Reactions with isoxazoles

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

Isoxazoles are also rather stable to nucleophilic attack by OH at carbon. For reactions with base at a ring hydrogen atom, leading, for example, to ring opening of isoxazoles, see Section 4.02.1.7.1. 

Isoxazolium salts can be prepared by reaction with alkyl iodides or sulfates, although the low basicity of isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. Isoxazolium salts containing bulky Af-substituents can be prepared by the reaction of isoxazoles with alcohols in the presence of perchloric acid. For example, the reaction of 3,5-dimethylisoxazole (53) with some alcohols in the presence of 70% perchloric acid gave isoxazolium salts, (54a) in 29%, (54b) in 57% and (54c) in 82% yield 79AHC(25)147, 68JOC2397). Attempts to quaternize 3,5-dimethyl-4-nitroisoxazole failed 71JCS(B)2365). 

The action of nucleophilic reagents with isoxazoles can take a number of courses involving (i) nucleophilic addition to the ring (ii) nucleophilic replacement of a substituent and (iii) deprotonation. Other processes such as thermal or photochemical reactions may precede reaction with a nucleophile (see Section 4.16.3.1.2). 

Other amino substituted isoxazoles undergo ring-opening reactions on treatment with base. Thus the amidine derivative (249) gave the triazole (250) (64TL149), while the triazene (251) on reaction with ammonia gave the tetrazole (252) (64X461). 

On the whole, the cycloaddition of alkynes to nitrile N-oxides is one of the most important routes to isoxazoles, but in spite of its potentially wide application, its synthetic utility is less than that of the corresponding reaction with alkenes for the following reasons. (1)... 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

Isoxazole, 3-acetyl-4-chloro-5-methyl-oxidation, 6, 27, 53 Isoxazole, 3-acetyl-4,5-dimethyl-oxidation, 6, 27, 53 Isoxazole, 5-acetyl-3-methoxy-reactions, 6, 53 Isoxazole, 3-acyl-furazans from, 6, 417 nucleophilic attack, S, 93 reactions with bases, 6, 30... 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

IV. The Reactions of Isoxazole Derivatives with the Retention of the Heterocyclic Nucleus... 

It should be expected that the orientation and rate of electrophilic substitution in the isoxazole nucleus would be affected by both hetero atoms. Because of the electron-accepting effect of the nitrogen atom, electrophilic substitution of the isoxazole nucleus should proceed less readily than in the case of benzene and should occur essentially at the position jS to the nitrogen atom, just as in pyridine and other azoles. Simultaneously the electron-donating oxygen atom should facilitate such reactions in isoxazole as compared with the substitution in pyridine. These predictions are confirmed by the available experimental evidence. 

It is most difficult to nitrate isoxazole itself. 4-Nitroisoxazole (51) is formed only under strictly controlled conditions (35-40°C), and in but 3.5% yield. Its structure was proved by reaction with aniline (see Section V,A) to give nitrocyanoacetaldehyde anil (52). 

Recently, Kochetkov and Khomutova have reported on the mercuration of isoxazoles with mercuric acetate. The reaction occurs quite smoothly, more readily than for benzene derivatives and results in a 90-100% yield of 4-acetoxymercury derivatives (74) whose structure was proved by converting them to known 4-bromoisoxazoles (75). Under these reaction conditions isoxazole itself is oxidized by mercuric acetate, mercurous salts being thereby produced. 

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. ... 

Reactions of isoxazole derivatives that take place with the cleavage of the heterocyclic nucleus are as characteristic in this series as the substitution reactions. They are due to the cleavage of the bond... 

Another group of reactions with the predominant cleavage of the ring comprises catalytic hydrogenation of isoxazole derivatives and has been investigated only recently. The most commonly used catalyst has been Raney nickel,but use has sometimes been made of platinum catalysts. Hydrogenolysis of the 0—N bond (172—>173) occurs in isoxazole, its homologs,and their functional derivatives, for example, isoxazole carboxylic acids- and 5-aminoisoxazoles. ... 

This presumably forms oxime, 120, on reaction with hydroxylamine that intermediate is not isolated as it cyclizes spontaneously to the isoxazole, 121. Acylation of the isoxazole with the sulfonyl chloride, 88, affords sulfisoxazole (98) after removal of the acetyl group. 

Both of the 4,5-tran.v-diaslereomers of 4,5-dihydro-4-(4-methoxyphenyl)-5-methyl-3-[(7 )-(4-methylphenylsulfinyl)methyl]isoxazole (24) show excellent stereoselection in reactions with aldehydes. Despite the bulky substituents at the 4,5-dihydroisoxazole nucleus, the stereochemical outcome of the reaction is controlled by the sulfoxide stereogenicity. The pairs of 4,5-dihydro-3-(2-hydroxyalkyl)-4-(4-methoxyphenyl)-5-methylisoxazoles, obtained by desulfurization of the corresponding aldol adducts, have the same configuration at the hydroxy-substituted carbon (C-2 ) and opposite configuration in the 4- and 5-positions of the dihydroisoxazole ring24. 

Chlorophenyl)-5-(4-methoxyphenyl)isoxazole has also been prepared from the dilithio derivative of 4-ehloroacetophenone oxime by two other methods (a) reaction with anisonitrile (4-methoxybenzoni-trile) followed by acid-catalyzed cyclization8 and (b) condensation of anisolyl chloride (4-methoxybenzoyl chloride) followed by acid-catalyzed cyclization. ... 

The resin-bound reagents thus obtained were reacted with a variety of nucleophiles to give different heterocycles (Scheme 13). So, reaction with hydrazine or hydroxylamine gave respectively pyrazoles and isoxazoles in excellent yields (94-99%, 34 examples) and excellent purities (> 95%). Reaction with guanidines afforded 2-aminopyrimidines. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU led to the formation of pyrrole 53. A solid-phase synthesis of 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCC177>. The reaction between 54 and secondary amines led to the corresponding resin-bound aminopyrroles after enamine formation and loss... 

Rearangement of furoxans leads to the formation of new heterocyclic systems derivatives of triazoles, diazoles, isoxazoles, and pyrimidinones. For example, on the basis of the experimental results using labeled compound 52-15N , the formation of 8-phenyltheophylline 53, the 1,3-dimethylalloxazines (54 n = 0, 1), and l,3,7,9-tetramethyl-l//,9//-pyrimido[5,4-g]-pteridine-2,4,6,8-tetraone 55 in the thermal reaction of the iV-oxide 52 with benzylamine, aniline, or piperidine and the generation of NO or NO-related species in the reaction with iV-acetylcysteamine were reasonably explained by... 

Imidazole nitrones 127 reacted with dimethyl acetylenedicarboxylate to yield imidazo[l,5-fc]isoxazoles 128, which in the presence of base afforded imidazoles 129 <00TL5407>. Chiral imidazoline nitrone 130 participated in a [3+2] cycloaddition reaction with various dienophiles to furnish imidazoisoxazoles 131 <00SL967>. A convenient synthesis of AyvyV -trisubstituted ethylenediamine derivatives from 2-methyl-2-imidazoline has been reported <00SC3307>. Dehydrogenation of 1,3-di- and 1,2,3-trisubstituted imidazolidines afforded l//-4,5-dihydroimidazolium salts <00SC3369>... 

Ammonium cerium(IV) nitrate on reaction with acetone or acetophenone generates acetyl- or benzoylformonitrile oxides, respectively (99). These nitrile oxides dimerize to furoxans and give, in the presence of alkenes and alkynes, 3-acetyl- or 3-benzoyl-4,5-dihydroisoxazoles and 3-acetyl- or 3-benzoylisoxazoles, respectively the yield of the isoxazole derivatives was improved on using ammonium cerium(III) nitrate tetrahydrate-formic acid (99). 

Dipolar cycloaddition of 2,4-(trimethylsilyl)- and 2,4-(trimethylgermyl)-substituted thiophene-1,1-dioxides as well as silylated 2,2 -bithiophene-1,1-dioxides was investigated. It was shown that only the C(4)=C(5) double bond of 2,4-disubstituted thiophene-1,1-dioxides interacts with acetonitrile oxide to give thienoisoxazoline dioxides. Bithiophene derivatives were inactive or their reaction with nitrile oxide was accompanied by desilylation. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structure of 3a-methyl-5.6a-bis(trimethylgermyl)-3a,6a-dihydrothieno 2.3-c/ isoxazole 4,4-dioxide was established by X-ray diffraction (263). ... 

Chromone-3-carbonitrile oxide undergoes cycloaddition reactions with phenyl-and diphenylacetylenes to give isoxazoles 205 (R = H, Ph). The nitrile oxide is obtained from 3-formylchromone oxime by bromination and subsequent dehy-drobromination (175). 

---