Synthesis of novel fused isoxazoles and isoxazolines by sequential Ugi/INOC reactions

We report the synthesis of novel fused isoxazoles and isoxazolines by employing an unprecedented Ugi/INOC synthetic sequence. The coupling of the Ugi multicomponent reaction with the intramolecular N-oxide cyclization provides access to unique heterocyclic ring systems in two steps from easily available starting materials in moderate to good overall yields.     

Intramolecular 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides

Intramolecular 1,3-dipolar cycloaddition of cyclo-1,3-diene- and -1,3,5-triene-tethered nitrile oxides gave tricyclic isoxazolines as a single stereoisomer in most cases. The relative stereochemistry of tricycle-fused isoxazolines resulting from 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides is cis-cis, whereas from cyclohepta-1,3,5-triene-tethered nitrile oxides the cis-trans isomer predominates.     

Diastereocontrol in the intramolecular cycloadditions of 2-substituted-erythro-3,4-isopropylidenedioxyhex-5-enenitrile oxides

The influence of the 2-substituent on the diastereoselectivity of the intramolecular cycloadditions in a series of 2-substituted-erythro-3,4-isopropylidene-dioxyhex-5-enenitrile oxides, generated in situ from selected sugar derivatives, was examined.     

Reactivity of the ester group attached isoxazoline, benzisoxazole, and isoxazole: a facial preparation of 3-acyl-substituted these heterocycles

A facile preparation of 3-acyl-substituted isoxazolines, benzisoxazoles, and isoxazoles from the corresponding 3-carboxylate esters is described. The process, involving reaction of the ester derivative of 3-carboxylic acid substituted heterocycles with Grignard or alkynyl lithium reagents, leads to direct generation of the corresponding 3-acyl heterocycle. The presence of α-imino ester moieties in the heterocyclic substrates for the reactions is thought to be a key feature governing the nature of these transformations. The synthetic utility of the new methodology is demonstrated by its application in a two-step route for the preparation of novel linked bis-heterocycles.     

A new and efficient approach to isoxazolines. First synthesis of 3-aryl-5-dichloromethyl-2-isoxazolines

An efficient synthetic method for 3-aryl-5-dichloromethyl-2-isoxazolines has been established. Reactions between anhydrous chloral and acetophenones in hot acetic acid lead to 1-aryl-4,4,4-trichloro-3-hydroxybutan-1-ones (chloralacetophenones), which provided 1-aryl-4,4-dichlorobut-3-en-1-ones (2,2-dichlorovinylacetophenones) by dehydration and subsequent electrochemical reduction. These β,γ-unsaturated enones reacted with hydroxylamine yielding oxime intermediates whose treatment with aqueous sodium hydroxide gave novel 3-aryl-5-dichloromethyl-2-isoxazolines in fair to high yields. The molecular structure of a member of this family of compounds, 5-dichoromethy1-3-(4-methoxyphenyl)-2-isoxazoline, was determined by X-ray crystallography.     

Copper-catalyzed radical oxytrifluoromethylation of alkenyl oximes at ambient temperature

A mild and efficient copper-catalyzed radical oxytrifluoromethylation reaction of alkenyl oximes was successfully developed. The method provides a straightforward access to a wide range of CF₃-containing isoxazolines in good to excellent yields.     

A tandem oximation-cyclization route to Δ-isoxazolines

3,5-Disubstituted Δ²-isoxazolines can be prepared from the corresponding β,γ-unsaturated ketones by treatment with hydroxylamine hydrochloride and sodium hydroxide. Evidence indicates that the mechanism of this reaction involves the formation of three intermediates; oximation of the ketone, rearrangement of the alkene, and intramolecular Michael addition of the resulting α,β-unsaturated oxime.     

Capping the upper and lower rims of calix[4]arenes by aryl dinitrile oxide reactions

1,3-Dipolar cycloadditions of upper- and lower-rim diallylcalix[4]arenes (1 and 3) with aryl dinitrile oxides provide a unique and efficient way of capping the calix[4]arenes. When dinitrile oxides reacted with 5-allylcalix[4]arene 7, they underwent a 1,3-dipolar cycloaddition on one side and an electrophilic substitution on the other side, which led to a novel type of asymmetric calix[4]arenes (9 and 12).     

1,3-dipolar cycloadditions of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives

The reactions of arylnitrile oxides 2 and 2-diazopropane 5 with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives 1 have been studied. 1,3-dipolar cycloaddition of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives is taking place regiospecifically. The asymmetric induction expected by the chiral centre of the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives was very effective, diastereoisomers 3 and 4 were formed in an approximate 90:10 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the 2-diazopropane with the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives are investigated. The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile, giving the isomer 6.     

Preparation of isoxazol(in)yl substituted selenides and their further deselenenylation reaction to synthesize 3,5-disubstituted isoxazoles

We report a mild 1,3-dipolar cycloaddition protocol for the preparation of 3-aryl-5-phenylselenomethyl isoxazoles and isoxazolines regioselectively. The former was further reacted with LDA and electrophilic substrates followed by selenoxide syn-elimination to afford 3-aryl-5-E-substituted-ethenyl isoxazoles stereoselectively and the latter was subjected to a ‘two-step’ elimination to afford 3-aryl-5-methyl isoxazoles.