Isoxazol-5-ones

Isoxazol-5-ones can exist in three different types of structures, cf. 45- 7 (R = H). Early investigators assigned structures to these compounds on the basis of unreliable chemical evidence thus the NH structure 47 was favored because the silver salt of 3-phenyl-isoxazol-5-one reacts with methyl iodide to give a product which was incorrectly (see reference 44) formulated as the iV-incthyl derivatives (cf. also reference 46). Bromine titration data led to assignment of an incorrect structure to 3,4-diphcnylisoxazol-5-one cf. article I (Volume 1), Section II,A. Comparison of the dipole moments of 3-phenyIisoxazol-5-one with those of the methyl derivatives 45 (R = Me) and 46... 

Recently a definitive study of several isoxazol-5-ones using infrared and ultraviolet spectroscopy (Table I) has shown that the balance between the various tautomers is a delicate one and that all three of the structural types can predominate depending upon the nature of the substituents and the conditions of the experiment. However, the hydroxy form is only found when it is stabilized by chelation (i.e., a carbonyl substituent in the 4-position). The other compounds exist in the CH form in nonpolar media increasing polarity of the solvent stabilizes increasing amounts of the more polar NH forms. 

The structural studies of isoxazol-5-ones have shown that these compounds can be found in one of the three tautomeric forms (45-47 59,90,96-98 establishcd that the 3-methyl-4-benzoyl... 

An interesting example of the organomagnesium synthesis is to be found in the use of 1,4-addition of the Grignard reagent to 4-alkyl-ideneisoxazol-5-ones (91) to prepare saturated isoxazol-5-ones (92). 

Shaw concluded that hydrogenation of 3-alkyl-4-aminomethylene isoxazol-5-ones (184) in the presence of palladium catalyst resulted in the saturation of either the endocyclic double carbon-nitrogen bond or the exocyclic double C—C bond with the retention of the heterocyclic nitrogen-oxygen bond. Recent data reported by Kochetkov et al. on the properties, and in particular on hydrogenation, of isoxazolid-5-ones - indicate, however, that Shaw had probably ob-... 

Isoxazol-5-ones 3,4-disubstituted synthesis, 6, 64 5-substituted tautomerism, 6, 11 synthesis, 6, 64 Isoxazolo[2,3-b][ 1,2]oxazines synthesis, 6, 633 Isoxazolophanes... 

The reactions of (aryhnethylene)isoxazol-5-ones (97) with pyridinium ylides (98) leads to the diastereoselective formation of olates (99) as a result of preferential Michael addition rather than 1,3-cycloaddition (Scheme 22). The stereoselectivity of the reaction has been rationalized by the involvement of the preferential transition state [(100) over (101)].86... 

The bicyclic isoxazol-5-ones 45 and 47 (Scheme 12) were regioselectively allylated at the nitrogen atom to afford compounds 46 and 48 with three different allylic systems featuring primary and secondary electrophilic cen-... 

Bicyclic 5-pyrazolones 59 and 63 (Scheme 15) also tend to be allylated at C-4 (pyrazolone numbering). However, as in the case of isoxazol-5-ones, steric hindrance militates against allylation at C-4 and allylation at N-2 occurs to a significant extent (94T515). 

Pyrazolo[2,3-a]imidazole possesses sedative and antipyretic action. Imidazo[2,l-fc]-[l,3,4]thiadiazoles are antithrombotic and thrombolytic agents. Furo[3,2-c]isoxazol-5-ones and their enantiomeric or racemic mixtures are used in the production of antitumor agents obtained from methyl-L-acosaminide and -daunosaminide. 

A formally similar rearrangement of isoxazol-5-ones probably proceeds by hydrolysis of the lactone linkage followed by recyclization.247... 

For the compounds where X = O, the OH form (115) does not normally contribute significantly to the equilibrium mixture unless it is stabilized by, for example, hydrogen bonding to a 4-carbonyl substituent. The proportions of the CH (113) and NH (114) isoxazol-5-one forms are influenced by both medium and substituent effects. Mass spectroscopic studies provide some evidence for the CH form (113) in the vapor phase.212 Appropriate 4-substituents can contribute further tautomerism. For example, there is evidence that 4-arylazo derivatives exist largely in the hydrazono form... 

Simple 4-hydroxy isoxazoles and 4-aminoisoxazoles (the 4-mercapto compounds are so far unknown) normally exist in the XH form. Appropriate 4-substituents in compounds such as isoxazol-5-ones may however tautom-erize as previously discussed. 

Ab initio and density functional theory (DET) methods have been exploited to determine the structures and the interaction energies of 2/7-isoxazol-5-one B, and its dimer and trimer structures in the gas phase. For the cyclic trimer, the computed structural parameters resulted in excellent agreement with the X-ray determination of the supramolecular aggregate of 4-(2-methoxybenzyl)-3-phenyl-4//-isoxazol-5-one, involving very strong intermolecular H-bonds of the NH tautomeric form, interpreted in terms of the RAHB (resonance-assisted hydrogen bond) model (see Section 4.03.3.1) <2002HCA2364>. 

The tautomeric composition in solution of 4-(arylmethyl)isoxazol-5-one derivatives has been determined on the basis of H NMR and infrared (IR) data. The CH form was predominant in chloroform solution, while the NH and OH forms are more common in polar solvents and in the solid state <1996T1443>. 5-Hydroxy- and 5-amino-2-isoxazo-lines show different tautomeric forms in solution. The presence of cyclic hemiacetal or hemiaminal moieties in such molecules allows the easy cleavage of the C-5-0 bond to form linear structures. Subsequent intramolecular addition of nucleophiles to the C=N bond gives rise to cyclic structures. Compounds 20 exist, in the crystalline state, as the isoxazoline form A. In solution, a ring-ring tautomeric equilibrium was observed between the isoxazoline form A and the pyrazoline form C. The tautomeric ratio depended on steric factors and on the solvent used. The tautomeric equilibrium was established after several days (Scheme 2) <2000CHE722>. 

Hantzsch 1,4-dihydropyridine 84 was exploited for selective reduction of the exocyclic double bond of 4-arylmethylene- and 4-alkylidene-4/7-isoxazol-5-ones 83 with high efficiency to give 2/7-isoxazol-5-ones 85 (Scheme 22) <2005SL1579>. 1,3-Dipolar cycloadditions of bromonitrilimine with (Z)-4-arylmethylene-4//-isox-azol-5-ones have been reported <2001HCA3313>. 

Cyclocondensation of mono- and disubstituted malonates with hydroxylamine afforded 4-substituted isoxazolidine-3,5-diones (Equation 93). Under the same conditions, cyanoacetate derivatives gave 3-amino-47/-isoxazol-5-ones (Equation 94) <2002JHC649, 2004HAC477, 2005JHC797>. 

Oxazoles 240 have also been prepared by flash vacuum pyrolysis or photolysis of A -acylisoxazol-5-ones 239 (Scheme 70) <1996TL675>. The acylisoxazol-5-ones were in turn prepared by the acylation of the corresponding isoxazol-5-ones 238. This method of oxazole production has been reported to give significantly better yields than the rearrangement of the acyltriazole precursors. 

Wentrup et al. (78AG731) (Scheme 52) condensed 4-nitrosopyrazol-3-one 194 with 3-phenylisoxazol-5(4//)-one 195 in ethanol at 50 °C with piperidine as catalyst and obtained 4-(3-oxopyrazol-4-ylimino)isoxazol-5-one 196 in about 60% yield. 

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