Triazoles Click reaction

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

Click chemistry refers to the reaction between an azido functional group and an alkyne to form a [3 + 2] cycloaddition product, a 5-membered triazole ring. This reaction has been used for many years in organic synthesis to form heterocyclic rings. Normally, the click reaction requires high temperatures, and this was the main reason that it was not used as a bioconjugation tool. However, it was discovered that in aqueous solutions and in the presence of Cu(I), the reaction kinetics are dramatically accelerated to provide high yields even at room temperature and ambient pressures (Rostovtsev et al., 2002 Tornoe et al., 2002 Sharpless et al., 2005). 

Aldehyde 126 was converted to the terminal alkyne (142) in 61% yield by Seyferth-Gilbert homologation (Scheme 23) [60]. These basic conditions were well tolerated and no C-8 epimerization or C-2 deacetylation was observed. Alkyne 142 was coupled with various azides under copper(I)-catalyzed click reaction conditions to afford 1,4-disubstituted-l,2,3-triazoles (143-145) in 88% yield. Similar conditions were used to generate unsubstituted 1,2,3-triazoles. Alkyne 142 was coupled to azidomethyl pivalate under click reaction conditions to give the pivalyl triazole (146) in 88% yield. The pivalyl triazole was then treated with IN NaOH to remove both the pivalyl group and the C-2 acetyl group. These conditions also led to C-8 epimerization. Acetylation of the epimeric mixture under standard conditions (AC2O, pyridine) and preparative scale separation by TLC furnished the C-8 epimeric N-unsubstituted triazoles (147) in 54% yield over three steps in a ratio of 4 6 (C-8 epi-C-8). 

Dabco-based ionic liquids have been recently used, together other basic and neutral ILs, in the copper(i)-catalyzed azide-alkyne click reaction (Scheme 4.3). The model cycloaddition of a sugar azide with a sugar acetylene has been carried out in ten ILs. With one exception, in all investigated ILs the reaction afforded exclusively the 1,4-disubstituted triazole, namely a triazole-linked C-dis-accharide, in high yields. 

A one-pot, copper-catalyzed formation of fully decorated triazoles was recently demonstrated by Ackermann. In the first step, a copper-catalyzed click reaction produces triazoles from alkynes and azides. In the second step, a direct, copper-catalyzed... 

Triazoles are generally prepared by the cycloaddition of an alkyne with an azide, which can be promoted thermally or by metal catalysis. This cycloaddition reaction of an azide and an alkyne is a typical Click reaction, that is, a highly efficient and reliable general reaction that can be used for linking moieties for various purposes, such as in combinatorial chemistry. Opinion is divided on whether Click is a useful or necessary concept but it seems to have become associated, almost synonymously, but incorrectly, solely with this triazole synthesis. 

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],... 

Triazole synthesis A heterogeneous catalyst for the click reaction is formed by treating CuCl2 with (i -BuOjsAl. 

By means of the click reaction compounds containing a 1,2,3-triazole unit (5, 6°) have been prepared. 

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... 

While these results clearly show, that the triazole ring is formed upon click reaction and that it is stable under amino acid deprotection conditions, further measurements are necessary to quantify the yield of the deprotection reaction. 

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. 

The SF5 group has become a focus of much recent attention in organofluorine chemistry. Shreeve and coworkers have also used click chemistry to prepare a series of SFs-substituted 1,2,3-triazoles by reaction of pentafluorosulfanyl acetylene with hydrazoic acid and substituted azides (Fig. 3.89). °... 

The X-ray of 2,2 -bibenzoxazole showed that the two rings are coplanar with an anti conformation (98AX(C)668) planar conformation and disorder resulting from the occurrence of cis and trans orientation were observed by X-ray of lH-3-trifluoromethyl-5-(2-thienyl)-pyrazole (OOJMS (526)59). l,l -Disubstituted 4,4 -bi-lH-l,2,3-triazols have been prepared by a click reaction. X-rays showed that the two triazole rings are perfectly coplanar (07EJIC4597). As expected, substitution in ortho positions of the pivot bond drastically changed the stereochemistry in this bi-heterocydic series. 

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." -" ... 

A series of 1,2,3-triazoles have been prepared using a Cu-catalyzed Huisgen [2+3] dipolar cycloaddition (click) reaction. The required azide was generated in situ from the corresponding halide and sodium azide (Scheme 4.7). Microwave irradiation dramatically reduced the reaction times from hours to minutes without affecting the 1,4-regioselectivity of the reaction. Since triazole products often crystallize readily... 

Triazole as the keystone in glycosylated molecular architectures constructed by a click reaction 07CAJ700. 

The first application we found was the Huisgen [3+2]-cycloaddition, between a terminal alkyne and an azide, to date the most practical and useful click reaction, regioselectively affording 1,4-disubstituted 1,2,3-triazoles (Schane 5.14). 

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)... 

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