The Sulfenylation of Pyrazolones with Heterocyclic Thiols or Disulfides in Water and Application to DNA-Compatible Chemistry

A practical and efficient method for synthesizing 4-sulfenylpyrazol-5-ol compounds has been established through a hydrogen peroxide (H₂O₂)-promoted cross-dehydrogenative coupling (CDC) reaction between heterocyclic thiols and pyrazolones in water. This transformation exhibits broad substrate scope, tolerating a range of functional groups on both pyrazolones and heterocyclic thiols, and affords the desired 4-sulfenylpyrazol-5-ol products in moderate to excellent yields. Mechanistic investigations suggest that H₂O₂ oxidizes heterocyclic thiols in situ to generate reactive disulfide intermediates, which subsequently undergo sulfenylation with pyrazolones to furnish the 4-sulfenylpyrazol-5-ol framework. Based on this mechanistic insight, we further developed an oxidant-free variant of the reaction, employing preformed disulfides directly for the sulfenylation of pyrazolones. This streamlined, oxidant-free strategy was also successfully applied to the synthesis of DNA-tagged 4-sulfenylpyrazol-5-ols, highlighting its utility and versatility in synthetic chemistry.