Ligand-Free Copper-Catalyzed Ullmann-Type C-O Bond Formation in Non-Innocent Deep Eutectic Solvents under Aerobic Conditions

An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeded under mild conditions (80 degrees C) in air, in the absence of additional ligands, with a catalyst [Cu-I or Cu-II species] loading up to 5 mol% and K2CO3 as the base, providing the desired aryloxy derivatives in up to 98 % yield. The potential application of the methodology was demonstrated in the valorization of cheap, easily available, and naturally occurring polyols (e. g., glycerol) for the synthesis of some pharmacologically active aryloxypropanediols (Guaiphenesin, Mephenesin, and Chlorphenesin) on a 2 g scale in 70-96 % yield. Catalyst, base, and deep eutectic solvent could easily and successfully be recycled up to seven times with an E-factor as low as 5.76.

Automated summary

The efficient protocol developed for Cu-catalyzed Ullmann-type aryl alkyl ether synthesis demonstrates high yield production of desired products, valorization of cheap polyols, and successful recycling of catalyst, base, and solvent multiple times.