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

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).