Isoxazole production

Table 10 Rearrangement of Isoxazoles with Suitable Three-atom Side Chains Starting isoxazole Product Ref.

Another early example that followed the discovery of CuAAC, the copper-catalyzed reaction of nitrile oxides, is shown in Scheme 10.9. Similarly to azides, the uncatalyzed 1,3-dipolar cycloaddition of nitrile oxides and acetylenes has long been known, but its applications to the synthesis of the corresponding heterocycle (isoxazoles) are scarce. Yields of isoxazole products are often quite low, side reactions are common, and both regioisomers may be formed (although the selectivity of nitrile oxide cycloadditions is usually higher than in reactions of azides, favoring the 3,5-isomer) [127]. Furthermore, nitrile oxides are not very stable and readily dimerize. 

Phototransformation of pyridazine 1,2-dioxides sharply contrasts with that of pyridazine 1-oxides. Pyridazine 1,2-dioxide derivatives give 3a,6a-dihydroisoxazolo[5,4- f]isoxazoles (53) through postulated bisiminoxyl radicals. 3,6-Diphenylpyridazine 1,2-dioxide gives, besides the corresponding bicyclic derivative (53), 3-phenylisoxazole (54) and 4,5-diphenyl-furoxan (55). The last two products can be explained by generation of the nitrile oxide from the intermediate (53) with subsequent dimerization to the furoxan (55 Scheme 18) (79T1267). 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

Scheme 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylamine gives, via the isolable monoxime (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-metrical 1,3-diketones result in both possible isomers (110) and (111), but the ratio of the isomeric products can be controlled by the right combination of the 1,3-dicarbonyl component and the reaction conditions used. These important considerations are described in Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed to yield diverse substituents in the resultant isoxazole. 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

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. 

Irradiation of 3,5-disubstituted isoxazoles in alcoholic solvents gave reaction products such as acetals incorporating the reaction solvent. The use of triethylamine in acetonitrile media produced ketene-aminals by reductive ring cleavage. The reductive ring cleavage product was also obtained by irradiation of the isoxazole in alcohol in the presence of copper(II) salts (Scheme 3) (76JCS(P1)783). 

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). 

It was soon found that the reaction of unsymmetrtcal 1,3-diketones (290) or their derivatives with hydroxylamine results in both possible isomeric isoxazoles (291) and (292), a complication which not only reduces the yield of desired product but also often leads to separation problems, particularly when R and R are similar. However, the reaction does give one isomer, or predominantly one isomer, if the right combination of the CCC... 

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. 

Isoxazole-3-carbaldehyde has been obtained as a minor product from the reaction of acetylene with a mixture of nitric oxide and nitrogen dioxide (61JOC2976). Although 3-aryl-4-formylisoxazoles have been synthesized in good yields from the reaction of benzonitrile Af-oxides with 3-(dimethylamino)-2-propen-l-one (71S433), the parent member of the series, isoxazole-4-carbaldehyde, has never been reported. It may possibly be obtained by the addition of fulminic acid to 3-(dimethylamino)-2-propen-l-one. 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

Bravo et al. studied the reaction of various ylides with monooximes of biacetyl and benzil. Dimethylsulfonium methylide and triphenylarsonium methylide gave 2-isoxazolin-5-ol and isoxazoles, with the former being the major product. Triphenylphosphonium methylide and dimethyloxosulfonium methylide gave open-chain products (Scheme 135) (70TL3223, 72G395). The cycloaddition of benzonitrile oxide to enolic compounds produced 5-ethers which could be cleaved or dehydrated (Scheme 136) (70CJC467, 72NKK1452). 

Alkynic esters react with nitrile oxides in a pH dependent reaction to product isoxazolin-5-ones (Scheme 145) (71JCS(C)86). Alkynic ethers also react with benzonitrile oxide to produce an isoxazole-ether which on treatment with HCl or HBr gave an isoxazolinone (Scheme 145) (63CB1088,58MI41600). The reaction of benzonitrile oxide with dimethoxyketene yielded a dimethyl acetal which was split with acid into the isoxazolinone (Scheme 145) (59G15H). 

In an attempt to prepare an isothiazolobenzodiazepine, ethyl 5-o-aminoanilino-3-methyl-isothiazole-4-carboxylate was treated with sodium methoxide, but the only reaction was transesterification to the methyl ester 76UC(B)394). Only the 5-ester group of dimethyl 3-methylisothiazole-4,5-dicarboxylate reacts with iV,iV -diphenylguanidine, as with the corresponding isoxazole compound, but the product could not be cyclized, even under drastic conditions. This is in marked constrast to the isoxazole compound which cyclized at room temperature (80JCS(P1)1667). 

Few reactions of sulfonylfuroxans with olefins have been reported. Depending on the substituents at the furoxan ring, nature of dipolarophile, and temperature, different types of products may be obtained. It is relatively simple to cyclore-vert disulfonylfuroxans to a-sulfonyl nitrile oxides on thermolysis (81TL3371, 85T727). These nitrile oxides were trapped by dipolarophiles to yield sulfonyl-substituted isoxazole derivatives. For example, 3,4-bis(phenylsulfonyl)furoxan reacts with an excess of styrene in xylene under reflux to afford the corresponding isoxazoline 290 (Scheme 189). 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

Further work by Adembri et al. describes the irradiation of 5-hydrazino-isoxazoles 291a-b under nitrogen, which gives a mixture of products analogous to that obtained by thermal isomerization 5-methylaminopyrazol-3-ones 292a-b, 4-aminopyrazol-3-ones 293a-b, and l,2,4-triazin-6-ones 294 -b (78TL4439). 

Isoxazol-5-ones can exist in three different types of structures, cf. 45- 7 (R = H). Early investigators assigned structures to these compounds on the basis of unreliable chemical evidence thus the NH structure 47 was favored because the silver salt of 3-phenyl-isoxazol-5-one reacts with methyl iodide to give a product which was incorrectly (see reference 44) formulated as the iV-incthyl derivatives (cf. also reference 46). Bromine titration data led to assignment of an incorrect structure to 3,4-diphcnylisoxazol-5-one cf. article I (Volume 1), Section II,A. Comparison of the dipole moments of 3-phenyIisoxazol-5-one with those of the methyl derivatives 45 (R = Me) and 46... 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

As already noted, the lability of the isoxazole nucleus toward the action of nucleophilic agents distinguishes this heterocyclic system from those of other azoles and of pyridine. The conditions which lead to ring opening, and the products of ring cleavage are quite varied and depend on the position and the nature of substituents, although it is invariably the N—0 bond which is broken. 

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