A research team at the Chinese Academy of Sciences has found a safer way to synthesize azides for use in click chemical reactions. The group describes how they discovered a safer way of transforming primary amines into azides in their paper published in the journal Nature. Joseph Topczewski and En-Chih Liu with the University of Minnesota have published a piece of News & Views that outlines the team's work in China in the same issue of the journal.
a, Synthesis of FSO2N3. Reaction conditions: 1 (7.9 g, 24 mmol), NaN3 (1.3 g, 20 mmol), MTBE/MeCN/H2O (84 ml, 10:1:10, v/v/v), 0 °C, air, 10 min. b, Diazotransfer reaction between amlodipine (2a) and FSO2N3. Reaction conditions: 2a and FSO2N3 in 1:1 molar ratio; KHCO3 (40 µmol), DMSO/MTBE/H2O (1 ml, approx. 94:5:1, v/v/v), room temperature (RT), 5 min. Conversions for reactions performed on different scales are shown on the right. c, Diazotransfer reaction between pazufloxacin mesylate (2b) and FSO2N3. Reaction conditions: 2b and FSO2N3 in 1:1 molar ratio; KHCO3 (40 µmol), DMSO/MTBE/H2O (1 ml, approx. 94:5:1, v/v/v), RT, 5 min. Conversions for reactions performed on different scales are shown on the right. KHCO3, potassium bicarbonate. Credit: Nature (2019). DOI: 10.1038/s41586-019-1589-1
The concept of click chemistry (CC), first introduced by K.B. Sharpless, describes chemistry tailored to generate substances quickly and reliably by joining small units together. It has been widely adopted for use in drug discovery, novel drug delivery systems (DDS), bioconjugation, radiochemistry, nanoscience and material sciences. It meets an ever-increasing need for rapid reaction as it fulfills the criterion of an ideal synthesis: efficiency, versatility, selectivity and high yield with variety of starting materials.
Click chemistry combines two reactive compounds that assemble in ways that reliably produce results without byproducts. CuAAC is the most popular click reaction and is used in a wide range of applications. But it's problematic to synthesize an azide for use in the process— it takes a long time and produces toxic emissions. Also, when stored, the reagents pose an explosion risk. The researchers report in this new effort that they have found a new way of synthesizing azides that removes both issues.
The researchers report that they were actually working on something else when they noticed that fluorosulfuryl azide (FSO2N3) was capable of converting primary amines into azides— and it took only a few minutes instead of taking hours. More testing showed that FSO2N3 can react with almost every primary azine, leading to a 100 percent yield almost always. The researchers note that before using FSO2N3 there is no need to purify, making it a cheap choice. They also note that there is no need to store it because, when necessary, it can be produced by mixing imidazolium fluorosulfuryl triflate salt with sodium azide. They also note that the initiating salt is not toxic—at least to test rodents that were exposed to it.
Topczewski and Liu say that the team's work in China can open the door to two-step methods that are very effective and scalable to convert primary amines into triazoles. They also note that the research is another step towards the ultimate goal of click chemistry— developing only a few reactions that can be used to build precursors for a wide range of applications.