Cycloaddition Of Nitrilimines Research Articles

Design, synthesis and characterization of functionalized pyrazole derivatives bearing amide and sulfonamide moieties from aza-aurones

In this work, we report the synthesis of new pyrazole derivatives bearing amide and sulfonamide frameworks from aza-aurones. Firstly, the intermediate spiropyrazolines were obtained through a highly regioselective 1,3-dipolar cycloaddition of nitrilimines with aza-aurones. Subsequently, the obtained cycloadducts were subjected to hydrochloric acid in hot ethanol which conducts to 5-(2-aminobenzoyl)-3,4-diaryl-1-phenylpyrazoles. Finally, the target compounds were obtained separately by the action of acetic anhydride, benzoyl chloride and tosyl chloride on the intermediates 2-aminobenzoylpyrazoles, respectively. Structures of all the synthesized compounds were established using IR, 1H NMR and 13C NMR and mass spectroscopy. Synthesis and characterization of novel heterocyclic systems encompassing pyrazole derivatives from aza-aurones are reported. The synthetic routes used in this work are efficient and relevant, involving the 1,3-dipolar cycloaddition and alkylation reactions. The outcomes show that spectroscopic data fit the structure of all synthesized compounds.

Structure Determination and Quantum Chemical Analysis of 1,3-Dipolar Cycloaddition of Nitrile Imines and New Dipolarophiles and POM Analyses of the Products as Potential Breast Cancer Inhibitors

The 1,3-dipolar cycloaddition of nitrile imines to 11-aryl-4-(arylmethylidene)-1,2,3,4,11,11a-hexahydrodibenzo[b,e][1,4]thiazepines possessing exocyclic C=C and endocyclic C=N bonds as dipolarophilic sites showed site selectivity, depending on the type of C-substituent in the nitrile imine. 1,3-Dipolar cycloaddition of C-aryl nitrile imines occurred selectively to the exocyclic C=C bond, whereas the endocyclic C=N bond was involved in the cycloaddition with C-ethoxycarbonyl nitrile imines. A combination of total energy and molecular orbital plots for the highest occupied and lowest unoccupied molecular orbitals was used to verify the proposed reaction mechanisms and stereoselectivity. Some of the isolated products exhibited moderate to good antitumor activity. The results of POM analysis of the relative cytotoxicity of these new derivatives in comparison to Doxorubicin are also reported.

Dual 1,3-dipolar cycloaddition of nitrilimines with cyclopenta[a]acenaphthylen-8-ones. A synthesis of hexacyclic bis-dihydropyrazoles

A regioselective 1,3-dipolar cycloaddition of nitrilimines, generated from hydrazonoyl chlorides, with both C = C double bonds of cyclopentadienone moiety of cyclopenta[a]acenaphthylen-8-ones in the presence of Et3N is described. This dual cycloaddition reaction affords a nearly 3:2 mixture of symmetrical and unsymmetrical hexacyclic bis-dihydropyrazol derivatives in good yields. The stereochemistry of diethyl 3,7-bis(4-chlorophenyl)-4-oxo-1,5-diphenyl-1H-naphtho[1′,8′:4,5,6]pentaleno[1,6a-c:3a,3-c′]dipyrazole-3a,4a(4H,5H)-dicarboxylate was established by X-ray crystallography.

Synthesis of Novel 1-(1,5-Diaryl-1,10b-Dihydropyrrolo- [1,2-A][1,2,4]Triazolo[3,4-C]Pyrazin-3-Yl)Ethanones Via 1,3-Dipolar Cycloaddition of Nitrilimine

The 1,3-dipolar cycloaddition of nitrilimine, generated in situ from (Z)-N-aryl-2-oxopropanehydrazonoyl bromide and Et3N, to 3-arylpyrrolo[ 1,2-a]pyrazine afforded novel 1-(1,5-diaryl-1,10b-dihydropyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazin-3-yl)ethanones in moderate yields. The structures of all the products were characterized thoroughly by NMR, IR, and HRMS.

3+2] Cycloaddition of Methylenedihydrobenzofurandiones and Nitrilimines: Synthesis of Sipropyrazole Compounds

3+2] Cycloaddition of Methylenedihydrobenzofurandiones and Nitrilimines: Synthesis of Sipropyrazole Compounds

Synthesis of Dihydropyrano[3,2-c]pyrazolone through 1,3-Dipolar Cycloaddition of Nitrilimines with Methyl Coumalate

Synthesis of Dihydropyrano[3,2-<i>c</i>]pyrazolone through 1,3-Dipolar Cycloaddition of Nitrilimines with Methyl Coumalate

DFT study of double 1,3-dipolar cycloaddition of nitrilimines with allenoates

The double 1,3-dipolar cycloaddition reaction between nitrilimine and allenoate, experimentally investigated by Guo and co-workers, was theoretically studied at the B3LYP/6-311G** and wB97XD/6-311G** computational levels in both gas phase and dichloromethane solution. The results indicated that the formation of the experimentally reported product is clearly explained by the analysis of the calculated Fukui function reactivity indices as well as transition states studies. Frontier molecular orbitals analysis showed that the HOMO orbital of nitrilimine as donor is also the frontier effective-for-reaction molecular orbital (FERMO). Finally, on the basis of the Wiberg bond indexes and AIM analysis, it was found that all of the reactive channels proceed through an asynchronous concerted mechanism.

Synthesis of spiropyrazolinyl/isoxazolinyl thienofuranones under green approach and their antimicrobial activity

A new class of spiroheterocycles—pyrazolinyl thienofuranones and isoxazolinyl thienofuranones were prepared from heteroarylmethylene thienofuranones exploiting 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides generated from araldehyde phenylhydrazones and araldoximes under green conditions using iodosobenzene and cetyltrimethylammonium bromide as surfactant. All the compounds are tested for their antimicrobial activity. Pyridine substituted pyrazolinyl and isoxazolinyl thienofuranones displayed prominent antibacterial activity against Bacillus subtilis and antifungal activity against Aspergillus niger greater than the standard drug chloramphenicol and ketoconazole.

Synthesis of 1,2,4-Triazol-3-imines via Selective Stepwise Cycloaddition of Nitrile Imines with Organo-cyanamides.

A convenient method for the synthesis of 1,2,4-triazol-3-imines through a selective, formal, 1,3-dipolar cycloaddition of organo-cyanamide ions with nitrile imine dipoles is reported. Hydrolysis of the 1,2,4-triazol-3-imines yields the corresponding 1,2,4-triazol-5-ones. A stepwise mechanism, supported by DFT calculations, is invoked to explain the reaction selectivity.

Nitrilimine cycloadditions catalyzed by iron oxide nanoparticles

Nitrilimine cycloadditions to ethylenes, acetylenes, and activated nitriles have been exploited in the presence of catalytic amounts of oleic-acid-coated iron oxide nanoparticles (diameter = 11.9 ± 1.0 nm). The reactions were fully regioselective with monosubstituted ethylenes and ethyl cyanoformiate, while mixtures of cycloadducts were obtained in the presence of methyl propiolate. The intervention of iron oxide nanoparticles allowed carrying out the cycloadditions at milder conditions compared to the metal-free thermal processes. A labile intermediate has been proposed to explain this behavior.

Green approach for the synthesis of thiophenyl pyrazoles and isoxazoles by adopting 1,3-dipolar cycloaddition methodology and their antimicrobial activity

A variety of N-((1,3-diphenyl-5-aryl-1H-pyrazol-4-yl)sulfonyl)thiophene-2-carboxamides (7) and N-((5-aryl-3-phenylisoxazol-4-yl)sulfonyl)thiophene-2-carboxamides (8) were prepared from (E)-N-(arylethenesulfonyl)thiophene-2-carboxamides (4) adopting 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides generated from araldehyde phenylhydrazones and araldoximes in the presence of iodosobenzene and CTAB followed by oxidation with I2 in DMSO. The compounds 4f, 7e, 7f, 8e and 8f showed potential antibacterial activity against B. subtilis whereas 8e and 8f exhibited potential antifungal activity against A. niger.

Synthesis of 2-polyfluoroalkyl-2,3-dihydro-1,3,4-thiadiazoles via regioselective [3+2] cycloaddition of nitrile imines to polyfluoroalkanethioamides

[3+2] Cycloaddition reactions of polyfluoroalkanethioamides with nitrile imines, generated in situ by dehydrochlorination of the corresponding hydrazonoyl chlorides, in the presence of triethylamine, were studied. A new method was proposed on the basis of these reactions for the synthesis of 2-polyfluoroalkyl-2,3-dihydro-1,3,4-thiadiazoles.

Synthesis of Novel Spiro(Indolizine-Pyrazole) Derivatives via 1,3-Dipolar Cycloaddition of Nitrilimine

The 1,3-dipolar cycloaddition of nitrilimine, generated in situ from N′-phenylbenzohydrazonoyl chloride and triethylamine, to 7-arylmethylidene-6,7-dihydroindolizin-8( 5H)-one afforded novel 4′-aryl-2′,5′-diphenyl-2′,4′,5,6-tetrahydro-8 H-spiro(indolazine-7,3′-pyrazol)-8-ones in moderate yields. The structures of all the products were characterised thoroughly by NMR, infrared spectroscopy and HRMS. The structure and stereochemistry was confirmed by X-ray diffraction analysis.

Synthesis of Spirobidihydropyrazole through Double 1,3-Dipolar Cycloaddition of Nitrilimines with Allenoates.

The double 1,3-dipolar cycloaddition of allenoates with nitrilimines has been achieved under mild reaction conditions, affording a variety of spirobidihydropyrazoles in moderate to excellent yields with excellent diastereoselectivities. The reaction diastereoselectively constructs double dihydropyrazole moieties and two chiral centers including a spiro carbon center.

3+2]-Cycloadditions of nitrilimines with heteroaryl thioketones

The in situ generated nitrilimines are trapped efficiently with heteroaryl thioketones bearing thiophen-2-yl or selenophen-2-yl substituents. The exclusive products observed in these reactions are 2,3-dihydro-1,3,4-thiadiazoles formed via regioselective [3+2]-cycloaddition. Competitive head-to-tail dimerization of the intermediate 1,3-dipoles was not observed in any of the studied reactions.

1,3-Dipolar Cycloaddition of Nitrile Imine with Carbon Dioxide: Access to 1,3,4-Oxadiazole-2(3H)-ones.

Efficient synthesis of 1,3,4-oxadiazole-2(3H)-one was achieved by CsF/18-crown-6 mediated 1,3-dipolar cycloaddition of nitrile imine and 2.0 MPa of CO2. CsF/18-crown-6 played a key role in enhancing the reactivity of CO2 as a 1,3-dipolarophile. The practical utility of this transition-metal-free approach to 1,3,4-oxadiazole-2(3H)-one is highlighted by the convenient synthesis of a commercial herbicide Oxadiazon and a MAO B inhibitor.

Microwave assisted regioselective synthesis of novel pyrazoles and pyrazolopyridazines via fluorine containing building blocks

A facile regioselective synthesis of novel pyrazole derivatives containing a fluorophenyl moiety via the 1,3-dipolar cycloaddition of nitrileimines and enamines using conventional as well as microwave irradiation conditions have been achieved. Fluorine-containing building blocks methodology was used in order to access the targeted fluorinated compounds. The structures of the synthesized products were confirmed by 1H NMR, FT-IR, mass spectrometry, and elemental analyses. Furthermore, the synthesized pyrazoles have been used in the synthesis of some new pyrazolo pyidazines containing pendent to fluorophenyl moiety. An unambiguous structural assignment of the obtained pyrazole regioisomers was determined using the 1H NMR analysis as a valuable tool.

Co-opting a Bioorthogonal Reaction for Oncometabolite Detection.

Dysregulated metabolism is a hallmark of many diseases, including cancer. Methods to fluorescently detect metabolites have the potential to enable new approaches to cancer detection and imaging. However, fluorescent sensing methods for naturally occurring cellular metabolites are relatively unexplored. Here we report the development of a chemical approach to detect the oncometabolite fumarate. Our strategy exploits a known bioorthogonal reaction, the 1,3-dipolar cycloaddition of nitrileimines and electron-poor olefins, to detect fumarate via fluorescent pyrazoline cycloadduct formation. We demonstrate hydrazonyl chlorides serve as readily accessible nitrileimine precursors, whose reactivity and spectral properties can be tuned to enable detection of fumarate and other dipolarophile metabolites. Finally, we show this reaction can be used to detect enzyme activity changes caused by mutations in fumarate hydratase, which underlie the familial cancer predisposition syndrome hereditary leiomyomatosis and renal cell cancer. Our studies define a novel intersection of bioorthogonal chemistry and metabolite reactivity that may be harnessed to enable biological profiling, imaging, and diagnostic applications.

ChemInform Abstract: Stoichiometry‐Controlled Cycloaddition of Nitrilimines with Unsymmetrical Exocyclic Dienones: Microwave‐Assisted Synthesis of Novel Mono‐ and Dispiropyrazoline Derivatives.

Microwave-assisted 1,3-dipolar cycloaddition of (E,E)-1,3-bisarylidenetetral-2-ones with nitrilimines, generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides, affords a series of spiropyrazolines in good to excellent yields. The presence of a second exocyclic CC bond also allows the preparation of dispiropyrazolines. The cycloaddition proceeds with high chemo-, regio- and diastereoselectivity. The structure of the spiranic adducts has been established on the basis of their spectroscopic data and elemental analyses. The stereochemistry of these N-heterocycles has been confirmed by two X-ray diffraction studies. The luminescence properties and fluorescence quantum yields of these heterocyclic compounds have been investigated revealing that some of them are fluorescent in solution.

ChemInform Abstract: 1,3‐Dipolar Cycloaddition of Carbodiimides and Nitrilimines: Synthesis and Mechanistic Study of 5‐Amino‐1,2,4‐triazoles.

Abstract1,3‐Dipolar cycloaddition of nitrilimines, generated from hydrazonoyl chlorides with carbodiimides (II) provides a novel synthesis of 5‐amino‐1,2,4‐triazoles.