Click chemistry, 1,4-disubstituted triazole

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

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). 

Scheme 18 Click chemistry synthesis of 1,4-disubstituted triazoles...

Scheme 7.1 Click chemistry synthesis of 1,4-disubstituted-l,2,3-triazoles by a 1,3-dipolar cycloaddition reaction of organic azides with terminal acetylenes.

The discovery of copper catalysis in 1,3-dipolar cycloadditions of terminal alkynes to azides (click chemistry) in 2002 <2002AGE2596, 2002JOC3057> has revolutionized the field . It is not only that the catalyzed reactions proceed faster under mild conditions, but full regioselectivity of the products is also achieved. Terminal alkynes generate only 1,4-disubstituted triazoles. A brief outline of the reaction mechanism is given in Scheme 253 . Some aspects of this new methodology are discussed in a review <2007ALD7>. 

Various miidazo[l,5-a]imidazoles (35), itnidazo[l,5-a] pyridines (36), and iniidazo[5,l-a]isoquinolmes (37), important ligands or precursors to pharmaceuticals," can be constructed via copper-catalyzed heterocyclization of Schiff s bases. A stepwise cycloaddition between azides and terminal alkynes is also catalyzed by copper salts in what has now been termed click chemistry, producing 1,4-disubstituted triazoles (38) in excellent yields." ... 

A somewhat different but mechanistically related reaction is the [2 -f 3] cycloaddition of a functionalized alkyne or nitrile to an azide to form a disubstituted triazole (120) or tetrazole ring (121, 122), linking the respective functionalities irreversibly (Scheme 14b). This click chemistry was used by Sharpless and co-workers (120) in 2001 as a tool to probe biochemical catalysis and substrate activation. The ease of the Cu(I)-catalyzed reaction has created a true explosion (120-160) of simple coupling-functionalization chemistry of all types of biochemical components (sugars, DNA, proteins, enzymes, substrates, inhibitors) (131, 135, 136, 139, 142, 155, 157-160), polymers (126, 134, 140, 147, 154),... 

Triazole-linked glycopeptides are relatively a new class of neoglycopeptides that incorporate the triazole unit via click chemistry hy applying the copper (I)-catalyzed 1,2,3-triazole. Click chemistry has emerged as a new strategy for the rapid and efficient assembly of molecules with diverse functionalities. Among these reactions is the copper (I)-catalyzed 1,2,3-triazole synthesis. It guarantees a reliable synthesis of 1,4-disubstituted... 

Click chemistry has been used to prepare a series of l,4-disubstituted-l,2,3-triazoles by a Cu(I)-catalyzed three-component reaction of alkyl halides, sodium azide, and alkynes. The method avoids isolation and handling of potentially unstable small organic azides and provides triazoles in the pure form and high yields (81-89%). Microwave irradiation dramatically reduces reaction times from hours to minutes [50]. 

Appukkuttan P, Dehaen W, Poking VV et al (2004) A microwave assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles via a copper (I) catalyzed three component... 

Insofar as heterogeneous Cu(I)-catalyzed click chemistry is concerned, new catalysts continue to appear. Nanoparticles of copper can be generated and used in aqueous solution, from which crystalline products often precipitate. Inclusion of copper (as CuCl) into Lewis acidic zeolites, using in particular Cu(I)-USY (pore size 6-8 A), is one such catalyst employed in toluene. Other solvents such as DCM, CH3OH, CH3CN, and benzene were not recommended, and yields of 1,4-disubstituted triazoles can be highly variable. 

Bottom-line comments. Copper-catalyzed click chemistry is experimentally too easy and works too well in most cases not to be strongly considered as a means of stitching together just about any terminal alkyne and azide. The regiospecificity for 1,4-disubstituted heteroaromatic triazoles is complemented by the corresponding ruthenium-catalyzed cycloadditions to afford 1,5-adducts. And with options for heterogeneous processes, microwave-assisted thermal rate enhancements, and solvent-free conditions, click chemistry has become, and rightfully so, a tremendously powerful tool in synthesis. 

Kumar, B. S. R. A., Reddy, K. H. V., Madhav, B., Ramesh, K., and Nageswar, Y. V. D. 2012. Magnetically separable CuEe204 nano particles catalyzed multi-component synthesis of 1,4-disubstituted 1,2,3-triazoles in tap water using click chemistry . Tetrahedron Lett. 53(34) 4595-4599. 

Lopez-Ruiz, H., de la Cerda-Pedro, J. E., Rojas-Lima, S., Perez-Perez, L, Rodriguez-Sanchez, B. V., Santillan, R., and Coreno, O. 2013. Cuprous oxide on charcoal-catalyzed ligand-free synthesis of 1,4-disubstituted 1,2,3-triazoles via click chemistry. Arkivoc. (iii) 139-l64. 

The 1,3-dipolar cycloaddition of primary, secondary, tertiary or aromatic azides and terminal alkynes to give triazole is possibly the most useful cycloaddition. This reaction has only recently been popularized under the name of click chemistry by Sharpless upon finding that it can be regioselectively catalyzed by Cu to quantitatively provide only 1,4-disubstituted l,2,3-triazoles. ... 

The [3+2] cycloaddition reaction of azides with terminal olefins is of considerable interest in the modification of biomolecules, because the azide group is abiotic in animals. Especially, the Cu(i) catalyzed cycloaddition reaction of azides with terminal alkynes achieves regioselective formation of 1,4-disubstituted 1,2,3-triazoles and this reaction is currently referred to as click chemistry . In the thermal reaction of azides with terminal alkynes, about 1 1 mixtures of 1,4- and 1,5-disubstituted 1,2,3-triazoles are obtained. Likewise, disubstituted alkynes afford mixtures of the stereoisomers. In order to avoid the cellular toxicity caused by the copper catalyst, Cu-free click chemistry is of considerable interest. The use of strained cyclooctyne derivatives as dipolarophiles was proposed recently. In this manner a novel 6,7-dimethoxyazacyclooct-4-yne was constructed from a glucose analogue s. The disadvantage of this reaction is its significantly slower reaction rate but introduction of fluoro groups adjacent to the triple bond achieves some rate enhancement. ... 

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