Tetrazoles preparation

Methyl and other alkyl esters were prepared in THF, also in high yields.[130] b) Arachidonic acid was converted via its tetrazolide with the aid of oxalyldi(l,2,3,4-tetrazole), prepared in situ, into the methyl ester.[1113... 

TABLE I Fused Tetrazoles Prepared According to Scheme 6... 

The literature abounds in examples of 5-substituted tetrazoles, 1-substituted tetrazoles and 1,5-disubstituted tetrazoles prepared via imidoyl azide intermediates and the reviews mentioned in Section 4.13.1 may be consulted for further examples of these. When the imidoyl azide moiety is part of another heterocyclic ring, the cyclization gives rise to fused tetrazolo heterocycles and in many such systems both forms are observed in equilibrium (77AHC(2l)323). Systems of this type are discussed in Chapters 4.15, 4.36 and 4.37. 

In contrast, there are many reports of trifluoromethyl- and other perfluoroalkyl-substituted tetrazoles prepared from fluorinated building blocks. For example, consistent with its high reactivity, trifluoroacetonitrile reacts exothermically with sodium azide to give sodium 5-trifluoromethyltetrazole 168 (Fig. 3.98). ... 

A useful tetrazole preparation is the addition of NaN3 (under acidic conditions) to nitrUes. Similar processes occur with Tri-n-butyltin Azide or TMSNs. ... 

Nitrilimines (621) are another class of 1,3-dipoles which provide a useful entry into the pyrazole ring. They are often generated by cycloreversion (79AG(E)72l) of tetrazoles, triazolopyridines and oxadiazolones (79JOC2957) (Scheme 55). Pyrazolines of known stereochemistry, pyrazoles and indazoles (Section 4.04.3.1.1(iii)) have all been prepared from nitrilimines. 

Cyanothiophenes have been converted to amidines, and thienyl-substituted tetrazoles have been prepared from them for pharmacological evaluation. ... 

The classical age of preparative organic chemistry saw the exploration of the extensive field of five-membered heterocyclic aromatic systems. The stability of these systems, in contrast to saturated systems, is not necessarily affected by the accumulation of neighboring heteroatoms. In the series pyrrole, pyrazole, triazole, and tetrazole an increasing stability is observed in the presence of electrophiles and oxidants, and a natural next step was to attempt the synthesis of pentazole (1). However, pentazole has eluded the manifold and continual efforts to synthesize and isolate it. 

The 4-unsaturated-5-oxazolones provide convenient starting materials for the synthesis of other nitrogen-containing heterocyclic systems. The preparation of tetrazoles and isoquinolines is discussed in Sections II,B, 1 and II,B,2,b. 

Ar-Arylbenzimidoyl)tetrazoles t, prepared from JV-arylbenzimidoyl chlorides and 5-(dimethylamino)- or 5-aryltetrazole, give 3//-l,3,4-benzotriazepines 4 on thermolysis. It has been proposed that the reaction proceeds by way of the dipolar compounds 2, which undergo [l,7]-antarafacial 871-electrocyclization to 3. The process is completed by a symmetry-allowed [1.5]-hydrogen shift. Selected examples are given.349-350... 

Naphtho analogues, naphtho[2,l-e]tetrazolo[l,5-6][l,2,4]triazine, naph-tho[l,2-e]tetrazolo[l,5-b][l,2,4]triazine, and naphtho[2,3-e]tetrazolo[l,5-Zj][1, 2,4]triazine, were prepared (82JOC3168 84JOC3199) by cyclization of the respective hydrazine with sodium nitrite in acetic acid or by azide displacement of a leaving group. Elucidation of the site of annulation of the tetrazole ring was accomplished by X-ray analysis and l3C-NMR spectroscopy (Scheme 189). 

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 tetrazole structure was featured in the stmctures of several medicinal agents whose synthesis was reported in 1996. Notable among these reports was the preparation of tetrazole-... 

Triazidochlorosilane ClSi(N3)3 708, which is readily prepared in situ by reaction of three equivalents of NaN3 with SiCU 57 in acetonitrile, reacts with acetophenone to give the tetrazoles 709 and 710 and with cyclohexanone to 6,7,8,9-tetrahy-dro-5H-tetrazolo[l,5-a]azepine 711, Si02, and HCl [210] (Scheme 5.70). 

Tetrazolium salts to a large extent are prepared from the corresponding formazans and to a lesser extent from tetrazoles. Therefore, synthetic methods for both formazans and tetrazoles will be discussed. Also discussed will be some properties of formazan dyes that influence the choice of the tetrazolium salt for any particular application. 

In general, tetrazolium salts are prepared by (a) oxidation of formazans and (b) alkylation of tetrazoles. Therefore, synthetic methods for formazans and tetrazoles are discussed first, followed by some direct and miscellaneous methods. 

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... 

Nitrous acid or alkyl nitrites react with a number of nitrogen compounds to yield tetrazoles. For example, hydrazidines (87), which can be prepared in situ from the corresponding iminoesters, react with nitrous acid or its derivatives to give 1-substituted tetrazoles (88).150-152 This reaction (Eq. 17), is one of the most extensively used methods for the synthesis of... 

Fused ring tetrazoles such as 96 are obtained from the reaction of nitrous acid with heterocyclic hydrazines (95) (Eq. 19).159 160 This method is also suitable for the preparation of fused ring ditetrazoles such as... 

Disubstituted tetrazoles are conveniently prepared from acyl hydrazines (98) and diazonium salts.166 The reaction proceeds through the intermediate tetrazenes (99) followed by cyclization to the tetrazole (100) (Scheme 13). The intermediate can be isolated under mildly basic conditions. Symmetrically 1,2-diacylated hydrazines yield 1-substituted tetrazoles through the elimination of one of the acyl groups.166 - 168 Diformyl-hydrazine is a very convenient starting material for 1-substituted tetrazoles.166, Unsymmetrically 1,2-diacylated hydrazine usually results in mixtures.169... 

Benson et al. 177 first reported the synthesis of tetrazolium salts by the alkylation of disubstituted tetrazoles. While selectivity is a major problem, alkylation can still be considered a viable method for the preparation of 1,3,5- and 1,4,5-trisubstituted as well as 1,5 and 2,5-disubstituted tetrazolium salts. 

Some of the methods used for the preparation of either formazans or tetrazoles can lead directly to tetrazolium salts when appropriate substituents are present. 

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