Insights into the isothiourea-catalyzed asymmetric [4 + 2] annulation of phenylacetic acid with alkylidene pyrazolone

A density functional theory (DFT) study was performed to explore the possible reaction mechanisms and the origin of stereoselectivity for the isothiourea-catalyzed [4 + 2] annulation reaction of in situ activated phenylacetic acid with alkylidene pyrazolone. The computed results reveal that the reaction contains several steps, including complexation of isothiourea with substrate, dissociation of the t-BuCO2- group, -C-H deprotonation of the acyl ammonium intermediate, stepwise [4 + 2] cycloaddition processes, and the dissociation of isothiourea. The C-C bond formation involved in the [4 + 2] cycloaddition process was identified as the stereoselectivity-determining step, in which the two chiral carbon centers emerge. The pathway associated with the RR configurational isomer is calculated to be most energetically favorable, which is consistent with the experimental observations. The origin of stereoselectivity was further studied through analyses of distortion/interaction and non-covalent interaction (NCI), and the role of isothiourea was discovered by the analyses of the global reaction index (GRI) and Parr functions. By analyzing the activity of different isothiourea catalysts, it was found that a stronger nucleophilicity of the center N atom of the isothiourea catalysts would result in a lower energy barrier of the reaction. The novel insights obtained in the present study would be useful for the rational design of more efficient catalysts for this kind of reaction.