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.     

Stereoselective preparation of 1,2,4-oxadiazole derivatives substituted by pentafluorophenyl by 1,3-dipolar cycloaddition reaction

1,3-Dipolar cycloaddition reactions of chiral imines obtained from optically active amino acids with nitrile oxides afforded 1,2,4-oxadiazole derivatives in moderate to good yields with good stereoselectivity. Investigation on the effect of bases suggested that triethylamine was prone to afford better stereoselectivity, while NaHCO₃ was prone to increase the reaction rates and yields.     

Synthesis of new polyhedral oligomeric silsesquioxane derivatives as some possible antimicrobial agents

1,3-Dipolar cycloaddition reactions were studied to synthesize Polyhedral oligomeric silsesquioxane (POSS)-based norbornyl imide derivatives containing izoxazoline groups in good yields. And also 1,3-dipolar cycloaddition reactions of azomethine ylides with POSS-based norbornene dipolarophiles for a synthesis of the novel POSS-based norbornane-fused spiro-1,3-indandionolylpyrrolidines are reported. All newly synthesized POSS compounds were structurally characterized by FTIR, ¹H, ¹³C NMR, HRMS and GC/MS analyses.     

1,3-Dipolar cycloaddition route to novel isoxazole-type derivatives related to combretastatin A-4

A series of compounds related to combretastatin A-4, containing a five-membered heterocyclic ring interposed between the two phenyl groups have been prepared. Synthetic approach involves 1,3-dipolar cycloaddition of various 3,4,5-trimethoxyphenyl units with an in situ generated nitrile oxide from a suitable aldoxime using sodium hypochlorite. Depending on the nature of the dipolarophile, 3,5-diarylisoxazole derivatives were obtained along with the 3,4-regioisomeric isomers.     

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.     

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.     

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 chiral bis(2-oxazolinyl)xanthene (xabox) ligands and their evaluation in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone

Chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) were synthesized and the chiral environments were evaluated in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones resulting in good to excellent enantioselectivities. 1,3-Dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone in the presence of a bis(2-oxazolinyl)xanthene (4c; xabox-Bn) and Mn(II) or Mg(II) complex as a chiral Lewis acid catalyst proceeded smoothly to give the corresponding cycloadducts ranging from 96:4 to >99:1 of endo:exo ratio and ranging from 91% to 98% ee for the endo adduct.     

Synthesis of spiroisoxazolidinyl-benzoisothiazolines by 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes with nitrones

The spiroisoxazolidinyl-benzoisothiazoline derivatives were synthesized through a highly diastereoselective 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes with nitrones. The regiochemistry of cycloaddition was assigned on the ¹H NMR chemical shift of methane-H in 3 and 5. The relative stereochemistry of cycloadducts was determined from the single-crystal X-ray crystallography.     

Unexpected opening of benzimidazole derivatives during 1,3-dipolar cycloaddition

Hydroxylamine hydrochloride adds via a Michael reaction on the acetonylidene moiety of (4Z)-(2-oxopropylidene)-1,2,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one, leading only to 2-[(5-methyl-isoxazol-3-yl)]methyl]benzimidazoles. This report describes the difference of reactivity of C-phenyl-N-phenyl formohydrazonoyl chloride with benzimidazole. For the N-substituted benzimidazole, an unexpected opening of the azole ring occurs, which was confirmed by single crystal X-ray diffraction analysis.     

Unexpected synthesis of aziridines under Cu(I) catalyzed Kinugasa conditions assisted by microwave irradiation

Cu(I)-catalyzed 1,3-dipolar cycloaddition between chiral nitrone and terminal alkynes under microwave irradiation afforded a series of enantiopure aziridines with the creation of two contiguous stereogenic centers.     

A facile synthesis of pyrazoles with multi-point structural diversity by 1,3-dipolar cycloaddition

We describe the synthesis of diverse pyrazoles by 1,3-dipolar cycloaddition of ethyl diazoacetate with various acetylenes in refluxing toluene. The product pyrazoles are useful starting points for preparing a diverse collection of trisubstituted pyrazole carboxamides. For aryl and heteroaryl alkynes a single product is obtained while alkyl alkynes afford a ca. 6:1 mixture of regioisomers. The observed regioselectivity for the cycloaddition step and the ease of reaction are consistent with predictions derived from computing the HOMO-LUMO energies of the reactants.     

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.     

Ruthenium-catalyzed 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols with azides

The 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols 1 with azides in the presence of catalytic [Cp*RuCl₂]_n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles 2 in high yields.     

Regioselective synthesis of novel spiroindane-1,3-diones through 1,3-dipolar cycloaddition reactions

A facile synthesis of novel spiroindane-1,3-diones has been achieved via 1,3-dipolar cycloaddition of an azomethine ylide, generated in situ from ninhydrin and 1,2,3,4-tetrahydroisoquinoline, with the conjugated double bond of chalcone derivatives. The regiochemistry and structures of the cycloadducts were determined with spectroscopic data and by X-ray crystal structure analysis.     

A facile synthesis and highly atom economic 1,3-dipolar cycloaddition of hexahydropyrido[3,4-c][1,5]benzothiazepines with nitrile oxide: stereoselective formation of hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines

A series of new 2-methyl-11-aryl-4-[(E)-arylmethylidene]-1,2,3,4,11,11a-hexahydropyrido[3,4-c][1,5]benzothiazepines were obtained by the reaction of o-aminothiophenol and (E)-1-methyl-3,5-bis(arylidene)-4-piperidones in the presence of a catalytic amount of acetic acid under solvent-free microwave irradiation. These dipolarophiles undergo a highly atom economic 1,3-dipolar cycloaddition with nitrile oxide to afford a series of novel 6-methyl-1-phenyl-8-aryl-4-[(E)-arylmethylidene]-4,5,6,7,7a,8-hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines stereoselectively.     

Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO₃ to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a–p in high yields via 1,3-dipolar cycloaddition reaction.     

Catalyst free three-component synthesis of (±)-pyrazolylpyrrolopyrroles by 1,3-dipolar cycloaddition reaction

Novel pyrazolylpyrrolopyrroles were prepared by the three-component reaction of pyrazole-4-carbaldehydes, α-amino acid esters and 1-arylmaleimides in toluene and in the absence of a catalyst. This protocol provided a simple one-step procedure for the synthesis of the title compounds with the advantage of an easy work-up, mild reaction conditions and endo-selectivity.