1,2,5-Oxadiazole oxides, phenyl

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... 

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]. 

Other non-traditional preparations of 1,2,3-triazoles have been reported. The rearrangement in dioxane/water of (Z)-arylhydrazones of 5-amino-3-benzoyl-l,2,4-oxadiazole into (2-aryl-5-phenyl-27/-l,2,3-triazol-4-yl)ureas was investigated mechanistically in terms of substituents on different pathways <06JOC5616>. A general and efficient method for the preparation of 2,4-diary 1-1,2,3-triazoles 140 from a-hydroxyacetophenones 139 and arylhydrazines is reported <06SC2461>. 5-Alkylamino-] //-], 2,3-triazoles were obtained by base-mediated cleavage of cycloadducts of azides to cyclic ketene acetals <06S1943>. Oxidation of N-... 

The Mukaiyama-Hoshino reaction between a nitroalkane and phenyl isocyanate generates a nitrile oxide, and this method has been used in the synthesis of 1,2,4-oxadiazoles as discussed in CHEC-II(1996) <1996CHEC-II(4)179>. In a more recent advance, nitroethane undergoes ultrasound-mediated cycloaddition with trichloroacetonitrile to give the extremely useful (see Equation 11) 5-trichloromethyl-l,2,4-oxadiazole 228 (Equation 45) <1995TL4471>. 

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>. 

MercaptomethyM-phcnyl-l,2,5-oxadiazol iV-2-oxide 102 and 3-(4-mercaptophenylmethylidenhydrazinocarbo-nyloxymethyl)-4-phenyl-l,2,5-oxadiazol iV-2-oxide 104 were successfully synthesized from 3-chloromethyl- or 3-hydroxymethyl-4-phenyl-l,2,5-oxadiazole iV-2-oxide 103 (Scheme 27) <2006AP59>. 

The reaction of 3,4-diacyl-l,2,5-oxadiazole 2-oxides (furoxans) with activated nitriles in ionic liquids and in ethanol unexpectedly resulted in 3-acyl-4-acylamino-l,2,5-°xadiazoles (furazans) <2003MC230>. 3-Formyl-4-phenyl-l,2,5-oxadiazole Ar-oxide 105 is a good precursor for the synthesis of functional substituted furoxans (Scheme 28) <1999JME1941, 2000MOL520, 2000JFA2995>. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Closure of the oxadiazole ring is still achieved through cycloaddition between pyridine iV-oxides and isocyanates, affording adducts such as 142 (Scheme 38) <1995T6451>. Nonaromatic imine fV-oxides exhibited similar reactivities, since azasugar-derived fV-oxides as a mixture of 143 and 144 underwent cycloaddition reactions in the presence of phenyl isocyanate or trichloroacetonitrile. Compounds 145 and 146 (Scheme 39) were obtained from the aldoxime W-oxide 143 two other regioisomeric heterocycles arose from the ketoxime derivative 144 <1996T4467>. 

Bipolar Molecular Glasses. Recently, bipolar molecular glasses have been described that allow both injection of holes and electrons (Fig. 3.30). 2- 4-[bis(4-methylphenyl)amino]phenyl -5-(dimesitylboryl)thiophene (PhAMB-lT, 68) and 2- 4-[bis(9,9-dimethylfluorenyl)amino]phenyl -5-(dimesitylboryl)thiophene (F1AMB-1T, 69) show oxidation potentials of 0.62 and 0.58 V, and reduction potentials of —2.13 and —2.01 V vs. Ag/0.01 Ag+, respectively [145]. Oxidation as well as reduction leads to stable radical ions. With the conversion rules given above, the HOMO and LUMO levels can be estimated to be approximately at —5.3 and —2.8 eV. In comparison, for the bipolar compound 70, consisting of triarylamine and oxadiazole moieties, the values are —5.5 and — 2.7eV [129]. However, in this case no data on the stability of the radical ions are available. 

The first examples of furazan and furoxan nitrile oxides have been reported in the early 1990s. 4-Aminofurazan-3-carbonitrile oxide (65) was generated from the hydroximoyl chloride with base and its cycloaddition reactions investigated <92KGS687>, and the 4-phenyl analogue (66) is formed via the nitrolic acid derivative by treatment of the aldoxime with dinitrogen tetroxide <93LA44i>. Furazan-3-amidoximes react in the usual way with nitriles to yield 3-(furazan-3-yl)-1,2,4-oxadiazoles <9013941 >. 

The reaction can be performed in one step by adding the nitrile to a mixture of benzhydroxamyl chloride and triethylamine. Unless activated by an electron withdrawing group, aliphatic nitriles do not react with benzonitrile oxide 33e). For example, acetylcyanide gives 3-phenyl-5-acetyl-oxadiazole in 60% yields [32a). 

Phenyl-l,2,5-oxadiazole-2-oxide (43) is cleaved by aqueous alkali at 0°C (27G124) and the 4-phenyl isomer (44) is an unstable compound which is cleaved even at pH 8.0 (72JOC593). The carboxylic acid (45) is decarboxylated and cleaved in an analogous manner when heated at 120°C (74TL627). 

The reaction of methylene triphenylarsorane with benzonitrile oxide in DMSO gave rise to 3,5-diphenylisoxazole (53) along with the 3-phenyl-4-benzoyl-2-isoxazoline oximes 54 and 55 ( /). When the reaction took place in ether instead of DMSO, a mixture of 3,5-diphenyl-l,2,4-oxadiazole (56) and 3,5-diphenylisoxazole (53) was obtained (31). 

The products of the thermolysis of 3-phenyl-5-(arylamino)-l,2,4-oxadiazoles and thiazoles have been accounted for by a radical mechanism.266 Flash vacuum pyrolysis of 1,3-dithiolane-1-oxides has led to thiocarbonyl compounds, but the transformation is not general.267 hi an ongoing study of silacyclobutane pyrolysis, CASSF(4,4), MR-CI and CASSCF(4,4)+MP2 calculations using the 3-21G and 6-31G basis sets have modelled the reaction between silenes and ethylene, suggesting a cyclic transition state from which silacyclobutane or a trcins-biradical are formed.268 An AMI study of the thermolysis of 1,3,3-trinitroazacyclobutane and its derivatives has identified gem-dinitro C—N bond homolysis as the initial reaction.269 Similar AMI analysis has determined the activation energy of die formation of NCh from methyl nitrate.270 Thermal decomposition of nitromethane in a shock tube (1050-1400 K, 0.2-40 atm) was studied spectrophotometrically, allowing determination of rate constants.271... 

Treatment of 3,4-diamino-l,2,5-oxadiazole with nitrosobenzene gives 3-amino-4-phenyl-azo-l,2,5-oxadiazole (160) which upon oxidation with lead tetraacetate gives the phenyl derivative (159 R=Ph) (74BCJ1493). 

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