A DFT study on the reaction mechanisms of isocyanide-based multicomponent synthesis of polysubstituted cyclopentenes

In this study, the reaction mechanisms of isocyanide-based three-component synthesis of polysubstituted cyclopentenes have been firstly investigated using density functional theory (DFT). Three possible reaction channels (including channels 1, 2, and 3) have been suggested and investigated in detail. For channels 1 and 2, the reaction is initiated by the nucleophilic attack of 2-morpholinoethyl isocyanide (R1) on 2-benzylidenemalononitrile (R2). While for channel 3, the reaction is initiated by the nucleophilic attack of reactant R1 on the reactant (E)-(2-nitrovinyl)benzene (R3). Our calculated results indicate that reaction channel 2 is the most energetically favorable channel. The computational results reveal that channel 2 contains three reaction steps. Firstly, it is the nucleophilic attack on R2 by R1. The second step is the formation of five-membered ring through a [3 + 2] cycloaddition process. The last step is a bimolecular proton transfer process. The 16.21 kcal/mol energy barrier for channel 2 demonstrates that the reaction can occur easily at the room temperature, which is in good agreement with the experiment. Moreover, the substituent effects have been considered by constructing four different model systems based on the experiments. The detailed reaction mechanisms should be helpful for people to understand the reaction at molecular level, and the suggested novel bimolecular proton transfer process provides some valuable insights on rational design of the suitable Brّnsted acid/base catalysts for this type of reaction.