Azide-Alkyne 1,3-Dipolar Cycloaddition

In an indirect strategy for the synthesis of neoglycopeptides, by means of the alkyne-azide 1,3-dipolar cycloaddition reaction as an assembling tool, MacMillan et al. [31] have used glycopyranosyl azides (18) for the synthesis of... 

Peptide conjugation via copper(I)-catalyzed alkyne azide 1,3-dipolar cycloaddition (CuAAC) chck chemistry 13MOL13148. 

T3506). Similarly, 2-halobenzaldehydes, isonitriles, amines, and propar-gylic acids underwent Ugi reaction, then copper(I)-catalyzed alkyne—azide 1,3-dipolar cycloaddition, and then intramolecular Ullmann-type triazole N-arylation to afford triazolo-flised benzodiazepines such as 136 (13EJ01223). Similar reactions involving a post-Ugi lactamization or a post-Ugi intramolecular imination process delivered benzo-l,4-diazepin-2,5-dione derivatives or 4,5-dihydro-3H-l,4-benzodiazepine derivatives (13ACO202,13T9056). 

Some related cyclic scaffolds, such as the azepines, were obtained by Ugi-4CR/ RCM combinations (Fig. 5a) [61], and fused benzodiazepine/triazole frameworks were derived from sequential Ugi-4CR/alkyne-azide dipolar cycloaddition (Fig. 5b) [62]. Both are considered as interesting (3-tum mimics. Similarly, bicyclic systems featuring fused DKP rings (Fig. 5c) have been reported to mimic the ten-membered pseudo-cycle of type 1 (3-tums [63, 64]. 

Though in case of the azide-alkyne 13-dipolar cycloaddition process, exclusively Cu(l) catalysts have been used (in 0.25-2 molcatalysts (Ru, Ni, Pd, and Pt salts) have also been employed. For Cu(l) catalysts, most methods directly use Cu(T) salts, while other methods generate Cu(I) by reduction of Cu(ll) salts with sodium ascorbate or metallic copper. The catalyzed cycloaddition reaction is experimentally simple, perfecdy rehable, quantitative, proceeds well in aqueous solutions under ambient conditions without protection from oxygen, requires only stoichiometric... 

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... 

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). 

Santoyo-Gonzdlez F, Hernandez-Mateo F (2007) Azide-Alkyne 1,3-Dipolar Cycloadditions a Valuable Tool in Carbohydrate Chemistry. 7 133-177 Saraboji K, see Ponnuswamy MN (2006) 3 81-147... 

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... 

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

F. Santoyo-Gonzalez and F. Hemandez-Mateo, Azide-alkyne 1, 3-dipolar cycloadditions A valuable tool in carbohydrate chemistry, Top. Heterocycl. Chem., 7 (2007) 133-177. 

S. Dedola, S. A. Nepogodiev, and R. A. Field, Recent applications of the Cul-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry, Org. Biomol. Chem.., 5 (2007) 1006-1017. 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Torn0e, C.W., Christensen, C., and Meldal, M. (2002) Peptidotriazoles on solid phase [l,2,3]-triazoles by regiospecific copper) I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 67, 3057-3064. 

The 1,3-dipolar cycloaddition of azides to alkynes is a versatile route to 1,2,3-tri-azoles. Different combinations of substituents on the azide and on the alkyne allow the preparation of diverse N-substitutcd 1,2,3-triazoles. Katritzky and Singh have described the synthesis of C-carbamoyl-1,2,3-triazoles by microwave-induced cydoaddition of benzyl azides to acetylenic amides (Scheme 6.220) [393]. Employing equimolar mixtures of the azide and alkyne under solvent-free conditions, the authors were able to achieve good to excellent isolated product yields by microwave heating at 55-85 °C for 30 min. In general, the triazole products were obtained as mixtures of regioisomers. Control experiments carried out under thermal (oil bath)... 

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. 

Deprotection of N-2 by ozonolysis furnishes triazoles 1225 (Scheme 202) <2003JA7786>. Finding that 1,3-dipolar cycloaddition of alkynes 1222 to trimethylsilyl azide, carried out in DMF/MeOH in the presence of Cul as a catalyst, leads directly to products 1225 with much higher yields provides a significant progress to the synthesis of N-unsubstituted 1,2,3-triazoles <2004EJO3789>. 

Disubstituted 1,2,3-triazoles are exclusive products of copper catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. A variety of substituents can be introduced in this way. Many examples of such reactions are discussed in Section 5.01.9. 

Scheme 17 Synthesis of cyclic peptidomimetics by sequential Zhu-3CR/azide-alkyne dipolar cycloaddition strategy...

Numerous organic and inorganic azides undergo 1,3-dipolar cycloaddition to alkynes to give... 

Cycloaddition of p-methoxyphenyl azide to alkynic dipolarophiles at room temperature gives triazoles (697) and (698) (Equation (54)). A regiospecific addition is only observed in the case of Z = CH(OMe)2 <89H(29)967>. Phenyl azide and substituted benzyl azides undergo 1,3-dipolar cycloadditions with DM AD, phenylacetylene, and ethyl propiolate to afford 1-phenyl- and 1-benzyl-... 

Anhydro-5-hydroxy-1,2,3,4-oxatriazolium hydroxides (4) are relatively stable at elevated temperatures under neutral and salt-free conditions. However, prolonged heating of (17) in the presence of lithium chloride gives rise to elimination of carbon dioxide with formation of an azide which can be trapped by 1,3-dipolar cycloaddition to an alkyne (Scheme 2) <68CB536>. 

Hlasta and Ackerman (72) reported a synthesis of the triazoles 379, related to the human leuokocyte elastase inhibitor WIN 62225 (380), based on an inter-molecular 1,3-dipolar cycloaddition of the azide 378 with alkynes (Scheme 9.72). They also investigated in detail the effect of steric and electronic factors on the regioselectivity of the cycloaddition reaction. (Azidomethyl)benzisothiazolone (378) underwent smooth 1,3-dipolar cycloaddition with various disubstituted acetylenes to give the corresponding triazoles (379) in 37-84% yields. Electron-deficient acetylenic dipolarophiles reacted more rapidly with the azide to give the respective triazoles. 

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