Giel, Marie-Claire, Smedley, Christopher, Mackie, Emily, Guo, Taijie, Dong, Jiajia, Costa, Tatiana Soares da, Moses, John (2019) Metal-Free Click Synthesis of Functional 1-Substituted-1,2,3-Triazoles. (Submitted)
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | chemistry > techniques > click chemistry |
| CSHL Authors: | |
| Communities: | CSHL labs > Moses lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2019 |
| Date Deposited: | 03 Oct 2023 21:04 |
| Last Modified: | 03 Oct 2023 21:04 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41124 |
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