Cycloaddition Of Azomethine Ylides Research Articles

Brønsted Base and Lewis Acid Cooperatively Catalyzed Asymmetric exo'-Selective [3 + 2] Cycloaddition of Trifluoromethylated Azomethine Ylides and Methyleneindolinones.

A Brønsted base and Lewis acid cooperatively catalyzed 1,3-dipolar cycloaddition is reported through chiral dinuclear zinc catalysts. An asymmetric exo'-selective [3 + 2] cycloaddition of CF3-containing N-unprotected isatin-derived azomethine ylides is realized. In the presence of 10 mol % of catalyst, azomethine ylides react efficiently with methyleneindolinones, giving a series of trifluoromethyl-substituted 2,3-pyrrolidinyl dispirooxindoles with highly enantio- (up to 99% ee) and exo'-selectivity (>20:1 dr). Up to four contiguous stereogenic centers, including two adjacent spiro quaternary stereocenters, are constructed in one step.

Catalytic Enantioselective Formal Synthesis of MDM2 Antagonist RG7388 and Its Analogues

Summary of main observation and conclusionThe catalytic asymmetric 1,3‐dipolar [3 + 2] cycloaddition of azomethine ylides with stilbenes has been established, affording structurally diverse pyrrolidines bearing four contiguous stereocenters with stereo‐diversity in generally high yields and good to excellent stereoselectivities (up to 98% yield, 99 : 1 dr, >99% ee). Meanwhile, this strategy allowed the formal synthesis of antitumor drug RG7388 (Phase III clinical study) and its analogues in high efficiency.

Regioselectivity of (3+2) cycloaddition of azomethine ylides to activated olefins in the synthesis of spiro[oxindole-3,2′-pyrrolidine] derivatives

The effect of the structure of the starting compounds on the regioselectivity of the (3+2) cycloaddition of azomethine ylides to olefins activated by electron-withdrawing groups in the synthesis of spiro[oxindole-3,2′-pyrrolidine] derivatives is generalized and analyzed.

Microwave accelerated azomethine ylide cycloaddition with Baylis–Hillman adducts

Azomethine ylides generated in situ from isatins and α-amino acids undergo smooth 1,3-dipolar cycloaddition with olefins derived from the Baylis–Hillman reaction to produce fused 2-quinolinone derivatives in good yields with high selectivity. The use of microwave irradiation makes this method quite simple and rapid to generate polycyclic frameworks in a single step.

Synthesis and cytotoxicity of oxindoles dispiro derivatives with thiohydantoin and adamantane fragments

An effective and highly regio- and diastereoselective one-pot synthesis of two types of dispiro heterocyclic systems (2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones and 2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones) comprising pyrrolidinyl-oxindole, thiohydantoin and adamantane moieties has been developed based on a 1,3-dipolar cycloaddition of azomethine ylides, generated from isatin and sarcosine or formaldehyde and sarcosine, to adamantane-containing electron-deficient alkenes. Several molecules have demonstrated a considerable cytotoxicity against A549, HEK293T, MCF7 and VA13 cancer cell lines. The possible mechanism of anticancer activity of the synthesized compounds based on literature data may be the inhibition of p53/MDM2 interaction; however, we did not observe significant p53 activation using a reporter construction in A549 cell line in the relevant concentration range.

1,3-Dipolar Cycloaddition of 3-Amino Oxindole-Based Azomethine Ylides and O-Vinylphosphonylated Salicylaldehydes for Diastereoselective Synthesis of Oxindole Spiro-P,N-polycyclic Heterocycles

An efficient stereoselective assembly strategy for the construction of pyrrolidin-2,3′-oxindole cis-fused phosphadihydrocoumarins was established. The process involves the condensation of O-vinylphosphonylated salicylaldehydes and 3-amino oxindoles followed by intermolecular cycloaddition with high diastereoselectivity and atom economy.

Synthesis of Spirocyclic Amines by 1,3-Dipolar Cycloaddition of Azomethine Ylides and Azomethine Imines

Simple ketone starting materials with a halide leaving group and an alkene were prepared in one step and heated with glycine or glycine esters to promote a tandem imine formation, cyclization, and dipolar cycloaddition cascade. The chemistry was also feasible with acetylhydrazide. In each case a single stereoisomer of the tricyclic amine or pyrazolidine product was formed and the stereochemistry was verified by single crystal X-ray diffraction. When the reaction with glycine, which occurs with loss of CO2, was unsuccessful, the cascade process could be promoted by cross metathesis to give the vinyl sulfone starting material that provides a more reactive dipolarophile. Reductive cleavage of the pyrazolidine gave a spirocyclic diamine product.

Substitution induced switch between Pictet-Spengler and Eschweiler-Clarke reactions: Selective synthesis of spiro acenaphthylene pyrrolo[1,2-b]-isoquinoline/pyrrolidine hybrids

The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the decarboxylative condensation of acenaphthenequinone and tyrosine or phenylalanine to β-nitrostyrenes afforded spiro acenaphthylene-pyrrolidine hybrids. The subsequent reaction of these spiro heterocycles with formaldehyde and trifluoroacetic acid led to the formation of either Pictet-Spengler or Eschweiler-Clarke products depending on the substitution in the benzyl ring. The unsubstituted compounds occurred via Pictet-Spengler route to afford spiro acenaphthylene pyrrolo[1,2-b]isoquinoline hybrids as expected, whereas the 4-OH substituted compounds proceeded via Eschweiler-Clarke route affording the unexpected N-methylated spiro acenaphthylene-pyrrolidine hybrids.

Synthesis and Electrochemical Estimation of DNA-Binding Capacity of Novel Ferrocene-Containing Pyrrolidines

The design, synthesis, spectral and electrochemical characterization of a series of novel pyrrolidine derivatives have been described. The synthesis was achieved by 1,3-dipolar cycloaddition of azomethine ylides and ferrocene-substituted chalcones, while detailed characterization of the compounds was performed by IR, NMR and elemental analyses, followed by X-ray diffraction experiment for one representative. The electrochemical properties of obtained ferrocene-containing heterocycles were examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). These techniques revealed the quasi-reversible one-electron oxidation process. DNA-binding capacity of all products was studied using CV and DPV, highlighting a derivative with five times better binding affinity than the others. DFT calculations and molecular docking studies were carried out to gain more exhaustive insight into the type of interactions of the distinguished compound and the nucleic acid.

Stereoselective synthesis of dispiro heterocycles by [3 + 2] cycloaddition of azomethine ylides with a thiazolo[3,2-a]indole derivative.

A green one pot three component [3 + 2] cycloaddition of a thiazolo[3,2-a]indole derivative (generated by the reaction of thieno[2,3-b]indole-2,3-dione and dimethyl acetylenedicarboxylate) with isatin derived azomethine ylides is reported here. An eco-friendly acetyl choline iodide-ethylene glycol (ACI/EG)-mediated deep eutectic solvent system was adopted for the reaction. Spiropyrrolidine oxindoles incorporating multiple stereocenters were obtained in a highly diastereoselective manner in excellent yields.

Regio- and stereoselective synthesis of spiropyrrolidine-oxindole and bis-spiropyrrolizidine-oxindole grafted macrocycles through [3 + 2] cycloaddition of azomethine ylides

A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.

Catalytic asymmetric synthesis of diazabicyclo[3.1.0]hexanes by 1,3-dipolar cycloaddition of azomethine ylides with azirines.

Substituted 1,3-diazabicyclo[3.1.0]hexanes with two contiguous quaternary stereocentres are readily prepared by catalytic asymmetric [3+2] cycloaddition of α-substituted iminoesters with azirines. High diastereoselectivities and enantioselectivities (up to 98% ee) are achieved using CuI/(R)-Fesulphos as the catalytic system.

Ming-Phos/Copper(I)-Catalyzed Asymmetric Intermolecular[3+2] Cycloaddition of Azomethine Ylides with Trifluoromethyl Enones

Ming-Phos/Copper(I)-Catalyzed Asymmetric Intermolecular[3+2] Cycloaddition of Azomethine Ylides with Trifluoromethyl Enones

Cu/TEMPO catalyzed dehydrogenative 1,3-dipolar cycloaddition in the synthesis of spirooxindoles as potential antidiabetic agents.

A series of spiro-[indoline-3,3′-pyrrolizin/pyrrolidin]-2-ones, 4, 5 and 6 were synthesized in a sequential manner from Cu–TEMPO catalyzed dehydrogenation of alkylated ketones, 1 followed by 1,3-dipolar cycloaddition of azomethine ylides via decarboxylative condensation of isatin, 2 and l-proline/sarcosine, 3 in high regioselectivities and yields. The detailed mechanistic studies were performed to identify the reaction intermediates, which revealed that the reaction proceeds via dehydrogenative cycloaddition. Additionally, the regio and stereochemistry of the synthesized derivatives were affirmed by 2D NMR spectroscopic studies. The synthesized derivatives were explored further with molecular docking, in vitro antioxidant, and anti-diabetic activities.

Ming-Phos/Copper(I)-Catalyzed Asymmetric[3+2] Cycloaddition of Azomethine Ylides with Nitroalkenes

Ming-Phos/Copper(I)-Catalyzed Asymmetric[3+2] Cycloaddition of Azomethine Ylides with Nitroalkenes

Kinetic resolution of 2H-azirines via Cu(i)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

An efficient kinetic resolution of racemic 2H-azirines via copper(i)-catalyzed asymmetric cycloaddition of azomethine ylides was developed and enantioenriched 2H-azirines and 1,3-diazabicyclo[3.1.0]hexane derivatives were obtained simultaneously.

Formal [3 + 2] cycloaddition of azomethine ylides generated in situ with unactivated cyclic imines: A facile approach to tricyclic imidazolines derivatives

AbstractA simple and efficient method for the synthesis of tricyclic imidazolines derivatives via [3 + 2] 1,3‐dipolar cycloaddition between nonstabilized azomethine ylide generated in situ with unactivated cyclic imines is reported here. The method provided easy and mild access to various fused tricyclic hexahydroimidazo[5,1‐a]isoquinolines in excellent yields (up to 96%). This protocol is simple and easy to handle.

Design and synthesis of novel spirooxindole-indenoquinoxaline derivatives as novel tryptophanyl-tRNA synthetase inhibitors.

In the current study, we used an integrated approach combining bioinformatics, rational drug design, one-pot synthesis, and biological experiments in vitro for the potential discovery of novel tryptophanyl-tRNA synthetase (TrpRS) inhibitors. Atom economic and diastereoselective syntheses were used to generate several Spirooxindole-indenoquinoxaline derivatives in situ from isatin and amino acids viz. proline, phenylglycine, and sarcosine through targeting the 1,3-dipolar cycloaddition of azomethine ylides. These compounds were assayed by biochemical TrpRS inhibition, using in vitro experiments to test against various gram-positive and gram-negative strains, and using diffuse large B cell lymphoma (DLBCL) cell lines. Compound 6e was found to be the most active in vitro with IC50 values of 225 and 74nM for tests against hmTrpRS and ecTrpRS, respectively. We also found a MIC90 value of 4µg/mL for tests against S. aureus and IC50 values which ranged from 2.9 to 4.8µM for tests against proliferation of DLBCL cell lines. Moreover, compound 6e was remarkably good at inducing bacterial autolysis in MRSA strains. Our results suggested that such an integrated approach could be an attractive and viable strategy for the discovery of novel TrpRS inhibitors as potential lead compounds for antibiotics and as novel anticancer agents. Discovery of novel spirooxindole-indenoquinoxaline TrpRS inhibitors as potential lead compounds with antibacterial and antitumor activities.

Electrochemical characterization and estimation of DNA-binding capacity of a series of novel ferrocene derivatives

The synthesis of a series of methyl 2-alkyl-5-aryl-4-ferrocenoylpyrrolidine-2-carboxylates has been achieved by [3 + 2] dipolar cycloaddition of azomethine ylides to acryloylferrocene. The electrochemical properties of novel products were examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). These techniques revealed the quasi-reversible one-electron oxidation process. The DNA-binding capacity of all the products was also studied using CV and DPV, and significant interactions between synthesized compounds and nucleic acid, mostly of the electrostatic type, were disclosed. DFT calculations and molecular docking tests were carried out to gain a more exhaustive insight into the interactions of the obtained products with nucleic acid. A detailed characterization of the new compounds was performed by IR, NMR and elemental analyses, followed by single-crystal X-ray diffraction experiments for two representatives.

Sequential decarboxylative [3+2] cycloaddition and Staudinger/aza-Wittig reactions for diastereoselective synthesis of tetrahydro-pyrroloquinazolines and tetrahedro-pyrrolobenzodiazepines

A method for diastereoselective synthesis of tetrahydro-pyrroloquinazolines and tetrahydro-pyrrolobenzodiazepines is developed through sequential reactions including decarboxylative 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, N-acylation or N-alkylation, and the Staudinger/aza-Wittig reactions.