Sustainable Copper-Catalysed Arylations for Chemical Manufacture

Abstract

Functionalised aromatic compounds are the backbone to most pharmaceutical and biologically active molecules, their synthesis heavily reliant on TM-catalysed arylation reactions. Pd dominates this field, but its scarcity and toxicity has motivated scientists to look for alternatives. This report demonstrates a more environmentally-friendly approach to Cu-catalysed Ullmann-type coupling through the development and application of a small library of structurally diverse picolinamide ligands, synthesised via T3P-mediated amide coupling. The ligands were prepared in good yield and subsequently evaluated in Cu-catalysed C–N and C–O coupling reactions under mild conditions, employing K₃PO₄ and i-PrOAc as more sustainable alternatives to conventional bases and solvents. Where successful coupling was achieved, yield varied depending on the ligand used, highlighting the importance of ligand structure in achieving efficient reactivity. Overall, this work demonstrates that Ullmann-type couplings can be achieved under more sustainable conditions, providing insight into the development of greener and more practical arylation methodologies.