Redox-active alkyl xanthate esters enable practical C-S cross-coupling by nickel catalysis

Sulfur-containing compounds are increasingly important for designing pharmaceutical candidates that have accumulated broad research efforts toward developing effective methods to forge C-S bonds from various sulfuration agents. However, most established methods are typically limited to using odorous and toxic thiols. We have developed a nickel catalysis strategy that unlocks a unique technology to harness readily accessible alkyl xanthate esters, which while previously well-studied as alkyl radical precursors are used herein as ideal sulfenylating agents via an unprecedented C-S bond activation pattern. The success of this strategy lies in utilizing alkyl xanthate esters as redox-active handles for nickel-catalyzed chemo- and regioselective C-S bond cleavage via a SET pathway, followed by C-S cross-coupling with a broad range of carbon electrophiles, including carboxylic acids, acid chlorides, and aryl/vinyl halides. This chemistry is distinguished by the high accessibility of alkyl xanthate esters with a particular emphasis on using nearly odorless, easy-to-handle, and extremely inexpensive KSCSOEt (<$20 per mol) as the parent sulfur source to avoid using thiols. A series of primary, secondary, and tertiary alkyl xanthate esters are eligible for the Ni-catalyzed cross-coupling to furnish invaluable thioesters and thioethers in a practical and modular fashion.

Automated summary

A nickel catalysis strategy was developed to utilize alkyl xanthate esters as sulfenylating agents for C-S bond cleavage and cross-coupling reactions. This strategy enables the synthesis of thioesters and thioethers from a variety of carbon electrophiles in a practical and modular fashion. The use of alkyl xanthate esters as redox-active handles allows for regio- and chemo-selective C-S bond activation and cross-coupling reactions.