Reactions of Isoxazoles

It was well established by previous work that electrophilic substitution in the isoxazole ring proceeds readily and occurs in the 4-position.1 Quantita- 

Kurihara, K. Yamanaka, S. Tsuruta, and S. Yasuda, Yakugaku Zasshi 88, 1289 (1968) S. Sumimoto, T. Makikado, and H. Kano, Japanese Patent 70/38,527 Chem. Abstr. 74, 87945(1971). 

Isoxazolium salts can be prepared by appropriate general methods, although the low basicity of the isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. The explosive nature of isoxazolium perchlorates must be noted.125 The preparation of isoxazolium salts containing bulky N-substituents can be very difficult, and the particular utility of such compounds in synthesis (see Section III,B,2) has prompted the development of new methods for preparing them. A noteworthy route involving the reaction of the isoxazole with a carbenium ion, formed from a suitable alcohol, is exemplified in Eq. (18).30,126 

A pathway of this type may be involved in the acid-catalyzed reaction of isoxazoles with mesityl oxide.127 

Although isoxazoles are comparatively weak electron donors, complexes with numerous metal ions, notably metal(II) ions, have been described. The ligands include, besides isoxazole and its methyl and phenyl derivatives, aminoisoxazoles and isoxazolones. An account of the analytical and in- 

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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). 

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. 

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... 

Keywords Diels-Alder reactions of isoxazoles, isoxazolines, isoxazolidines, oxazoles and oxazolines... 

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... 

Sections VI,A, B, D, and E give information about indazoles, oxazole, benzoxazole, isoxazole, benzisoxazoles, isothiazole, benziso-thiazoles, and benzothiazole. In addition, Sections II and VI,F,1 refer to quaternization reactions of isoxazole and benzisothiazoles, respectively. 

During the reaction of isoxazole with nitronium tetrafluoroborate 4-nitroisoxazole is isolated with a yield of 35% [167], With nitronium tetrafluoroborate as nitrating agent it is possible to realize nitration in a neutral medium without protonation of the azole ring. In this case it was possible to isolate /V-nitroimidazoles [324] and 1,2,4-triazoles [348], or their formation as intermediate products was inferred [349, 350] (Scheme 36). 

B. Reactions of Isoxazoles and Isoxazolium Salts with Nucleophiles.170... 

Reaction of isoxazoles Iron(II) chloride is capable of isomerizing isoxazoles to azirenecarboxylic esters or effecting ring cleavage to enamino ketones. 

Reactions of Isoxazoles. The kinetics of the isoxazole azirine rearrangement (336) -> (337) and those of the isoxazole oxazole transformation (338) (339) have been determinedPalladium(II) chloride-triphenyl-phosphine catalyses the cross-coupling of 4-iodo-3,5-dimethylisoxazole with styrene to yield the trans- compound (340). 3,5-Dimethylisoxazole can be lithiated in two stages, first at the 5-methyl group and then at the 3-methyl group. Isoxazoles add hypochlorous acid to form 4-chloro-2,3-dihydro-... 

Other articles on the formation and reactions " of isoxazoles should be noted. 

Reactions of Isoxazoles. Three instances of reductive cleavage of the isoxazole... 

Nucleophiles react with isoxazoles and even faster with isoxazolium salts, but differently in each case and usually with ring cleavage. A special and synthetically useful reaction of isoxazoles unsubstituted in the 3-position is the ring-opening by bases, e.g. ... 

The reactions of isoxazoles differ considerably from those of oxazoles, although both systems are aromatic. The reason for this lies in the relatively weak N-0 bond in the isoxazole molecule, which is cleaved in all ring-opening reactions. Moreover isoxazoles, unlike oxazoles, do not react with dieno-philes to form Diels-Alder adducts [82]. 

In spite of the low r-electron density on the C-atoms, 1,2,5-oxadiazoles do not react at all or only slowly with nucleophiles. Nucleophiles which are also strong bases, e.g. sodium hydroxide in methanol, bring about ring-opening to form sodium salts of a-oximinonitriles. The mechanism corresponds to that occurring in the analogous reaction of isoxazoles (see p 139). 

Reactions of Isoxazoles. The chloroisoxazolium salt (483) activates carboxylic acids for condensation with alcohols and amines.The Lewis-acid-catalysed addition of ammonia to the unsaturated acid (484) yields ( )-homoibotenic acid... 

Reactions of isoxazoles are less prolific due to facile isoxazole ring cleavage. Isoxazoles can be treated with V-bromosuccinimide to brominate the C4-position of the isoxazole. In contrast to oxazoles, when an isoxazole engages in a [4 + 2] cycloaddition, the isoxazole acts as a dienophile, not a diene. ... 

Batra and eo-workers have investigated the MBH reaction of isoxazole-5-carboxaldehydes 268 with a,P-unsaturated cyclic ketones in the presence of... 

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