Synthesis of Isoxazoles

Xu and Zhang developed an efficient aryl C-H amination reaction by using AT-methoxybenzamides and A/ -Boc-hydroxylamine for the synthesis of ben-zoisoxazolones 22 (Eq. (5.21)) [15]. In this reaction, the unstable nitroso intermediate was generated by in situ Cu(I)-catalyzed aerobic oxidation of AT-Boc-hydroxylamine. 

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In 1888 Claisen (1888CB1149) first recognized a general synthesis of isoxazoles (283) by the condensation-cyclization of 1,3-diketones (280) with hydroxylamine. It is now generally accepted that the monoxime (281) of the 1,3-diketone and the subsequent 5-hydroxy-isoxazoline (282) are the intermediate products of the reaction. The isolation of the monoxime (281) and 5-hydroxyisoxazoline (282), which were both readily converted into the isoxazole (283) by treatment with acid or base, has been reported (62HC(17)l). 

Nitrile A-oxides, under reaction conditions used for the synthesis of isoxazoles, display four types of reactivity 1,3-cycloaddition 1,3-addition nucleophilic addition and dimerization. The first can give isoxazolines and isoxazoles directly. The second involves the nucleophilic addition of substrates to nitrile A-oxides and can give isoxazolines and isoxazoles indirectly. The third is the nucleophilic addition of undesirable nucleophiles to nitrile A-oxides and can be minimized or even eliminated by the proper selection of substrates and reaction conditions. The fourth is an undesirable side reaction which can often be avoided by generating the nitrile A-oxide in situ and by keeping its concentration low and by using a reactive acceptor (70E1169). 

This variation provides a regiospecific synthesis of isoxazoles with a great variety of substituents. The nitrile A-oxide does not react with the doubly activated methylene group in neutral or acidic medium, but under alkaline conditions the reaction proceeds exother-... 

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

A particular case of the synthesis of isoxazoles via -diketone derivatives is the preparation of 3-halogenoisoxazoles (11) from -nitroketones (9) treated with hydrogen halides. This inter-... 

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... 

The synthesis of isoxazoles by use of azolides is illustrated by the following example of 3,4-diphenyl-5-methylisoxazoles, prepared by conversion of the deoxybenzoin oximes with JV-acetylimidazole with the aid of butyllithium 1381... 

The 3,4-bis(4-fluorophenyl)-l,2,5-oxadiazole 2-oxide 324 was found as a side product in the synthesis of isoxazole derivatives (Scheme 82, method A) <2006AXEo4827>. Dimerization of 3- and 4-nitrobenzonitrile A-oxides gave corresponding 1,2,5-oxadiazole A-oxides (Scheme 82, method B) <1999MI111>. 

Moustafa and Ahmed reported the synthesis of isoxazoles [92,93]. These compounds are related to pyrazoles except that an oxygen replaces the amine nitrogen. Scheme 49 shows the synthesis of 182 from the corresponding chal-cone 183 by reaction with hydroxylamine. Although these compounds were not tested for cytotoxicity as tubulin binders, they were found to possess antibacterial and anti-fungal activity. 

Scheme 29 Synthesis of isoxazole-3-hydroxamic acid derivatives...

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

By means of a synthesis of isoxazol derivs with fulminic acid, it was establish that the structure of the acid reported in Ref a is incorrect. It should be 3-isoxazole carboxylic acidl... 

A new synthesis of isoxazoles is by successive treatment of a ketoxime with butyllithi-um, the ester of a carboxylic acid and sulfuric acid, e.g. 1 -> 2 (94S989). Hitrovinyl oximes 3 (R1, R3 = alkyl or aryl) undergo oxidative cyclization to isoxazoles 4 by the action of DDQ or iodine/potassium iodide (94JHC861). Flash-vacuum pyrolysis of the 1,3-dipolar cycloadduct 5 of acrylonitrile oxide to norbornadiene results in a retro-Diels-Alder reaction to give cyclopentadiene and 3-vinylisoxazole 6 (94CC2661). 

Let us now consider the synthesis of isoxazole 4.28, a drug for the treatment of bronchial asthma. The most direct preparation of isoxazolyl ketone 4.24 is the cycloaddition of unstable bromonitrile oxide 4.22 (prepared in situ by dehydrobromination of 4.21) with acetylenic ketone 4.23. Observe the regioselectivity of this reaction. Both electron-donating and electron-withdrawing groups on the acetylenic components in such cycloadditions tend to occur at the C5 position in the final isoxazole and not at C4. Bromination of ketone 4.24 affords bromoketone 4.25 which is 4.23 n... 

Azine approach. Acid-catalyzed cyclization of 2-/3 -oxoalkylpyridine 1-oxides (37) constitutes a general method for the preparation of the isoxazolo[2,3-a]pyridinium ring system (77JOC1364). By analogy to the synthesis of isoxazoles from nitrile oxides, the oxo chain should be replaceable by an alkynyl or ethenyl chain, the latter containing a substituent which can readily be eliminated from the cyclic product. 

An appropriate diketone or a ketoalcohol may also be used as starting point for the synthesis of isoxazoles ... 

The two main routes for the synthesis of isoxazoles are the attack of hydroxylamine (NH2OH) on diketones and 1,3-dipolar cycloadditions of nitrile oxides. They thus form a link between the strategy... 

When recent advances in the chemistry of isoxazoles were reviewed by Kochetkov and Sokolov1 in this Series in 1963 (and by Quilico2 in 1962), the main features of isoxazole chemistry had been established. Since then some important new discoveries have been made, but probably the most significant advances have concerned the exploitation of the known features of their chemistry in synthesis. Particularly noteworthy developments include the further application of the cycloaddition of nitrile oxides in the synthesis of isoxazoles (Section II,C and D), the use of isoxazolium salts in peptide synthesis (Section III,B,2), syntheses involving the products of reductive cleavage of isoxazoles as intermediates (Section III,D and E) and annelation reactions via deprotonation of alkylisoxazoles (Section 1II,E). 

The chemistry of nitrile oxides has been well reviewed (see, for example, Grundmann et a/.59-61), and only those features which are pertinent to the synthesis of isoxazoles are summarized here. The electronic structure may be represented as a hybrid of the canonical forms 19-23. The formula 20 is commonly used, but formula 19 embodies their 1,3-dipolar character, and formula 23 their nitrosocarbenoid nature. 

Nitrile oxides display three types of reactivity (apart from isomerization and deoxygenation) 1,3-cycloaddition, 1,3-addition, and dimerization to furoxans. The first can give isoxazolines and isoxazoles directly. The second can give isoxazolines and isoxazoles indirectly. The third (which may be regarded as a carbenoid reaction,62 but see also Lo Vecchio et al.63) is an undesirable side reaction as far as the synthesis of isoxazoles is concerned. Thus, although many methods for generating nitrile oxides are available, and in some cases they may be isolated and used, methods capable of generating them in the presence of the substrate are preferred. 

Scheme 14 Coupling-cycloaddition three-component synthesis of isoxazoles 23...

Willy B, Rominger F, Muller TJJ (2008) Novel microwave-assisted one-pot synthesis of isoxazoles by a three-component coupling-cycloaddition sequence. Synthesis 293-303... 

Gyclocondensation processes of 1,3-dicarbonyl derivatives or their analogues are widely employed for the synthesis of isoxazoles (see Section 4.03.9.1.1) but are less frequently reported for 4,5-dihydroisoxazoles. 

Warren has applied the Homer reaction to the synthesis of isoxazoles (equation 60). Either the 3-alkyl or the 5-alkyl substitution is effective, and in either case good yields of ( )-alkenes are obtained. The isoxazoles can be cleaved with Mo(CO)6. The Homer reaction can be utilized in the synthesis of polyenes. For example, Nicolaou utilized this methodology in the synthesis of a pentaene (equation 61). The addition was carried out with LDA and the elimination effected with KOBu to give the ( )-isomer (258). 

The reaction of 1,3-dicarbonyl compounds with hydroxylamine, usually as the hydrochloride, is widely used for the synthesis of isoxazoles. The reaction is... 

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