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 ortho -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, N -aryl, N -heteroaryl, and N -alkyl sulfonamides bearing highly encumbered ortho 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 NH 2 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.