Safe and efficient tetrazole synthesis in a continuous-flow microreactor.

Tetrazoles are an important class of heterocycles in a wide range of applications, such as, organocatalysis and transition metal catalysis, propellants, explosives, and perhaps most commonly, as nonclassical isosteres of carboxylic acids in medicinal chemistry. This broad utility has prompted significant effort toward tetrazole synthesis, and notable among these is that of Sharpless, in which aqueous zinc bromide (ZnBr2) facilitates the assembly of tetrazoles from nitriles and sodium azide (NaN3). [3e] Nevertheless, the majority of reported methods are generally not suited for large scale synthesis; they require explosive and/or expensive reagents, toxic metal-containing compounds, or excess azide. The most significant hazard is the generation of hydrazoic acid (HN3), particularly in reactions conducted in the presence of even trace amounts of Brønsted acids. Continuous flow synthesis is emerging as a powerful technology complementary in several contexts to batch synthesis in flasks or vessel reactors. As only small quantities of reagents and products are exposed to the reaction conditions at a given time, the risks associated with hazardous materials are minimized, and transformations using them are thus rendered much safer. Flow would thus appear to be an appropriate reaction format for the synthesis of tetrazoles from nitriles and an azide source. During the preparation of this manuscript a collaborative effort between Kappe and Lonza reported an exquisitely engineered system for the continuous flow synthesis of tetrazoles using HN3. [6] Generated in situ from NaN3 and acetic acid, HN3 (approx. 2.5 equiv at 1.6 M) may be used at elevated temperatures and pressures to prepare a range of tetrazoles from the corresponding nitriles. Figure 1. (A) Photographs of flow reactor for tetrazole synthesis. See Supporting Information for parts list and instructions for assembly and operation (video). (B) Summary of the function of each reactor feature.