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

Abstract

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.