Mechanochemical base-catalyzed isomerization and deuteration of allylbenzenes

Abstract

Trideuteromethylation has gained significant importance in modern drug development for its ability to fine-tune pharmacokinetic properties and enhance metabolic stability through the deuterium kinetic isotope effect. Currently, most methods for alkene double-bond migration (e.g., transition-metal catalysis) suffer from drawbacks such as substantial waste generation, high reaction temperatures, and extended reaction durations. Herein, we report a universal mechanochemical strategy for the rapid and metal-free isomerization and deuteration of allylbenzenes. Utilizing only catalytic KOtBu and stoichiometric DMSO-d₆, this method enables precise CD₃ incorporation within 15 minutes under ambient conditions. The protocol exhibits broad functional group tolerance, is scalable, and applicable to late-stage deuteration of natural products, offering a practical and sustainable approach to deuterated pharmaceuticals. In addition, mechanistic studies indicate that the H/D exchange catalyzed by KOtBu is a radical process.