These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Manuscript ChemRxiv.docx (4.43 MB)

Metal-Free Click Synthesis of Functional 1-Substituted-1,2,3-Triazoles

submitted on 04.10.2019, 05:25 and posted on 15.10.2019, 09:07 by Marie-Claire Giel, Christopher J. Smedley, Emily R. R. Mackie, Taijie Guo, Jiajia Dong, Tatiana P. Soares da Costa, John E. Moses
The 1,2,3-triazole group is one of the most important connective linkers and functional aromatic heterocycles in modern chemistry. The boom in growth of, in particular, 1,4-disubstituted triazole products since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles, has been surprisingly more challenging. We report a straightforward and scalable click-protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene-surrogate, ethenesulfonyl fluoride (ESF). The transformation proceeds through a thermal 1,3-dipolar cycloaddition of the azide and ESF to give a sulfonyl fluoride substituted triazoline, that itself spontaneously aromatizes through formal loss of HF/SO2 to give the stable triazole products with excellent fidelity. The new click reaction tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield, and without need for additives or chromatographic purification. Further, under controlled conditions, the 1-substituted-1,2,3-triazole products undergo Michael reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts, demonstrating the versatility and orthogonal reactivity of ESF. The importance of this novel method is evidenced through the late-stage modification of several drugs and drug fragments, including the synthesis of a new improved derivative of the famous antibiotic, chloramphenicol.


Developing next generation click chemistry

Australian Research Council

Find out more...


Email Address of Submitting Author


La Trobe University



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest