Cycloaddition Reaction Of Azomethine Ylides Research Articles

Diastereoselective Synthesis of NH-Unprotected Spiropyrrolidines via the Huisgen Reaction of Acenaphthoquinone-Derived Azomethine Ylides with β-Nitrostyrenes

Abstract4′-Nitro-2H-spiro[acenaphthylene-1,2′-pyrrolidine]-2-one derivatives are prepared via [3+2] cycloaddition reactions of azomethine ylides, generated in situ from acenaphthoquinone and primary amines, with β-nitrostyrenes in the presence of ( i Pr)2NEt in methanol. Evidence for the structures of the products was obtained from single-crystal X-ray analysis. The important feature of this diastereoselective synthesis of NH-unprotected spiropyrrolidines is the formation of four contiguous stereogenic centers, one of which is quaternary, with high selectivity.

Synthesis and SARs study of novel spiro-oxindoles as potent antiproliferative agents with CDK-2 inhibitory activities.

A series of 16 novel spirooxindole analogs 8a-p were designed and constructed via cost-effective single-step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a-d) with suitable amino acids (7a-c) and ethylene-engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF-7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF-7 and HepG2 cell lines, with IC50 values of 0.189 ± 0.01 and 1.04 ± 0.21 µM, respectively. The candidate 8c exhibited more potent activity (10.10- and 2.27-fold) than the standard drug roscovitine (IC50 = 1.91 ± 0.17 µM (MCF-7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC50 values of 96.6 nM compared with 67.3 nM for erlotinib. The IC50 value of 8c (34.98 nM) exhibited cyclin-dependent kinase 2 (CDK-2) inhibition, being more active than roscovitine the (IC50 = 140 nM) in targeting the CDK-2 kinase enzyme. Additionally, for apoptosis induction of compound 8c in MCF-7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases-3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold-change, respectively, and downregualted the level of the antiapoptotic gene for Bcl-2 by 0.14-fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK-2 inhibition.

Azomethine Ylides-Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds.

Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades.

1,3-Dipolar cycloaddition reactions of isatin-derived azomethine ylides for the synthesis of spirooxindole and indole-derived scaffolds: recent developments.

The unique therapeutic and biological characteristics of spirooxindole have led to the presentation of numerous reactions for the synthesis of spirooxindoles through 1,3-Dipolar cycloaddition of highly reactive isatin-derived azomethine ylides with activated olefins as the main tool for the formation of spirocyclic oxindoles during the last 4 years. Therefore, there is a need to highlight the recent developments in this area, along with the representative synthetic methods and relevant reaction mechanisms from 2018 to 2021. The representative synthetic methodologies were listed in four sections based on the procedure to form the azomethine ylide species including isatins and amino acids, isatin-derived α-(trifluoromethyl)imine, isatins and benzylamines, and from isatin-derived cyclic imine 1,3-dipoles.

Synthesis, molecular docking, anti-cancer activity, and in-silico ADME analysis of novel spiroacenaphthylene pyrrolizidine derivatives

A short and efficient multicomponent sequence for synthesizing spiroacenaphthylene pyrrolizidine analogs 5a-svia 1,3-dipolar cycloaddition reaction of azomethine ylide with chalcones 4a-s without any catalyst. Synthesized compounds 5a-s were characterized by spectral data and single crystal X-ray diffraction study. In-vitro anti-proliferative activity of compounds 5a-s against K562-leukemia showed that compounds 5e, 5i, 5l, 5m and 5o have an IC50 value of 54.07, 47.48, 50.57, 53.85 and 49.57 µg/ml respectively and exhibited H-bonding with LYS 875 in the molecular docking studies against the 2J5F protein and showed favourable in-silico ADME properties. Compound 5o showed favourable in-vitro anti-proliferative activity against K562-leukemic cell line and favourable in-silico ADME properties. It can serve as a template to develop further as a lead molecule and act as a tyrosine kinase inhibitor.

Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones: A combined experimental and theoretical study

Functionalized oxindoles and pyrrolizidines form the central structural framework for numerous natural products with extensive biological and pharmacological applications. The requirement for high regio- and stereoselectivity is the main obstacle in the synthesis of such five-membered heterocycles. Multicomponent cycloaddition reactions often provide an efficient and straightforward approach for the preparation of specific regio- and stereoisomers. In this article, the regio- and stereochemistry of the polar [3 + 2]-cycloaddition (32CA) reaction of azomethine ylides prepared by the reaction of isatin derivatives and L-proline with a series of ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones was investigated by experimental and theoretical methods. Among the isatin and ( E )-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives, a remarkable inversion of regioselectivity was observed in the 32CA reaction of azomethine ylide generated by the reaction of L-proline and 5-chloroisatin or N -methyl-5-chloroisatin with ( E )-5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one. The regio- and stereochemical assignment of the structures of the cycloaddition products was determined by one- and two-dimensional (1D&2D) homonuclear and heteronuclear correlation nuclear magnetic resonance spectroscopy. The molecular mechanism as well as the regio- and stereoselectivity of the cycloaddition were investigated by means of global and local reactivity indices and a density functional theory (DFT) and explained in detail on the basis of the transition state stabilities of the reactants.

Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles.

A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range.

A robust three-component synthesis of dispiroheterocycles containing aurone scaffold via 1,3-dipolar cycloaddition reaction of azomethine ylides: regioselectivity and mechanistic overview using DFT calculations

A robust three-component synthesis of dispiroheterocycles containing aurone scaffold via 1,3-dipolar cycloaddition reaction of azomethine ylides: regioselectivity and mechanistic overview using DFT calculations

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.

Dispirooxindole-pyrrolothiazoles: Synthesis, anti-cancer activity, molecular docking and green chemistry metrics evaluation

A modest library of a set of dispirooxindole-pyrrolothiazole derivatives 5a–n has been synthesized through multicomponent technique employing 1,3-dipolar cycloaddition reaction of azomethine ylide with novel dipolarophiles, 2,6-di (arylmethylidene) -4-methylcyclohexanones 4a–n without any catalyst. The reaction provides simple and efficient access to synthetically useful and biologically important dispirooxindole-pyrrolothiazoles in high yield (86–98%) with high degree of stereo-, regio-, and chemo-selectivities. All the synthesized compounds were characterized using popular spectral methods like IR, 1H NMR, 13C NMR and 2D NMR techniques. Further, the molecular structure of 5a was confirmed by single crystal XRD. The synthesized compounds were subjected to cytotoxicity evaluation using K562-leukemia cell line. Compound 5 k has been found to be an effective compound of this class in targeting K562-leukemia cell with IC50 value of 13.28 ± 0.11 µg/ml. From the molecular docking data, it is realized that these compounds 5a–n showed a binding energy between -8.1 and -10.8 kcal/mol and thereby inhibit Tyrosine Kinases. Smaller E-factor (0.13), high atom-economy (89.74%), percentage yield (98.00%), reaction mass efficiency (88.43%), and carbon efficiency (96.97%) are successful achieved for compound 5j.

β-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight.

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various β-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C═C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

Straightforward Synthesis of Succinimide-Fused Pyrrolizidines by A Three-Component Reaction of α-Diketone, Amino Acid, and Maleimide

AbstractAn efficient, one-pot, three-component [3+2] cycloaddition reaction of azomethine ylide obtained from α-dicarbonyl compounds (cyclic and acyclic diketone or keto ester) and amino acids with maleimides under catalyst-free conditions has been developed. This cascade protocol shows high efficiency and remarkable functional group tolerance, and the ubiquitous succinimide-fused pyrrolizidines with a highly compact and strained scaffold were obtained with high yield and excellent diastereoselectivity. Furthermore, this novel and atom-economical strategy could be performed on a gram scale with comparable reaction efficiency.

1,3-Dipolar cycloaddition reactions of azomethine ylides with seven-membered cyclic N-sulfony imines access to polycyclic sulfonamides

Abstract A straightforward and efficient strategy for the synthesis of novel functionalized polycyclic sulfonamides containing e-sultams motif under metal-free catalysis via [3 + 2] 1,3-dipolar cycloaddition reactions of azomethine ylides generated in situ with seven-membered cyclic N-sulfony imines has been achieved. The present process was carried out under mild reaction conditions to give polycyclic sulfonamides in high yield (up to 95%). Additionally, the conversion of the cycloadduct to other useful structure has also been developed. The structure of the typical product was clearly established by X-ray crystallography.

Unveiling the Reactivity of Cyclic Azomethine Ylides in [3+2] Cycloaddition Reactions within the Molecular Electron Density Theory

The [3+2] cycloaddition (32CA) reactions of cyclic azomethine ylides with a series of acetylene derivatives have been studied within the Molecular Electron Density Theory (MEDT). Analysis of the Conceptual DFT indices allows the characterisation of the ambiphilic character of these cyclic AYs, thus participating as strong electrophiles and strong nucleophiles in polar 32CA reactions. The activation enthalpies associated with the 32CA reactions of these cyclic AYs are found in reasonable agreement with the experimental outcomes. These reactions proceed through a one‐step mechanism. The 32CA reactions with 1‐dimethylamino‐1‐propyne and dimethyl acetylenedicarboxylate take place through highly asynchronous polar transition states (TSs). On the other hand, the strain present in cyclooctyne allows explaining its participation in a non‐polar 32CA reaction via a synchronous TS. The present MEDT study allows establishing that the substitution in these cyclic AYs changes their parent pseudodiradical‐type reactivity to the zwitterionic‐type one.

Catalyst-Free [3+2] Cycloaddition of Electron-Deficient Alkynes and o-Hydroxyaryl Azomethine Ylides in Water.

A catalyst-free [3 + 2] cycloaddition reaction of electron-deficient alkynes and o-hydroxyaryl azomethine ylides in water was developed, affording pyrroline derivatives in moderate to high yields (up to 90%).

Synthesis and dynamic NMR study of spiroheterocycles containing a 1,2,4-triazolidine moiety

A one-pot synthesis of spiro-heterocyclic systems containing a 1,2,4-triazolidine moiety via 1,3-dipolar cycloaddition reaction of azomethine ylides (generated in situ from α-amino acids and ninhydrin) with diisopropyl azodicarboxylate in 50% aqueous MeOH at room temperature, is described. The structure of a typical product was confirmed by X-ray crystallography. The 1H NMR spectra of diisopropyl 1,3-dioxo-1,3-dihydrospiro[indene-2,3′-[1,2,4]triazolidine]-1′,2′-dicarboxylate exhibited dynamic NMR effects, which were attributed to the fast positional change of the ester groups and their interaction with N–H as well as with methylene protons, and restricted bond rotation of the carbamate groups. The calculated free-energy of activation (ΔG#) for these dynamic processes are 64 ± 2 kJ mol−1 and 55 ± 2 kJ mol−1, respectively.

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.

Unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with benzylidene thiazolidinediones: synthesis of pharmacologically active spiroindoline oxazepine derivatives and theoretical study.

An unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with 5-benzylidenethiazolidine-2,4-diones has been successfully developed for the synthesis of the novel pharmacologically active 4',5'-dihydro-3'H-spiro[indoline-3,2'-[1, 3] oxazepin]-2-one derivatives in basic condition. Easy purification, high yield, short experimental time and operational simplicity are specific advantages of this protocol. Furthermore, all the synthesized compounds have been evaluated for antioxidant and antibacterial activities. According to the results, most of the synthesized compounds exhibited DPPH radical scavenging activity and nine of them showed antibacterial properties. The reaction mechanism and 1H NMR spectrum have been evaluated by B3LYP/6311G method.

A Regioselective Synthesis of Carbazole‐Appended Dispiropyrrolothiazoles/Pyrrolidines: Synthesis, Computational Studies and In Vitro Anticancer Activity

AbstractAnti‐oncological active carbazole appended dispiroindenoquinoxalinepyrrolothiazoles and dispiroacenaphthylenepyrrolidines were synthesized regioselectively via 1,3‐dipolar cycloaddition reaction of azomethine ylide to exocyclic linkage of dipolarophile. The synthesized spiranic compounds are fully characterized by means of spectral, X‐ray crystallography and elemental analysis. Computational details of theoretical calculations have been discussed for compound 4 g (p‐Cl‐phenyl substituted pyrrolothiazole‐carbazole system) using DFT (Density Functional Theory) approach at the M06‐2X/LANL2DZ level of theory. The cytotoxic effects of the dispiro compounds were examined on cancerous cell lines such as lung cancer (A549) and breast cancer (MCF‐7) cell lines. Compound 4 g was found to be the most promising derivative against A549 (20±1.0 μg/ml) and MCF‐7 (21±1.5 μg/ml) cells. Furthermore, the morphological changes and apoptotic induction of the promising candidates have been studied by AO/EB (Acridine Orange/Ethidium Bromide) and DAPI (4′,6‐diamidino‐2‐phenylindole) staining methods.

Azomethine ylide cycloaddition: a versatile tool for preparing novel pyrrolizidino-spiro-oxindolo hybrids of the doubly conjugated alkamide piperine.

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.