Isoxazole opening, reductive

Isothiazoles are readily prepared from isoxazoles. Thus, reductive ring opening of isoxazoles 41 gives enaminones 42, which on treatment with phosphorus pentasulfide and chloranil give the corresponding isothiazoles 295, Scheme 81. Because isoxazoles are readily available, this method provides a valuable route to a variety of substituted isothiazoles (69T389). 

Isoxazoles undergo reductive ring-opening by Na in liquid NH3 in the presence of tBuOH to yield fl-amino ketones, which on heating or by acid are converted to a,P-unsaturated ketones by elimination of NH3 ... 

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. 

Most of the reactions of interest involve the opening of the isoxazole ring. This reductive opening has been known for years and was reported in CHEC(1984) and CHEC-II(1996). Over the years, many different reagents have been used and/or developed for this ring-opening process examples of the most useful ones are collected in Table 5 and give an overview of the protocols available for N-O bond reduction. 

Reductive ring opening of isoxazoles (135) followed by cyclodehydration of the intermediates (136) offers an alternative route to imidazo[2,l-6]thiazoles (137) (74JHC91). 

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... 

The oxidation of 123 with chloranil (tetrachloro-/)-benzoquinone) in toluene at reflux temperature yielded the isoxazole 124, whereas treatment of 123 with Ra-Ni and H3BO3 in Me0H/H20 led to the oxime 125 in moderate yield. Attempts at reductive ring opening of 123 failed (Scheme 27) <1996T14323>. 

As described later, however, attempted reduction of an isoxazole to an isoxazolidine in most cases causes ring opening. Cyclization of open-chain systems at the 1 5 bond is often a good method (c), but for the isoxazolidine ring this method is not particularly convenient. A few examples of ring enlargement of azetidine /V-oxides are reported (d). Almost all the isoxazolidines so far reported have been prepared by process a. 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

Irradiation triethy lamine Reductive isoxazole ring opening mEtjN c... 

First, cyclohexanone is alkylated by 32 giving rise to the masked triketone 33. On catalytic hydrogenation of 33, the isoxazole ring is reductively opened to give the enaminone 34, which cyclizes in situ to the enamine 35. On treatment with aqueous NaOH, 34 is converted to the 1,5-dione 36 (by enamine hydrolysis and acid cleavage of the 1,3-dicarbonyl system of the triketone intermediate), which undergoes base-induced intramolecular aldol condensation to the bicycloenone 37 (in analogy to a Robinson annulation) [317] ... 

Reduction of 4,5-dihydroisoxazole can be carried out by various methods and leads, again in analogy to isoxazole, to ring-opening at the N-O bond. 

Some monofluoro amino derivatives have been prepared with excellent stereocontrol exploiting the potential of inter- and intra-molecular 1,3-dipolar cycloadditions (72) with fluorinated dipolarophiles. An intermolecular application is shown in Scheme 19 (73J4). Nitrile oxides 78 were reacted with fluorinated chiral enol ethers 79 4,5-dihydroisoxazoles 80 were obtained with total regio- and stereo-selectivity. By subsequent elimination of methanol and reductive opening of the isoxazole ring 81, fluoroiminoalcohol 82 was obtained in fair yield. 

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