3-Isoxazolones

The isoxazolecarboxylic acids are the most intensively investigated of the isoxazole derivatives, and a detailed compilation of their physiochemical properties has been made 62HC(17)l,p. 177). Similar studies have also been carried out with the 5-isoxazolones (62HC(17)l,p. 124), and pK values of 1,2-benzisoxazole derivatives are listed in Table 4. 

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. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

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). 

Italian investigators have recently shown by infrared spectroscopy that 3-hydroxy-5-phenylisoxazole exists as such and not in the isoxazolone form. This conclusion is supported by a spectroscopic investigation of the 4,5-dimethyl and other dialkyl analogs. ... 

Benzenediamine (365) and 3-phenyl-4,5-dihydro-5-isoxazolone (366) gave 2-phenylquinoxaline (368), probably via the tetrahydro intermediate (367) (MeCN, reflux, 4 h 65%) " " several substituted-phenyl analogs were prepared similarly and in comparable yields." " When an unsymmetrically substituted benzenediamine was used, two isomeric products were expected, but only one could be detected in each such case tried." " ... 

Amongst other N-nucleophilic species, hydroxylamine exhibits some abnormal behavior besides oxime formation (p. 25). Thus it reacts with diphenyl cyclopropenone42 probably by 1,4-addition and subsequent oxidation and/or decarboxylation giving rise to 3,4-diphenyl isoxazolone (328) and desoxybenzoin oxime. With pentyl cyclopropenone48 hydroxylamine undergoes addition followed by normal oxima-tfon after ring fission yielding 2,3-dioximino octane (329). 

Although the synthesis of 3-isoxazolols from P-keto esters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum s acid 4 followed by aminolysis gave rise to p-keto hydroxamic acids 6 that cyclised to the corresponding 5-substituted 3-isoxazolols 7 without formation of any byproduct <00JOC1003>. Cyclisation of N-substituted salicylhydroxamic acids 9 under... 

Pyrazolone 5(4//)-Pyrazolone 4-Isoxazoline 4(5//)-Isoxazolone 4-Thiazolone 4(5//)-Thiazolone 9-Acridone 9(10//)-Acridone ... 

In a recent review [83], the present authors discussed the tautomeric equilibria of 2-hydroxypyridine/2-pyridone and the 5-(2//)-isoxazolone system in considerable detail, focusing on the application of several different continuum solvation models. The following presentation will be somewhat more broad in terms of the different equilibria discussed and will not recapitulate all of the analysis previously presented for the above two systems. 

Karelson et al. [268] used the AMI D02 method with a spherical cavity of 2.5 A, radius to study tautomeric equilibria in the 3-hydroxyisoxazole system (the keto tautomer 13 is referred to as an isoxazolone). AMI predicts 13 to be 0.06 kcal/mol lower in energy than 14 in the gas phase. However, the AMI dipole moments are 3.32 and 4.21 D for 13 and 14, respectively. Hydroxy tautomer 14 is better solvated within the D02 model, and is predicted to be 2.6 kcal/mol lower in energy than 13 in a continuum dielectric with e = 78.4. Karelson et al. note, however, that the relative increase in dipole moment upon solvation is larger for 13 than for 14 (aqueous AMI dipole moments of 5.05 and 5.39 D, respectively). This indicates that the relative magnitude of gas-phase dipole moments will not always be indicative of which tautomer will be better solvated within a DO solvation approach — the polarizability of the solutes must also be considered. In any case, the D02 model is consistent with the experimental observation [266] of only the hydroxy tautomer in aqueous solution. 

Introduction of the azido group into the azine heterocycle can also be accomplished starting with azine derivatives bearing a five-membered heterocycle as a leaving group in this position. Table 8 shows three such conversions where the leaving groups are isoxazolone (entry a), imidazole (entry b), and triazole (entry c) substituents. 

The catalytic hydrogenation of isoxazolones (408) over 10% Pd—C or Raney-nickel catalysts in ethanol gave the half-esters of aminomethyl-enemalonates (409) in good yields (74G715). The half-esters (409) were... 

The heating of N-hydroxy-/V-phenylaminomethylenemalonate (300) in dioxane or cyclohexane for 2 hr, or in the melt at 140°C, afforded 5-isoxazolone (1321, R = Ph) in 60-90% yields (24JCS1456 63TL1365 65T2735). 5-Isoxazolones (1321, R = Ph, 4-MePh, PhCH2) were also pre-... 

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