Isoxazoles nucleophilic substitution

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. 

No direct nucleophilic substitution of the hydrogen atoms in the isoxazole nucleus a or y to the nitrogen is as yet known. Thus, the Chichibabin reaction fails in the isoxazole series because of the cleavage of the heterocyclic nucleus under these conditions. It is the lability of the isoxazole ring toward nucleophilic reagents that makes the chemical behavior of isoxazole fundamentally different from that of pyridine. 

The nucleophilic substitution of a halogen atom at C-5 in the isoxazole nucleus without further functional substituents is so far unknown, but recently reports appeared on the nucleophilic substitution reactions at C-5 in isoxazole derivatives with benzoyl (78 79), ester, and cyano groups (81—>80, 82) in the 4-position. ... 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Intramolecular nucleophilic substitution of electrogenerated phenoxonium ions has been investigated . In connection with naturally occurring bromo compounds, methyl 3,5-dibromo-4-hydroxyphenyl pyruvate oxime (98) was subjected to anodic oxidation (-1-1.3 V Vi. SCE 2.1 Fmol ) in MeOH to afford spiro-isoxazole 99 in almost quantitative yield . Methyl 3-bromo-4-hydroxyphenyl pyruvate oxime (100) was also electrolyzed under similar conditions to give three compounds 101, 102 and 103 in 34, 14 and 17% yields, respectively. The latter two products are formed by C—O and C—C radical couplings, respectively, as shown in Scheme 19 °. 

Numerous examples of nucleophilic substitution in isoxazoles have been reported these reactions have been used for the preparation of AI (Section IV.B.2). A strong electron-donating effect of the amino group hampers the nucleophilic substitution, which is rarely observed in AI. Treatment of 5-chloro-4-AI 1 with the lithium salt of 2-aminoethanethiol gave 4-AI 2 (89MI1) (Scheme 1). 

Unsaturated jS-diketones (e.g. 122 R = H) and hydroxylamine generally yield isoxazoles. However, the nitro derivative (122 R = N02) with hydroxylamine in acetonitrile or acetic acid at 50°C yields the chloroisoxazoloan-thranil 124 (X = 0) by nucleophilic substitution and cyclization of the initially formed isoxazoline 123 as outlined in Eq. (6).149... 

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

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