Meldal-Sharpless reaction

Investigations with deuterated alkynes and deuterated zeolites proved that this Cu(I)-zeolite-catalysed click reaction exhibited a mechanism different from the one reported for the Meldal-Sharpless version, which relies on the intermediate formation of copper acetylides (Scheme 5.15). Therefore, if such species were also formed within zeolites, deuteroalkynes would not give deuterated triazoles as observed. (Scheme 5.16)... 

Thus, the corresponding triazoles 106, 111,112, and 115 were synthesized from the reaction of deprotected aceteylenic compounds 105,109,110, and 114 employing two sets of reaction conditions, in the first, Cu(I)-catalyzed Sharpless-Meldal click reaction with benzylazide was accomplished using... 

Following reports of efficient Cu(I)-catalyzed alkyne/azide cycloaddition on solid phase and in solution by Meldal [42] and Sharpless [43], respectively, the formerly obscure Huisgen reaction soared to prominence as a versatile tool for covalent chemical ligation. The so-called click reaction can be catalyzed by a number of copper sources in a variety of media (Equation 9.14). 

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],... 

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],... 

The mechanism of the CuAAC reaction was rst proposed by Meldal (Tomoe et al., 2002) and Sharpless (Rostovtsev et al., 2002) and later veri ed by computational methods by Sharpless (Himo et al., 2005) in a series of papers. The proposed catalytic cycle based on a concerted mechanism via a Cu-acetylide intermediate is shown in Fig. 12.7. The most effective variant of the catalyzed 1,3-dipolar azide-alkyne cycloaddition system uses terminal alkynes in combination with copper sulfate and sodium ascorbate. The sodium ascorbate reduces copper sulfate to Cu(I), which forms a Cu-acetylide by reaction with the terminal alkyne via an initial r-complex formation. The copper acetyhde formed is considerably more reactive toward the azide so that a rate enhancement of the 1,3-dipolar cycloaddition results (Englert et al., 2005). 

The advent of azide/alkyne click chemistry, reintroduced by Sharpless and Meldal earlier this century, has prompted an avalanche of publications in the fields of biochemistry, material science and biopolymers. As of 2008, more than 1000 publications on this subject are listed on the Sharpless website. I have noticed that gradually other [3+2] and [4+2] cycloaddition reactions are included, indicating that cycloaddition chemistry is useful for construction and modification of biopolymers. Especially, the [3+2] Huisgen chemistry is useful because in addition to azides many other 1,3-dipolar species react with dipolarophiles at room temperature and the yields often approach quantitative. There is also renewed interest in [4+2] Diels-Alder chemistry. 

To date, the Huisgen 1,3-dipolar cycloaddition is described as nonconcerted when catalysts, processing via metallacycle intermediates, are used, leading to snbstituted heterocycles in excellent selectivity (for specific examples, see Sections 9.2 and 9.5). The outstanding discovery of the Cu(I)-catalyzed azide-aUcyne cycloaddition by Meldal and Sharpless particularly improved the rates as well as the regioselectivity of the reaction (see subsequent chapter) and is now the most commonly used 1,3-dipolar cycloaddition in organic synthesis. ... 

In the meantime, MeldaL " and Fokin-Sharpless" discovered independently that 1,3-dipolar cycloadditions of terminal alkynes to azides could be very efficient and regioselec-tive when catalyzed by copper(I) salts. This 1,4-disubstituted triazole synthesis became very popular, as the ideal member of the family of click reactionsIts mild reaction conditions, its remarkable efficiency and its wide scope due to a high tolerance of other sensitive functional groups prompted a few research teams, " including ours (see Section... 

The 1,3-cycloaddition of alkyl azides to terminal alkynes is very slow, but can be catalyzed by Cu(l) (mechanism Straub, 2007)3 This formation of 1,2,3-triazoles, popularized as click reaction , was used by Sharpless and Meldal (both 2002) for the selective and biocompatible ligation of peptides, proteins, and especially for the introduction of biomarkers. In vivo applications in aqueous medium are feasible. The bioresearch community applauded this new tool which aroused fresh enthusiasm in azide chemistry. 

The reaction between organo-azides and alkynes, called the Huisgen cycloaddition reaction, was reported many years ago [84]. However, intense attention has been given to this reaction only recently. In 2001, the groups of Fokin and Sharpless [85] and Meldal [86] independently discovered that a catalytic amount of Cu(l) drastically increased the reactivity and regioselectivity of the reaction. This discovery sparked intensive efforts on the integration of CuAAC in interdisciplinary research. 

The 1,3-dipolar cycloaddition of organic azides onto dipolarophiles is a versatile method of synthesizing 1,2,3-triazole derivatives [6]. The thermal cycloaddition without metal catalysts [Scheme 16.4, Eq. (a)] of organic azides 1 to alkynes 2 was utilized for triazole formation, but frequently with low regioselectivity. Recently, this reaction has been improved in terms of the reaction rate and regioselectivity by using copper(I) catalysts, which were reported independently by Sharpless et al. [7] and Meldal et al. [8] [Scheme 16.4, Eq. (b)]. 

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... 

The thermally induced 1,3-dipolar cycloaddition of alkynes with azides to obtain 1,2,3-triazoles is well known and further developed by Huisgen [1]. A Cu(I)- and Ru(I)-catalyzed variation of this cycloaddition to a regioselective synthesis of 1,4-and 1,5-substituted (Scheme 2.1) and functionalized 1,2,3-triazoles, respectively (Scheme 2.2), termed as click reaction, was developed independently by Sharpless et al. [2] and Meldal et al. [3] as delineated. 

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