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.

Recent Advances in Cyclization Reactions of 1,6‐Enynes

“…In 2022, a practical AIBN‐promoted cascade cyclization of 1,6‐enynes with thiols has been demonstrated by Deng and colleagues, which proceeded through a selective 5‐ exo ‐dig process and enabled access to various sulfur‐substituted 4‐enyl‐2‐pyrrolidones in the presence of AIBN in CH 3 CN at 90 °C (Scheme 114). [89] A number of enynes were easily converted to the heterocyclic compounds with a five membered γ ‐lactam skeleton in moderate to good yields. It is worth noting that the electron‐rich thiophenols were compatible with this protocol and furnished the desired products with reverse stereoselectivities.…”