Copper-catalyzed azide-alkyne 1,3-dipolar

Expanding on the work by Francis and coworkers to target Tyr residues on the exterior of TMV for chemical conjugation, Wang and coworkers have utilized copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition, or click chemistry, in combination with the diazonium coupling... 

Around the time that the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click reaction was emerging as a powerful tool for the constmction [110, 111] of MIMs, we became interested in using this reaction to prepare polyrotaxanes. Our first attempt turned up compelling evidence that the folded solid-state stmctures described in Sect. 2 also persist to a large extent in solution. 

To highlight the utility of the enantioselective azidation further, transformations of the resulting azides were carried out (Scheme 15.11). For example, an a-azido ester could be converted smoothly into a-amino ester by palladium-catalyzed hydrogenolysis, which may provide a useful method for the synthesis of highly substituted cx-amino acid derivatives. On the other hand, the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), as a click reaction, has been... 

The Huisgen 1,3-dipolar cycloaddition to triazoles can be performed under copper-catalysis and is then known as Copper-Catalyzed Azide-Alkyne Cycloaddition... 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

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. 

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. 

The copper-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes (click chemistry) has been the subject of intense research due to wide functional group tolerance, operational ease, and clean formation of the 1,2,3-triazoles. These reactions are particularly amenable to microwave heating, and a host of new compounds and materials have been created using this methodology." -" ... 

The turning point for the above mentioned 1,3-dipolar cycloaddition occurred with the independent discovery that copper(I) not only promotes the speed of the reaction (often referred to as click reaction), but also improves regioselectivity. The copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) of terminal alkenes with organic azides to yield 1,4-disubstituted 1,2,3-triazoles discovered by Meldal [51] and Sharpless [50] exhibits remarkably broad scope and exquisite selectivity [59,60]. The most prominent application of click reactions in recent years has been in drug research [61,62],... 

Copper-catalyzed 1,3-dipolar cycloaddition of azides to alkynes has become the most popular click reaction, and is... 

Applications are found in a wide variety in modem chemistry including biocompatible synthesis methods (54). For example, adhesive polymers can be formed when polyvalent azides and alkynes are assembled into crosshnked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition (55). The polycondensation is efficiently promoted by copper ions. 

As 1,4-disubstituted 1,2,3-triazoles are usually prepared through copper-catalyzed 1,3-dipolar cycloadditions of terminal alkynes with organic azides, the use of a single copper complex for a direct arylation-based sequential catalysis was probed. Thereby, a modular chemo- and regioselective synthesis of fully-substituted 1,2,3-triazoles was achieved (Scheme 9.43). Notably, the overall reaction involved the selective coupUng of four components through the formation of one C—C- and three C—N-bonds [58]. 

The second step is the copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC). CuAAC produces only 1,4-disubstituted-1,2,3-triazoles at room temperature in excellent yields. Formally, it is not a 1,3-dipolar cycloaddition and thus should not be termed a Huisgen cycloaddition. 

While this copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition selectively produces 1,4-disubstituted 1,2,3-triazoles, Forkin and Jia et al. have disclosed a complementary ruthenium-catalyzed process for preparing 1,5- and 1,4,5-substituted 1,2,3-triazoles from terminal and internal alkynes, respectively (Scheme 16.6) [10]. 

Metallic copper efficiently catalyzes azide-alkyne cycloadditions under ultrasound or simultaneous ultrasound/microwave irradiation. Ultrasound favors mechanical depassivation in reactions involving metals and enhances both mass and electron transfer from the metal to the organic acceptor. It has been applied to accelerate the preparation of 1,2,3-triazole phthalimides via a 1,3-dipolar cycloaddition of phthalimidoethyl-azide [67]. 

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). 

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. 

Click chemistry has been used extensively since its introduction in organic chemistry, due to the high efficiency and technical simplicity of the reaction [40]. The most popular click reaction has been the copper-catalyzed dipolar cycloaddition of a terminal alkyne and an azide to form... 

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>. 

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