Transition-metal-free formal cross-coupling of aryl methyl sulfoxides and alcohols via nucleophilic activation of C-S bond

Guolin Li, Yexenia Nieves-Quinones, Hui Zhang, Qingjin Liang, Shuaisong Su, Qingchao Liu, Marisa C. Kozlowski () and Tiezheng Jia ()
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Guolin Li: Southern University of Science and Technology
Yexenia Nieves-Quinones: University of Pennsylvania
Hui Zhang: Southern University of Science and Technology
Qingjin Liang: Southern University of Science and Technology
Shuaisong Su: Southern University of Science and Technology
Qingchao Liu: Northwest University
Marisa C. Kozlowski: University of Pennsylvania
Tiezheng Jia: Southern University of Science and Technology

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.

Date: 2020
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DOI: 10.1038/s41467-020-16713-8

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