Isoxazoles, preparation from

The stability of the heterocyclic ring toward oxidation by permanganate depends on the experimental conditions. In acid media the ring is not cleaved, and acetylisoxazoles are readily prepared from isopropenyl derivatives.2-Isoxazolines are dehydrogenated into isoxazoles (cf. 192 193). The stability of the heterocyclic ring is also observed when this oxidation is carried out in acetone solution. It is of interest that this method allows the preparation both of... 

There is obtained from 4-[)3-[5-methyl-isoxazolyl-(3)-carboxamido]-ethyl]-benzene-sulfonamide (prepared from 5-methyl-isoxazole-(3)-carboxylic acid chloride and 4-()3-aminoethyl)-benzene-sulfonamide hydrochloride, MP 213° to 214°C in pyridine) and chloroformic acid methyl ester, in a yield of 69%, the compound N-[ [-4-[)3-[5-methyl-isoxazolyl-(3)-carbox-amido] -ethyl] ] -benzene-sulfonyl] ] -methyl-urethane in the form of colorless crystals of MP 173°C. 

Chlorophenyl)-5-(4-methoxyphenyl)isoxazole has also been prepared from the dilithio derivative of 4-ehloroacetophenone oxime by two other methods (a) reaction with anisonitrile (4-methoxybenzoni-trile) followed by acid-catalyzed cyclization8 and (b) condensation of anisolyl chloride (4-methoxybenzoyl chloride) followed by acid-catalyzed cyclization. ... 

Isomeric 3,5-disubstituted isoxazoles can be prepared from vinylogous azolides and hydroxylamine hydrochloride. 1391 In this reaction the ratio of the two isomers A and B formed can be controlled by the nature of the base ... 

D,L-Cycloserine 26 and its 3-methyl analog, derivatives of isoxazolinone, were prepared from D,L-Ser or o.L-Thr. The transformation involved replacement of the hydroxyl group by chlorine and subsequent treatment with hydroxylamine (57HCA1531). After being transformed into its 3-chloro derivative, l-G1u was transformed in a multistep conversion into 27, an intermediate in the synthesis of an antitumoric isoxazole-5-acetic acid (81JA7357). 

Our synthesis started with ethyl 5-methyl-4-isoxazole carboxylate (50), prepared from ethyl acetoacetate and DMF dimethyl acetal (Scheme 5.4).14 Ester 50 was reduced with LiAlH4 and the resulting alcohol was oxidized to afford aldehyde 51. Enone 52 was obtained from aldehyde 51 using conditions developed by McCurry and Singh.15 The next step was the aromatization of the cyclohexane ring of 52 to produce the aromatic "A" ring of the monomer. Treatment of enone 52 with iodine in the presence of sodium ethoxide produced phenol 53.16... 

The synthesis of ( )-D-homotestosterone and ( )-progesterone has been accomplished via a now classical procedure involving the use of an isoxazole as an annelating agent (67JA5464). The enolate (424), prepared from 10-methyl-A1,9-octalin-2,5-dione, was alkylated by the 4-chloromethylisoxazole (425). The octalindione (426) was treated sequentially with one equivalent of sodium borohydride, hydrogenated, hydrogenolyzed and refluxed with sodium methoxide and then with sodium hydroxide to afford the crystalline enone (427). 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

Ullman and Singh46-47 first showed that 1-azirines could be prepared from isoxazoles. While studying the photochemical rearrange-... 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

Substituted isoxazole-3,5-dicarboxylic acids have been prepared from ethyl nitroacetate and an aldehyde (63BCJ1150). A related reaction leads to diethyl 4-hydroxyisoxazole-3,5-dicarboxylate (334) and involves the reaction of acetonedicarboxylic acid ester (333) with nitrosyl chloride (78JHC1519). 

Azine approach. The fused uracil (58) has been prepared from 5-amino-l,3,6-trimethyl-uracil diazotization of the latter yields a fused triazine A-oxide (57), which has its triazine ring transformed into an isoxazole ring by tin(II) chloride treatment (62USP3056781). 

Substituted pyran-4-ones can be prepared from isoxazoles through reductive cleavage with Mo(CO)6 and acid-catalysed cyclisation of the generated enaminoketone <02TL3565>. 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

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. 

A beautiful application of Scheme 25 originated by Cornforth229 and developed by Stevens230-231 is the strategy for synthesizing corrins. The relevant part of the approach used is illustrated by the reduction of the isoxazole (98), prepared from the appropriate nitrile oxide and alkyne (see Section II,C,2), leading, via intramolecular attack on an ester carbonyl, to the intermediate (99), which on treatment with ammonia gave the semi-corrin (100).231... 

A particularly useful application of the types of reaction described above is the formation of a ring by intramolecular base-induced condensation of a methylisoxazole (or isoxazolium salt) with a conveniently placed carbonyl function. The required starting materials are often conveniently prepared from the 4-chloromethyl derivatives.236 The initial products can undergo various transformations via cleavage of the isoxazole ring. One of the earliest examples, which illustrates the principles well, is shown in Scheme 28. 

Starting from 4- or 5-tributylstannanyl isoxazoles, prepared via 1,3-DC with chlorooximes and tributylethynyltin in the presence of base, a series of isoxazolyl tetrahydropyridinyl oxazolidinones 42 were synthesised and their in vitro antibacterial activity evaluated <03BMCL4117>. 

This is prepared from 4-(A -benzylamino)isoxazole by the same procedure as for A -(4-isoxazolyl)formamide above. Thus, reaction of 4-(A7-benzylamino)isoxazole (0.843 g, 4 mmol) gives, after flash chromatography [34] (ethyl acetate-isopropyl ether, 2 8), a yellow solid (0.714g, 88%), m.p. 71-73 C. 

Methylpyrrolo[3,4-f]isoxazoles 48, prepared from 3-(l-aminoalkyl)isoxazole-4-carboxylic esters (see Section 4.03.9.1.6), after deprotonation and condensation with aromatic aldehydes afforded compounds 49 that were subjected to N-O bond cleavage the use of Mo(CO)6 gave 3-enoyltetramic acids 50, whereas H2-catalyst allowed further reduction to 3-acyltetramic acids 51 (Scheme 12) <2004SL2815>. 

Isoxazoles can be easily prepared from isoxazoline precursors through dehydrogenation or elimination processes. This aspect (see Section 4.03.6.2) is not discussed in detail in this section. 

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