H₂O₂-Mediated Oxidative S-H/P(O)-H Cross-Coupling to Access Thiophosphates

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Sustainable Synthesis

Background:

• Thiophosphates are vital building blocks in drug discovery and organic synthesis.
• Existing synthetic routes for thiophosphates are often limited in scope and sustainability.

Purpose of the Study:

• To develop general, sustainable, and atom-economic methods for thiophosphate synthesis.
• To provide access to a wide range of S-P architectures with high functional group tolerance.

Main Methods:

• Developed a hydrogen peroxide (H2O2)-mediated oxidative S-H/P(O)-H cross-coupling reaction.
• Established an Et3N/air-mediated dehydrogenative cross-coupling of thiols and trialkyl phosphites.

Main Results:

• Synthesized 46 diverse S-P architectures with yields up to 95%.
• Demonstrated exceptional functional group compatibility and operational simplicity.
• Confirmed facile scalability and direct applicability to bioactive molecule synthesis.

Conclusions:

• The developed methods offer efficient and sustainable pathways for thiophosphate construction.
• Mechanistic studies suggest a radical pathway is involved in the thiophosphate synthesis.
• These strategies advance the synthesis of thiophosphates for pharmaceutical and chemical applications.