Accelerated Thioarylation of Arenes Using Lewis Acid and Lewis Base Dual Catalysis

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Biaryl sulfides are crucial structural motifs in pharmaceuticals and materials science.
• Efficient synthesis of biaryl sulfides under mild conditions is highly desirable.
• Previous methods using iron-activated saccharin reagents were limited with electron-deficient thioaryl groups.

Purpose of the Study:

• To develop an improved method for synthesizing biaryl sulfides, particularly those involving electron-deficient thioaryl groups.
• To enhance the reactivity and broaden the substrate scope of iron-catalyzed thioarylation.
• To enable late-stage functionalization of complex molecules using a mild and efficient catalytic system.

Main Methods:

• Development of a dual catalytic system employing iron and diphenyl selenide.
• Utilizing saccharin-based thioaryl reagents for the reaction with arenes.
• Optimization of reaction conditions for room temperature thioarylation.

Main Results:

• The dual catalytic system significantly accelerates the iron-catalyzed thioarylation of electron-deficient reagents.
• The improved procedure operates efficiently at room temperature, reducing reaction times.
• Successful application in the synthesis of the HIV-1 reverse transcriptase inhibitor L-737,126 and late-stage functionalization of naproxen.

Conclusions:

• The dual catalytic system provides a robust and versatile method for biaryl sulfide synthesis.
• This approach overcomes limitations of previous methods, enabling broader substrate scope and late-stage functionalization.
• The reaction's utility is demonstrated in synthesizing biologically relevant molecules and functionalizing pharmaceuticals.