Disubstituted isoxazoles

Characteristic bands occur in the 1300-1000 cm region for 3,4- and 3,5-disubstituted isoxazoles (7i PMh(4)265, p. 330), while bands below 1000 cm contain modes for most substitution patterns (71PMh(4)265, p. 332). Total assignments for isoxazole and isoxazole-d have been made (63SA1145, 7lPMH(4)265,p. 325) and some of the thermodynamic functions calculated (68SA(A)361, 71PMH(4)265,p.330). 

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). 

Electrophilic mercuration of isoxazoles parallels that of pyridine and other azole derivatives. The reaction of 3,5-disubstituted isoxazoles with raercury(II) acetate results in a very high yield of 4-acetoxymercury derivatives which can be converted into 4-broraoisoxazoles. Thus, the reaction of 5-phenylisoxazole (64) with mercury(II) acetate gave mercuriacetate (88) (in 90% yield), which after treatment with potassium bromide and bromine gave 4-bromo-5-phenylisoxazole (89) in 65% yield. The unsubstituted isoxazole, however, is oxidized under the same reaction conditions, giving mercury(I) salts. 

Meso-substituted /3-diketones have been found useful to synthesize 3,5-disubstituted isoxazoles with some reactive group in position 4. For example, 3,5-dimethyl-4-(2, 4 -dinitrophenyl) isoxazole (7) was... 

Though not extensively proven, the reaction path leading to only one of the possible isomers is peculiar to this synthesis of 4-chloroisoxazoles. The not infrequent formation of a mixture of two isomeric 3,5-disubstituted isoxazoles, which are difficult to separate, is recognized as one of the chief disadvantages of the use of -diketones to synthesize isoxazoles. 

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 ... 

Reaction of tetrasulphur tetranitride antimony pentachloride complex (S4N4.SbCl5) with a series of primary (3-enaminones and P-enamino esters 79 in toluene at 100 °C gave reasonable yields of 3,4-disubstituted 1,2,5-thiadiazoles 80. The formation of 80 was explained by the same mechanism as that proposed for the formation of 1,2,5-thiadiazoles from 3,5-disubstituted isoxazoles with S4N4.SbCl5 complex <00H159>. 

Very interesting transformations were reported in terminal alkynes RC=CH (R = alkyl, aryl, alkoxy, carboxylate, etc.). They react readily with nitric acid, in aqueous nitromethane (1 1) and in the presence of catalytic amounts of tetra-butylammonium tetrachloroaurate to give 3,5-disubstituted isoxazoles 15 in 35% to 50% isolable yield (92). The reaction might proceed via a nitrile oxide intermediate by attack of an electrophile (AuCh or H+) and of a nucleophile (N02 ) on the triple bond to form a vinyl nitrite, which is converted to a nitrile oxide by the action of gold(III) or of nitric acid (Scheme 1.8). 

Acetylenic oximes undergo in a similar manner conversion to 3,5-disubstituted isoxazoles. Thus, oximes 195 in the system K2C03/Me0H at room temperature afforded isoxazoles 196 in excellent yields (equation 85). a, S-Unsaturated ketoximes 197 can be also easily transformed to the corresponding 5-arylisoxazoles 198 (yield up to 95%) by treatment with iodine and potassium iodide. The presence of isoxazoline was detected in the reaction mixture (equation 86) . a, S-Unsaturated ketoximes in the presence of palladium catalyst afforded isoxazolines . 

Base-induced cleavage of 3-unsubstituted isoxazoles was discussed in Section II,A>5. When the 3-position is substituted and the 5-position is unsubstituted, a different type of base-induced ring-opening takes place, which follows course B in Scheme 2. 3,5-Disubstituted isoxazoles are resistant to base-induced cleavage. 

Themal ring contraction of 3,5-disubstituted isoxazoles (93) gives 1-azirines (94). 

Nitrile oxides undergo efficient [3-1-2] cycloadditions with alkynes and alkenes to generate isoxazoles and 4,5-dihydroisoxazoles, respectively. With unsymmetrical dipolarophiles there exists the possibility of regioisomeric mixtures of products however, it is generally found that steric effects control the regioselectivity and the more encumbered end of the dipolarophile becomes attached to the oxygen of the nitrile oxide. Thus, terminal alkynes and alkenes afford almost exclusively 3,5-disubstituted isoxazoles and dihydroisoxazoles, respectively (Scheme 91). 

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