Efficient Synthesis of Cannabinoid Acids

Cannabinoid acids are the carboxylic acid precursors of cannabinoids, which are present in high abundance in fresh cannabis plants. During heating and storage, cannabinoid acids undergo decarboxylation to produce the corresponding cannabinoids. Cannabinoid acids have been prepared through the reaction of cannabinoids with methyl magnesium carbonate (MMC); however, this method has a limited substrate scope, and Δ 9 ‐tetrahydrocannabinolic acid cannot be produced using this approach. In this study, an alternative synthesis of cannabinoid acids was developed based on an O → C acyl rearrangement. Specifically, this strategy involved regioselective bromination followed by halogen–lithium exchange and intramolecular nucleophilic addition, which led to successful carboxylation. The key reaction was identified as a regioselective bromination using cyclopentyl methyl ether as the optimal solvent, affording the 2‐brominated product in high yield. This rearrangement strategy enabled the efficient synthesis of cannabinoid acids from cannabinoids.