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.
Highlights
Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored
The first systematic study employing alkyl aryl sulfoxides as electrophiles emerged in 2017 from the Yorimitsu group[27]. They demonstrated that synthetically accessible aryl methyl sulfoxides could undergo nickel-catalyzed oxidative addition of C–S bond, which was compatible with a Negishi coupling procedure to afford biaryl products (Fig. 1e)
The methyl sulfoxides utilized as coupling partners in our protocol were generally prepared by methylation of corresponding thiophenol derivatives, followed by oxidation by NaIO4 or m-CPBA
Summary
Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. We envisioned that a neglected S-tetracovalent dialkoxyl alkyl aryl intermediate (Fig. 1f, see key intermediate), which was pioneered by Martin group several decades ago[37,38,39], could potentially be utilized to activate the C–S bond, facilitating alkyl aryl sulfoxides as electrophilic coupling partners in the subsequent transition-metal-free coupling reactions with alcohols. This strategy would allow selective conversion of thio or sulfoxide groups to alkoxy groups. We report a transition-metal-free cross-coupling strategy enabled by a base-substrate interaction mode and apply it to the reaction of aryl methyl sulfoxides with alcohols
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