A Mild and Catalyst‐Free Synthesis of Cannabidiols and Regioisomers Mediated by Fluorinated Alcohols

This study presents a novel and practical strategy for synthesizing cannabinoids using a fluorinated alcohol solvent for the first time. Hexafluoroisopropanol (HFIP) was found to efficiently promote intermolecular Friedel-Crafts alkylation between allylic alcohols and electron-rich aromatics. This approach enabled the successful synthesis of cannabidiol (CBD) derivatives bearing various alkyl substituents, as well as the corresponding unnatural regioisomer (abnCBD), achieving moderate to high yields under mild conditions without the need for additional catalysts or other reagents. Insights in the mechanistic details were obtained through DFT calculations. Furthermore, a streamlined three-step synthesis of 5-alkyl resorcinol derivatives, essential starting materials for CBD synthesis, from the readily available chalcones was developed. Preliminary cytotoxicity assays using MTT revealed that some synthetic CBD derivatives exhibited promising anticancer activities.