Catalyst-free Huisgen cycloadditions

Catalyst-free Huisgen cycloadditions of alkynes activated by electron-withdrawing substituents have been reported to occur at room temperatures (Li et al., 2004) however, these compounds can undergo Michael reaction (see Section 14.2.2) with biological nucleophiles, thus effectively deleting the bioorthogonality of the system. 

An alternative method of catalyst-free activation of alkynes with azides is indicated as ring strain. The study of the strain-promoted azide cycloadditions precedes the Huisgen era and starts when Alder and Stein discovered that dicyclopentadiene reacted... 

A homogeneous Ag(I)-catalyst (65) has been developed for the 3 -I- 2-cycloaddition reaction of azides to terminal alkynes to form the corresponding 1,4-triazoles. A simple metal-free synthesis of pentafluoroalkylated 1,2,3-triazoles has been developed from the 1,3-dipolar cycloaddition reaction of azides with methyl 2-perfluoroalkynoates. Again, the intramolecular alkyne-azide Huisgen 3 -I- 2-cycloaddition reaction in water is an example of Click reaction in the absence of a metal catalyst. The Cu(I)-catalysed azide-alkyne 3-1-2-cycloaddition reaction yielded 1,4-disubstimted 1,2,3-triazoles in excellent yields in 2-25 min under solvent-free conditions. The use of 16-electron... 

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