Reaction Of Azomethine Ylides Research Articles

Novel spirooxindole-triazole derivatives: unveiling [3+2] cycloaddition reactivity through molecular electron density theory and investigating their potential cytotoxicity against HepG2 and MDA-MB-231 cell lines.

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl-s-triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide (AY) with the corresponding chalcones (6a-d). Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif. A comprehensive investigation of the 32CA reaction mechanism was conducted using Molecular Electron Density Theory (MEDT). The viability of all compounds was evaluated through an MTT assay, and the IC50 values were determined using Prism Software. The antiproliferative efficacy of the synthesized chalcones and the corresponding spirooxindole derivatives was assessed against two cancer cell lines: MDA-MB-231 (triple-negative breast cancer) and HepG2 (human hepatoma). These findings were compared with Sorafenib, which was used as a positive control. The results revealed that chalcones (6c and 6d) were the most active among the tested chalcones, with IC50 values of 7.2 ± 0.56 and 7.5 ± 0.281µM for (6c) and of 11.1 ± 0.37 and 11.0 ± 0.282µM for (6d), against MDA-MB-231 and HepG2, respectively. Spirooxindoles (9b, 9c, 9h, and 9i) exhibited the highest activity with IC50 values ranging from 16.8 ± 0.37µM to 31.3 ± 0.86µM against MDA-MB-231 and 13.5 ± 0.92µM to 24.2 ± 0.21µM against HepG2. In particular, spirooxindole derivatives incorporating 2,4-dichlorophenyl moiety were the most active, with an IC50 of 16.8 ± 0.37µM for (9h) against MDA-MB-23 and 13.5 ± 0.92µM for (9i) against HepG2. Interestingly, the IC50 of compound (6c) (7.2µM) exhibited better activity than that of Sorafenib (positive control) (9.98µM) against MDA-MB-231. Molecular docking, ADMET, and molecular dynamic simulations were conducted for the promising candidates (6b, 6c, and 9h) to explore their binding affinity in the EGFR active site.

Enantioselective organocatalyzed one-pot synthesis of N-phenyl thioether-tethered tetrasubstituted dihydropyrrole-3-carbaldehydes.

An efficient method for the asymmetric one-pot synthesis of N-phenyl thioether-tethered tetrasubstituted chiral 4,5-dihydropyrrole-3-carbaldehydes have been developed using readily available benzothiazolium salts and α,β-unsaturated aldehydes as starting materials in the presence of the chiral organocatalyst (R)-diphenylprolinol trimethylsilyl ether. The protocol afforded various functionally enantioenriched chiral tetrasubstituted 4,5-dihydropyrrole-3-carbaldehydes in high yields, with excellent enantio- and diastereoselectivity (≤90% yield, ≤98% ee, and >20 : 1 d.r.). This asymmetric one-pot reaction starts with the reaction of azomethine ylides with dipolarophiles to yield pyrrolo-thiazine-2-carbaldehydes as intermediates. Subsequently, the electrophile alkyl halide is attacked by the sulfur atom of the intermediate, followed by C-S bond cleavage (ring-opening), which furnishes the desired chiral tetrasubstituted 4,5-dihydropyrroles.

Electron-rich benzofulvenes as effective dipolarophiles in copper(i)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides.

A series of benzofulvenes without any electron-withdrawing substituents were employed as 2π-type dipolarophiles for the first time to participate in Cu(i)-catalyzed asymmetric 1,3-dipolar cycloaddition (1,3-DC) reactions of azomethine ylides. An intrinsic non-benzenoid aromatic characteristic from benzofulvenes serves as a key driving force for activation of the electron-rich benzofulvenes. Utilizing the current methodology, a wide range of multi-substituted chiral spiro-pyrrolidine derivatives containing two contiguous all-carbon quaternary centers were formed in good yield with exclusive chemo-/regioselectivity and high to excellent stereoselectivity. Computational mechanistic studies elucidate the origin of the stereochemical outcome and the chemoselectivity, in which the thermostability of these cycloaddition products is the major factor.

Synthesis and anti-Cancer Activity of a New Hybrid Based Spirooxindole-Pyrrolidine -Thiochromene Scaffolds via [3 + 2] Cycloaddition Reaction: Computational Investigation

A combined experimental and theoretical study of a newly synthesized cycloadduct of spirooxindole based thiochromene scaffold via [3 + 2] cycloaddition (32CA) reaction approach has been performed. The final adducts occurred via reaction of azomethine ylide (AY) with the ethylene derivative via ortho/endo 32CA protocol in respective regio- and diastereoselective fashion. In the light of the importance of intermolecular interactions in the crystal stability, Hirshfeld calculations were employed to predict all possible contacts affecting the molecular packing in the solid state of the studied systems. The results shed the light on the importance of O…H, F…H and H…C interactions as well as the π-π stacking interactions on the molecular packing. DFT calculations were used to compute the minimum energy structures and predict their electronic properties such as dipole moment, charge population and conceptual DFT reactivity descriptors. The 1H- and 13C-NMR spectra of the studied systems were calculated and the resulting chemical shifts correlated very well with the experimental data (R2= 0.991-0.978). The anti-cancer activity of the synthesized spirooxindole based thiochromene motif was assessed and showed IC50 of 8.34 ± 0.64, 11.25 ± 0.28, 16.0 ± 0.7, and 25.3 ± 0.25 µM against the four cancer cell lines MCF-7, MDA-MB231, PC3, and HeLa, respectively.

FAM-Ag-catalyzed asymmetric synthesis of heteroaryl-substituted pyrrolidines.

New derivatives of FAM (ferrocenyl aziridinyl methanol) ligands NFAM1-4 (naphthyl ferrocenyl aziridinyl methanol) and CFAM1-4 (cyclohexyl ferrocenyl aziridinyl methanol) were synthesized to form a small ligand library and used as chiral catalysts with AgOAc for the asymmetric synthesis of heteroaryl-substituted pyrrolidines by the 1,3-dipolar cycloaddition (1,3-DC) reaction of azomethine ylides. 2-Thienyl, 2-furyl, 2-, 3-, and 4-pyridyl aldimines were prepared and used with N-methylmaleimide, dimethyl maleate, tert-butyl acrylate, methyl acrylate, and acrylonitrile to form the corresponding heteroaryl-substituted pyrrolidines. 1,3-DC reactions yielded the expected cycloadducts in up to 89% yield and up to 76% ee that could be increased up to 95% ee upon crystallization. New chiral ligands NFAM1-4 and CFAM1-4 were fully characterized, and their absolute stereochemistry was determined by single-crystal X-ray analysis.

Rapid synthesis of hexahydropyrrolo[3,4-b]pyrrole-fused quinolines via a consecutive [3 + 2] cycloaddition and reduction/intramolecular lactamization cascade

An unprecedented synthesis of novel hexahydropyrrolo[3,4-b]pyrrole-fused quinolines is achieved through the sequential [3 + 2] cycloaddition reaction of azomethine ylides with maleimides followed by intramolecular lactamization.

Enantio‐ and Diastereoselective Synthesis of β‐Aryl‐β‐pyrazolyl α‐Amino Acid Esters via Copper‐Catalyzed Reaction of Azomethine Ylides with Benzylidenepyrazolones

AbstractA fully stereoselective synthesis of unnatural chiral β‐aryl‐β‐pyrazolyl α‐amino acid esters via copper‐catalyzed addition reactions of azomethine ylides with benzylidenepyrazolones bearing two contiguous stereogenic centers was developed. A 1H‐pyrazol‐5‐ol was introduced by the aromatization of 3H‐pyrazol‐3‐one in the reaction. The transformation operated at room temperature and afforded β‐1H‐pyrazol‐5‐ol‐α‐amino esters in high yields with good to excellent levels of diastereo‐ and enantioselectivity.magnified image

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.

A one-pot three-component synthesis of fused Spiro-Indoline/Indene derivatives derived from ethynyl azaindole by 1,3-dipolar cycloaddition reaction

A one-pot method for the simple, efficient, and environmentally benign protocol for the synthesis of Spiro-Indoline/Indene derivatives containing Aza indole moiety as a side chain is outlined. The 1,3-dipolar cycloaddition reaction of azomethine ylides derived from ethynyl Azaindole under mild conditions is accomplished. The low cost, easy availability of the starting material, and simple reaction conditions suggest the possible use of the present method for large-scale preparations.

Efficient synthesis of spirooxindole-pyrrolizidines and dispirooxindole-piperazines

ABSTRACTA simple and efficient approach for the construction of spirooxindole-pyrrolizidines and dispirooxindole-piperazines by cycloaddition reaction of azomethine ylide generated by isatin and proline has been demonstrated successfully. The formation of two different types of frameworks by two different modes of cycloaddition is explored. The developed protocol highlights simple reaction conditions, easy workup processes, and very good yields of products.

Tandem [3 + 2] Cycloaddition/1,4-Addition Reaction of Azomethine Ylides and Aza-o-quinone Methides for Asymmetric Synthesis of Imidazolidines.

An enantioselective synthesis of biologically important imidazolidines has been achieved via a tandem [3 + 2] cycloaddition/1,4-addition reaction of azomethine ylide and aza-o-quinone methides. With the use of this tool, various imidazolidine derivatives are obtained in good yields with excellent diastereoselectivities and enantioselectivities.

Chemical functionalization of boron nitride nanotube via the 1,3-dipolar cycloaddition reaction of azomethine ylide: a quantum chemical study

The first principle exploration at the M05-2X/6-31+G(d,p) level was performed to investigate the chemical functionalizations of (6,0) zigzag single-walled BNNT via the 1,3-dipolar cycloaddition reaction of azomethine ylide. Two types of functionalized BNNTs (D and A complexes) were found in the reaction between 2-methoxy-N,N-dimethylethanamine (MDE) and BNNT. It is energetically favorable for the MDE functional group to interact with the B–N bonds slanted to the tube axis (in D-type complexes). The configuration of the lowest minimum energy corresponds to geometry D1, which the functional group interacts with the end of N-terminated BNNT. The results show that the functionalization of BNNT by MDE functional group is accompanied by a decrease in the band gap, so that this decrease in A complexes is greater than that in the corresponding D ones. Also, the results obtained by natural bond orbital analysis showed that the charge transfer occurs from nanotube to MDE functional group.

Concerted vs. Non‐Concerted 1,3‐Dipolar Cycloadditions of Azomethine Ylides to Electron‐Deficient Dialkyl 2,3‐Dicyanobut‐2‐enedioates

AbstractThe quantum‐chemical calculations of the thermal ring opening of 1‐methyl‐2,3‐diphenyl‐ and 1,2,3‐triphenylaziridine with formation of the corresponding azomethine ylides of S‐, U‐, and W‐type as well as their cycloaddition to dimethyl acetylenedicarboxylate (DMAD) and dimethyl 2,3‐dicyanobut‐2‐enedioate, were performed at the DFT B3LYP/6‐31G(d) level of theory with the PCM solvation model. The calculations are in complete accordance with experimental results and explain the switch from the concerted to the non‐concerted pathway depending on substituents in the dipolarophile and the ylide. It was found that strong electron‐withdrawing substituents in dipolarophiles, such as in dialkyl dicyanobutenedioates, significantly reduce the barrier for the formation of zwitterionic intermediates in the reaction of azomethine ylides with such dipoles. This can render the stepwise cycloaddition competitive with the concerted one. However, the concertedness of the cycloaddition even to dipolarophiles with several electron‐withdrawing substituents is governed by a fine balance of electronic and steric effects in both ylide and dipolarophile counterparts. The hypothesis that introduction of substituents in the azomethine ylide that destabilize the positive charge in a corresponding zwitterion will favor the concerted cycloaddition even with dialkyl dicyanobutenedioates was tested theoretically and experimentally.

Synthesis of new spiro-oxindolo-(pyrrolizidines/pyrrolidines) via cycloaddition reactions of azomethine ylides and dibenzylideneacetone

A comparative study of the synthesis of novel spiro-oxindolo(pyrrolizidine/pyrrolidine) ring systems by the cycloaddition reaction of azomethine ylides generated by a decarboxylative route from sarcosine/proline and isatin with dibenzylideneacetone using various conditions is described.

Regioselective Synthesis of Dispiro Pyrrolizidines as Potent Antimicrobial Agents for Human Pathogens

Synthesis of a series of novel dispiro pyrrolizidines has been accomplished by 1,3-dipolar cycloaddition reaction of azomethine ylide generated from secondary amino acids and diketones with bischalcones. These compounds were evaluated for their antibacterial activity. Most of the synthetic compounds exhibited good antibacterial activity against microorganisms.

Novel One Pot Regioselective Multicomponent Synthesis of Highly Functionlaized Spiro Pyrrolidines Through 1,3-Dipolar Cycloaddition Approach

One-pot multicomponent synthesis of novel highly functionalized spiro pyrrolidine oxindoles has been accomplished in good yields through 1,3-dipolar cycloaddition reaction of azomethine ylide derived from sarcosine and oxindole with various benzimdazole substituted Baylis–Hillman derivatives. The regiochemical and stereochemical outcome of the multicomponent cycloaddition reaction is ascertained by spectroscopic studies, and one of the products was characterized through x-ray crystallographic analysis.

Chiral Brønsted Acid Catalyzed Stereoselective [3+3] Cycloaddition Reaction of Azomethine Ylide to Vinylimine Intermediates: Constructing Fully Functionalized Chiral Tetrahydro-β-Carboline

An asymmetric three-component formal (3+3) cycloaddition reaction of aldehyde, diethyl 2-aminomalonate and substituted indolyl alcohols, has been investigated with chiral BINOL-derived monophosphoric acids as catalysts. The active azomethine ylide intermediate can be readily formed from the condensation of aldehyde and diethyl 2-aminomalonate under the promotion of the chiral phosphoric acids and is thereby able to undergo nucleophilic addition reaction to elec- tron-deficient carbon-carbon double bonds as reported previously in the multicomponent reactions. On the other hand, the indolyl alcohols are able to participate in a dehydration reaction in the presence of the phosphoric acids to generate transient vinyliminium intermediates, which are principally reactive toward nucleophiles. Thus, we envisioned that the two types of active intermediates could undergo an asymmetric formal (3+3) cycloaddition to stereoselectively produce functionalized tetrahydro-β-carbolines under the catalysis of the chiral phosphoric acids. Consequently, a variety of 3,3'-disubstituted BINOL-phosphoric acids were initially evaluated for the reaction. As a result, the 3,3'-bis(p-ClPh) BINOL-phosphoric acid proved to perform most successfully in non-polar solvents, such as toluene. This reaction actually provides a highly straight- forward access to functionalized tetrahydro-β-carboline derivatives. A number of substituted indolyl alcohols bearing either electronically donating or withdrawing groups are well tolerated, affording highly functionalized tetrahydro-β-carbolines in high yields ranging from 70% to 91% and with excellent enantioselectivities of up to 93% ee. A representative procedure for the enantioselective formal (3+3) cycloaddition reaction is as following: After a mixture of p-nitrobenzaldehyde (0.06 mmol), diethyl 2-amino-malonate (0.05 mmol), 3 A MS (100 mg) and chiral phosphoric acid (10 mol%) in toluene (1.0 mL) was stirred at the r.t. for 15 min, the substituted indolyl acohol (0.1 mmol) was added. After completion of the addition, the reaction mixture was stirred for additional 12 h at the same temperature. The reaction solution was filtrated and the residue was washed three times with ethyl acetate (5 mL×3). The combined organic solutions were evaporated under the reduced pressure to give corresponding crude products, which were purified by column chromatography on silica gel (eluent: light petroleum ether∶ethyl acetate, V∶V=3∶1) to give analytically pure tetrahydro-β-carboline derivatives. Keywords chiral phosphoric acid; azomethine ylide; (3+3) cycloaddition; tetrahydro-β-carboline; asymmetric catalysis

Synthesis of Pyrrolo[2,3-a]pyrrolizidino Derivatives Through Intramolecular 1,3-Dipolar Cycloaddition in Ionic Liquid Medium

An ecofriently method for the synthesis of pyrrole-fused polycyclic heterocycles through intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides derived from pyrrole-2-carbaldehyde and secondary amino acids in ionic liquid [bmim][BF4] as green solvent is reported.

Facile Synthesis of β-Lactam-Grafted Spirooxindolopyrrolidine Through Regioselective 1,3-Dipolar Cycloaddition Reaction

One-pot synthesis of novel β-lactam-grafted spiropyrrolidines has been accomplished in good yield via a facile [3 + 2] cycloaddition reaction of azomethine ylides, derived from β-lactam aldehyde and sarcosine, with various p-substituted (E)-2-oxoindoline-3-ylidene acetophenone derivatives as dipolarophiles. The reaction gave excellent yields of the products when carried out under microwave irradiation.

ChemInform Abstract: Azomethine Ylide Annulations: Facile Access to Polycyclic Ring Systems.

AbstractNew 1,6‐annulation reactions of azomethine ylides are reported.