Nitriles reaction with azide

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Tetrazoles of general structure 8.24 can be prepared in a very similar manner to triazoles, except that nitriles are used rather than acetylenes. Once again the reaction with azides is a concerted cycloaddition process. 

The 1,3-dipolarophiles participating in the [3+2] cycloaddition reaction with azides include carbon-carbon multiple bonds, such as alkynes, olefins, vinyl ethers and ketene acetals, but addition across C=N multiple bonds, such as in nitriles and isocyanates, C=S and P=C bonds is also observed. The yields observed for many of these reactions approach quantitative. 

As a direct appUcation a potent C2-symmetric HIV-1 protease inhibitor (with two tetrazoles as carboxyl group bioisosteres) was prepared in one pot [77]. The process involved microwave-promoted cyanation followed by conversion of the nitrile group in a tetrazole with azide (Scheme 64). It is notable that the fimctionahzation was achieved so smoothly without side reactions such as the ehmination of water. 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

The kinetics of the reaction is first order in both nitrile complex and azide.909 NaN3 reacts with [Co(tetren)(NCMe)]3+ at pH 5.7 to give the 5-methyltetrazolato complex [Co(tetren)(N4CMe)]2+. The reaction is biphasic, involving the initial rapid formation of the AM-bonded tetrazole followed by the slow linkage isomerization to the N2-bonded complex.907... 

Some cycloaddition reactions of 4 are summarized in Scheme 1. This shows that silylene 4 undergoes reactions with nitriles [14], phosphaalkynes [15], silyl azides [16], diazabutadienes [17], 2,2 -bipyridyl and its derivatives [18, 19], a-ketoimines [19], and pyridine-2-aldimines [19]. 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

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. 

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

Trinitromethyl)tetrazole (166) and 5-(dinitrofluoromethyl)tetrazole (167) have been synthesized and isolated as their ammonium salts from the reactions of trimethylsilyl azide with the corresponding nitriles followed by reaction with ammonia in diethyl ether. ... 

The seemingly complex imidazolone (78-3) is in fact obtained in a single step by reaction of the amino-ester (78-1) with the iminoether (78-2) derived from capro-nitrile. The relatively acidic proton on the heterocyclic ring is next removed by reaction with sodium hydride. This anion is then alkylated with the same biphenyl-methyl bromide (77-2) that was used to prepare losartan to afford (78-4). The nitrile group is in this case converted to the tetrazole by means of tributyltin azide, a reagent that involves milder conditions than the traditional acidic medium used to generate hydrazoic acid. Thus, treatment of (78-4) with the tin reagent affords irbesartan (75-5) [82]. 

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

Alkyl halides undergo Sn2 reactions with a variety of nucleophiles, e.g. metal hydroxides (NaOH or KOH), metal alkoxides (NaOR or KOR) or metal cyanides (NaCN or KCN), to produce alcohols, ethers or nitriles, respectively. They react with metal amides (NaNH2) or NH3, 1° amines and 2° amines to give 1°, 2° or 3° amines, respectively. Alkyl halides react with metal acetylides (R C=CNa), metal azides (NaN3) and metal carboxylate (R C02Na) to produce internal alkynes, azides and esters, respectively. Most of these transformations are limited to primary alkyl halides (see Section 5.5.2). Higher alkyl halides tend to react via elimination. 

Nitriles can be obtained in one step by treatment of primary nitro compounds with PC13 and pyridine,420 R may be alkyl or aryl and may contain C=C double bonds or various functional groups. Yields are moderate to good. The reaction has also been carried out with Me3N-S02 and with HMPA.421 Primary azides RCH2N3 have been converted to nitriles RCN with Pd metal.422 Primary nitro compounds RCH2N02 were converted to nitrile oxides 0... 

In reactions with aliphatic azides gas evolution did not usually begin until approximately 5 min had elapsed from the time of initial addition. In contrast, immediate gas evolution was observed after the initial addition of azido nitriles and phenoxy azides to the nitrosonium salt. Total gas evolution was measured on the closed system by water displacement from a calibrated gas buret. Total gas evolution reflected the total amount of reacted azide and the different pathways for the production of gaseous products (nitrosative decomposition and Curtius rearrangement). The rate of production of gaseous products slowed markedly after the evolution of 40-60 mL (1-2 mmol of reacted azide) with the exception of nitrosative reactions wi th 4-azidobutanonitrilc and 5-azidopentanonitrile, gas evolution terminated when approximately 50 % of the azide had reacted. Gas evolution in the nitrosative reactions of aliphatic azides continued to completion as a result of protonic decomposition. Reactions were usually complete within 2 h. 

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