Convenient synthesis of isoxazolines via tandem isomerization of allyl compounds to vinylic derivatives and 1,3-dipolar cycloaddition of nitrile oxides to the vinylic compounds

A novel effective method for the synthesis of new isoxazolines via tandem isomerization of QCH(X)CHCH(Y) to QC(X)CHCH₂(Y) (Q = RO, RS, R₂N, R₃Si, etc.; X = H, R, OR; Y = H, R; R = alkyl, aryl) catalyzed by ruthenium complexes and 1,3-dipolar cycloaddition of the latter compounds to arenenitrile oxides is presented. The cycloaddition of QCH(X)CHCH(Y) to 2,6-dichlorobenzonitrile oxide is also described. The regio- and stereoselectivity of the cycloaddition of nitrile oxide to allyl and 1-propenyl (vinylic in general) compounds is discussed.     

Stereoselective intramolecular 1,3-dipolar nitrile oxide cycloaddition reaction of N-formyl-β-nitroamides

The stereoselective intramolecular nitrile oxide cycloaddition (INOC) reaction was achieved from N-formyl-β-nitroamides, which were prepared through the Michael addition of allylic formamides to nitroalkenes, and cis-pyrroroisoxazoles and trans-piperidinoisoxazoles were obtained in a stereoselective manner.     

New route synthesis of indolizines via 1,3-dipolar cycloaddition of pyridiniums and alkynes

A convenient synthesis of 2,3-di and 1,2,3-trisubstituted indolizines has been achieved via a 1,3-dipolar cycloaddition of pyridiniums and alkynes. Various alkynes and diynes were used instead of dimethyl acetylenedicarboxylate (DMAD) and its analogues in the traditional method. The corresponding 1,2,3-trisubstituted indolizines are useful building blocks for the construction of complex indolizine derivatives.     

Selectivities in the 1,3-dipolar cycloaddition of nitrile oxides to dicyclopentadiene and its derivatives

The 1,3-dipolar cycloaddition of nitrile oxides, generated from aldoximes and nitroalkanes, to dicyclopentadiene proceeds with complete chemo- and stereoselectivity. The approach of the dipole takes place exclusively from the exo-face of the bicycloheptane moiety providing a mixture of regioisomers in approximately 55:45 ratio. On the other hand, nitrile oxide cycloaddition to dimethyldicyclopentadiene dicarboxylate (Thiele's ester), besides exhibiting chemo- and stereoselectivity as in the case of dicyclopentadiene, exhibits complete regioselectivity as well providing a single isomer in good yield. The Influence of remote substituents, including sterically ‘sterile’ ones, on the regioselectivity has also been investigated using 8-hydroxy and 1-keto derivatives of dicyclopentadiene. These experimental observations have been investigated through gas phase and solvent model MO calculations on the transition state geometries at semiempirical (PM3) and hybrid ab initio-DFT levels of theory. The Computational methods employed in this study were rigorously tested by performing model calculations on well-established experimental observations.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to 3,3-methylene-5,5-dimethyl-2-pyrrolidinone

Summary Nitrile oxides add regioselectively to the carbon-carbon double bond of 3,3-methylene-5,5-dimethyl-2-pyrrolidinone (1), giving exclusively spiro-isoxazolines: 3-aryl-6-oxo-8,8-dimethyl-1-oxa-2,7-diazaspiro[4.4]non-2-enes3 a–l. The regiochemistry of the 1,3-dipolar cycloaddition to 1 seems to be controlled by the steric effect of the methyl groups at the ring junction and by frontier orbital interactions.Part XXV in the series 1,3-Dipolar Cycloaddition on Heterocycles. Part XXIV Ref. [10]     

The synthesis and biological activity of novel spiro-isoxazoline C-disaccharides based on 1,3-dipolar cycloaddition of exo-glycals and sugar nitrile oxides

A series of novel spiro-isoxazoline C-disaccharides were synthesized by the key step of 1,3-dipolar cycloaddition reactions of exo-glycals and sugar nitrile oxides, and followed by catalytic debenzylation in the presence of Pd(OH)₂/C. The cycloaddition reactions were carried out stereoselectively and afforded α-isomers exclusively except in the case of galactose. The biological activities of the novel disaccharides against the glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and HIV and BVDV were evaluated.     

Synthesis of new aza-bicyclic 2-isoxazolines by 1,3-dipolar cycloaddition of endocyclic enecarbamates and enamides with nitrile oxides

Novel aza-bicyclic 2-isoxazolines, 4,5-dihydroisoxazole[5,4-b]pyrrolidines, and 4,5-dihydroisoxazole[5,4-b]piperidines were synthesized in a highly regioselective manner through a 1,3-dipolar cycloaddition reaction of 5- and 6-membered endocyclic enecarbamates and enamides with several nitrile oxides in good to excellent yields. Hydrogenolysis of 5- and 6-membered Cbz-cycloadducts led to secondary amines, which presented distinctive stabilities. 2-Isoxazoline bisamides were obtained in good yields through a N-benzoylation, followed by ammonolysis of the secondary amine, or directly from ammonolysis of the cycloadducts.     

Asymmetric 1,3-dipolar cycloaddition of nitrile oxides with optically active vinylboronic ester

Pinanyldioxy styrylboronic ester (1) was employed for asymmetric 1,3-dipolar cycloaddition with nitrile oxides, optically active △2-isoxazolines (3) or 4-hydroxy-△2-isoxazolines (4) were obtained. The effect of different bases on the selectivity of the cycloaddition reaction was studied.     

Tricyclic-isoxazolidine analogues via intramolecular 1,3-dipolar cycloaddition reactions of nitrones

The tricyclic-isoxazolidine analogues tetrahydrothiochromenoisoxazoles, hexahydroisoxazolequinolines and tetrahydroisoxazolepyranopyridines were prepared by an intramolecular 1,3-dipolar cycloaddition reaction of a nitrone with an alkene. For N-alkylated hexahydroisoxazolequinolines, reduction of the reaction time from two days to 40 min was achieved using microwave heating. The cyclization to form tetrahydroisoxazolepyranopyridines only proceeded when the alkene was substituted with an electron withdrawing group.     

Synthesis of polyfluorophenyl substituted-4,5-dihydropyrazole derivatives via 1,3-dipolar cycloaddition of nitrile imine with ethyl acrylate

Oxidation of aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhydrazones (1) with [bis(acetoxy)iodo]benzene leads to the formation of nitrile imines (2) which reacted in situ with ethyl acrylate to produce 3-substituted-1-(4-chloro-2,3,5,6-tetrafluorophenyl)-5-ethoxycarbonyl-4,5-dihydropyrazoles (3) in moderate to good yields. The structures of new compounds were fully confirmed by their spectral data, elemental analyses and X-ray diffraction (XRD) analysis. A plausible reaction mechanism for the synthesis of title compounds is presented.     

An expeditious synthesis of an analogue of (−)-steviamine by way of the 1,3-dipolar cycloaddition of a nitrile oxide with a 1-C-allyl iminosugar

In our continuing effort to develop inhibitors of the mycobacterial galactan biosynthesis, we planned to synthesize original iminosugar-based analogues of UDP-galactofuranose by way of the 1,3-dipolar cycloaddition reaction between a 1-C-allyl iminosugar and a nitrile oxide, followed by the reductive cleavage of the resulting isooxazoline. In initial studies, it was found that this last step led in one pot to a new polyhydroxylated indolizidine derivative closely related to the recently isolated (−)-steviamine, in good yield, by way of a sequence involving at least five individual reactions. The activity of this new compound as a glycosidase inhibitor was evaluated against a panel of glycosidases and compared to (−)-steviamine.     

Regio- and stereoselective 1,3-dipolar cycloaddition of arylnitrile oxides to 5-acetoxy-2(5H)-furanone

Summary Arylnitrile oxides undergo regio- and stereo-specific 1,3-dipolar cycloaddition reactions with 5-acetoxy-2(5H)-furanone. In each case a single product3a–3g results from ananti approach to the 5-acetoxy substituent, the oxygen of the 1,3-dipole being attached to C-4 of furan. Under similar conditions 5-benzoyloxy-2(5H)-furanone yields3h–3i. The structures of the adducts were determined by¹H- and¹³C-NMR spectroscopy.

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Regio- und stereoselektive 1,3-dipolare Cycloaddition von Arylnitriloxiden mit 5-Acetoxy-2(5H)-furanon

Zusammenfassung Arylnitriloxide reagieren mit 5-Acetoxy-2(5H)-furanon in einer regio- und stereoselektiven 1,3-dipolaren Cycloaddition. In jedem der untersuchten Fälle ergaben sich die einheitlichen Produkte3a–3g als Folge eineranti-Annäherung an den 5-Acetoxysubstituenten, wobei der Sauerstoff des 1,3-Dipols an das C-4 des Furans addiert. Unter ähnlichen Bedingungen ergab 5-Benzoyloxy-2(5H)-furanon die Produkte3h–3i. Die Strukturen der Addukte wurden mittels¹H-und¹³C-NMR bestimmt.

     

Study on the 1,3-dipolar cycloaddition reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one with nitrile oxides

1,3-Dipolar cycloaddition (1,3-DC) reaction of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one 1 with nitrile oxides was studied. It was found that besides its CC participating in the formation of isoxazole rings, trifluoromethyl activated CO also underwent 1,3-DC reaction with nitrile oxides to afford 1,4,2-dioxazole rings. Single crystal diffraction analysis also evidenced the diheterocyclic configuration.     

An efficient 1,3-dipolar cycloaddition between aromatic selenoaldehydes and nitrile oxides or nitrile imines: an easy access to selenium-containing five-membered heterocyclic ring system

1,3-Dipolar cycloaddition between aromatic selenoaldehydes, generated by thermal retro Diels-Alder reaction of anthracene cycloadducts, and nitrile oxides or nitrile imines proceeded efficiently to give the corresponding [3+2] cycloadducts as a single isomer in good yields, being 1,4,2-oxaselenazoles or 1,3,4-selenadiazoles, respectively.     

Synthesis of novel pyrano[2,3-b]quinolines from simple acetanilides via intramolecular 1,3-dipolar cycloaddition

Some novel isoxazole and pyrazole fused pyrano[2,3-b]quinolines were synthesized from simple acetanilides via intramolecular 1,3-dipolar cycloaddition reactions involving nitrones, nitrile oxides and nitrile imines as 1,3-dipoles, in a regioselective manner.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to N-(3,5-dichlorophenyl)itaconimide

Summary The regioselectivity of the nitrile oxide cycloaddition with 3,3-methylene-1-(3,5-dichlorophenyl)-2,5-pyrrolidindione (1) is discussed. Arylnitrile oxides add regioselectively to the carboncarbon double bond of1, giving exclusively spiro-isoxazolines3a–k, whereas acetonitrile oxide gives both adducts3l and4l. AM1 calculations of the reactants and cycloadducts were performed, the regiochemistry of the cycloaddition seems to be controlled by steric effects. Reduction of3a with NaBH₄ in the presence of magnesium perchlorate at –20 °C was regio-and stereoselective to yield the hydroxylactams9a and10a, whereas hydroxymethylisoxazoline14a was obtained in the absence of Mg(ClO₄)₂.Part XXX in the series 1,3-Dipolar Cycloaddition on Heterocycles. Part XXIX [27]     

Intramolecular cycloaddition of N-phthalimidoaziridines to double and triple carbon-carbon bonds

Thermolysis of 3-(2-allyloxyphenyl)- or 3-(2-propargyloxyphenyl)-1-phthalimidoaziridine-2-carboxylic acid derivatives results in stereospecific intramolecular cycloaddition of intermediate N-phthalimidoazomethine ylides to double or triple carbon-carbon bonds. This leads to condensed N-phthalimidopyrrolidines, N-phthalimidopyrrolines, or products of their subsequent transformations. On the other hand, thermolysis of similar dimethyl 3-aryl-1-phthalimidoaziridine-2,2-dicarboxylates gives exclusively 5-methoxyoxazoles, the products of a competitive 1,5-dipolar electrocyclization.     

1,3-Dipolar cycloaddition reaction of aryl nitrile oxides with alkenes using imidazole and pyridine containing reusable polymeric base catalysts

Cross-linked poly-1-(4-vinylbenzyl)imidazole and cross-linked poly-4-vinylpyridine have been prepared from respective vinyl monomers using different quantities of divinylbenzene as a cross-linker by radical polymerization. The polymeric bases were characterized by FT-IR, TGA, field emission-scanning electron microscopy (FE-SEM), and Brunauer-Emmett-Teller (BET) surface area analysis. Their swelling behavior was also studied. They were used as base catalysts for 1,3-dipolar cycloaddition reaction of aryl nitrile oxides, generated in situ from N-hydroxyimidoyl chloride, with N-phenylmaleimide and ethyl acrylate, to obtain 3-arylisoxazolines. Both the bases gave excellent results. These polymers were reusable, safe to use, and provided good alternative for organic nonreusable bases like pyridine and triethylamine which are hazardous.     

Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction

Herein described was a straightforward method for the highly regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldimethylsilyl (TBDMS) group as the directing group in the 1,3-dipolar cycloaddition reactions. 4-tert-Butyldimethylsilyl-5-trifluoromethyl-1,2,3-triazole nucleoside analogues were generated as the only cycloaddition products in moderate yields (15-79%) via the treatment of glycosyl azides with 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne 1 in toluene at 85 °C. Removal of TBS groups in these triazole cycloadducts with tetrabutylammonium fluoride (TBAF) smoothly afforded the various 5-trifluoromethyl-1,5-disubstituted 1,2,3-triazole nucleoside analogues in good yields (40-88%).     

Diastereoselective synthesis of 2,3,4,5-tetrasubstituted isoxazolidines via 1,3-dipolar cycloaddition

The 1,3-dipolar cycloaddition reactions of α-2-methoxyaryl nitrones with nitrostyrenes and chalcones have been investigated. The regiochemistry and stereochemistry of the resultant cycloadducts have been determined with the help of NMR spectroscopy and X-ray analysis. β-Nitrostyrenes add to nitrones to give two geometrical isomers, while the β-methyl-β-nitrostyrene gives a single isomer in relatively low yield. The chalcones give a single cycloadduct upon 1,3-dipolar addition.