Addition of Azides to Nitriles

A review on 5-substituted-l//-tetrazoles as carboxylic acid isosteres in medicinal chemistry has been published <02BMC3379>. The mechanisms of tetrazole formation by addition of azides to nitriles have been investigated by density functional theory calculations <02JA12210>. 

Himo F, Demko ZP, Noodleman L, Sharpless KB (2002) Mechanisms of tetrazole formation by addition of azide to nitriles. J Am Chem Soc 124 12210-12216... 

Some 1,3-dipolar cycloadditions to hetero ft bond systems have been reported, including a couple of examples of additions of azides to the activated nitrile function of tnfluoroacetonitrile [30, 3I (equation 27)... 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

However, when the addition is performed in a nucleophilic solvent such as methanol, cleavage of the lmine linkage occurs to give difluoroamino compounds [78] (equation 12) A.A-Difluorotri lluoromethylamine can be prepared from azides or from thiocyanates, as shown in equation 13 [79, 80] Another way to produce difluoroamino compounds is the addition of fluorine to nitriles by means of AgF2 [Si] or CoF3 [Si]... 

Figure 4-17. The nucleophilic addition of azide to a nitrile to generate a co-ordinated tetrazole. The complex that is initially produced tautomerises to the isomer shown.

The direct addition of azide to aliphatic and aromatic nitriles allows convenient access to a variety of tetrazoles, which are useful compoimds for a variety of apphcations. We have found that this transformation can be carried out simply by heating the nitrile substrates (e.g. 17 and 19 Fig. 11.4) with sodium azide and a zinc salt in water. Under these conditions, the zinc salts of the tetrazole products are formed, from which the 1 H-tetrazole products (18 and 20) can be generated by acidification of the solution. 

The use of diphenylmethylenecyclopropanes, as opposed to methylenecyclo-propanes, greatly enhances the Pd°-induced [3 + 2] cycloaddition with alkenes to produce five-membered rings. A one-carbon ring-contraction route to cyclopentanes involves a high-pressure version of the known 1,3-dipolar addition of azides to O-silylated enolates, which removes some of the previously observed steric limitations of the reaction, so that the adduct (47) fragments, as shown, to produce the ring-contracted product (48). The intramolecular nitrile oxide... 

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... 

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-... 

The addition of sodium azide to nitriles to give IH-tetrazoles is shown to proceed readily in water with zinc salts as catalysts. The scope of the reaction is quite broad a variety of aromatic nitriles, activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. 

Addition of azide ion and metal azides to nitriles and nitrilium ions... 

The addition of azide ion to nitriles remains the main synthetic route to 5-substituted tetrazoles. The distinction between this approach and the imidoyl azide route (Section 4.17.9.1.1) is blurred... 

There are several methods available for the electrophilic addition of hydrogen and nitrogen to alkenes, dienes and alkynes. While the direct electrophilic addition of amines to these substrates is not feasible, aminomercuration-demercuration affords a very useful indirect approach to such amines. The addition of amides to C—C multiple bonds can be effected directly through the Ritter reaction or by the less direct, but equally useful, amidomercuration-demercuration process using either nitriles or amides. Similarly, H—N3 addition to alkenes can be carried out directly or via mercuration to produce organic azides. 

Addition of azide ion to nitriles, nitrilium ions and isonitriles The addition of the azide anion to nitriles is the most widely used route to 5-substituted tetrazoles (203). This reaction can prove highly sensitive to the nature of the cation and the type of solvent used. It is also sensitive to the nature of the substituent R of the nitrile and it works best when R contains electron-withdrawing groups. In hydroxylic or alcoholic solvents the reaction usually requires a few days at reflux temperatures and the yields may be medium or poor. The best conditions tend to be in dipolar aprotic solvents such as DMF, using ammonium azide as the source of azide ion. The work-up procedures... 

The uncatalysed addition of organic azides to nitriles to form tetrazoles can be affected only if the nitriles are activated by electron-withdrawing groups. The reaction of octyl azide and trifluoro-acetonitrile at 120-150° yielded (96%) the tetrazole 278. Such good yields can be obtained only when the azide employed is stable at the high reaction temperature. With the less stable phenyl azide the yield was only 22%... 

That the reaction occurs as expected between the HOMO of azide (which is, after all, an anion) and the LUMO of the electrophilic nitrile is confirmed by reactions with aryl nitriles ArCN with sodium azide. The yields are all close to quantitative but the reaction is faster when R is an electron-withdrawing group. Not everyone agrees that the reaction is concerted as the approach of the two linear molecules looks very hindered. However, a stepwise addition of azide ion 92 followed by cyclisation 93 looks, if anything, worse as two negatively charged atoms must attack each other in the cyclisation 93. However, this too is pericyclic (electrocyclic) and not ionic. 

Addition of halogens to olefins in a nitrile solvent containing silver perchlorate leads to nitrilium ions, which may be trapped with azide ion to yield 1,5-disubstituted tetrazoles, e.g., 138 [Eq. (17)].341 343 The... 

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