Isoxazolones synthesis

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. 

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... 

Both enantiomers of 2-amino-3-(3-hydroxy-5-/< t/-butylisoxazol-4-yl)propanoic acid (ATPA) 69, an analogue of the neuroexcitant 2-amino-3-(3-hydroxy-5-methylisoxazoM-yl)propanoic acid (AMPA), were synthesized in 33% overall yield (from pinacolone) and 99% ee. The enantiomerically pure glycine derivative (A )-66 was coupled with 4-bromomethyl-2-methoxymethyl-5-A r/-butyl-3(2//)-isoxazolone 67 to give the intermediate (26, 5A )-68, which was hydrolyzed under mild conditions to give enantiopure (A )-69. The use of (R)-66 allowed the synthesis of R)-69 (Scheme 17) <2000TA4955>. 

Photocycloaddition of 2-TMSO-buta-1,3-diene to enone (89) affords the adduct (90) which is a key intermediate in an approach to the synthesis of homoerythrinan alkaloids. The principal product obtained by irradiation (298-310 nm) of the dione (91) in the presence of the isoxazolone (92) has been identified as (93, 38%). ... 

A protected form of a 1,2-diamine is a 4-amino-5(4//)-isoxazolone, which generates another amino functionality by hydrogenolysis of the isoxazole ring with loss of carbon dioxide. The regiospecific synthesis of 2(l//)-pyrazinones (Scheme 34) has been achieved in a two-step reaction sequence starting from 3,4-disubstituted isoxazolones (145) <9lS86i>. 

On the basis of Betti s initial work, the Betti reaction has been extended to both primary amines and secondary amines. The resulting Betti amines have been applied as ligands or chiral auxiliaries in asymmetric synthesis. In addition, the Betti reaction has also been extended to the reaction among aldehydes, secondary amines, and compounds of active methylene moiety, such as dibenzyl ketones which can tautomerize to enols and mimic naphthol. Moreover, the reaction of aromatic aldoximes and 0-keto esters to afford isoxazolones should also be considered as an extension of the Betti reaction. 

Scheme 13.20 Snider and Zhou s synthesis of the isoxazolone fragment. Reagents and conditions a) Pd(OAc)2, S-Phos, K3PO4, H2O (cat), toluene, reflux b) Zn, NH4CI, THF/MeOH/ H2O, sonication, 25°C c) MsCl, EtjN, CH2CI2, 0°C, 15 min d) NajCOj, 1 1 THF/H2O, 40 min...

DBN and (dichloromethyl)benzene added to a soln. of 4-benzyl-3-methyl-A -5-isoxazolone in acetonitrile, and refluxed for 5 h - product. Y 72%. F.e. and from the corresponding N-sodio-isoxazolone with NEt3 s. E.M. Beccalli et al.. Synthesis 1988, 630-1. 

Hydrazine sulfate added to a cooled soln. of Na in ethanol, stirred 0.5 hr. at room temp., 4-benzoyl-3-methyl-5-isoxazolone added, and refluxed 32 hrs. 4-benzoyl-3-methyl-5-pyrazolone. Y 54%. F. e., also with phenylhydrazine, s. H. Wamhoff, D. Schramm, and F. Korte, Synthesis 1971, 216. 

Further examples in the weU-estabHshed use of isoxazolones as precursors for substituted pyrrole synthesis include pyrolysis of the esters 45 to give the pyrroles 46 (Scheme 9 2001ARK(vii)88). 

Synthesis of mono isoxazolinyl derivatives are reported from the reaction of chloro-heterocycles with some isoxazolones under microwave irradiation and solvent-free conditions. The main advantages of this scheme are ... 

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