1.2.4- Oxadiazoles, 3-hydroxy- from

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

Cycloaddition of nitrile oxides to the double bond of aldoximes under BF3 catalysis affords 4,5-dihydro-4-hydroxy-l, 2,4-oxadiazoles, from which water can be eliminated. Oxadiazoles are obtained in low yields <86izv2i5i, 90IZV625>. 

Tautomerism involving substituents is not favored and even the 3-hydroxy compounds for which lactam tautomers can be proposed (Scheme 3) react exclusively in the conjugated from. Thus N-ethyl-l,2,5-oxadiazol-3(2/ -one (49) is prepared via a 3-silyloxy derivative rather than by direct alkylation of lactam (50) <93T5905>. 

Apart from 1,3,4-oxadiazole (b.p. 150°C), its lower alkyl derivatives and some dihydro compounds, 1,3,4-oxadiazoles are generally solids. In synthesis, the common method of purification is by crystallization of the crude reaction product. A few oxadiazoles, for example, alkyl ethers and acetates derived from 2,5-dihydro-2-hydroxy-2,5,5-trialkyl-l,3,4-oxadiazoles (cf. (38)), have been purified by distillation under reduced pressure. In some cases, chromatography over silica gel has been used. 

It must be pointed out that the "amide process allows the preparation of oxadiazole containing acylable group in the substituent. For example, 3-phenyl-5-hydroxy methyl oxadiazole has been obtained in 55% yields from benzamidoxime formate and glycolamide. 

Treatment of the pyrazolium[4,3-r/][l,2,3]oxadiazolium diiodide 124 with -hydroxy- or /)-dimethylaminobenzalde-hyde yielded the pyrazolo[4,3-r/][l,2,3]oxadiazole styryl and azastyryl cyanines 83a and 83b in modest yields. Parallel reaction with -nitrosophenol furnished 83c. Reaction of 124 with 1-ethylquinolinium iodide afforded 84a directly. However, 3-anilinocarbomylmethyl-2,4-diethyl-(N-phenylcarbomylmethyl)pyrazolium(4,3-r/)[l,2,3]oxadiazolium diiodide 125 arising from reaction of 124 with diphenylformamidine in refluxing acetic anhydride, is the precursor to 84b which follows from subsequent reaction with 2-methylisoquinolinium iodide (Scheme 16) <1994MI905-1>. 

Acylation of A-hydroxy-2-phenylbutyramidine (112-1) with 3-chloropropionyl chloride in the absence of an added base proceeds as might be expected to give the product (112-2) from acylation on the more basic nitrogen. Heating this compound leads to the formation of the oxadiazole (112-3) almost certainly via the enol tautomer of the amide. Displacement of the terminal chlorine with diethylamine leads to the tertiary amine and thus proxazole (112-4) [123], a compound that is said to exhibit antispasmodic activity. 

Katritzky and co-workers60 used infrared spectra to distinguish O-methyl from TV-methyl derivatives of 3-hydroxy-5-phenyl-1,2,4-oxadiazole and suggested assignments for the ring and the phenyl group absorptions. 

Unlike the mesoionic 1,2,3-oxadiazoles (see Chapter 5.03), mesoionic 1,2,3,4-oxatriazoles 5 and 6 do not undergo 1,3-dipolar cycloaddition reactions. Azides formed by loss of carbon dioxide from anhydro-5-hydroxy-l,2,3,4-oxatria-zolium hydroxides 4, on prolonged heating with lithium chloride, may be trapped by cycloaddition to an alkyne < 1996CHEC-II(4)679>. 

Mixtures of the examined solvents are frequently used to obtain ICC. Thus, an aqueous-ethanol mixture was used for the preparation of 678 from 5-(2-hydroxy-phenyl)-3-phenyl-l,2,4-oxadiazole and copper(II) acetate [249] ... 

Hydroxy- (8a), 2-mercapto- (8b) and 2-amino-l,3,4-oxadiazoles (8c) are in equilibrium with the tautomeric oxadiazolines (9a), (9b) and (9c) respectively. Evidence from UV (72CJC3079) and IR (Section 4.23.2.2.3) spectra supports structure (9a) for A2-l,3,4-oxadiazolin-5-ones and structure (9b) for A2-l,3,4-oxadiazoline-5-thiones. The UV and IR spectra, fluorescence and p/iT values of 2-amino-l,3,4-oxadiazoles indicate that the amine tautomer (8c or d) rather than the imine tautomer (9c or d) predominates (69BSF870, 874, 64CR(258)4579>. 

Irradiation 3-Hydroxy-l,2,4-oxadiazoles from N-acylcarbamic acid azides m 0... 

Scheme 32 Possible pathway for the formation of 5-aryl-3-hydroxy-l,2,4-oxadiazoles 157 (X=0) and 5-aryl-3-hydroxy-l,2,4-thiadiazoles 157 (X=S) respectively, starting from aroyliso cyan ate 153 (X=0) or thioaroylisocyanate 153 (X=S) and TMSA (146) [111]...

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