Continuous flow azide formation: Optimization and scale-up

The intrinsically small volumes and highly controlled reaction conditions render continuous flow microreactors ideal systems for the synthesis of potentially explosive compounds such as organic azides. In this article, we report the formation of benzyl azide from benzylamine using imidazole-1-sulfonyl azide hydrochloride as diazotransfer reagent. In a small scale (semi-automated) continuous flow setup the diazotransfer reaction was optimized using minimal amounts of reagents; less than 400 mg of benzylamine was required to perform 60 optimization reactions. The optimal reaction conditions were indentified to be room temperature. 600 s of residence time and an imidazole-1-sulfonyl hydrochloride to benzylamine stoichiometric ratio of 3 to 4. Furthermore, we successfully scaled up the reaction with a factor of 200 to gram scale using one single continuous flow reactor. (C) 2010 Elsevier B.V. All rights reserved.