Isoxazole acids

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. 

R)-3-(4-fluorophenyl)-2-hydroxy propionic acid 1 is a building block for the synthesis of Rupintrivir, a rhinovirus protease inhibitor currently in human clinical trials to treat the common cold (Fig. 1) [1, 2], Retrosynthetically, Rupintrivir was prepared from four fragments the lactam derivative Pi, the chiral 2-hydroxy acid P2 (compound 1), the valine derivative P3, and an isoxazole acid chloride P4 (Fig. 1). In this chapter the preparation of 1 using a biocatalytic reduction performed in a membrane reactor will be discussed in detail. 

Isocyanates can react with other heterocycles as well as with acyclic unsaturated compounds. An example is the reaction of isoxazolone 2.147 with phenyl isocyanate to give 2.148. Subsequent hydrolysis led to 3-amino-3-phenylprop-2-enoic acid, 2.149. A different example involves the conversion of isoxazole acid 2.150 to... 

D,L-a-ammo-3-hydroxy-5-methyl-4-isoxazole-4-propiomc acid [77521-29-0]... 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

Isoxazoles substituted in the 3-position, but unsubstituted in the 5-position, react under more vigorous conditions to give acids and nitriles (Scheme 24). Anthranils unsubstituted in the 3-position are similarly converted into anthranilic acids by bases (Scheme 25) (67AHC(8)277). Attempted acylation of anthranils gives benzoxazine derivatives via a similar ring opening (Scheme 26) (67AHC(8)277). 

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

The reaction is illustrated by the conversion of the 1,2,4-oxadiazole oxime (504) into the 3-acylamino-l,2,5-oxadiazole (505). This irreversible rearrangement occurred on heating (504) in hydrochloric acid (81AHC(29)l4l). Isoxazoles also undergo this rearrangement and these are discussed in Chapter 4.16. 

The first 1,2-benzisoxazole, 3-phenyl-l,2-benzisoxazole, was obtained from the treatment of o-bromobenzophenone oxime with alkali in 1892 (1892CB1498,1892CB3291). 2,1-Benzisoxazole has been known since 1882, being obtained as a reduction product of o-nitrobenzaldehyde with tin and hydrochloric acid (1882CB2105). In general, benzisoxazoles behave much like substituted isoxazoles. Numerous structural ambiguities occur in the early literature of these two systems, and these have been discussed in the above reviews. 

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

The acid-base properties of isoxazole and methylisoxazoles were studied in proton donor solvents, basic solvents or DMSO by IR procedures and the weakly basic properties examined (78CR(Q(268)613). The basicity and conjugation properties of arylisoxazoles were also studied by UV and basicity measurements, and it was found that 3-substituted isoxazoles were always less basic than the 5-derivatives. Protonation increased the conjugation in these systems (78KGS327). 

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. 

On the basis of UV studies, 1,2-benzisoxazoles are considered to be weaker bases than the above isoxazoles (8lAHC(29)l, p. 9) and the values for l,2-benzisoxazole-3-carboxylic acids are comparable with those of o -nitrobenzoic acids. 

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). 

The parent isoxazole was nitrated under strictly controlled conditions (35-40 °C) in only 3.5% yield whereas 3,5-dimethylisoxazole was nitrated in mixed acid at 100 °C to give... 

The iso)tazole ring is rather resistant to sulfonation. However, on prolonged heating with chlorosulfonic acid, 5-methyl-, 3-methyl- and 3,5-diraethyl-isoxazoles are converted into a mixture of the sulfonic acid and the corresponding sulfonyl chloride. The sulfonic acid group enters the 4-position even when other positions are available for substitution. The sulfonation of the parent isoxazole occurs only under more drastic conditions (20% oleum) than that of alkyl isoxazoles isoxazole-4-sulfonic acid is obtained in 17% yield. In the case of 5-phenylisoxazole (64), only the phenyl nucleus is sulfonated to yield a mixture of m-and p-arenesulfonic acid chlorides (65) and (66) in a 2 1 ratio (63AHC(2)365). 

A good general method for iodination or bromination of isoxazoles is to use iodine or bromine in concentrated nitric acid. For example, the iodination of 3,5-dimethylisoxazole (53) with iodine in nitric acid gave 4-iodo-3,5-dimethylisoxazole (79 X = I) in 85% yield (60DOK598). 

Isoxazoles are stable toward peracids and are fairly stable to other acidic oxidizing agents such as chromic and nitric acids, and acidic permanganate. 3-Substituted isoxazoles are... 

Unsubstituted 3-alkyl- or 3-aryl-isoxazoles undergo ring cleavage reactions under more vigorous conditions. In these substrates the deprotonation of the H-5 proton is concurrent with fission of the N—O and C(3)—-C(4) bonds, giving a nitrile and an ethynolate anion. The latter is usually hydrolyzed on work-up to a carboxylic acid, but can be trapped at low temperature. As shown by Scheme 33, such reactions could provide useful syntheses of ketenes and /3-lactones (79LA219). 

The treatment of 4-benzoyl-3-phenylisoxazolin-5-one with KOH generated 3,5-diphenyl-isoxazole-3-carboxylic acid via a ring-opened intermediate as shown in Scheme 69 (61CB1956). 

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). 

The reaction of the steroidal )3-ketoaldehyde (293) with hydroxylamine hydrochloride in acetic acid gave a mixture of the 3- and 5-substituted isoxazoles (294) and (295a). In sodium acetate buffer the reaction provided exclusively the 5-substituted isomer (29Sb) (66JOC3193). 

The reaction of methyl acetylpyruvate (312) with hydroxylamine hydrochloride gave the 3-carboxylate (313) in 76% yield together with traces of the isomeric 5-carboxylate (314) (78MIP41600). However, the sodium salt (315) of acetylpyruvic acid resulted in 3-methyl-isoxazole-5-carboxylic acid (316) as the major product. 

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