Mechanistic insights into the stereoselective C2-functionalization of 1-substituted imidazoles with cyanophenylacetylene and aldehydes

In this present study, two possible channels including channels A and B on the stereoselective synthesis of imidazoles by the reaction between 1-substituted-2-methylimidazoles (R1), cyanophenylacetylenes (R2), and acetaldehydes (R3) have been studied using the density functional theory (DFT). There are both four processes involved in both the two channels: the nucleophilic attack of R1 on R2 for the formation of E- or Z-configurational zwitterionic intermediate, the proton transfer process, the addition of another reactant R3, and the rearrangement to form the final product. The calculated results demonstrate that the first step is the rate-determining step, and is associated with the energy barrier of 25.32 in Channel A and 19.24 kcal/mol in Channel B respectively, which show Channel B is more energy favorable. This is in good agreement with the experimental result that the Z-isomer is the single product. Moreover, the distortion/interaction reactivity analysis was performed to explain why the transition state in Channel B is more stable. Furthermore, the calculations on the solvation effects using IEFPCM model have also been carried out.