Isoxazole 3- -, ring synthesis

Isoxazoles are readily cleaved under reducing conditions, and many examples have been reported (79AHC(25)147,63AHC(2)365). In the last three decades the potential of these reactions in synthesis has finally been realized, and the isoxazole ring has become a major tool as a masked enaminone (137) or 1,3-diketone, particularly for the synthesis of heterocycles. 

Applications of the isoxazole ring as a masked enaminone for the synthesis of various heterocycles are shown in Scheme 38. 

The synthesis of isoxazolecarboxylic acids has been well investigated. They can be prepared either from compounds which already contain an isoxazole nucleus or by isoxazole ring-closure methods using appropriate starting materials containing carboxy or alkoxycar-bonyl groups. 

The nucleophilic substitution reactions are still more limited in scope owing to the instability of the isoxazole ring toward nucleophilic reagents. Homolytic reactions appear to be unknown though some of the reactions being studied are possibly of this type. Besides those reactions which are characteristic of the reactivity of the isoxazole nucleus itself, we shall consider in this section some substitution reactions in the side chain organomagnesium synthesis in the isoxazole series, condensation reactions of the methyl groups of methyl-isoxazoles, and finally some miscellaneous reactions. 

Mention must also be made of an interesting reaction (103 —> 104) that makes use of the isoxazole nucleus of anthranil as a diene in the reaction with A-phenylmaleimide. This instance is of considerable interest, for it has proved impossible to introduce into the diene synthesis other derivatives with a noncondensed isoxazole ring. ... 

Although a number of reagents can be used to reduce an isoxazole ring, molybdenum hexacarbonyl31 was selected for use in this synthesis. The action of this reagent on 24 reduces the weak N-0 bond of the isoxazole ring and produces a //-amino-a,//-unsaturated aldehyde (i.e. a vinylogous formamide) (see Scheme 19). Intermediate 87 forms smoothly upon deprotection of the terminal acetylene carbon with basic methanol-THF. 

Isoxazole ring systems play an important role in organic synthesis, and 4-nitroisoxazoles have been used as dienophiles in Diels-Alder reactions, as shown in Eq. 8.23.36... 

Macrocycles containing isoxazoline or isoxazole ring systems, potential receptors in host—guest chemistry, have been prepared by multiple (double, triple or quadruple) 1,3-dipolar cycloadditions of nitrile oxides, (prepared in situ from hydroxamoyl chlorides) to bifunctional calixarenes, ethylene glycols, or silanes containing unsaturated ester or alkene moieties (453). This one-pot synthetic method has been readily extended to the preparation of different types of macrocycles such as cyclophanes, bis-calix[4]arenes and sila-macrocycles. The ring size of macrocycles can be controlled by appropriate choices of the nitrile oxide precursors and the bifunctional dipolarophiles. Multiple cycloadditive macrocy-clization is a potentially useful method for the synthesis of macrocycles. 

Sprio et al. reported the preparation of 6-acetylimidazo[2,l-Z)]thiazoles derivatives 57 (74JHC91). TTie synthesis involves substituted 4-(2-thiazo-lyl)aminoisoxazoles 56, which were obtained in good yield by the reaction of N-(3,5-dimethylisoxazol-4-yl) thiourea 55 with a-chloro ketones. Subsequent isoxazole ring opening led to intermediates which readily underwent cyclization by refluxing in acetic acid or ethanol/hydrochloric acid. 

A highly modified methyl testosterone derivative also exhibits antiandrogenic activity. One synthesis of this compound involves initial alkylation of methyl testosterone (35) by means of strong base and methyl iodide to afford the 4,4-dimethyl derivative 6. Formylation with alkoxide and methyl formate leads to the 2-hydroxymethyl derivative 37. Reaction of this last with hydroxyl amine leads to formation of an isoxazole ring. There is then obtained azastene (38) . 

No further advances in the synthesis of isoxazolo[5,4-. ]pyridines by closure of the isoxazole ring have been reported since the original chapter in 1996CHEC-II(7)283. 

The use of isoxazole derivatives in organic synthesis is of great interest, but little has been done on the utilization of such compounds as a part of a diene system in [4 + 2]-cycloadditions. 3-Methyl-5-vinylisoxazole 236 gave cycloaddition reactions in a sealed tube in benzene solution at 120°C for 3 days. With the dienophiles acrolein and methyl acrylate, aromatiza-tion of the isoxazole ring via a 1,3-proton shift occurs readily under the reaction conditions, allowing the direct isolation of compounds 237, which are also detected in the mass spectrum of the raw reaction material. The reactions are regioselective (85H2019). 

A synthesis of 2-cyanocyclohexanone 4.45 from cyclohexanone is shown below. Formylation of cyclohexanone produces a mixture of keto/enol tautomers 4.42 and 4.43, the equilibrium lying to the side of the enol 4.42. Treatment with hydroxylamine affords isoxazole 4.44, and base-induced fragmentation of the isoxazole ring affords 4.45. Explain the regioselectivity of the isoxazole formation, and the mechanism of the fragmentation process. 

Since then, several other examples of this photoinduced isomerization (though not always of synthetic utility) have been reported, sometimes as a typical photochemical reactivity of the isoxazole ring [2, 3]. Representative examples include (i) the synthesis of 2-trifluoromethyloxazole 77 from a preparative-scale irradiation at 254 nm in acetonitrile of the easily accessible 3-trifluoromethylisoxazole 76 [51] and... 

Azole approach. The isoxazole ring can be regarded as analogous to the phenyl ring in the synthesis of quinazolines. One method is to react a vicinal aminocarboxamide with an activated carboxylic acid derivative to form the fused pyrimidine the isoxazole (50) is reacted in this manner (67T687). Sometimes it is advantageous to carry out this type of reaction in two steps, such as in the reaction via the 5-ethoxymethyleneamino intermediate (51) (64JOC2116). 

Many of the reactions of functional groups attached to an isoxazole ring are unexceptional. This section is therefore confined to an account of two topics the first, rearrangements involving three-atom side chains, is of intrinsic interest, and the second, reactions proceeding via deprotonation at an a-carbon atom, is very useful in synthesis. 

After the failure of cyclization reactions by intramolecular condensations, a modified version of the Wmtz reaction was first selected as the key reaction in synthesis of Garuga components. 1,3-dioxo functionality was introduced in a masked form as an isoxazole ring. 

Lipophilic 1,4-dihydropyridines, such as 4-aryl-1,4-dihydropyridines, exhibit significant calcium channel antagonist activity. N.R. Natale et al. have synthesized a series of 4-isoxazolyl-1,4-dihydropyridines bearing lipophilic side chains at the C5 position of the isoxazole ring." The Hantzsch synthesis was carried out in an aerosol dispersion tube at 110 °C in ethanol in the presence of 2 equivalents of ethyl acetoacetate and aqueous ammonia solution. 

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