Regioselective N-2 Alkylation of Tetrazoles with Phenacyl Halides under Mechanochemical Conditions and Its Application to a Solid-State Synthesis of the Antiepileptic Drug Cenobamate

Tetrazole derivatives are very important compounds in medicinal chemistry, and their preparation typically requires multistep sequences. Therefore, the regioselective N-alkylation of tetrazoles is a highly significant synthetic objective. We have explored the alkylation of tetrazoles with phenacyl halides under mechanochemical conditions to enhance the selectivity for N-2 regioisomers. The yield and regioisomeric ratio were found to depend on the nature of the grinding auxiliary, which can be explained by the ion pair formation. This methodology enabled the fully mechanochemical synthesis of the antiepileptic drug cenobamate, representing a substantial improvement over existing methods from a sustainability perspective.