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/SO<sub>2 </sub>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.
Silver-catalysed azide–alkyne cycloaddition (AgAAC): assessing the mechanism by density functional theory calculations
