Isoxazolones, reaction with

Isocyanates can react with other heterocycles as well as with acyclic unsaturated compounds. An example is the reaction of isoxazolone 2.147 with phenyl isocyanate to give 2.148. Subsequent hydrolysis led to 3-amino-3-phenylprop-2-enoic acid, 2.149. A different example involves the conversion of isoxazole acid 2.150 to... 

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). 

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. 

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). 

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>. 

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... 

Structure 159 has been erroneously assigned to the product of the reaction between 3-benzoyl-3-methyl-47/-isoxazol-5-one 157 and SOCI2 (53GA192). In reality, the compound has the structure of isoxazolone 158 (74HCA1934). The reactions of chloro compound 158 with ammonia, phenylenediamine, and phenylhydrazine produce enamine 160, isoxazolo[5,4-e]1.4-diazepine 161, and isoxazolo[5,4-c]pyrazole 162, respectively (59ZOB3446). The formation of 161 and 162 represents examples of substitution at the keto group in position 5 (Scheme 71). 

Pyrazolones (154) and isoxazolones (155) can also be used in the Knoevenagel reaction. Thus condensations with aliphatic aldehydes, aromatic aldehydes and ketones in the presence of ethylenediammon-ium diacetate or other typical catalysts provide the corresponding alkylidene and benzylidene compounds in good yields (for stereochemistry see Section 1.1A new method involves the use of dicyclohexylcarbodiimide at 20 C without an additional catalyst. ... 

---