Solvent-Free O-Propylation of Phenol and Cresol Isomers Catalyzed by Cu(acac)2 with Polyhalomethane Promoters

Arylalkyl ethers are important organic compounds used in the synthesis of pharmaceuticals, fragrances, and plasticizers. Traditional synthesis methods (Williamson and Mitsunobu reactions) are inefficient due to high waste generation. Catalytic O-alkylation of phenols with alcohols is a promising alternative; however, it faces challenges such as competition between O- and C-alkylation, and the low reactivity of n-propanol compared to methanol or ethanol. Copper-based catalysts combined with polyhalomethanes (CHBr3, CBr4) offer a promising route for one-step ether synthesis. The present study investigates the O-propylation of phenol and isomeric cresols with n-propanol using copper salts and polyhalomethane promoters. The goal is to identify optimal conditions (temperature, catalyst type, and promoter) to overcome the low reactivity of n-propanol and ensure high selectivity and yield in solvent-free conditions.The study demonstrated that copper-based catalysts combined with polybromomethane promoters (CHBr3, CBr4) facilitate the O-propylation of phenols with n-propanol at 150–220oC in solvent-free conditions. The best results were achieved using the Cu(acac)2–CHBr3 system (10 mol.%, 220oC). It was established that polybromomethane is a critical component, as copper catalysts remain inactive in its absence. The reactivity of the substrates follows the order: phenol > p-cresol > m-cresol > o-cresol, which is attributed to the steric and electronic effects of the methyl group. At high temperatures and extended reaction times, competing C-alkylation of the aromatic ring leads to the formation of propyl- and dipropylphenols, thereby reducing the overall O-selectivity of the process.