Sustainable synthesis of cannabinoids via metal-free aromatic deformylation

Abstract

Cannabinoids, the bioactive compounds of the Cannabis genus, have gained considerable attention for their potential therapeutic applications variety of health conditions. Cannabidiol, in particular, has been studied for its diverse pharmacological properties, including antioxidant, anticancer, anti-inflammatory, and neuroprotective effects. To enhance the accessibility and efficacy of cannabinoids, synthetic approaches have been explored, focusing on improving yields and reducing the creation of unwanted byproducts. This study introduces a novel metal-free deformylation method for synthesizing cannabinoid derivatives from their corresponding cannabinoid aldehyde. We have developed optimized reaction conditions that utilize trimethyl orthoformate as a methanol donor in combination with p-toluenesulfonic acid, which enables high-yield conversion of 3-formyl-cannabinoid to cannabinoid with minimal formation of byproducts. Furthermore, we successfully applied this methodology to a range of other cannabinoid aldehydes, producing cannabinoids with varying alkyl chain lengths. The reaction pathway revealed a nucleophilic substitution mechanism that facilitates the removal of the aldehyde group and promotes efficient cannabinoid synthesis. This metal-free approach offers a sustainable alternative to traditional catalytic methods, which could be really valuable for advancing cannabinoid research and pharmaceutical development.