Azide-Alkyne Huisgen 1,3-Dipolar Cycloaddition

Copper-Catalyzed Azide-Alkyne Cycioaddition (CuAAC) Click Reaction 

Sharpless [9] and Meldal [10] independently reported a Cu(I)-catalyzed version of the cycioaddition reaction between azides and terminal alkynes, which is 10 times faster than the uncatalyzed reaction. The interaction between Cu(I) and terminal alkynes makes the latter a better 1,3-dipolarophile, enhancing its reaction 

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The Cu(I) catalyzed azide/alkyne Huisgen 1,3-dipolar cycloaddition is a very powerful conjugation reaction for surface modification of liposomes. The... 

In the last few years, click reactions, as termed by Sharpless et al. [280] received attention due to their high specificity, quantitative yields, and good fidelity in the presence of most functional groups. The click chemistry reaction includes a copper-catalyzed Huisgen dipolar cycloaddition reaction between an azide and an alkyne leading to 1,2,3-triazole. Recent publications on this click reaction indicate that it is a useful method for preparation of functional polymers [281]. 

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. 

A specific peptide sequence for nuclear targeting (NLS) has been conjugated to gold NRs via click chemistry. In particular, a thiol with an azide end group has been reacted via Huisgen 1,3-dipolar cycloaddition to an alkyne-terminated NLS peptide and then anchored to CTAB-protected gold NRs.250... 

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

Cycloaddition reactions between azides and alkynes—exemplified by the Huisgen 1,3-dipolar cycloaddition—have tremendous potential for the development of biomolecules and have been employed for conjugation of sugars to peptides [184]. Drawbacks of the Huisgen cycloadditions, however, are poor regioselectivity and incompatibility with physiological conditions. These limitations, which hinder MOE applications in living cells, were first overcome by cop-... 

Another chemoselective ligation reaction is the [2 + 3] cycloaddition between an azide and an alkyne. This reaction has been discovered by Huisgen and was lately named click-reaction by Sharpless and Meldal [180, 181]. Whereas the Huisgen 1,3-dipolar cycloaddition leads to two isomeric triazole products at high temperature, click chemistry is performed under the catalysis of Cu(I), thus changing the reaction mechanism from a concerted to a step-wise route and resulting in the formation of the 1,4-substituted triazole as the only product, usually isolated in high yields [174, 182-186],... 

Huisgen 1,3-dipolar cycloaddition (click reaction) between terminal alkynes and azides is a highly efficient approach for the post modification of polymers. This technique is tolerant to a wide rage of reaction conditions and functional groups allowing fast coupling reactions under simple reaction conditions with... 

As mentioned already in Section 2.6, it is somewhat arbitrary to discuss diazo transfer reactions to alkenes in isolation from those to activated methylene compounds. The most important activation in methylene compounds is that of a neighboring carbonyl group and, as a consequence, the active methylene compound is in equilibrium with the corresponding enol, i.e., with an alkene as established by the systematic work of Huisgen (review Huisgen, 1984), typical diazo transfers involve 1,3-dipolar cycloaddition of a 1,3-dipole (azides) to a multiple-bond system, the dienophile (see Chapt. 6). In diazo transfer, this dienophile is an alkene or an alkyne, and the primary product is a A -l,2,3-triazoline or a A -l,2,3-triazole,... 

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. 

Click chemistry has also been applied in carbohydrate chemistry. Thus, Huisgen cyclization involving a sugar azide or alkyne has been extensively used for the preparation of a wide range of carbohydrates bearing a triazole moiety in different positions. In this volume, Santoyo Gonzalez and Herndndez-Mateo present a contribution concerning azide-alkyne 1,3-dipolar cycloadditions, mostly devoted to non-anomeric positions. 

The outstanding characteristics mentioned for both the imcatalyzed and the catalyzed reactions have led to the 1,3-dipolar cycloadditions of azide and alkynes being considered the most efficient reaction under the new concept of click chemistry [ 12], The term coined by Sharpless and coworkers refers to a modular synthetic approach based on a set of the most practical end rehable chemical reactions. These are wide in scope, highly efficient in terms of both conversion and selectivity under very mild and simple reaction conditions, and use simple product isolation procedures. An indicative parameter of the importance of the 1,3-dipolar cycloaddition of azide and alkyne as a prototype of a click chemistry reaction is the exponential number of applications based on this reaction that have appeared in the literature since the description in 2002 of the catalyzed version. Currently, it can be asserted that click chemistry and the Huisgen 1,3-dipolar cycloaddition of azides and alkynes are synonymous. 

Click chemistry was defined as an approach for the rapid synthesis of druglike molecules using a few practical and reliable reactions. " An example of a click reaction is the Huisgen 1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles. The reaction is efficient, mild, and requires no protecting groups and purification in many cases. The triazole is an isostere of the amide bond, however, it does not tmdergo cleavage like amides. They are also resistant to oxidation and reduction. 

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