Cycloaddition, of azides with alkynes

SCHEME 10.5 Cycloaddition of azides with alkynes to form triazoles... 

Wang s group constructed a coumarin library by using so-called click chemistry, which involves Cu(I)-catalyzed Husigen 1,3-dipolar cycloaddition of azides with alkynes to afford quantitative formation of a triazole ring under mild conditions.20 They prepared seven 3-azidocoumarin derivatives and one 4-azidocoumarin, each of which was reacted with 24 acetylenes (Fig. 18.5). 

In the last decade, the combination of CRP techniques and newly found or reinvented highly effective and selective organic reactions termed as the click chemistry has been demonstrated to be a versatile tool for the specific constmction of novel functional macromolecules [28]. In 2001, Sharpless et al. [29] introduced the term click chemistry with its famous representative, the cycloaddition of azides with alkynes under copper catalysis. He defined a click reaction with a set of criteria The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific (but not... 

Azides are very versatile and valuable synthetic intermediates, known for their wide variety of applications, and have been employed for the synthesis of a number of important heterocyclic compounds. Azides also represent a prominent class of 1,3-dipoles, and their cycloaddition to multiple tt-bonds is an old and widely used reaction (1988CR297). The dipolar cycloaddition of an azide to an alkene furnishes a triazoline derivative (2003MI623). Azide-alkene cycloadducts can extrude nitrogen at elevated temperatures to form aziridines or imines, depending upon the substrate and reaction conditions. The cycloaddition of azides with alkynes affords triazolidine derivatives which have been a focus in the area of chemical biology and have received much recent attention (2008AGE2596, 2008CR2952). In this section of our review, we recount some developments of the 1,3-dipolar cycloaddition reaction of azides that have been used for the synthesis of various alkaloids. 

Triazoles are an interesting class of heterocyclic units widely used in the discovery and modulation of drug candidates, development of new materials, supramolecular chemistry, design of new supported organocatalysts, and biotechnology area [55], Therefore, several elegant methods for the synthesis of this classic nitrogen heterocyclic compounds have been reported by 1,3-dipolar cycloaddition of azides with alkynes under thermal [56] conditions as well as copper catalysis. 

Triazoles are attractive compounds and widely used in materials, drugs, and bioconjugation chemistry [124-136]. 1,2,3-Triazoles could be synthesized by 1,3-dipolar cycloaddition of azides with alkynes under thermal conditions via the activation of C-H bond of alkyne [137-141]. The developments of Click reaction, copper-catalyzed azide-alkyne cycloaddition (CuAAC), provide an efficient pathway for the synthesis of 1,2,3-triazoles [142, 135, 143, 144]. They have been well reviewed and we don t discuss it in detail in this chapter. 

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). 

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). 

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

Duran Pachon, L., van Maarseveen, J.H. and Rothenberg, G. (2005) Click chemistry copper clusters catalyze the cycloaddition of azides with terminal alkynes. Adv. Synth. Catal., 347, 811. 

The kinetically driven copper(I)-catalyzed cycloaddition of azides and alkynes requires hours of reaction time to obtain quantitative yields [63]. However, in the case of no-carrier added radiochemical synthesis the ratio of reactants and catalysts differs considerably from that in traditional chemistry. In particular, the azide component and catalyst are in huge excess compared with the [18F]fluoroalkyne. The quantitative incorporation of [18F]fluoroalkyne could be achieved in 10 minutes when an optimized catalytic system was used [81]. Re versed-phase HPLC analysis of all 18F-labeled peptides showed only a single product, indicating that the reaction proceeded regioselectively to yield 1,4-disubstituted 1,2,3-triazoles as previously reported [64]. 

Li Z, Seo TS, Ju J (2004) 1,3-Dipolar cycloaddition of azides with electron-deficient alkynes under mild condition in water. Tetrahedron Lett 45 3143-3146... 

The Huisgen 1,3-dipolar cycloaddition of azides to alkynes or nitriles as dipolaro-philes, resulting in 1,2,3-triazoles or tetrazoles, is one of the most powerful click reactions . A limitation of this approach, however, is the absence of regiospecificity normally found in thermal 1,3-cycloaddition of nonsymmetrical alkynes this leads to mixtures of the different possible regioisomers. In other reports, classical 1,3-dipolar cycloadditions of azides to metal acetylides, alkynic Grignard reagents, phosphonium salts and acetylenic amides have been described. Extended reaction times and high temperatures are required in most of the reactions, but they can also be performed more effectively with the aid of microwave irradiation. The main results reported are reviewed in this section. 

The synthesis of aromatic heterocycles by 1,3-dipolar cycloadditions was also treated in some detail in Chapter 30. There we discussed the important related reaction of azides with alkynes to make triazoles (p. 774). 

The ruthenium-catalyzed cycloaddition of azides to alkynes to form 1,5-disubstituted triazoles is complimentary to the copper catalyzed route. The Cu(I)-catalyzed reaction is limited to terminal alkynes, and the Ru(II)-catalyzed reaction is active with internal alkynes. 

The most popular click reaction is Huisgen 1,3-dipolar cycloaddition of azides to alkynes applicable to a very wide range of macro molecular architecture. It has been employed for the preparation of various polymer topologies including linear, star, hyperbranched, and H-shaped polymers. The general approach is illustrated in Scheme 70 for the preparation of linear block copolymer of EO with MMA and St. Anionically prepared PEO was functionalized with azide and used in copper-catalyzed click reaction with PMMA or PSt with alkyne moiety synthesized by using alkyne-flinctional ATRP initiator. It should be noted that alkyne functionality of hetero-functional ATRP initiator was protected with a trimethylsilyl... 

Iridium dimer complexes catalyse the 3 + 2-cycloaddition reactions of organic azides with bromoalkynes to furnish 1,5-disubstituted 4-bromo-1,2,3-triazoles in excellent yields under mild conditions. Ruthenium(II)-azido complexes undergo 3 + 2-cycloaddition reactions with strained cyclooctynes under ambient temperatures. No reaction was observed with non-activated terminal or internal alkynes under the same conditions. Dithioic acid copper catalysts (60) catalyse the 3 + 2-cycloaddition reaction of azides with alkynes to form 1,4-disubstituted-1,2,3-triazoles in various solvents and under various temperatures. Thermal Huisgen 3 + 2-cycloaddition reactions of azides and bis(trimethylsilyl)acetylene formed 4,5-bis(trimethylsilyl)-l/f-l,2,3-triazoles in low to high yields (15-95%). The Cu(I)-catalysed 3 + 2-cycloaddition... 

Typically, cycloaddition of azides with nonactivated alkynes leads to a regioiso-meric mixture of 1,2,3-triazoles. Dramatic improvement in the methods was achieved with a copper catalyst discovered in 2002 by two independent groups. " Since then, the number of studies concerning 1,3-dipolar cycloadditions of azides and terminal alkynes has increased dramatically. The introduction of the copper catalyst solved many problems, including long reaction times, high reaction temperatures, and poor... 

Click chemistry, as introduced by Kolb and Sharpless in 2001 relates mainly to the Cu(i) eatalyzed [3+2] cycloaddition reaction of azides with alkynes. This copper catalyzed cycloaddition reaction is highly useful for attaching fluorescent or other markers to a wide variety of biomolecules. Although azides are often unstable at elevated temperatures, they are stable at physiological conditions, have no intrinsic toxicity and have extraordinary chemical selectivity. Proteins and glycans have already been labeled with azides in laboratory mice using enzyme inhibitors and sugar azides. 

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