Zinc-induced one-pot coupling of alkyl halides and alcohols to access CD3-labeled alkyl sulfides

Deuterium labeling of organic molecules with high efficiency is a promising and challenging task in organic synthesis and drug discovery. Here we report two practical and robust strategies based on zinc-mediated one-pot reductive coupling of alkyl halides and (deuterated) alcohols utilizing ArSO2SNa as crucial sulfur shuttle in absence of thiols. The approaches feature nickel and base-free conditions, broad substrate scope, and late-stage molecule modification, providing a wide range of trideuteromethyl alkyl sulfides and other important analogs with the examples of sulfoxide, sulfone, and sulfoximine. Initial mechanistic studies show that an active adduct of Zn into thiosulfonates is formed in nearly quantitative yield, and it could be further applied to the nucleophilic substitution of alkyl electrophiles to construct a variety of Csp3–S bonds.