Azides, cycloaddition with

Perfluoroisobutylene undergoes cycloadditions with azides only at elevated temperatures, the reaction can lead to subsequent loss of nitrogen [6] (equation 4) In another high-temperature reaction, chlorotrifluoroethylene undergoes cy cloaddition with the azomethineylide generated from the thermal electrocyclic nng opening of an azindine, a reaction that contributes to a good overall synthesis of 3,4-difluoropyrroles [7] (equation 5)... 

Use of unsubstituted acetylene as a substrate in 1,3-dipolar cycloadditions with azides results in 4,5-unsubstituted triazoles. The reactions have to be carried out under pressure. In an example given in Equation (23) showing synthesis of an antibacterial agent, a solution of azide 1049 in dimethoxyethane is transferred to a pressure bomb that is then charged with acetylene and heated at 90 °C for 12 h to give triazole derivative 1050 in 74% yield <2003BMC35>. 

After acetylenedicarboxylates, esters of propiolic acid are the second common group of reagents for 1,3-dipolar cycloaddition with azides. They react fast, and the yields of products are high. However, because the reacting... 

The formation of the tetrazoles 66 and 67 from 62 and 63, respectively, has been rationalized on the basis of the solvent-assisted opening of the initially formed iodonium ion to give the Ritter reaction intermediate 68, which undergoes cycloaddition with azide... 

Alkenic bonds undergo 1,3-dipolar cycloadditions with azides to give A -l,2,3-triazolines. Azides can add to a wide range of angle-strained, unstrained, and inactivated double bonds to electron-... 

The formation of silanimines can further be proven by trapping reactions. One such reaction is the [2 + 3] cycloaddition with azides to give siladihydrotetrazoles 344a (equation 227). 

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

DipoIar cycloadditions of fiiUerenes gave expected products. In cycloadditions with azides triazolines 25 were formed, while with diazo compounds such as 9-diazofluorene 22, spiro cyclopropane products 24 were directly prepared. In this case initially formed pyrazoline intermediate 23 was not isolated (Scheme 7.6) [13]. 

Figure 2.22 The advantage of strained alkyne in cycloadditions with azides.

Cycloaddition with Azides, Alkynes, Alkenes and Allenes. 113... 

Cycloaddition with Azides, Alkynes, Alkenes and Allenes. The copper-catalysed azide-alkyne cycloadditiOTi reaction is typically catalysed by simple, monometallic Cu(I) salts. However, the mechanism of catalysis was recently determined to involve a bimetalhc process. Similar bimetallic mechanisms have also been discovered in the cycloaddition of alkynes with alkenes, allenes and other alkynes using Au catalysts. This reaction is discussed for its broad application to many areas of chemistry and for the potential of bimetalhc catalyst design to enhance the reaction. 

Figure 16 Cyclooctynes for strain-promoted cycloadditions with azides in living systems. Fluorination accelerates the cycloaddition because the electron-withdrawing fluoro substituents increase the reactivity of the ring-strained cyclooctyne.

In modifications of the click synthesis of 1,2,3-triazoles, enol ethers (esters), or enamines have been introduced as alkyne equivalents in the thermal cycloaddition with azides [496]. Primarily, 4,5-dihydro-l,2,3-triazoles 29 are formed, which are transformed to the triazoles 27 by HX-elimination. 

A number of approaches to tetrakis(trifluoromethyl)-pyrroles was developed using tetrakis(trifluoro-methyl)-Dewar-thiophene (183) [71]. The 1,3-dipolar cycloaddition with azides led to the tricyclic thiiranes 184. Subsequent desulfurization by treatment with PPha afforded the cyclobutenes 185 in good to quantitative yields. The result of thermolysis of 185 was strongly depended on the substituent on the amine nitrogen. Pyrroles 188 were formed in high yields (cases a and d), while only cyclopropene 189, or a mixture of 188 and 189 (cases b and c) were isolated. Pyrrole 188a was also synthesized by the reaction of 183 with aniline in 19 % yield [72]. 

Several other approaches are known to produce tetrazoles via cycloaddition with azides. Fang et al. investigated the synthesis of tetrazoles by a one-pot tandan reaction. It was shown that alcohols and aldehydes can be transferred into the corresponding nitriles, which undergo successive cycloaddition through the addition of azides (Scheme 9.10). 

Scheme 2.2 Use of electron-deficient alkynes in catalyst-free cycloadditions with azides. (Reproduced with permission from A.J. Inglis and C. Bamer-Kowollik, Ultra rapid approaches to mild macromolecular conjugation, Macromolecular Rapid Communications, 2010, 31, 14, 1247-1266. Wiley-VCH Verlag GmbH Co. KGaA.)...

Popik s group also synthesized a masked cyclooctyne 67 by the Friedel-Crafts arylation method as the key step (Scheme 6.10). Irradiation of the CPN 67 results in the efficient and clean regeneration of the corresponding dibenzocyclooctyne 68, which undergoes facile catalyst-free cycloadditions with azides to give corresponding triazoles 69 under ambient conditions, although 67 does not react with azides in the dark [39]. 

A CPN-fused dibenzocyclooctyne 70 was prepared by Boons (Scheme 6.11). It undergoes fast strain-promoted cycloadditions with azides under catalyst-free conditions to yield a triazole 71, displaying more than 1000-fold brighter fluorescence than 70 [40]. 

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