1.2.5- Oxadiazole 2-oxides, 4-acetyl

In a significant addition to the synthesis of 1,2,4-oxadiazoles (Scheme 41), Itoh et al. discovered that the treatment of nitriles with iron(lll) nitrate in the presence of acetone or acetophenone gives the 3-acetyl- or 3-benzoyl-l,2,4-oxadiazoles 260, proposing that enolization and nitration gives an a-nitroketone, which then undergoes an acid-catalyzed dehydration to give the nitrile oxides 259 <2005S1935>. 

Di-(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)-l,2,5-oxadiazole 2-oxide 306 was synthesized from D-mannose 305 by a route involving dimerization of mannopyranosyl nitrile oxide as the key step. Three methods were used for the generation of the nitrile oxide isocyanate-mediated dehydration of nitromethylmannose derivatives, treatment of aldoxime with aqueous hypochlorite, and base-induced dehydrochlorination of hydroximoyl chloride (Scheme 76) <2001TL4065, 2002T8505>. 

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). 

Ring opening is the most common reaction of A2-oxadiazolines, either thermally or on attack by nucleophiles. A rare example of oxidation to a 1,3,4-oxadiazole is the conversion of 4-acetyl-2,5-diphenyl-A2-l,3,4-oxadiazoline into 2,5-diphenyl-l,3,4-oxadiazole on treatment with LTA (67JOC3318). 

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>. 

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