Copper–Iron-Catalyzed Cross-Coupling of <i>ortho</i> -Substituted Sulfonamides with Sterically Hindered (Hetero)aryl Chlorides and Alkyl Halides: Synthesis of Sulfonamide Drugs

We describe for the first time an effective copper-iron-catalyzed cross-coupling strategy that enables the reaction for a diverse array of <i>ortho</i>-substituted primary (hetero)aryl and aliphatic sulfonamides with challenging sterically hindered (hetero)aryl chlorides, bromides, and alkyl halides under solvent-minimized conditions. The developed methodology efficiently affords the corresponding products, <i>N</i>-aryl, <i>N</i>-heteroaryl, and <i>N</i>-alkyl sulfonamides bearing highly encumbered <i>ortho</i> substituents, in good to excellent yields with vast substrate scope (104 examples), tolerating several sensitive functionalities. In addition, selective C-N coupling of substrates containing multiple nucleophilic NH₂ groups was effectively accomplished. This economically attractive protocol was effectively utilized for the synthesis of 10 commercially available sulfonamide-based drugs and 11 drug-like molecules. Notably, the methodology offers several other important advantages, including gram-scale synthesis, reusability of the catalyst, synthetic transformations of synthesized cross-coupled products, and elimination of conventional workup. Several spectroscopic experiments were conducted to identify the oxidation state involved in the active catalytic species. To explore the reaction mechanistic pathway, a radical clock experiment employing a radical probe and control reactions with radical scavengers were carried out.