5-Aryl-substituted isoxazoles

Antiviral drug compounds based on amantadine- and aryl-substituted isoxazole have been investigated using solid-state NMR spectroscopy. Measurements of N and chemical shifts, distances and... 

Regardless of the mechanism, three clear generalizations concerning the reactions can be made. First, in cycloadditions to monosubstituted (alkyl/ aryl) alkynes only the 5-substituted isoxazole is obtained. Only in the case of perfluoroalkylalkynes has any significant amount of the 4-substituted isomer (31) been observed.89 Second, the reaction is hindered by bulky substituents on the alkyne. Finally, the reaction is not appreciably hindered by bulky substituents on the nitrile oxide, even when they are so large as to inhibit dimerization almost completely.59 Competition for phenylethyne between pentachloro- and pentabromobenzonitrile oxide gave approximately equimolar amounts of the two adducts (32)90... 

Several 3/3-(aryl)-2/3-(3-substituted isoxazol-5-yl)tropanes 375 were synthesized from methyl esters 374 by reaction with the dilithium salt of the appropriate ketone or aldehyde oxime (Scheme 90) <2004JME296>. The same procedure was applied to 7-ethoxycarbonyl-2-azabicyclo[2.2.1]heptanes for the synthesis of novel epibatidine analogues, such as 376 <2004JOC5328>. The reaction of a-bromoketone oximes with isocyanides and sodium carbonate led to 5-aminoisoxazole derivatives in good yields. Probably, isocyanides are involved in a [4-1-1] cycloaddition with nitrosoalkene intermediates <1997TL8027>. 

Cycloaddition of a nitrile oxide to an alkyne generates an aromatic isoxazole directly. Monoalkyl- or -aryl-substituted alkynes lead to 5-substituted isoxazoles "" with other mono-substituted alkynes, mixtures are obtained." ... 

In the synthesis of aryl-substituted pyrrolo[2,3-d]isoxazoles 46, the oxidative pyrrole ring cyclization was found to be efficiently achieved using sodium hypochlorite in PEG 400 (Scheme 26) [50]. From a variety of screened solvents, PEG 400 led to the best yields of the desired product within shorter reaction time. 

Polarization and dipole moment studies for alkyl-, aryl-, carbonyl- hydroxy- (keto-) and amino-isoxazoles have been compiled and likewise support the low electron nature of the ring 63AHC(2)365, 62HC(l7)l,p. 177). More recent studies predict the order of electrophilic substitution to be 5>4> 3 on frontier electron density values of 0.7831, 0.3721 and 0.0659, respectively 7lPMH(4)237,pp.245,247). This contrasts with earlier reports of 4>5>3 on density values of —0.09, -t-0.14 and -t-0.18 in that order 63AHC(2 365). 

The presently known electrophilic substitution reactions all occur at the 4-position of the isoxazole nucleus, corresponding to the j3-position in pyridine. Thus the influence of the nitrogen atom is predominant. The introduction of alkyl and, particularly, aryl substituents into the isoxazole nucleus markedly increases its reactivity (on the other hand, during nitration and sulfonation the isoxazole nucleus also activates the phenyl nucleus). 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

Synthesis of 3,5-diarylisoxazoles 200 and 201 (overall yield up to 85%) by the reaction of asymmetrically substituted -diketones (199) with hydroxylamine was investigated (equation 87). It has been found that the reaction occurs with a low degree of site selectivity unless steric effects are operating. The isoxazole that has the more electron-deficient aryl group in position 3 is formed preferably when the reaction is performed with hydrox-ylamine hydrochloride. When the reaction is carried ont in a nentral medium, a reversed site stereoselectivity is observed. Similar cycUzation occurred using / -dioximes as starting material . 

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>. 

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