Safe and Efficient Tetraz0le Synthesis in a Continuous-Flow Microreactor

摘要

Tetrazoles are an important class of heterocycles in a wide range of applications, such as, organocatalysis and transitionmetal catalysis, propellants, explosives, and perhaps most commonly, as non-classical 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). Nevertheless, the majority of reported methods are either less straightforward or 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 Br0nsted acids.