Tetrazoles nitriles

Tetrazoles Nitriles undergo Cu-catalyzed cycloaddition with Me3SiN3 and adducts are desilylated in situ to furnish five-substituted tetrazoles. 

Keywords Bioorthogonal reaction Photo-triggered reaction Photoclick Tetrazole Nitrile imine Azirine Cyclopropenone o-Naphthoquinone methide o-Quinodimethanes Hetero Diels-Alder reaction... 

Tetrazole synthesis (torn azides by dipolar cycloadd ition with activaled n ltnies or intramolecularly with nitriles in the presence of acids. 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

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. 

The parent tetrazole derivative of glyphosate 78 has been reported as a product of the 1,3-dipolar cycloaddition of n-Bu3SnN3 across the nitrile linkage in 76 and subsequent hydrolysis of the resulting diester 77 (62). 

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... 

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... 

The 1,3-dipolar cycloadditions of N3 with coordinated nitriles (211) may result in formation of 5-substituted tetrazole complexes (212). Some examples include [Co(NH3)5(N4R)]2+-(R =p-methylphenyl, /uchlorophenyl, /unitrophenyl (N1 bound), m-formylphenyl N2 bound)). 

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... 

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>. 

Photoelimination of nitrogen from the tetrazole 429 results in the formation of the dihydropyrazole 430, presumably via intramolecular addition of the photochemically generated nitrile imine 431.358 Other examples of this type of behavior have been reported.359... 

A. Dondoni and A. Marra, Addressing the scope of the azide-nitrile cycloaddition in glycoconjugate chemistry. The assembly of C-glycoclusters on a calix[4] arene scaffold through tetrazole spacers, Tetrahedron, 63 (2007) 6339-6345. 

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. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

An improvement of the palladium-catalyzed cyanation of aryl bromides, in which zinc cyanide was used as the cyanide source, was reported in the middle of the nineties [49], Typically, the conversion from halide to nitrile takes at least 5 h by this route and the subsequent cycloaddition to the tetrazole is known to require even longer reaction times. 

A single-mode microwave procedure has been reported for the palladium-catalyzed preparation of both aryl and vinyl nitriles from the corresponding bromides. The reaction times were short and full conversions were achieved in just a few minutes (Eq. 11.33) [50], The cycloadditions to yield the tetrazoles needed slightly longer reaction times, from 10 to 25 min, but only 20 W of power was required as a temperature of 220 °C was reached after 10 min heating. The yields in this step ranged from 36% to 96%. This method for transforming halides into tetrazoles has been used for the synthesis of a novel HIV-protease inhibitor [50],... 

The scope of this reaction (Scheme 16) has been extended to other 5-substituted tetrazoles, readily prepared by the reaction of nitriles with aluminium azide <2002J(P1)1543>. Using triphenylphosphine under mild conditions, the resulting dithiazolimines 169 are rapidly converted into cyanothiadiazoles 170 in high yield (Equation 61 and Table 10). 

The 1,3-dipoles were generated by the addition of Et3N in 20% excess. Only imidazole was basic enough to generate a nitrile oxide in the absence of triethy-lamine. Due to prototropic tautomerism, reactions of triazoles and tetrazoles led to mixtures of two isomers. With unsubstituted pyrazole and imidazole only one hydroximoylazole was formed (117). 

D. P. Curran, S. Hadida, S. Y. Kim, Tris(2-Perfluorohexyl-ethyfltin Azide A New Reagent for Preparation of 5-Substituted Tetrazoles from Nitriles with Purification by Fluorous Organic Liquid-Liquid Extraction , Tetrahedron 1999, 55, 8997. 

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

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-... 

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>. 

A subsequent report outlined the synthesis of a diastereomer of tetrazole 58 that used similar methodology <1997TL4655>. Treatment of nitrile mesylate 60 with sodium azide affords D-talonotetrazole 62, presumably by intramolecular [1,3] dipolar cycloaddition of a 4-azido-4-deoxy-D-talonitrile intermediate 61. Acid hydrolysis affords the deprotected tetrazole 63 (Scheme 5). 

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. ... 

Excerpt 4F is taken from an article written by Demko and Sharpless. (Barry Sharpless was a co-recipient of the Nobel Prize in Chemistry in 2001 for his work on chirally catalyzed oxidation reactions.) In this article, the authors propose a way to synthesize aromatic tetrazoles from nitriles in water, using only sodium azide and a zinc salt. Water, despite its obvious advantages (i.e., safe and inexpensive), rarely succeeds as a solvent in organic synthesis. Thus, a synthesis that uses water successfully is an important scientific accomplishment. 

Let s examine the use of compound labels in excerpt 4F. The authors first use compound labels in their eq 1 (our eq 4.1) to illustrate the conversion of an unspecified nitrile 1 to an unspecified tetrazole 2 ... 

In Table 2 of excerpt 4F, labels for specific tetrazoles (2a, 2b, 2c,... 2j) are introduced. Table 2 also provides the information needed to unlock the specific structures of 1 and 2 in the authors eq 1. For example, in table entry 2a, the R group on the tetrazole is phenyl hence, R is also phenyl on the nitrile, and their eq 1 becomes explicitly (our eq 4.2)... 

We report here a safer and exceptionally efficient process for transforming nitriles 1 into tetrazoles 2 in water the only other reagents are sodium azide and a zinc salt (eq 1). 

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