One-pot synthesis of unsymmetrical disulfides using 1-chlorobenzotriazole as oxidant: Interception of the sulfenyl chloride intermediate

A high-yielding and low temperature one-pot procedure is described for unsymmetrical disulfide synthesis from two different thiols using 1-chlorobenzotriazole (BtCl) as oxidant. The mechanism of the coupling involves in situ trapping of the sulfenyl chloride intermediate R 1 SCl by nucleophilic benzotriazole (BtH) to form R 1 SBt, which protects R 1 SCl from forming the homodimer R 1 SSR 1 . The methodology is applicable to all types of thiol (aliphatic, aromatic, heteroaromatic), with a variation developed for aliphatic–aliphatic couplings. Differentially N-protected cysteines couple to afford the unsymmetrical cystine derivatives in high yield (90%), which serves as a model for the one-pot intermolecular coupling of cysteine-containing peptides to form peptide disulfide heterodimers. Minimal exchange in aromatic–aromatic disulfide synthesis is noted on account of the mild conditions.