Acyl tetrazoles, synthesis

Scheme 22 The Acyl-Tetrazole Rearrangement Route in the synthesis of fluorinated 1,3,4-oxadiazoles 65, 5-perfluoroalkyl-2-phenyl-l,3,4-oxadiazoles 76 and 1,3-bis(2-phenyl-1,3,4-oxadiazol-5- yl)hexafluoropropane 78...

The first examples of a direct 1,5-substituents tetrazole synthesis via an intermolecular [2 + 3]-cycloaddition reaction of organic azides (based on the results for a similar synthesis of triazoles) were developed by Sharpless et al. in 2002 using sulfonyl or acyl cyaiudes (Scheme 9.8). In both cases, the Click reaction involved simple heating of the organic azides (hindered, aliphatic or aryl azides) and the nitriles into a homogenous liquid at higher reaction temperature (80-100 °C), in which no further purification was necessary. 

Scheme 9.8 [2 + 3] Dipolar cycloaddition for the synthesis of 1,5-disubstituted sulfonyl tetrazoles (A) and acyl tetrazoles...

Tefrazolo[2,3-e]isoxazole, 2-methyl-IR spectra, 6, 978 Tetrazol-5-one, 1-aryl-acylation, 5, 821 Tetrazol-5-one, 1,4-dimethyl-2-oxides synthesis, 3, 533... 

Ceforanide Ceforanide, (6R, 7R)-7[2-(a-amino-o-tolyl)acetamido]-3-[[[l-carboxymethyl-17/-tetrazol-5-yl]-thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (32.1.2.27), is also structurally related to cefamandole, differing in that the acylating acid was o-aminomethylphenylacetic acid, and also in the presence of a carboxyl group in the methyl substituent of the tetrazol ring. It is also synthesized by methods analogous to the synthesis of cefamandole [124-128]. 

The synthesis of valsartan (2) by Novartis/Ciba-Geigy chemists is highlighted in Scheme 9.5. Biphenylbenzyl bromide 18 is converted to biphenyl acetate 19 in the presence of sodium acetate in acetic acid. Hydrolysis of 19 followed by Swern oxidation delivered the biphenyl aldehyde 20, which underwent reductive amination with (L)-valine methyl ester (21) to give biphenyl amino acid 22. Acylation of 22 with penta-noyl chloride (23) afforded biphenyl nitrile 24, which is reacted with tributyltin azide to form the tetrazole followed by ester hydrolysis and acidihcation to provide valsartan (2). [See Biihlmayer et al. (1994, 1995).]... 

The reaction of lactim ethers with hydrazine and its derivatives proceeds readily. The resulting compounds are highly reactive and can be used in different reactions involving the side chain and the cyclic nitrogen atom.5,54,76> 80-82 For example, the treatment of caprolactam hydrazone (40) with nitrous acid results in pentamethyl-enetetrazole (41),54,80,81 and the use of diiferent lactim ethers gives other tetrazoles.32,35 The synthesis of polymethylenetetrazoles from lactim ethers and HN3,83 and also84 from HN3 and O-acyl lactims (or imidochlorides of lactams), obtained from lactams and sulfochlorides or phosphoryl chloride, may be mentioned. 

A neurokinin inhibitor whose strueture differs markedly from aprepitant (200) incorporates a substituted tetrazole ring. The synthesis of the tetrazole-containing moiety of vofopitant (241) start by acylation of substituted aniline 231 with trifluoroaeetyl ehloride to afford the amide (232). Reaction of that under Mitsonobu eonditions leads to the enol chloride (233). Treatment of 233 with sodium azide probablty starts with addition-elimination of azide ion this undergoes internal 1,3-cycloaddition to form the tetrazole ring. Catalytie hydrogenation then removes the benzyl... 

Vinylsilanes 227 in various ElZ ratios are formed in high yields in the reactions of acyl(trialkyl)silanes 225 with anions generated from tetrazolyl sulfones 226 <03OL2789>. The synthesis and chemistry of tetrazolylacroleins has been reported <03T7485>. Fused tetrazole derivatives were obtained from intramolecular iodocyclization of tetrazolyl olefins <03T6759>. 

Sekine has reported the synthesis and anticancer activity of Phosmidosine (18) and its demethylated parent (19). The Phosmidosines were obtained by reaction of an appropriately protected 8-oxoadenosine 5 -0-phosphoramidite and N-protected prolinamide in the presence of 5-(3,5-dinitrophenyl)-l//-tetrazole, followed by in situ oxidation with t-BuOOH to form the iV-acyl phosphoramidate linkage. These syntheses required extensive work with regard to the choice of protecting groups on the adenine moiety, as this was crucial for successful P-N bond formation. ... 

Treatment of acylhydrazines with diazonium salts gives rise to tetrazenes (199) which can be readily dehydrated with base to give 1,5-disubstituted tetrazoles (Scheme 33). The reaction is also effective with 1,2-diacylhydrazines since one of the acyl groups is cleaved during the dehydrative cyclization, which may be conveniently carried out in situ without isolation of the tetrazene. This reaction can be useful for the synthesis of 1-aryltetrazoles using 1,2-diformylhydrazine as substrate (B-67MI41300). Mesoionic tetrazolium 5-oxides (8a) are obtained on treatment of bis(alkylsulfonyl)methanes with diazonium salts. Hydra-zones of type (200) are also obtained from these reactions and the tetrazenes... 

The indole-based drug 129 is clearly made by acylating an indole 127 and this was the last step in the synthesis, The problem here is chemoselectivity. The answer is the usual one of last in, first out . The anion of the indole will be needed to ensure reaction at nitrogen but the anion of the tetrazole will be formed first. Two molecules of NaH make the dianion 128 and the less stable anion, that of the indole, reacts first.14... 

Tetrazoles alkylate and acylate on N-l(4) and/or N-2(3), the regioselectivity depending, in part, on the substituent at C-5. The fonnation of mixtures is the usual outcome for alkylation and this is a significant problem in medicinal chemistry. Although a range of specifically N-1-substituted tetrazoles are available by ring synthesis, the direct synthesis of N-2-substituted compounds is more problematic. 

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