Alkynes cycloaddition, with azide

Functionalized 1,2,3-triazoles 86 and 87 were prepared by [2 + 3] cycloadditions of resin-bound a-azido esters 85 with substituted alkynes <02TL4059>. Regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of resin-bound alkynes 88 with azides afforded solid-supported 1,2,3-triazoles 89, which were ligated further to give 1,4-substituted-1,2,3-triazole peptide compounds <02JOC3057>. 

In comparison with alkynes, cycloaddition of azides to alkenes proceeds at a much slower rate. Ring strain and substitution of the double bond with electron-withdrawing groups have been found to lead to enhancement of the cycloaddition rate (68T349, 2757). Double bonds which are part of strained bicyclic systems are particularly reactive. Thus, the addition of phenyl azide to norbornene leads in a very fast reaction to the triazoline (256), the... 

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

Figure 2.22 The advantage of strained alkyne in cycloadditions with azides.

Cycloaddition with Azides, Alkynes, Alkenes and Allenes. 113... 

Cycloaddition with Azides, Alkynes, Alkenes and Allenes. The copper-catalysed azide-alkyne cycloadditiOTi reaction is typically catalysed by simple, monometallic Cu(I) salts. However, the mechanism of catalysis was recently determined to involve a bimetalhc process. Similar bimetallic mechanisms have also been discovered in the cycloaddition of alkynes with alkenes, allenes and other alkynes using Au catalysts. This reaction is discussed for its broad application to many areas of chemistry and for the potential of bimetalhc catalyst design to enhance the reaction. 

Yamamoto has since shown this same reaction protocol can provide multicomponent access to tetrazoles, via the replacement of alkyne cycloaddition with that of substituted nitriles (Scheme 6.68) [95], This transformation proceeds with good product diversity. More recently, Barluenga has developed a bimolecular version for this reaction employing vinylbromides and sodium azide, providing access to N-unsubstituted triazoles [96]. 

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. 

In modifications of the click synthesis of 1,2,3-triazoles, enol ethers (esters), or enamines have been introduced as alkyne equivalents in the thermal cycloaddition with azides [496]. Primarily, 4,5-dihydro-l,2,3-triazoles 29 are formed, which are transformed to the triazoles 27 by HX-elimination. 

Scheme 2.2 Use of electron-deficient alkynes in catalyst-free cycloadditions with azides. (Reproduced with permission from A.J. Inglis and C. Bamer-Kowollik, Ultra rapid approaches to mild macromolecular conjugation, Macromolecular Rapid Communications, 2010, 31, 14, 1247-1266. Wiley-VCH Verlag GmbH Co. KGaA.)...

Copper(l)-Catalyzed Azide—Alkyne Cycloaddition with Integrated Copper Scavenging Unit [61]... 

Figure 11.18 Microfluidic setup for copper(l)-catalyzed azide—alkyne cycloaddition with integrated copper scavenging unit...

Unactivated aziridines, such as 24, are not as reactive as their N-sulfonyl analogues. Nevertheless, in aqueous conditions they react with different nucleophiles, as Scheme 12.23 illustrates. Treatment with buffered azide at 50 °C gave 25 in 90% yield. Hydrazine proved potent even at room temperature and 26 was fonned in 95 % yield, while phenyltetrazole required heating at reflux in water. The resulting amines participated in dipolar cycloadditions with alkynes and condensations with P-diketones. 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

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]. 

Normally, copper-catalysed Huisgen cycloadditions work with terminal alkynes only. The formation of a Cu-acetylide complex is considered to be the starting point of the catalyst cycle. However, the NHC-Cu complex 18 was able to catalyse the [3-1-2] cycloaddition of azides 17 and 3-hexyne 23 (Scheme 5.6). 

Recently, Li et al. have reported an efficient 1,3-dipolar cycloaddition of azides with electron-deficient alkynes without any catalysts at room temperature in water.128 The reaction has been applied successfully to the coupling of an azido-DNA molecule with electron-deficient alkynes for the formation of [l,2,3]-triazole heterocycle (Eq. 4.66). 

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

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... 

Triazole derivatives are very interesting compounds that can be prepared by 1,3-dipolar cycloadditions between azides and alkynes. Loupy and Palacios reported that electron-deficient acetylenes react with azidoethylphosphonate 209 to form the regioisomeric substituted 1,2,3-triazoles 210 and 211 under microwaves in solvent-free conditions (Scheme 9.65) [114]. This procedure avoids the harsh reaction conditions associated with thermal cycloadditions (toluene under reflux) and the very long reaction times. 

CuO Nanostructures of Variable Shapes as an Efficient Catalyst for [3+2] Cycloaddition of Azides with Terminal Alkyne... 

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