Nitrile oxides 1,2,4-oxadiazoles from

It has been found [44b) that the formation of nitrile oxides from hydroxamyl chlorides is not always necessary. When heated in an inert solvent without any base, an equimolecular mixture of a nitrile and a hydroxamyl chloride produces the expected oxadiazole with evolution of HCl. 

The cycloaddition of nitrile oxide 235 to the 4-iminobenzopyran-2-one 236 gave the fully conjugated 1,2,4-oxadiazole 238 directly, a reaction that most likely proceeds via loss of methanol from the intermediate 237 (Scheme 36) <1996JHC967>. Similarly, nitrile oxide 239 reacted with imine 240 to give the 1,2,4-oxadiazole 242 via the nonisolable intermediate 241 <2002PJC1137>. 

Dimerization of nitrile oxides derived from 4-amino- and 4-R-substituted l,2,5-oxadiazole-3-carbohydroximoyl chlorides 201 leads to the formation of tricyclic furoxans 200 or compound 202 (Scheme 45) <2001RJ01355>. 

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>. 

Dipolar cycloaddition of nitrile oxide at the C=N bond of indole imino esters 130, followed by elimination of the alcohol moity gives oxadiazole derivatives 131 (Scheme 1.26) (298). Reaction of N-arylbenzamidines with arenenitrile N-oxides (generated in situ from oximoyl chlorides) produce unstable 5-amino-4,5-dihydro-1,2,4-oxadiazoles which, on aqueous acidic treatment hydrolyze to open-chain N-benzoyloxy-N -arylareneamidines (299). 

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>. 

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 methods M, N, O, P in which nitrile oxides or hydroxamyl chlorides are used are more particular because of the instability of the starting materials. Nevertheless, when the unstable reagents can be produced in situ from easily available substances, the preparations of oxadiazoles become very attractive. 

Several processes to prepare oxadiazoles start from nitrile-oxides or their precursors, hydroxamyl chlorides. Aromatic nitrile oxides are obtained by treating the corresponding hydroxamyl chlorides with... 

Trifluoromethyl substituted 1 -oxadiazoles 113 were prepared by heating the bis(oximes) 112 with dry silica <99H(51)627>. l -Oxadiazole-2-oxides(furoxans)are often produced by dimerisation of nitrile oxides and some novel examples of the method, which produces 3,4-disubstituted derivatives bearing medium and large rings, have been described <99JOC8428>. Two examples of compounds prepared in this way from bis(nitrile oxides) are the ftiroxans 114 (84%) and 115 (86%). 

Kurabayashi and Grundmann have reported the preparation of the 1,2,4-oxadiazoles (34) from 1,3,5-triazine and aryl nitrile oxides in the presence of boron trifluoride. The mechanism has not been fully elucidated, but it is most likely that the initial stage is the formation of the complex (33) (78BCJ1484). 

Oxadiazoles can also be prepared from amides via acylamidines, ° or via the cycloaddition of nitrile oxides to nitriles, as illustrated. "" 3-Alkylamino-l,2,4-oxadiazoles result from the reaction of N-acyl-l-benzotriazolyl-l-carboximidamides with hydroxylamine. " ... 

The cycloaddition of an arylnitrile oxide to methyl ethynylmethylphosphinate in an inert solvent at 5 °C produces a (5) -phosphinoylated-isoxazole 513 in high yield " and phosphorylated 1,2,4-oxadiazoles 514 are obtainable in a similar addition to (R0)2P(Z)CN (Z = O or Phosphorylated nitrile oxides, e.g. 515, are generally prepared by the Et3N-dehydrobromination of the product from the bromination of the oxime of a j5-(dialkoxyphosphinoyl)acetaldehyde, and then used in situ in reactions with alkenes to give isoxazolines and with alkynes to give isoxazoles . The chlorination and subsequent dehydrochlorination of diethyl (nitromethyl)phosphonate yield the nitrile oxides 516 (R = EtO Pr O or morpholinyf and these, with unsaturated centres, yield isomerically phosphorylated isoxazolines and isoxazoles. 

The steroidal oc/ -unsaturated nitriles (424) and (425), chosen to test the reactivity of the olefinic bond to 1,3-dipolar addition of a nitrile oxide, were found to react instead at the cyano-group. Benzonitrile oxide, generated in situ from benzhydroxamoyl chloride, gave the 1,2,4-oxadiazoles (426) and (427). ... 

A-phenylmaleimide/ ° The complex nitrile oxide (736), prepared from dichloroglyoxime (HON=CCl—CC1=N0H) and dipropargylamine, forms the intramolecular cyclo-adduct 137) 3,6-Diphenylpyridazine 1,2-dioxide (738) rearranges photochemically to the isoxazolo-isoxazole (739), which is also produced by the oxidation of the dioxime HON=CPhCH=CHCPh=NOH. Regiospecific cycloaddition of benzonitrile oxide to the pyrazoline (740) affords the pyrazolo-oxadiazole (741)/ ... 

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