Computational Chemistry-Assisted Highly Selective Radical Cascade Cyclization of 1,6-Enynes with Thiols: Access to Sulfur-Substituted 4-Enyl-2-Pyrrolidones

Abstract

In this study, an efficient method for the synthesis of sulfur-substituted 4-enyl-2-pyrrolidones was successfully developed through AIBN-promoted highly selective 5-exo-dig radical cascade cyclization of 1,6-enynes with sulfur sources with the aid of theoretical and computational chemistry. This protocol enables the first practical and green synthesis of an array of 4-enyl-2-pyrrolidones in moderate-to-good yields with broad substrate scopes and high regioselectivities (>20:1). Moreover, excellent stereoselectivities have also been achieved (up to >20:1, Z/E). Most interestingly, when the sulfur source is electron-rich thiophenol, reverse stereoselectivities were discovered. In addition, the control experiments indicate that the cascade cyclization is realized by radical reactions, and the detailed reaction mechanism and regioselectivities have also been explained by theoretical studies.