3.5- Disubstituted isoxazoles, formation

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. 

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>. 

A series of 3-acyl and 3-aroyl-4-substituted 1,2,5-thiadiazoles 82 have been synthesised by reaction of 3,S-disubstituted isoxazoles 81 with tetrasulfur tetranitride antimony pentachloride (S4N4.SbCl5) in toluene at 90 C to reflux temperature. Compounds 82 are produced regioselectively and a plausible mechanism for their formation discussed. Under the same conditions, 3,4-dialkyl and 5-alkyl(aryl)-isoxazoles furnished chloroketones of type 83 <98JCS(P1)2175>. 

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... 

Compounds of this type are regarded as 4,5-disubstituted isoxazoles, and as such they react. Their formation from 2-acylcyclohexanones and hydroxylamine is a special case of the general method of isoxazole formation from /9-diketones. 2-Formyl (hydroxymethylene) cyclohexanones, obtained from the respective cyclohexanones and ethyl formate, give 3-unsubstituted derivatives [Eq. (7)].84-91 This reaction has been applied to a stereospecific synthesis of estrone.87,89... 

These trends correspond to pseudo-first order rate constants of 0.5 x 10 , 2.0 x 10 , >650 X 10 and >30 x lO min" for prodnction of the 3,4- and 3,5-disubstituted isoxa-zoles from reaction of 4-ferf-butylbenzonitrile oxide (ImM) with propynamide (5mM) and the cyclodextrin derivative (5mM), respectively (Fignre 3.14). Thus, the cyclodextrin moiety increases the rate of formation of the 3,4-disubstitnted isoxazole by more than three orders of magnitude. Even the rate of formation of the 3,5-disubstituted isoxazole is increased more than fifteen times by the cyclodextrin, despite templating of the other isomer being preferred. Under analogous conditions, the pseudo-first order rate constants for production of the 1,5- and 1,4-disubstituted triazoles from reaction of A-tert-butylphenylazide with propynamide and the cyclodextrin derivative are <0.1 x 10 , ... 

A theoretical study using the density functional theory (DFT) method has been performed to rationalize the mechanism of the reactions between 1,3-dialkynes and hydroxylamine or hydrazine for the formation of 3,5-disubstituted isoxazoles or pyrazoles, respectively The computational results support a bimolecular proton transfer as the rate-determining step providing valuable clues for the use of Bronsted acid/base catalysts to promote the cyclization reaction (14OBC7503). 

The CDC between A-f-butyl nitrones and terminal alkynes to form alkynylated nitrones in good to excellent yields, catalysed by zinc trifiate, was achieved using 3,3, 5,5 -tetra-tertbutyldipheno-quinone and O2 as oxidants. The alkynylated nitrones were transformed to regioisomerically pure 3,5-disubstituted isoxazoles. Experimental and DFT computational studies of Pd(OAc)2/pyridine-catalysed intramolecular aerobic oxidative amination of alkenes supported a stepwise mechanism that involved (i) the formation of a Pd(ll)-amidate-alkene chelate with release of 1 equiv. of pyridine and AcOH from the catalyst centre, (ii) insertion of alkene into a Pd—N bond. 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

In some cases, mixtures of 2,4-disubstituted and 2,5-disubstituted oxazoles were isolated. For example, pyrolysis of 2-benzoyl-3-phenyl-isoxazol-5-one 106 gave the expected 2,4-diphenyloxazole 110 in 60% yield together with 10% of 2,5-diphen-yloxazole 111 and 15% of benzanilide (Scheme 1.30). The authors explained these products by initial formation of a singlet iminocarbene 107. This then... 

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