CA reactions in various recent works [13,[31][32][33]. Transition states were ascertained through the observation of a single imaginary frequency, while minima were confirmed by the absence of any imaginary frequencies.…”