From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds. However, there are limited synthetic methods for unsymmetrical polysulfides. Conventional strategies entail two pre-sulfurated cross-coupling substrates, R–S, with higher chances of side reactions due to the characteristic of sulfur. Herein, a library of broad-spectrum polysulfurating reagents, R–S–S–OMe, are designed and scalably synthesized, to which the R–S–S source can be directly introduced for late-stage modifications of biomolecules, natural products, and pharmaceuticals. Based on the hard and soft acids and bases principle, selective activation of sulfur-oxygen bond has been accomplished via utilizing proton and boride for efficient unsymmetrical polysulfuration. These polysulfurating reagents are highlighted with their outstanding multifunctional gram-scale transformations with various nucleophiles under mild conditions. A diversity of polysulfurated biomolecules, such as SS−(+)-δ-tocopherol, SS-sulfanilamide, SS-saccharides, SS-amino acids, and SSS-oligopeptides have been established for drug discovery and development.

A novel reagent, which introduces two sulfur atoms in one step, was designed and used for the construction of diverse disulfanes by copper-catalyzed oxidative cross-coupling under mild reaction conditions. By applying this stable and readily prepared reagent, late-stage modification of pharmaceuticals and natural products can be achieved straightforward. The scaled-up experiments further indicated the practicality of this protocol. The pH value of the system plays a key role in achieving highly selective cleavage of the C-S bond instead of a S-S bond in the transformation.

A novel Pd-catalyzed double C-S bond formation coupling reaction has been developed. This protocol, in which Na2S2O3 was used as sulfurating reagent in metal-catalyzed reactions, provides an efficient method for the synthesis of substituted 1,4-benzothiazine derivates, which are structural elements of numerous bioactivity molecules rendering this protocol attractive to both synthetic and medicinal chemistry.