Microwave-Driven Solventless Nickel Metalloradical-Catalyzed [2 + 2 + 1 + 1] Cascade Annulation of Polysubstituted Pyridines

We demonstrate an eco-friendly and efficient method for the synthesis of biologically relevant polysubstituted pyridines, including pentasubstituted derivatives, using a homogeneous nickel-metalloradical catalyst. This solvent-free strategy under microwave (MW) irradiation employs readily available primary and secondary aryl alcohols along with ammonium acetate to form pyridine scaffolds <i>via</i> catalytic dehydrogenative alcohol oxidation, yielding 68-93% under neat conditions. The MW-assisted four-component (4CRs) domino [2 + 2 + 1 + 1] annulation proceeds through consecutive C-C and C-N bond formations, followed by catalytic dehydrogenative aromatization. The nickel-metalloradical drives dual catalytic cycles: alcohol dehydrogenation and ring aromatization, both <i>via</i> single-electron-transfer (SET) pathways. This one-pot methodology requires only 20 mol % base loading, achieving excellent turnover number (TON ≈ 10⁴) with short residence time (2 h). A wide variety of primary and secondary alcohols have been successfully utilized as substrates (<i>61 examples</i>). Notably, this open-air sustainable approach generates only benign byproducts (H₂O, H₂O₂) without external oxidants or additives. This convenient and cost-effective strategy aligns with green chemistry principles, ensuring simplicity and excellent <i>E</i>-factor values (0.3-0.5), marking a significant advance in highly functionalized pyridine synthesis.