Isoxazoles, reduction

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

The first 1,2-benzisoxazole, 3-phenyl-l,2-benzisoxazole, was obtained from the treatment of o-bromobenzophenone oxime with alkali in 1892 (1892CB1498,1892CB3291). 2,1-Benzisoxazole has been known since 1882, being obtained as a reduction product of o-nitrobenzaldehyde with tin and hydrochloric acid (1882CB2105). In general, benzisoxazoles behave much like substituted isoxazoles. Numerous structural ambiguities occur in the early literature of these two systems, and these have been discussed in the above reviews. 

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. 

Irradiation of 3,5-disubstituted isoxazoles in alcoholic solvents gave reaction products such as acetals incorporating the reaction solvent. The use of triethylamine in acetonitrile media produced ketene-aminals by reductive ring cleavage. The reductive ring cleavage product was also obtained by irradiation of the isoxazole in alcohol in the presence of copper(II) salts (Scheme 3) (76JCS(P1)783). 

SnCl2 reduction produced the 4-hydrazinoisoxazole (243). In ethanol the diazonium salt reacted with the 4-aminoisoxazole to produce the linear triazine (244) (Scheme 85). Diazoisoxazoles can also be treated with KI or H20/urea to produce the 4-iodo or 4-hydroxy derivatives (63AHC(2)365). These Sandmeyer reactions have been extended to a variety of isoxazole systems (77JMC934, 63AHC(2)365). 

Oxidation and reduction can initiate changes leading to heterocycle-heterocycle conversions. The reaction of tetraphenylfuran with singlet oxygen (Scheme 34) (B-73MI50303) and that of isoxazoles with LAH (Scheme 35) are examples. 

Isoxazole, 3,5-bis(dimethylamino)-4-fluoro-synthesis, 6, 86 Isoxazole, 3-bromo-reduction, 6, 58 synthesis, 6, 86 Isoxazole, 4-bromo-re actions... 

Isoxazole, 5-( p-bromophenyl)-3-phenyl-synthesis, 6, 63 Isoxazole, 3-chloro-reduction, 6, 58 4-substituted reactions, 6, 58... 

C. Reductive Cleavage of Isoxazoles and of Their Hydrogenated Derivatives... 

The reduction of isoxazoles is often rather peculiar and its course depends on the nature both of the isoxazole and of the reducing agent. Together with a normal reduction of groupings in the side chain, cleavage of the nitrogen-oxygen bond of the heterocyclic nucleus often occurs. 

The degradation which occurs on reduction with the alkali metals involve a mechanism that is considered to be firmly established and in the isoxazole series appears to proceed according to the usual scheme,... 

The cleavage of the isoxazole ring by organomagnesium compounds may proceed by either one or both of two alternative mechanisms. Magnesium subhalides produced during the associated reaction may act as reducing agents as proved in specific cases.Another possibility is that the reduction involves a six-membered cyclic complex (171). 

The monoimines of the substituted -diketones formed can usually be isolated but sometimes they undergo further reactions. Thus, 5-substituted 3-chloroisoxazoles yield / -ketonitriles, and hydrogenation of 5-acylaminoisoxazoles (174) is a general method of synthesizing 4-hydroxypyrimidines (175). 2 3,214 One should note the increased stability of the isoxazole ring in styrylisoxazoles toward reduction. No hydrogenolysis of the 0—N... 

Under the conditions used for the reductive cleavage of the O—N bond in isoxazoles, a similar reaction readily occurs with isoxa-zolines, e.g. on treatment with organomagnesium compounds and on catalytic hydrogenation.- Hydrogenolysis of the O—N bond (180 181 182 183) was used to elucidate the structure of isoxa-zolones from -ketoesters. -... 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

On the other hand, 4-alkoxycarbonyl- and 4-aminocarbonyl-substituted isoxazoles 6 undergo unusual conjugate reduction with sodium borohydride and sodium... 

Syntheses of Carbocyclic Compounds (1.V.2.V )-2 (.V )-Amino(4-metho-xyphenyl)methyl]cyclopropan-l-ol 392 (Scheme 1.45) has been prepared by a stepwise procedure involving a 1,3-dipolar nitrile oxide cycloaddition to allyl alcohol followed by a constmction of the cyclopropa d isoxazole system, and reduction of the bicycle (436). 

The synthesis of new 11-deoxyprostaglandin analogs with a cyclopentane fragment in the oo-chain, prostanoid 418, has been accomplished by a reaction sequence involving nitrile oxide generation from the nitromethyl derivative of 2-(oo-carbomethoxyhexyl)-2-cyclopenten-l-one, its 1,3-cycloaddition to cyclopenten-l-one and reductive transformations of these cycloadducts (459). Diastereoisomers of a new prostanoid precursor 419 with a 4,5,6,6a-tetrahydro-3aH-cyclopent[d isoxazole fragment in the oo-chain have been synthesized. Reduction of 419 gives novel 11-deoxyprostanoids with modified a- and oo-chains (460). 

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. 

Coupling comparable with that found in awft -oximes is also observed in cyclic systems such as pyridine, quinoline, 5-phenylisothiazole and isoxazole in which the nitrogen lone-pair lies E(cis) to the adjacent hydrogen. Confirmation of the importance of the lone-pair orientation is further derived from the fact that removal of the nitrogen lone-pair by protonation or quatenization results in the reduction of H) to the value found in... 

---