A General Mechanochemical Copper Catalyzed Three-Component Sulfonamidation Reaction

Sulfonamides are privileged organic synthesis scaffolds, particularly in pharmaceuticals and bioactive domains. Conventional synthetic strategies often rely on expensive metal cross-coupling protocols, availability of preexisting sulfur functionality, amine nucleophilicity, elevated reaction temperatures, and inherently unstable and expensive SO2 surrogates. Herein, we unveil a concise, mechanochemical driven, copper-catalyzed three-component protocol that involves aryl radical precursors and K2S2O5 with amine carbonates, to furnish a diverse array of sulfonamide products, including biologically active and late-stage functionalized molecules, in good to excellent yields. Central to this approach was the deployment of mechanochemical force to drive the chemical transformation under solvent-free conditions, reducing waste and enabling unique reactivity. Mechanistic insights, including radical trapping experiments, support the involvement of a copper-mediated aryl, sulfonyl and N-centered radical intermediate, leading to the product formation. This mechanochemical-copper dual activation paradigm offers a strategically distinct entry to sulfonamide architectures and confers notable advantages over existing methodologies, including (i) use of cheap catalyst; (ii) bench-stable and cheap SO2 surrogate; (iii) ambient aerobic conditions; (iv) short reaction time; (v) operationally simple; (vi) broad substrate scope; and (vii) scale-up synthesis. By bridging mechanochemistry and copper catalysis, this strategy collectively establishes a sustainable and versatile platform for synthesizing sulfonamides with potential applications in medicinal chemistry and beyond.