Isoxazole derivatives

Isoxazole was first synthesized by Claisen in 1903 from propargylaldehyde diethyl acetal and hydroxylamine (03CB3664). It has also been obtained by addition of fulminic acid to acetylene in methanol-dilute sulfuric acid solution, by acidic hydrolysis of 5-acetoxyisoxazo-line, by reaction of /S-chloroacrolein or/3-alkoxyacrolein with hydroxylamine hydrochloride 

A large variety of 3-chloroisoxazolium chlorides were prepared by stirring 4-isoxazolin-3-ones with a two-fold molar excess of phosgene in benzene [2043]  

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Table 1 Melting (Boiling) Points of Various Isoxazole Derivatives (62HC(17)1, p, 159)...

Tables pK Values of Some Isoxazole Derivatives (71PMH(.iu. p. 2.1)...

The isoxazolecarboxylic acids are the most intensively investigated of the isoxazole derivatives, and a detailed compilation of their physiochemical properties has been made 62HC(17)l,p. 177). Similar studies have also been carried out with the 5-isoxazolones (62HC(17)l,p. 124), and pK values of 1,2-benzisoxazole derivatives are listed in Table 4. 

Prototropic tautomerism of isoxazole derivatives has been well studied over a number of years and has recently been reviewed in context with similar behavior in other five-membered heterocycles (70C134, 76AHC(Sl)l, 79AHC(25)147, p. 202). Several generalizations are summarized below. 

The rearrangement represented by the conversion of (274) into (275) involves derivatives of a considerable number of azoles, including the isoxazoles. These are of general interest and isoxazole derivatives which undergo this rearrangement are shown in Table 10. 

In a unique approach to the synthesis of isoxazole derivatives, a-isonitroso ketone... 

Few reactions of sulfonylfuroxans with olefins have been reported. Depending on the substituents at the furoxan ring, nature of dipolarophile, and temperature, different types of products may be obtained. It is relatively simple to cyclore-vert disulfonylfuroxans to a-sulfonyl nitrile oxides on thermolysis (81TL3371, 85T727). These nitrile oxides were trapped by dipolarophiles to yield sulfonyl-substituted isoxazole derivatives. For example, 3,4-bis(phenylsulfonyl)furoxan reacts with an excess of styrene in xylene under reflux to afford the corresponding isoxazoline 290 (Scheme 189). 

High-temperature gas-phase pyrolysis of isoxazole derivatives 99M127. 

Although isoxazole derivatives have been known for more than 80 years, the investigation of their chemistry commenced rather slowly. Earlier studies were mainly devoted to the development of synthetic methods. It is only recently that attention was focused on the investigation of chemical properties and in particular on the peculiarities of the behavior of isoxazole derivatives and the elucidation of their physicochemical characteristics. This enabled new data to be obtained that are of considerable importance. 

Previous reviews on the chemistry of isoxazole dealt primarily with the synthetic routes and the nucleophilic cleavage of isoxazole derivatives. The first part of the present review is concerned with new investigations in the synthetic field, but the main attention is devoted to a study of the properties of isoxazoles. The review covers studies undertaken during this decade though some earlier works are mentioned when necessary. No complete coverage of the chemistry of partly or fully reduced isoxazoles and their oxo derivatives is attempted, but those aspects of the chemistry of isoxazolines and isoxazolidines that are closely related to the problems under discussion are also mentioned. 

As shown by the Italian school, the formation of isoxazole derivatives by the action of nitric acid or nitrogen oxides on acetylene derivatives and related reactions proceeds through intermediate nitrile oxides and must, therefore, be included with this type of synthesis. 

Concluding this review of recent work on the synthesis of isoxazole derivatives, one should mention an interesting reaction, although at present it is of no preparative value. This reaction cannot, strictly speaking, be included in either of the two groups discussed in the foregoing because its mechanism is not yet known. It is a reaction of esters of a, -unsaturated-a-nitroacids (43) with butylamine resulting in isoxazole-3,5-dicarboxylic amides (44)." There is some indication... 

This decade has brought a number of investigations of the physicochemical properties of isoxazole derivatives and the elucidation of some details concerning their structure. The data obtained are in a good agreement with the conceptions as to the structure of isoxazole as reviewed by Barnes. We shall therefore be concerned only with recent work. 

The IR spectra of isoxazole derivatives have been extensively investigated. " The most exhaustive and precise data, including both the characteristic frequencies and intensities, were reported by Katritzky and Boulton " for isoxazole and its homologs, aryl- and alkoxy-isoxazoles, acids, and some other derivatives. 

Spectroscopic methods have been successfully applied to the elucidation of some details of the fine structure of isoxazole derivatives. Thus IR spectra revealed steric hindrance in the case of some 3,4,5-trisubstituted isoxazoles for phenylisoxazoles this results in the nonplanarity of the benzene and isoxazole rings and decreasing mutual interaction. 

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

To understand the general character of the isoxazole nucleus and to establish its place among the other heterocyclic aromatic systems, it is of the greatest interest to investigate the reactions of isoxazole derivatives in which the heterocyclic nucleus remains intact, especially substitution reactions. 

A characteristic peculiarity of isoxazole derivatives is the relatively facile ring cleavage under suitable conditions, and this is a severe limitation on reactions of substitution in the isoxazole series. The best, though as yet inadequately, studied reactions, are the... 

Further, isoxazole derivatives were subjected to two related reactions. 3,5-Dimethylisoxazole was found to react in the presence of dry hydrogen chloride with aromatic aldehydes (chlorobenzylation, 72- 71),and with formaldehyde in the presence of sulfuric acid it undergoes hydroxymethylation (72- 73). ... 

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. ... 

Reactions involving the introduction and substitution of functional groups in the side chain of isoxazole derivatives are of synthetic value and have been used to synthesize various substituted isoxazoles. 

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. ... 

As already mentioned, on passing from the aromatic system of isoxazoles to the nonaromatic ones of isoxazolines and isoxazolidines, the N—O bond becomes more labile. In these compounds the ring is extremely readily cleaved. Many such reactions are useful to determine the structure of reduced isoxazole derivatives and are also of preparative value. 

Heating isoxazole derivatives with aqueous-alkaline permanganate leads to a complete degradation of the heterocycle. With arylisoxa-zoles this results in readily identifiable aromatic acids, from which can be deduced the orientation of electrophilic substitution reac-tions. ° Also, the stability of various heterocycles can be compared. Thus, under these reaction conditions, the pyrazole ring is more stable than that of isoxazole (cf. 197198). ... 

Isoxazole derivatives are stable toward peracids but can be ozonolyzed. This, as is well known, enabled the 0-benzoyloximes of a-diketones with a well established configuration to be obtained, which were used to investigate the Beckmann rearrangement mech-anism. ... 

Some hydroxamic acids of the isoxazole series also display a marked antituberculosis activity. The penicillin derivatives, acylated with isoxazole carboxylic acids possess an antibacterial activity similar to that of penicillin, against resistant species.Among other isoxazole derivatives possessing activity one should especially mention the sulfonamides of this series, and 4-hydroxyiminoisoxazol-5-... 

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