Triazole from click chemistry reaction

Figure 7.18 Representative in situ Click chemistry reaction analysis by HPLC-SIM-MS the triazole product is indicated by the dashed line, (a) Triazole products obtained by conventional synthesis with Cu(l) catalysis, (b)-(d) Microfuidic device reactions performed at 37 °C for 40 h (b) in the presence of CA II, (c) in the presence ofCA II and potent CA inhibitor to block the CA active site and (d) in the absence of CA II. (e) Reaction performed at 37° C for 40 h in microtitre plate. Reproduced with permission from Wang,., Sui, C., Mocharla, V.P., Lin, R.J., Phelps, M.E., Kolb, H.C. and Tseng, H.-R., Integrated microfluidics for parallel screening of an in situ click chemistry library. Angewandte Chemie International Edition 2006, 45, 5276-5281. Copyright Wiley-VCH Verlag GmbH.

The simplicity and efficiency of the click chemistry is attractive to fluorine-18 chemistry, where time plays an important role in synthesis due to the relative short half-life of fluorine-18. This one-pot reaction provides a versatile tool for coupling drug-like fragments in high yield and under mild conditions. The product 1,2,3-triazole formed from cycloaddition is biologically stable with polarity and size similar to an amide group that is a common functional group in many radiopharmaceuticals [77],... 

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],... 

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]. 

S.2.2.4. Triazoles from Azides. Cycloadditions of this type constitute a valuable synthetic route to the triazole ring system. This is shown in Scheme 5.30. This combination dates back to the early work of Huis-gen, but in more recent times it was discovered to be subject to catalysis by Cu(I) compounds. The reactions are fast under mild conditions, have high regiospecificity, and occur in a variety of solvents including water. In addition, reaction products are easily isolated. Reactions with these characteristics have become known as comprising click chemistry this term was coined by K. B. Sharpless. The first and most commonly used reaction referred to by this name is indeed the azide-alkyne cycloaddition, and new interest has developed in triazole hemistry since the discoveiy of the copper catalysis. In addition to its use in organic... 

Scheme 30.17 The convergent synthesis of triazole dendrimers using CuAAC click chemistry, (a) CuAAC coupling reaction and (b) nucleophilic substitution with sodium azide. R = chain-end group, X = internal repeat unit. Reproduced with permission from Ref [112] 2004, john Wiley. Sons, Inc.

In 2010, a methodology for the synthesis of 1,2,3-triazole-fused iso-indolines and dihydroisoquinolines was reported. Starting from easily available terminal allgmes and (2-haloaryl)allq7lazides, the desired products were formed in good to exeellent yields. This method is based on a cycloaddition reaction, via Click chemistry, followed by a transition-metal-catalyzed functionalization of a C-H bond. Later on, a one-pot procedure was reported as well. °... 

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. ... 

In situ click chemistry was used to assemble inhibitors for acetylcholinesterase derived from tacrine and phenylphenanthridinium azides. The in situ generated inhibitors were extremely potent acetylcholinesterase inhibitors and care should be observed in handling these neurotoxic compounds. A potent inhibitor of human o -l,3-fucosyltransferase was similarly identified from a 1,2,3-triazole library of 85 compounds prepared by the [3-1-2] cycloaddition reaction of azides with terminal alkynes . Also, protein tyrosine phosphatase inhibitors are synthesized in a similar manner. ... 

Whereas the click chemistry-based synthesis of rotaxanes has been well illustrated in the course of the last few years, very different is the situation as far as the making of catenanes is concemed. It is likely that this reaction will be more often used in the future for making rings and, in particular, catenanes. The field of catenanes, rotaxanes and molecnlar machines will certainly benefit in a significant way from the new synthetic methodology based on copper-catalyzed triazole synthesis. 

Click chemistry is now a popular concept, more specifically when it is used to indicate a copper-catalyzed cycloaddition reaction between alkyl or aryl azides and terminal alkynes. Due to the fact that Cu(I) catalysts dramatically accelerate the original Hiiisgen thermal reaction with perfect control of the mechanistic pathway to lead only to l,4-disubstituted-l,2,3-triazoles, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has become one of the most representative examples of click chemistry. It was proposed that this reaction proceeds first through the formation of a copper(l)-acetyhde from a copper(I) catalyst and a terminal alkyne, followed by cycloaddition with a copper(l)-bound azide to generate a triazolyl copper(I) complex, which is released by protonation of the Cu—C bond. 

MCM-41 has a high surface area ( 1000 m /g), a large pore volume, and pore diameters that can be tuned between 20 and 100 A. In click chemistry, the MCM-41-supported copper(II) allows the one-pot synthesis of 1,2,3-triazoles from alkyl bromides, sodium azide, and alkynes. The reaction maybe carried out in water, at room temperature. Short reaction times give high yields (70-98%) [42]. 

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