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

The 1,2,3-triazole group is one of the most importantconnective linkers and functional aromatic heterocycles in modern chemistry.The boom in growth of, in particular, 1,4-disubstituted triazole products sincethe early 2000’s, can be largely attributed to the birth of click chemistry andthe discovery of the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Yetthe synthesis of relatively simple, albeit important,1-substituted-1,2,3-triazoles, has been surprisingly more challenging. Wereport a straightforward and scalable click-protocol for the synthesis of1-substituted-1,2,3-triazoles from organic azides and the bench stableacetylene-surrogate, ethenesulfonyl fluoride (ESF). The transformation proceedsthrough a thermal 1,3-dipolar cycloaddition of the azide and ESF to give asulfonyl fluoride substituted triazoline, that itself spontaneously aromatizesthrough formal loss of HF/SO2 to give the stable triazole productswith excellent fidelity. The new click reaction tolerates a wide selection ofsubstrates and proceeds smoothly under metal-free conditions to give theproducts in excellent yield, and without need for additives or chromatographicpurification. Further, under controlled conditions, the1-substituted-1,2,3-triazole products undergo Michael reaction with a secondequivalent of ESF to give the unprecedented 1-substituted triazolium sulfonylfluoride salts, demonstrating the versatility and orthogonal reactivity of ESF.The importance of this novel method is evidenced through the late-stagemodification of several drugs and drug fragments, including the synthesis of anew improved derivative of the famous antibiotic, chloramphenicol.