Alkynes reaction with azide

Reaction with alkenes 2, 1.6.6.1 Reaction with alkynes 2, 1.6.6.1 Reaction with arenes 2, 1.6.6.1 Reaction with azide 2, 1.5.2.1.2 Reaction with carbon at high temperatures 2. 

Alkyne-modilied libraries containing 5-ethynyl-2 -deoxyuridine [12] (EdU, Fig. 4A) instead of thymidine are prepared. Functionalization of the library is achieved by copper-catalyzed click reaction with azide containing compounds. As a proof of principle, 3-(2-azidoethyl)indole was used and successful selection was performed against cycle 3 GFP [175]. The amplification step after selection is carried out in the presence of EdU to restore an enriched alkyne-modified library for subsequent rounds of selection. At this point, correct amplification of the functionalized template strand by DNA polymerases is stiU a requirement for successful selection, and can restrict the size of the azide-modified compounds used. 

In 2013, Hackenberger and coworkers [66], in Berlin, reported the cycloaddition of a borane-protected alkyne-phosphonite with azides to form borane-protected triazole-phosphonites (Scheme 9.24). In this reaction protocol, we have a sequence of two different couplings with two different azido reagents in the first, we have a CuAAC cycloaddition, followed by a metal-free Staudinger phosphonite reaction. 

The alkyne-azide [3 + 2] cycloaddition has been used as a fast and effective method of preparing triazoles, recently described as click chemistry. An interesting variant of this chemistry has utilized the propargyl cation in reaction with azides. For example, alkyne (88) reacts with benzyl azide to give the triazole product (89) upon aqueous quench. The conversion is thought to proceed by ionization to the propargyl cation (90),... 

To avoid the direct manipulation with hazardous azides, methods using Cu(I)situ generation of azides were developed as one-pot procedures, for example, with substitution reaction of alkyl hahdes by NaN3 [493] or with nitrosation of aromatic primary amines by tBuONO followed by trimethylsilyl azide [494]. Vice versa, the alkyne component has been generated in situ, for example, by sequential Seyferth-Gilbert reaction (homologation of aldehydes with diazophosphonates) and reaction with azides in a Cu(l)-catalyzed cycloaddition [495]. 

The 1,3-dipolarophiles participating in the [3+2] cycloaddition reaction with azides include carbon-carbon multiple bonds, such as alkynes, olefins, vinyl ethers and ketene acetals, but addition across C=N multiple bonds, such as in nitriles and isocyanates, C=S and P=C bonds is also observed. The yields observed for many of these reactions approach quantitative. 

The field of dipolar cycloaddition reactions with azides in peptide chemistry has developed rapidly since Tompe and Meldal first described the copper(l)-catalyzed cycloaddition between azides and peptide-linked terminal alkynes to exclusively form the... 

Agard, N.J., Prescher, J.A., and Bertozzi, C.R. (2004) A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. Journal of the American Chemical Society, 126,15046. Agard, N.J., Baskin, J.M., Prescher, JAl. et al. (2006) A comparative study of bioorthogonal reactions with azides. ACS Chemical Biology, 1,644. 

Azidofurazans and -furoxans undergo dipolar cycloaddition reactions with unsaturated compounds, in some cases regiospecifically. Thus, reaction of 3-amino-4-azidofurazan with l-morpholinyl-2-nitroethene (toluene, reflux, 70 hours) gives 4-nitro-l,2,3-triazole 204 in 87% yield (99MI1, 000KGS406). Cycloaddition of the same azide to alkynes was accomplished by formation of a mixture of position isomers 205 and 206. Regiospecific addition was observed only in singular cases... 

Besides short ELPS, longer ELPs have also been conjugated to synthetic polymers. In one approach, Cu(I)-catalyzed azide-alkyne cycloaddition click chemistry was applied. For this purpose, ELPs were functionalized with azides or alkynes via incorporation of azidohomoalanine and homopropargyl glycine, respectively, using residue-specific replacement of methionine in ELP via bacterial expression [133]. More recently, an alternative way to site-selectively introduce azides into ELPs was developed. Here, an aqueous diazotransfer reaction was performed directly onto ELP[V5L2G3-90] using imidazole-1-sulfonyl azide [134]. 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

Figure 7.7 The synthesis of dendrimer molecules using click chemistry proceeds with high yield. Each step results in the cycloaddition reaction between azide-containing molecules and alkyne molecules to form triazole linkages.

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