Isoxazoles from 1,3-dicarbonyl compound

The synthesis of isoxazoles from dicarbonyl compounds The synthesis of isoxazoles by 1,3-dipolar cycloaddition... 

With hydroxylamine, diphenylbuta-l,3-diyne gives the isoxazole 30, isomeric to the isoxazole 32 obtained from dicarbonyl compound 31 and hydroxylamine (69JOC999). 

The problem of regioselectivity remains. Monosubstituted alkynes usually react cleanly using the HOMO of the alkyne and the LUMO of the nitrile oxide. The product is exactly that type of isoxazole (72 or 73) that was so difficult to make from dicarbonyl compounds and hydroxylamine. Here regioselectivity is controlled because the two substituents (R1 and R2) are on different reagents. Conditions are very mild. 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

SUylated 2-oxidienes and bis-silylated 2,3-dioxidienes are prepared from a , -unsaturated ketones and 1,2-dicarbonyl compounds, respectively in the latter case, the reagent employed for the first silylation is tiimethylsilyl bromide while TMSOTf is required for the second silylation. 1,3-Bis-silyloxydienes are prepared by direct silylation of 1,3-dicarbonyl compounds with TMSOTf(Et3N. They also can be obtained as mixtures of Z/E-isomers by lithium reductive cleavage of isoxazoles followed by the slow addition of an excess of TMSOTfKEt3N (eq 38). ... 

Reactions of heterocycles ch29 How to make pyridazines and pyrazoles How to make pyrimidines from 1,3-dicarbonyl compounds and amidines How to make thiazoles How to make isoxazoles and tetrazoles by 1,3-dipolar cycloadditions The Fischer indole synthesis Making drugs Viagra, sumatriptan, ondansetron, indomethacin How to make quinolines and isoquinolines ... 

In most cases of formation of 1,3-dicarbonyl compounds from isoxazoles derivatives, catalytic hydrogenation has been used, and we are not aware of any cases wherein an exocyclic olefinic bond survived during the reductive cleavage. Likewise in our case, attempted hydrogenation of 9 (R = )-9-tridecenyl) using either Raney nickel or platinum resulted in both the N-0 moiety and the side chain olefinic bond being reduced at similar rates. Additionally, when considering possible alternative reduction procedures, not only must the exocyclic olefinic bond be considered as a site of unwanted reduction, but also the keto and ketol ups as well. Further, Ae selected method must avoid overreduction of the enamine in the initial product 10. 

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