Mechanistic studies on an isothiourea-catalyzed reaction of an aromatic ester with an imine

Abstract

Increasing attention is being paid to divergent chemical reactions as a strategy for synthesizing complex organic molecules simply by regulating and adjusting reaction conditions. However, the factors controlling this switchable transformation remain unclear. A systematic study was conducted using density functional theory (DFT) at the M06–2X level to determine the mechanism of an isothiourea-catalyzed divergent chemical reaction of an aryl acetic acid ester with an imine in different solvents (acetonitrile and ethanol). The origins of the stereoselectivity and chemoselectivity of the reaction were determined using noncovalent interaction (NCI) and electrostatic potential surface (EPS) analyses. Lactamization reaction occurs preferentially in acetonitrile, and esterification proceeds preferentially in ethanol. The reaction of an ammonium enolate intermediate with an alkynyl imine preferentially generates the SS-configured isomer. The results of this theoretical study provide insight into the general mechanism of isothiourea-catalyzed reactions in which the key intermediate is ammonium enolate.