2025/10/08 by Debashis Jana, Sampad Malik, Gopal Kanrar +1
Biochemistry, Genetics and Molecular Biology · Chemistry · #Ammonium acetate #Annulation #Aryl #Asymmetric Hydrogenation and Catalysis #Cascade reaction #Catalysis #Catalytic Cross-Coupling Reactions #Chemical Synthesis and Analysis #Dehydrogenation #Domino #Pyridine
paper · doi:10.1021/acs.joc.5c01531
openalex publication_date 2025/10/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
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 via 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 via single-electron-transfer (SET) pathways. This one-pot methodology requires only 20 mol % base loading, achieving excellent turnover number (TON ≈ 10 4 ) with short residence time (2 h). A wide variety of primary and secondary alcohols have been successfully utilized as substrates ( 61 examples ). Notably, this open-air sustainable approach generates only benign byproducts (H 2 O, H 2 O 2 ) without external oxidants or additives. This convenient and cost-effective strategy aligns with green chemistry principles, ensuring simplicity and excellent E -factor values (0.3–0.5), marking a significant advance in highly functionalized pyridine synthesis.