Cycloadditions of azide and nitrile

In addition, the mechanism of the zinc-catalyzed [3+2] dipolar cycloaddition of azides and nitriles to form tetrazoles was examined <2003JA9983>. The energy barrier of the reaction is lowered by 5-6kcalmol 1 which corresponds to an acceleration of 3 1 orders of magnitude. The source of the catalytic activity seems to be the coordination of the Lewis acidic zinc halide to the nitrile, which is supported by model calculations. Also AICI3 was examined as another Lewis acid which catalyzes the reaction to a greater extent than ZnBr2-... 

Intramolecular cycloaddition of azides and nitriles has often been used for the preparation of fused tetrazoles, tetrazoloazines, or similar compounds. In protic solvents, 2-azidobenzaldehyde undergoes base-catalyzed condensation with cyanocarbanions to yield tetrazolo[l,5-tf]quinolines 553 (Scheme 81) <1997S773>. 

The tetrazole functionality has an important role in organic synthesis, medicinal chemistry, and various materials science applications. The simplest method to prepare this heterocyclic ring is the 1,3-dipolar cycloaddition of azides and nitriles. The reaction mechanism was recently revised. ... 

Stable tetrazoles 215 are formed by high-pressure 1,3-dipolar cycloaddition of azides and nitriles (Scheme 52) [80]. In this case, heating up to 140 °C could be combined with high pressure. 

Another theoretical investigation deals with the intramolecular [3+2] dipolar cycloaddition (Huisgen reaction) of azides and nitriles (Scheme 2) to form tetrazoles <2003JOC9076>. 

Dipolar cycloaddition between azides and nitriles is also a well-established route to tetrazoles. If these two functional groups are closely located within one molecule, intramolecular cyclization can occur to yield fused tetrazoles. The present survey of the recent literature shows that this approach has also been successfully applied in some cases and led to the synthesis of novel ring systems belonging to this chapter. These results are depicted in Scheme 25. 

Density functional theory methods using the hybrid B3LYP functionals have been performed to study geometries and energetics of several intramolecular [2+3] dipolar cycloadditions of azides to nitriles (Section 11.06.6.1) toward fused tetrazole formation, including tetrazoles 14 and 15 <2003JOC9076>. 

Fleet and co-workers (75a) synthesized various tetrazoles from manno- and rhamnopyranoses, as well as furanoses, based on the intramolecular 1,3-dipolar cycloadditions of azides with nitriles (Scheme 9.75). All of these tetrazoles were tested for their inhibitory activities toward both glycosidases and other sugarprocessing enzymes. D-Mannopyranotetrazole (397) was prepared from L-gluono-lactone (393). Azide 394 on ring opening with ammonia followed by dehydration with trifluoroacetic anhydride gave the azido nitrile 395. Intramolecular 1,3-dipolar cycloaddition of 395 in refluxing toluene followed by deprotection produced the D-mannopyranotetrazole 397 in 86% overall yield. 

The rate of cycloaddition reactions of azides and nitriles can be greatly enhanced when the azide and the nitrile moieties are part of the same molecule. Some groups have reported the synthesis of polycychc tetrazoles via intramolecular cycloaddition reactions, whereby the nitrile is attached to a carbon atom (Scheme 59, Z = CR2) [202-207]. 

Scheme 9.11 Synthesis of tetrazolopiperazines and triazolopiperazines by cycloaddition of azides to nitriles ...

Since 1901, conventional synthesis of 5-substituted l//-tetrazoles has been reported to proceed via [3-1-2] cycloaddition between azide and nitriles. Drawbacks from this procedure are the use of expensive and toxic azide, highly moisture-sensitive reaction conditions, strong Lewis acids, and hydrazoic acid. 

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... 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

The characteristics of the 1,3-dipolar cycloaddition mechanism of azides and other 1,3-dipoles (such as diazoalkanes, azo-methine imines, nitrones, nitrile imines, nitrile oxides) have been described in detail by Huisgen.191 19 According to the author, the addition of a 1,3-dipole (a b c) to a dipolarophile (d e) occurs by a concerted mechanism in which the two new a bonds are formed simultaneously although not necessarily at equal rates (32). As a consequence, a stereoselective cis addition is observed. Thus, the addition of p-methoxyphenyl azide to dimethyl fiynarate (33) yields l-(p-methoxyphenyl)-4,5-froiw-dicarbomethoxy-AMriazoline (34),194 and 4-nitrophenyl azide gives exclusively the respective cis-addition products 35 and 36 on addition to irons- and cis-propenyl propyl ether.196... 

Since 1996, interest in fused heterotetrazole ring systems has grown. These compounds are synthesized via [2+3] cycloaddition of organic azides and nitriles substituted with a heteroatom within the same molecule (Equation (106) Table 36) <20010L4091>. 

Density functional theory calculations using the hybrid functional B3LYP have been performed to study tetrazole formation by intramolecular [2+3] dipolar cycloaddition of organic azides and nitriles <03JOC9076>. 

Simple 1,1-enediamines undergo 1,3-dipolar cycloaddition readily with 1,3-dipolar reagents. The 1,3-cycloadducts, which are stable and have been isolated in some cases, undergo further deamination by heating or in the presence of acid to give heteroaromatic products. This behavior resembles that of the parent enamines . Thus, 1,1-enediamines react with azides - and nitrile imines smoothly to give high yields of the cycloaddition products 217 and 219, and triazoles 218 and pyrazoles 220 after deamination (equations 89 and 90). 

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. 

Sharpless ° found that the formation of IH-tetrazole was achieved with excellent yield by zinc salt-catalyzed cycloaddition of activated and inactivated nitriles with sodium azide in water (generally under heterogeneous conditions) at reflux (Scheme 5.31). The reaction occurs at pH 8, which minimizes the release of hydrazoic acid even at 100°C. Several zinc salts were effective. ZnBr2 was chosen as the best compromise between cost, selectivity, and... 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

Aryl and vinyl nitriles have been prepared very efficiently from the corresponding bromides by palladium-catalyzed reactions under microwaves. This energy source has been employed for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions with sodium azide (Scheme 9.66). The direct transformation of aryl halides to the aryl tetrazoles in a one pot procedure could be accomplished both in solution and on a solid support [115], The reactions were complete in a few minutes, a reaction time considerably shorter than those previously reported for the thermal reactions. The cydoadditions were performed with sodium azide and ammonium chloride in DMF and, although no explosion occurred in the development of this work, the authors point out the necessity of taking adequate precautions against this eventuality. 

Finally, in our 1997 Science paper,1451 we introduced a number of fluorous phase switching techniques, and one of these is illustrated in Figure 12. Cycloaddition of nitriles with fluorous tin azide 20 provides... 

Kinetic studies using the water-soluble nitrile li revealed first-order dependence in both nitrile and azide and one-half order dependence for zinc bromide. The mechanism of the addition of hydrazoic acid/azide ion to a nitrile to give a tetrazole has been debated, with evidence supporting both a two-step mechanism (Scheme 1, eq 2) and a concerted [2 + 3] cycloaddition (Scheme 1, eq 3). Our mechanistic studies to date imply that the role of zinc is not simply that of a Lewis acid a number of other Lewis acids were tested and caused little to no acceleration of the reaction. In contrast, Zn exhibited a 10-fold rate acceleration at 0.03 M, which corresponds to a rate acceleration of approximately 300 at the concentrations typically used. The exact role of zinc is not yet clear. 

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