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Current Organic Synthesis

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ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

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Research Article

Coupling of Thiols and Aryl Halides Mediated by Dicyclohexano-18- crown-6 and Potassium Carbonate

Author(s): Zhong-Lin Liu, Jing-Xiu Xu, Ning Deng*, Zheng Dong, Xiao Shen, Jun Xu and Hua-Jian Xu*

Volume 19, Issue 7, 2022

Published on: 15 June, 2022

Page: [824 - 837] Pages: 14

DOI: 10.2174/1570179419666220412084111

Price: $65

Abstract

Aims: A simple, transition-metal-free C-S coupling protocol for the synthesis of aryl thioethers is reported.

Background: Sulfur-containing moieties are ubiquitous in pharmaceutical drugs and materials and therefore methods for their construction are of great importance. One approach entails the catalytic coupling of an aryl halohydrocarbon with a thiol, but the transition metal catalysts usually used are prone to poisoning by participating sulfur species and efficient catalysis is usually only achieved after complex ligand optimization.

Objective: New transition-metal-free approaches to the synthesis of C-S bonds are urgently need.

Methods: We screened the reaction conditions such as alkali, crown ether, solvent, temperature, etc., tested the compatibility of the reaction substrate, and analyzed the mechanism process.

Results: The optimized reaction conditions were determined to be 1.0 equiv of aryl halides and 1.2 equiv of thiols at 110 ℃ in toluene with K2CO3 (1.5 equiv) as a base, promoted by 10 mol% dicyclohexano-18-crown-6. Up to 33 examples of thioethers were synthesized under transitionmetal- free conditions in good to excellent yields.

Conclusion: We have developed a simple and efficient method for the C-S cross-coupling of a wide variety of (hetero)aryl halides and thiols mediated by dicyclohexano-18-crown-6 and without the need for transition-metal catalyst. In addition, the preparation and gram-scale experiments of a variety of drug molecules further verify the practicability of our developed method.

Keywords: Carbon-sulfur coupling, SNAr, aryl halides, thiols, dicyclohexano-18-crown-6, potassium carbonate.

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