Isoxazolones, reactions

The following reaction sequence provides a regiospecific route to 3,4-disubstituted 5-isoxazolones (328) (73ACS2802). The /3-ketoesters (325) were heated under reflux with benzylamine in benzene in the presence of molecular sieves (3 A) to give the )3 -benzylamino-a,)3-unsaturated esters (326). The latter reacted first with hydroxylamine hydrochloride in... 

Chloro- and 5-bromo-isoxazoles have been prepared by reaction of 5-isoxazolones with the appropriate phosphoryl halide (77JMC934). 3-Phenyl-5-trifluoromethylisoxazole has been synthesized by reaction of benzonitrile iV-oxide with 3,3,3-trifluoropropyne (77JMC934). 

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline IV-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

It should be noted that furoxan amides and hydrazides could only be prepared in aqueous solution. In ether solution, reaction of diethyl furoxandicarboxylate with amines and hydrazine derivatives have been shown to give isoxazolones 93 (Scheme 45) (08CB3512, 09LA52, 09LA80). 

Carbon-Oxygen Bond Formation The cathodic reduction of some nitrocarhonyl compounds in aqueous acidic medium gives the hydroxylamino derivatives that can undergo a ring-closure reaction affording anthrandic compounds or isoxazolones [102-104] (Schemes 70 and 71). 

Photolysis of 3-phenyl-5(4//)-isoxazolone 152 gives 2,5-diphenylpyrazine 154 in 67% yield (Scheme 41) <1997JIC648>, probably through diradical intermediate 153. Radical chain reactions of a-azido ketones 155 with tributyltin hydride lead to symmetrical alkylpyrazines 156, albeit in low to moderate yields (Scheme 42) <2002T3485>. 

Nucleophilic displacement of a hydroxy (or keto) function is a common procedure for making chloroisoxazoles. Reaction of 5(4//)-isoxazolones (77) with phosphoryl chloride in the presence of triethylamine gave the... 

Stoffel and Bresse328 have found that the cyclohexyl-V-hydroxy-thiourea derivative of anthranilic acid 211 undergoes cyclization in base to give the dihydrobenz[c]isoxazolone compound 212. With substituents other than cyclohexyl, however, the products of the reaction are quinazolines (see above). 

It was reported in 1977 that reaction of 3-phenyl-5-isoxazolone with excess of POCI3 in DMF under Vilsmeier conditions gave the isoxazoline 1. Treatment of 1 with MeOH/NaOMe and with 10% NaOH solution was claimed to give the aldehyde 2 and the azirine 3 respectively. 

Subsequent attempts to repeat this work failed. Instead, reaction of 3-pbenyl-5-isoxazolone with POCI3/DMF, first at room temperature then for 30 minutes at 60°C, gave the isoxazolone 4 in 35% yield after standard aqueous quench and neutralisation with 5% NaHC03 solution. When longer reaction times were employed, or when the reaction temperature was raised to 80°C, the product, isolated in 71% yield, was the 1,3-oxazinone 5, and 4 was shown to be the precursor to 5. 

A higher reaction temperature is necessary when pyrazolones such as 15 and isoxazolones are used. The selectivity in these reactions depends on the substituent at the hetero-aromatic compound and the substituents at the dienophile moiety (Scheme 5.4) [10]. 

Methyl isoxazolone is obtained by reaction between ethyl aceto acetate and nitrous acid... 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

Different reaction pathways can be observed in the reaction of isatins with carbanions under photochemical or thermal conditions. Thus, the reaction of isatin and isoxazolone under thermal conditions led to addition at position C-3, whilst under UV irradiation cleavage of the isatinic N1-C2 bond occured yielding isatic acid, which subsequently condensed with isoxazolone446 (Scheme 106). 

Isoxazolones, electron transfer ring opening reactions of 89YGK629. 

Reactions of 4-aryl-5(2f/)-isoxazolones with 1,2-dibromoethane in acetonitrile in the presence of 1 equiv of triethyl-amine gave 2-bromoalkyl-4-aryl-5(2/f)-isoxazolones as major products that were converted to heterocyclic ketene AjO-acetals by treatment with sodium methoxide in boiling methanol <1997T10433>. The preparation of quinoline derivatives was achieved by catalytic hydrogenation of 2-(2-formylaryl)-5(2//)-isoxazolones <2003T9887>. 

The hydroxylamino group may react further. A Gatterman reaction has, however, been observed only in the reduction of 2,3-dinitrotoluene. When a carboxyl group is neighbor to the hydroxylamino group, an isoxazolone may be formed this reaction has been used as an indication of which nitro group is most easily reduced in dinitrobenzoic acids [152]. 

Apparently, the isoxazolones (203) can exist in different tautomeric forms and these compounds are photochemically reactive and yield different products from the different tautomeric forms.Some of the reactions encountered are shown in Scheme 4. Sigmatropic migrations are used to explain the formation of the products 3-ethoxy-2-phenylindole and 6-ethoxy-2-phenylin-dole from irradiation of l-ethoxy-2-phenylindole in methanol. The de-ethoxylated compound 2-phenylindole is also formed. The photostability of the novel antibiotic (204) has been assessed. 

Analogous reactions in the aliphatic series cyclize alkylenediamines in which one amino group has been acylated (i.e., a-(acylamino)enaminones). These substrates can be made by catalytic reduction of 4-aminoisoxazoles <85TL3423, 87JOC27l4> or 4-amino-5(4W)-isoxazolones <91S127>. These a-(acylamino)enaminones (188) cyclize in the presence of bases to form a wide range of 2-substituted 4-acylimidazoles. If the isoxazole has no A-substituent, treatment of the enaminone with... 

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