Reusable Iron‐Copper Catalyzed Cross‐Coupling of Primary Amides with Aryl and Alkyl Halides: Access to N‐Arylamides as Potential Antibacterial and Anticancer Agents

Abstract We present, for the first time, an efficient ligand‐free iron‐copper catalyzed cross‐coupling reaction involving a variety of aryl, heteroaryl halides (including chlorides, bromides, and iodides), and alkyl bromides with diverse aryl and aliphatic primary amides, conducted under solvent‐minimized conditions. This economically competitive protocol successfully yielded the corresponding cross‐coupling products, N ‐arylamides and N ‐alkylamides, in good to excellent yields with broad substrate scope (65 examples) and tolerance to several sensitive functionalities (including heterocycles). No conventional work‐up is required for this protocol, and the developed method is applicable for gram‐scale synthesis. Notably, the catalyst is inexpensive, environmentally friendly, and can be reused at least four times with minimal loss of catalytic activity. A series of experiments, including X‐ray photoelectron spectroscopy (XPS), UV spectroscopy, cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and X‐ray diffraction (XRD) were conducted to identify the oxidation state of active catalytic species and radical clock experiment was performed using a radical probe to investigate the reaction mechanism. Furthermore, we evaluated the antibacterial and anticancer properties of selected synthesized products ( 3 ii , 3 xii , and 3 xxxx ) in‐vitro . The results indicated that the prepared compounds exhibited promising antibacterial and anticancer activities (MTT and Molecular Docking).