Isoxazole ketones

Numerous isoxazole ketones have been described (62H(i7)l, p. 79). They have been synthesized by the many different methods available for the preparation of the isoxazole 

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The reactions of 2-substituted 6-methyl-4/7-l,3-oxazin-4-ones 98 with isoxazole ketones 99 in the presence of potassium / -rt-butoxide furnished 3-acetyl-5-(3-methylisoxazol-5-yl)-2-pyridones 101 in good to excellent yields (Scheme 14). The formation of 2-pyridones 101 presumably proceeds via nucleophilic addition of the methylene carbon of 99 to the carbon atom at position 2 of the l,3-oxazin-4-ones 98, followed by ring opening to give the acetoacetyl intermediates 100, which are transformed into 101 by intramolecular aldol condensation <2005H(66)299>. 

The action of molybdenum hexacarbonyl on the isoxazole ketones 5 (R = Me, Ph or n-hexyl) leads to the pyridones 6 with cleavage of the nitrogen-oxygen bond (94H853). The nitrenium ion 8 is produced by photolysis of 1-t-butyl-3,5-dimethyl-2,1-benzisoxazolium tetrafluoro-borate 7 (94TL4943). 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

Since an electron-withdrawing group such as ethoxycarbonyl at the a-carbon atom enhanced the electrophilicity of the )3-carbon atom, the reaction of a-ethoxycarbonyl-)3-ethoxyvinyl ketones (298) with hydroxylamine hydrochloride gave solely 5-substituted isoxazole-4-carboxylates (299) (55JOC1342, 59YZ836). 

To synthesize isomeric 3-substituted isoxazoles (301) the reaction of ethylene acetals of )3-ketoaldehydes (300) (readily available from -chlorovinyl ketones (57IZV949)) with hydroxylamine was employed. Owing to the comparative stability of the dioxolane group, this reaction gave exclusively 3-substituted isoxazoles (301) (60ZOB954). The use of noncy-clic, alkyl S-ketoacetals in this reaction resulted in a mixture of 3- and 5-substituted isoxazoles (55AG395). 

The treatment of 3-acylisoxazoles (438) with hydroxylamine hydrochloride gives furazan ketones (439). On the other hand, furazan ketones (439) rearrange to 3-acylisoxazoles (438) with a loss of hydroxylamine under the influence of a mineral acid. Thus, by refluxing phenacylphenylfurazan with concentrated alcoholic hydrogen chloride, 3-benzoyl-5-phenyl-isoxazole is formed similarly, phenyl(phenacylphenyl)furazan gives 3-benzoyl-3,5-diphenyl-isoxazole (62HC(17)1, p. 35). 

Phenyldiazonium salts react with malonaldioxime to produce a 2-isoxazoline (7 IGEPl 920245), and the diazo ketone (484) when photolyzed gave a mixture of 2-isoxazoline and an isoxazole by a 1,5 carbon-hydrogen insertion. A phenyl migration was apparently not involved (Scheme 124) (66CC689). 

In a unique approach to the synthesis of isoxazole derivatives, a-isonitroso ketone... 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

Isoxazoles are stable toward many reagents yet undergo alkylation and hydrogenolysis readily. These features make isoxazoles, which may be considered masked diketones, a useful grouping in synthesis (22). Alkylation of 3,5-dimethyllsoxazole, followed by hydrogenolysis and hydrolysis, have been used to prepare a number of diketones (44) and tetraones (4i). Isoxazoles can be opened readily lo the amino ketone, a vinylogous amide (9). 

The possible routes leading to azides 2 are outlined in Scheme 1. The only pathway which we can exclude the 2=>C=>D=>E=>2 sequence since neither intermediate E nor its possible derivative E could be detected in the reaction mixture. (P-Azido a,P-unsaturated ketones are known to afford isoxazoles via nitrenes derived by loss of nitrogen (refs. 4,10). Azides 2 may form either via intermediate A (Sn + E route) or via allyl bromide-type intermediate B (E -f Sn route), both routes may operate on the basis of experimental results obtained so far. 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

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