Isoxazoles, nitro-, synthesis

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

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. 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

The first demonstration of fluorous synthesis was in the preparation of small (8-12 members) isoxazo-line and isoxazole libraries by the three-step procedure outlined in Figure 8.1461 All reactions were purified by three-phase liquid-liquid extraction. The starting substrates were simple allylic alcohols which were tagged with the fluorous silyl halide 5 to make substrates 6 for an ensuing dipolar cycloaddition. This was conducted by the Mukaiyama method with a large excess of nitro compound and... 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

The use of nitro aromatics as dipolarophiles in cycloaddition reactions has shown great utility in heterocyclic synthesis. The reaction of 3-substituted-4-nitroisoxazoles (299) with trisubstituted oxazolium 5-oxides (300) affords an intermediate adduct (301) which eliminates carbon dioxide and nitrous acid to afford 3,4,6-trisubstituted pyrrolo[3,4-r/]isoxazoles (302) (Scheme 56) <93G633>. 

The construction of a heterocyclic ring from two reagents, one of which contains a nitro group, is widely used in the synthesis of the nitro derivatives of pyrazole, isoxazole, and 1,2,3-triazole. Thus, for example, the reaction of sodionitromalonal-dehyde with substituted hydrazines leads to the corresponding derivatives of 4-nitropyrazole [33, 61, 471 173] (Scheme 63). 

The product from the reaction of citraconic acid (or its anhydride) with nitric acid was initially assigned the structure of 3-methyl-5-(l,l,2-trinitroethyl)isoxazole [588], However, it was subsequently established that this compound was 5-methyl-4-nitro-3-(l,l-dinitroethyl)isoxazole [589], As mentioned earlier, the antibiotic azomycin (2-nitroimidazole) and some of its derivatives can be obtained by microbiological synthesis [331, 450, 590, 591],... 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

Solid-phase synthesis of 3-hydroxymethyl isoxazoles 17 was accomplished in acceptable yields and purity through 1,3-DC of different alkynes 15 to resin bound nitrile oxides, generated from nitro compounds 14 under Mukaiyama conditions. This method is robust enough to be carried out by an automated synthesiser <01TL4951>. 

Benzylamine added to a mixture of benzylidenebenzylamine and ethyl nitro-acetate, refluxed 2 hrs. 4-phenyl-3,5-bis (benzylcarbamyl) isoxazole. Y 84%.— This is a new synthesis of isoxazole derivatives. F. e. s. S. Umezawa and S. Zen, Bull. Ghem. Soc. Japan 36, 1150, 1146 (1963). 

Dipolar cycloadditions of nitrile oxides to the various unsaturated alditol derivatives 92 led to pairs of isoxazolidine regio-isomers, e.g. 93 and 94, each as predominantly one stereoisomer (Scheme 16). The isoxazole 95 was the major product from addition of bromoformonitrile oxide to the nitro-alkene. The nitrile moiety of D-mannononitrile pentabenzoate was transformed into either a 3-substituted 5-methyl-1,2,4-oxadiazole moiety (with NH2OH then AC2O) or a 5-substituted 2-methyl-1,3,4-oxadiazole moiety (with NH4N3 then AC2O, Py) cf. Vol.24, p.l35. The synthesis of 2-(alditol-l-yl) substituted 2-aza-3,7-dioxabicy-clo[3.3.0]octanes by intramolecular dipolar cyclization of 2-0-d y -aldehydo-sugar nitrones is covered in Chapter 24. 

In 1960 a new access to nitrile oxides was provided by dehydration of primary nitro compounds 4, achieved with 2 equiv of phenyl isocyanate, which is converted into diphenylurea, beside the substituted furoxan isoxazole derivatives are obtained in the presence of suitable dipolarophiles (Scheme 8.1) [6,7]. This method for the synthesis of isoxazoles has become popular in turn and both methods have been widely employed over the past 50 years the subject has been repeatedly reviewed [8-15]. 

The methods leading to isoxazole synthesis from nitro compounds are summarized and assembled according to the procedures employed heating combined with acids, by... 

No mechanism is reported for the synthesis of isoxazole derivatives from various primary nitro compounds by... 

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