Enaminoketones reduction

Isoxazoles are susceptible to attack by nucleophiles, the reactions involving displacement of a substituent, addition to the ring, or proton abstraction with subsequent ring-opening. Isoxazolium salts are even more susceptible to attack by a variety of nucleophiles, providing useful applications of the isoxazole nucleus in organic synthesis. Especially useful is the reductive cleavage of isoxazoles, which may be considered as masked 1,3-dicarbonyl compounds or enaminoketones. 

The intermolecular addition of an alkyl radical to an enaminoketone in a 6-exo-trig mode has been investigated [95TL417]. Reductive cyclization of 212 provides a diastereomeric mixture of 213 in excellent yield. Compound 213 has been transformed to the piperidine alkaloid dihydropinidine 214. 

Substituted pyran-4-ones can be prepared from isoxazoles through reductive cleavage with Mo(CO)6 and acid-catalysed cyclisation of the generated enaminoketone <02TL3565>. 

As early as 1891 Claisen noted that isoxazoles, when treated with sodium and either pentyl alcohol or moist diethyl ether, undergo reductive ring opening to give 1,3-enaminoketones. These products may then be hydrolyzed to 1,3-dicarbonyl compounds. In more recent times the use of readily available isoxazoles as masked 1,3-dicarbonyl compounds has found wide application in synthesis, although dissolving... 

Other reagents recommended for the reduction of isoxazoles to 1,3-enaminoketones include samarium diiodide, molybdenum hexacarbonyl in aqueous acetonitrile, and diiron nonacarbonyl in water. Electrochemical methods have also been employed." A particularly mild method involves reaction with the reduced form of the coenzyme lipoamide (LA2) complexed with iron(II). Birch reduction (sodium and... 

An interesting approach to the canthin-4-one alkaloid family has recently been reported by Tremmer and Bracher and involves a 1,3-dipolar cycloaddition of the readily available 1-ethynyl-p-carboline 301 with various nitrile oxides (Scheme 54) (2015T4640). The initially formed isoxazoles 302 were then cleaved reductively, and this was followed by heating the resulting enaminoketones 303 in DMF at 150 °C to give 6-substituted canthin-4-ones 304 in high yields. 

Conversion of an isoxazole to a 1,3-diketone simply requires reductive cleavage of the N-O bond followed by hydrolysis of the resulting enaminoketone. 

For the conversion of 9 to 3 (Scheme 1), catalytic hydrogenation (or NaBH iC MF) had achieved the first half of fhe sequence (9 - 10), and aqueous NaOn had effected the hydrolysis of 10 (in this case an iminoenol instead of an enaminoketone) (If)). The transformation 16 11 proceeded differently in each Step reduction of the carbonyl of 16 tended to conq>ete with reduction of die N-O bond, and the reduction product 17 was stable to aqueous base. 

The next stage of the synthesis called for conversion of the terminal olefin to an aldehyde. This was accomplished using a Johnson-Lemieux oxidation. The resulting ketoaldehyde was then converted to fr-ketal 15. Basic hydrolysis of the formamide provided 16 and hydrolysis of the acetals afforded a mixture of diastereometic enaminoketones 17. An acid-promoted intramolecular Mannich reaction gave 2. Presumably epimerization of the ketone allowed both diastereomers of 17 to follow the path to 2. Reduction of ketone 2 with sodium borohydride provided an alcohol, which underwent formal dehydration upon treatment with thionyl chloride and pyridine, to give porantherine (1) as a racemic mixture. 

Mannich bases in aq. solution N-Methylnorazaadamantane could be easily prepared by cyclization of pseudopelletierine tosylhydra-zone . Isothiazoles previously difficult to obtain can be readily prepared from isoxazoles via reduction to enaminoketones... 

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