Copper(II)-Catalyzed One-Pot Synthesis of Chlorinated Phenolic Esters from Natural Phenols and Molecular Docking Evaluation

Abstract Chlorophenols are widely used intermediates in several chemical industry sectors, including pharmaceuticals and agrochemicals, and their esterification represents an attractive strategy for generating compounds with new physicochemical properties and added value. In this context, the study aimed to modify the natural phenols eugenol, thymol, and carvacrol via a sequential chlorination–esterification process using a simple, efficient catalytic system. The reactions were performed in a single reactor under an oxygen atmosphere, employing copper(II) chloride as the sole catalyst for both steps and acetic anhydride as the esterifying agent. This one-pot tandem approach enabled the synthesis of four unprecedented chlorinated and esterified derivatives with high conversion and selectivity: 4-allyl-2-chloro-6-methoxyphenyl acetate, 4-chloro-2-isopropyl-5-methylphenyl acetate, 2,4-dichloro-6-isopropyl-3-methylphenyl acetate, and 4-chloro-5-isopropyl-2-methylphenyl acetate. Reaction parameters, regioselectivity, and mechanistic aspects were experimentally investigated. In parallel, molecular docking studies were conducted to rationalize how chlorination and esterification influence the interaction profiles of these phenolic derivatives with xanthine oxidase, an enzyme involved in oxidative metabolism. The docking results revealed a consistent structure–affinity relationship, indicating that chlorination improves binding affinity, while esterification enhances geometric complementarity within the enzyme active site. It should be noted that these conclusions are based on in silico predictions; in vitro validation is required to confirm biological activity. Overall, this work demonstrates an efficient and sustainable synthetic route for the functionalization of natural phenols and shows that tandem catalysis can generate structurally optimized scaffolds for future structure–activity and enzyme-modulation studies.