Bromocyclization of Unsaturated Thioester and Access to Functionalized Sulfur-heterocycles

The alkene halocyclization reaction is a significant synthetic organic chemical transformation, especially for the versatile synthesis of heterocycles. Although oxygen, nitrogen, and carbon have been extensively studied as nucleophilic elements in this transformation, sulfur-based nucleophiles are relatively unexplored. This is particularly intriguing given the prevalence of S-heterocycle- containing bioactive natural products. In this study, we investigated halocyclization chemistry involving unsaturated thioesters, with a focus on their use as potential S-nucleophiles. Despite their electron-withdrawing nature, thioesters are greater nucleophile rather than sulfides according to our previous study, which encouraged us to consider thioesters as viable halocyclization candidates. Thioesters, which are readily synthesized from alcohols or alkyl halides, are convenient starting materials. Here, we developed a novel bromocyclization method that uses alkenoic thioesters and N-bromoacetamide (NBA) to form cyclic bromosulfides. The resulting 5-exo products are labile and can be used in various nucleophilic substitution reactions. Furthermore, the reaction pathways involving bromonium intermediates and the HBr-promoted auto-activation of NBA were revealed by DFT calculations. This study provides new avenues for the synthesis of S-heterocyclic scaffolds and a pathway for future investigations into asymmetric variants with the aim of developing effective catalysts.