Catalyst‐free Three‐Component Halophosphorothiolation of Enamides/Enoates for Regioselective Synthesis of <i>β</i>‐Halogenated Phosphorothioates

A three‐component regioselective phosphorothiolation‐halogenation of enamides/enoates with P(O)SH compounds and NXS ( X = Cl, Br) under catalyst‐ and additive‐free conditions has been demonstrated. This strategy readily affords an array of valuable amide/ester‐ and halogen‐containing phosphorothioates in good to excellent yields, featuring simple operations, diverse functional group tolerance, and easy scale‐up. Preliminary studies reveal that the electrophilic phosphoranesulfenyl chlorides/bromides generated in situ may be a key intermediate. Furthermore, phosphorothioated lactams can be easily obtained through the intramolecular substitution reaction of chlorophosphorothiolated amides. Notably, all of the tested products displayed potent and selective inhibitory activity toward butyrylcholinesterase.