1.2.5- Oxadiazole N-oxides

The other common synthetic procedure for Bfx and Fx preparation is the oxidative cyclization of 1,2-dioximes. 1,2-Dioximes are excellent starting materials for the syntheses of the 1,2,5-oxadiazole N-oxide system in presence of oxidizing conditions to promote the cyclization. Its utiUty is restricted for Bfxs syntheses because the restriction of o-quinone dioximes availability, contrarily a-glyoximes, which are useful to prepare Fx, are more easily to prepare. In Table 1, products, conditions, and comments for the most recent Fx synthesis using 1,2-dioximes are shown. 

Klyuchnikov et al. have described an alternative substrate for the cycli-zation process, namely o-hydroxylaminonitro derivatives. These entities, previously synthesized or generated in situ, cycle in presence of a base, i.e., sodium bicarbonate and sodium acetate, producing the 1,2,5-oxadiazole N-oxide system (Fig. 2) [21-23]. 

Olea-Azar et al. have also explored the use of 1,2,5-oxadiazole N-oxides in the treatment of Chagas disease. Spectra of radicals were obtained by both electrochemical and microsomal reduction. The calculated electron affinities of the compounds correlated well with the measured reduction potentials, which were... 

Cerecetto H, Maio RD, Gonzalez M, Risso M, Saenz P, Seoane G, Denicola A, Peluffo G, Quijano C, Olea-Azar C (1999) 1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal dmgs structure-activity relationships. J Med Chem 42 (11) 1941-1950. doi 10.1021/jm9805790... 

Boiani, M., Cerecetto, H., Gonzalez, M., Risso, M., Olea-Azar, C., Piro, OJi., Castellano, E.E., Lopez de Cerain, A., Ezpeleta, O., and Monge-Vega, A. (2001). 1, 2, 5-Oxadiazole N-oxide derivatives as potential anti-cancer agents Synthesis and biological evaluation. Part Iv. Eur. J. Med. Chem. 36,771-782. 

N N 3-( p-Bromophenyl)-4-methyl- 1,2,5-oxadiazole 2-oxide 3-(p-bromo-phenyl)-4-methyl-l,2,5-oxadiazole 5-oxide 3,4-diphenyl-l,2,5-oxadiazole... 

Furazane (1,2,5-Oxadiazole) und Furoxane (Furazan-oxide) werden als Anhydride von 1,2-Dioximen bzw. als die entsprechenden N-Oxide durch Lithiumalanat zu 1,2-Diaminen reduziert z. B.8 ... 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Two molecules with comparable geometry in an asymmetric unit were found for 3,4-bis(4-fluorophenyl)-l,2,5-oxadiazole 2-oxide. The bond length of the dipolar N-O bond is 1.107 (7) A <2006AXEo4827>. In the molecule of 5-(6,7-dimethoxy-l,2,3,4-tetrahydroisoquinolin-2-yl)-4-phenyl-l,2,5-oxadiazole Ar-oxide, the six-membered heterocyclic ring has a flattened boat form. Intermolecular C-H- O hydrogen bonds link the molecules into dimers, which may be effective in the stabilization of the crystal structure <2006AXEo3130>. 

Table 2 NMR chemical shifts ( H, C, N, O) for the 1,2,5-oxadiazole ring atoms of furazan, benzofurazan and their A -oxides.

Oxadiazoles undergo thermal and photochemical ring cleavage at the 0(1)-N(2) and C(3)-C(4) bonds to yield nitrile and nitrile oxide fragments, and products derived therefrom. Thus, diphenylfurazan (30, X = 0) decomposes under flash vacuum pyrolysis conditions (600°C, 10-3 mm... 

Dicyclopentadienefurazan N-oxide, see 4a,5,7a,8-Tetrahydro-4,8-methano-4//-indeno[5,6-c]-l,2,5-oxadiazole 1-oxide, 3275 Dicyclopentadienefurazan /V-oxide, see 4a,5,7a,8-Tetrahydro-4,8-methano-4//-indeno[5,6-c]-l,2,5-oxadiazole 3-oxide, 3276 Dicyclopentadienylpentafluorophenylcerium, 3689b Dicyclopentadienylperoxyniobium chloride, 3265 Dicyclopentadienyltrifluoromethyltitanium(l+) fluoride, 3388b Dicyclopropyldiazomethane, 2820 Dideuterodiazomethane, 0335... 

Oxadiazole 4-oxides 157 (Ar, Ai = Ph or/ -Tol) are formed from amidoximes 155 and nitrile oxides 156 <97X1089, 97T1787>. l,2,4-Oxadiazolidine-3,5-dione 158 is benzylated at N-2 by benzyl bromide <97SL263>. 3,6-Dimethylpyridazinol4,5-c]furoxan 159 is converted into 3-acetyl-4-(l,l-dinitroethyl)furoxan 160 by the action of nitric acid <96ZOR957>. 

Among 1,2,5-oxadiazoles, their N-oxides as well as their benzo-fused systems are biologically active compounds which show anthelmintic, fungicidal, bactericidal, herbicidal, and antitumor properties. 

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