Nickel‐Catalyzed Negishi Coupling for Modular and Diverse Synthesis of Sulfonyl Fluorides and Sulfonamides †

Comprehensive Summary Sulfonyl groups represent one of the most encountered structural motifs in medicinal chemistry. They serve as stable linkers that connect pharmacophoric elements within a molecule and as modulators of physicochemical properties, including lipophilicity, conformational flexibility, and metabolic susceptibility. This versatility makes sulfonyl‐containing compounds highly attractive in drug discovery campaigns, particularly for protease inhibitors, kinase modulators, and covalent inhibitors. Among the various sulfonyl derivatives, sulfonyl fluorides have garnered interest due to their stability under ambient conditions and their ability to participate in sulfur(VI) fluoride exchange (SuFEx) reactions. Despite these advantages, the practical synthesis of sulfonyl fluorides remains a significant bottleneck. Conventional methodologies, such as oxidation of thiols or fluorination of sulfonyl chlorides, often suffer from narrow substrate scopes, incompatibility with sensitive functional groups, harsh reaction conditions and unsatisfactory regioselectivity when applied to polyfunctionalized molecules. These limitations severely impede the rapid assembly of sulfonyl fluoride libraries for biological screening and late‐stage functionalization of complex drug candidates. To address this unmet need, we have developed a nickel‐catalyzed Negishi cross‐coupling protocol that utilizes bromomethyl sulfonyl fluoride (BMSF) as a readily available radical precursor. This approach enables the efficient construction of phenylmethylsulfonyl fluorides. The reaction proceeds under remarkably mild conditions, operates with high catalytic efficiency, tolerates a broad array of functional groups and exhibits excellent site selectivity even in the presence of multiple reactive sites. The synthetic utility of this method is further demonstrated by the facile conversion of the obtained products into a diverse range of sulfonamide derivatives through simple nucleophilic substitution reactions. This modular transformation provides a straightforward and scalable route to sulfonyl‐linked molecular architectures, thus offering a versatile platform for medicinal chemistry efforts.