Theoretical Study of the Mechanism of the Formation of Azomethine Ylide from Isatine and Sarcosine and Its Reactivity in 1,3-Dipolar Cycloaddition Reaction with 7-Oxabenzonorbornadiene.

The reaction mechanism of tthe formation of azomethine ylides from isatins and sarcosine is addressed in the literature in a general manner. This computational study aims to explore the mechanistic steps for this reaction in detail and to assess the reactivity of formed ylide in a 1,3-dipolar cycloaddition reaction with 7-oxabenzonorbornadiene. For this purpose, density functional theory (DFT) calculations at the M06-2X(SMD,EtOH)/6-31G(d,p) level were employed. The results indicate that CO2 elimination is the rate-determining step, the activation barrier for 1,3-dipolar cycloaddition is lower, and the formed ylide will readily react with dipolarophiles. The substitution of isatine with electron-withdrawal groups slightly decreases the activation barrier for ylide formation.

2,5-Di-tert-butyl-2,5-diethylpyrrolidine-1-oxyls: Where Is a Reasonable Limit of Sterical Loading for Higher Resistance to Reduction?

The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N-O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and enzymatic systems. This makes them valuable molecular tools for studying the structure and functions of biomolecules directly in a living cell and for functional EPR and NMR tomography in vivo. The first example of highly strained pyrrolidine nitroxides with both ethyl and tert-butyl groups at each of the α-carbon atoms of the nitroxide moiety with cis-configuration of the tert-butyl groups was prepared using a three-component domino reaction of tert-leucine and 2,2-dimethylpentan-3-one with dimethyl fumarate with subsequent conversion of the resulting strained pyrrolidine into 1-pyrroline-1-oxide and addition of EtLi. The nitroxide has demonstrated unexpectedly fast reduction with ascorbate, the rate constant k2 = (2.0 ± 0.1) × 10-3 M-1s-1. This effect was explained by destabilization of the planar nitroxide moiety due to repulsion with the two neighboring tert-butyl groups cis to each other.

Visible-light promoted catalyst-free (VLCF) multi-component synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids: evaluation of in vitro anticancer activity, molecular docking, MD simulation and DFT studies.

A new and highly efficient visible-light-promoted catalyst free (VLCF) strategy for neat and clean synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids (6a-d) has been introduced. We have performed visible-light triggered 1,3-Dipolar cycloaddition reaction of maleimide (5a-d) with azomethine ylide generated in situ derived from tryptanthrin (3) and L-proline (4) to obtain desired products (6a-d) in good to excellent yield. Authentication and characterization of product was done using various spectroscopic techniques such as IR, 1H NMR, 13C NMR, Mass spectrometry and single crystal XRD analysis. To explain the reaction spontaneity, product stability, reactivity as well as possible mode of the interaction a quantum chemical investigation was performed and depicted through DFT studies. The synthesized compound 6a was also evaluated for anti-proliferative activity against a panel of five cancer cell lines (MCF-7, MDA-MB-231, HeLa, PC-3 and Ishikawa) and normal human embryonic kidney (HEK-293) cell line by using MTT assay. Compound 6a showed very good in vitro anti-proliferative activity (IC50  = 6.58-17.98 µM) against four cancer cell lines and no cytotoxicity against normal HEK-293. In order to evaluate the anticancer potential of compounds 6a-d, molecular docking was performed against wild type and mutant EGFR. The results suggest that all the compounds occupied the active site of both enzymes, with a strong binding energy (-10.2 to -11.5 kcal/mol). These results have been confirmed by molecular dynamics simulation by evaluating root mean square deviation (RMSD) and root mean square fluctuation (RMSF), along with principal component analysis (PCA).Communicated by Ramaswamy H. Sarma.

An efficient one-pot synthesis and docking studies of bioactive new antiproliferative dispiro[oxindole/acenaphthylenone‒benzofuranone] pyrrolidine scaffolds.

A new and efficient method has been developed to synthesize dispiro[oxindole/acenaphthylenone-benzofuranone]pyrrolidine compounds. This is done by triggering the 1,3-dipolar cycloaddition reaction of azomethine ylides by reacting isatin/acenaphthoquinone with L-picolinic acid/L-proline/sarcosine/L-thioproline/tetrahydroisoquinolines, in a highly regioselective manner in an ionic liquid [DBU][Ac] with 4'-chloro-auron[2-(4-chlorobenzylidene)benzofuran-3(2H)-one]. Single-crystal X-ray diffraction data support the proposed structures of the new compounds. The heterocycles derived from amino acids such as L-picolinic acid, L-proline, and L-thioproline showed significant inhibitory effects against six human solid tumors, including lung, breast, cervix, colon, and others. These new structures were also tested in the active sites of the MDM2 receptor to further study their antiproliferative effects.

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds.

The [3 + 2] cycloadditions of stabilized azomethine ylides (AMYs) derived from amino esters are well-established. However, the reactions of semi-stabilized AMYs generated from decarboxylative condensation of α-amino acids with arylaldehydes are much less explored. The [3 + 2] adducts of α-amino acids could be used for a second [3 + 2] cycloaddition as well as for other post-condensation modifications. This article highlights our recent work on the development of α-amino acid-based [3 + 2] cycloaddition reactions of N-H-type AMYs in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse heterocycles related to some bioactive compounds and natural products.

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a-b, a number of α-amino acids 2a-e and (E)-2-aryl-1-nitroethenes 3a-e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using 1H and 13C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3'-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3'-oxindoles] analogs 4a-w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3'-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC50 = 34.99-47.92 µM; SI = 0.96-2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC50 = 41.56-86.53 µM; SI = 0.49-0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC50 = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC50 = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].

Photocatalyzed (3+2) Cycloaddition for the Dearomatization of Electron-Poor Arenes under Flow Conditions.

The photocatalyzed dearomative reaction between various electron-deficient aromatic compounds and a non-stabilized azomethine ylide is successfully performed in a flow system. Whereas the use of supported eosin as organic photocatalyst exhibits limited efficiency, turning to the soluble Rose Bengal allows to transform a broad range of substrates from hetarenes (indole, benzofuran, quinoline, pyridine) to naphthalenes and benzenes. This photocatalyzed (3+2) dearomative cycloaddition under green light irradiation provides a simple and efficient access to tridimensional pyrrolidino scaffolds with a tetrasubstituted carbon center at ring junction and can be performed in the friendly ethyl acetate. Computational studies support the mechanism involving azomethine ylide as reactive species toward the electron-poor arene.

Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties.

Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80-95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d, 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC6H4, Ph; R' = H, Cl, respectively) with considerable selectivity index values. Mpro-SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the Mpro inhibitory properties. The presumed mode of action was supported by both experimentally investigated Mpro-SARS-CoV-2 inhibitory properties and explained by docking observations.

1,3-Dipolar Cycloaddition of 3-Chromonyl-Substituted Glycine Imino Esters with Arylidenes and in†situ Diastereodivergent via Retrocycloaddition.

1,3-Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal-free AcOH-activated 1,3-dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3-formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endo-cycloadduct. Under prolonged reaction time at room temperature or heating; the endo-adduct underwent diastereodivergent via a sequence of retro-cycloaddition, stereomutation of the generated syn-dipole into anti-dipole and recycloaddition; to furnish the scarcely known exo'-cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR- and X-ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal-catalyzed processes.

Catalytic Enantioselective [3+2] Cycloaddition of N-Metalated Azomethine Ylides.

Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations.

K2CO3-Promoted Formal [3+3]-Cycloaddition of N-Unsubstituted Isatin N,N'-Cyclic Azomethine Imine 1,3-Dipoles with Knoevenagel Adducts.

The synthesis of dicyclic spiropyridazine oxoindole derivatives by using [3+3]-cycloaddition of N-unsubstituted isatin N,N'-cyclic azomethine imine 1,3-dipoles was reported. The products bearing two consecutive stereocenters, including spiroquaternary stereocenters in one ring structure, can be effectively obtained in moderate to excellent yields (20-93%) and low to moderate diastereoselectivities (1:9-10:1 dr). The synthesized compounds (>35 examples) were characterized by single-crystal XRD, FTIR, NMR, and mass spectral analysis.

Understanding the mechanism and regio- and stereo selectivity of [3 + 2] cycloaddition reactions between substituted azomethine ylide and 3,3,3-trifluoro-1-nitroprop-1-ene, within the molecular electron density theory.

The selectivity and the nature of the molecular mechanism of the [3 + 2] cycloaddition (32CA) reaction between 2-(dimethylamino)-1H-indene-1,3(2H)-dione (AY11) and trans(E)-3,3,3-trifluoro-1-nitroprop-1-ene(FNP10) has been studied, in which the molecular electron density theory using density functional theory methods at the MPWB1K/6-31G(d) computational level was used. Analysis of the global reactivity indices permits us to characterize FNP10 as a strong electrophile and AY11 as a strong nucleophile. Four reactive pathways associated with the ortho/meta regioselective channels and endo/exo stereoselective approaches modes have been explored and characterized in the gas phase and in the benzene solvent. The analysis of the relative energies associated with the different reaction pathways indicates that the 32CA reactions of the azomethine ylide (AY) with the nitroalkene (FNP) is meta regioselective with high endo stereoselectivity. This result is in good agreement with the experimental observations. electron localization function topological analysis of the most favored reactive pathways allows for characterizing the mechanism of this 32CA reactions as a non-concerted two-stage one-step mechanism. Finally, non-covalent interactions and quantum theory of atoms in molecule analyses at the meta/endo transition state structure indicate that the presence of different several weak interactions, namely, CF and NH contributed in favoring the formation of a meta-endo cycloadduct.

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.

Diastereoselective Synthesis of Novel Spiro-Phosphacoumarins and Evaluation of Their Anti-Cancer Activity.

Herein we present the regio- and diastereoselective synthesis of novel pyrrolidine-fused spiro-dihydrophosphacoumarins via intermolecular [3 + 2] cycloaddition reaction. The presented approach is complementary to existing ones and provides an easy entry to the otherwise inaccessible derivatives. Additionally, the unprecedented pathway of the reaction of 4-hydroxycoumarin with azomethine ylides is described. The anti-cancer activity of the obtained compounds was tested in vitro, the most potent compound being 2.6-fold more active against the HuTu 80 cell line than the reference 5-fluorouracil, with a selectivity index > 32.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units.

The [3+2] cycloaddition (32CA) reaction of an azomethine ylide (AY) with an electrophilic ethylene linked to triazole and ferrocene units has been studied within the Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) level. The topology of the electron localization function (ELF) of this AY allows classifying it as a pseudo(mono)radical species characterized by the presence of two monosynaptic basins, integrating a total of 0.76 e, at the C1 carbon. While the ferrocene ethylene has a strong electrophilic character, the AY is a supernucleophile, suggesting that the corresponding 32CA reaction has a high polar character and a low activation energy. The most favorable ortho/endo reaction path presents an activation enthalpy of 8.7 kcal·mol-1, with the 32CA reaction being exergonic by -42.1 kcal·mol-1. This reaction presents a total endo stereoselectivity and a total ortho regioselectivity. Analysis of the global electron density transfer (GEDT) at the most favorable TS-on (0.23 e) accounts for the high polar character of this 32CA reaction, classified as forward electron density flux (FEDF). The formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounts for the unexpected ortho regioselectivity experimentally observed.

Biological Evaluation of 3-Azaspiro[Bicyclo[3.1.0]Hexane-2,5'-Pyrimidines] as Potential Antitumor Agents.

A series of heterocyclic compounds containing spirofused barbiturate and 3-azabicyclo[3.1.0]hexane frameworks have been studied as potential antitumor agents. Antiproliferative activity of products was screened in human erythroleukemia (K562), T lymphocyte (Jurkat), and cervical carcinoma (HeLa) as well as mouse colon carcinoma (CT26) and African green monkey kidney epithelial (Vero) cell lines. The most effective among the screened compounds show IC50 in the range from 4.2 to 24.1 µM for all tested cell lines. The screened compounds have demonstrated a significant effect of the distribution of HeLa and CT26 cells across the cell cycle stage, with accumulation of cells in SubG1 phase and induced apoptosis. It was found, using a confocal microscopy, that actin filaments disappeared and granular actin was distributed diffusely in the cytoplasm of up to 90% of HeLa cells and up to 64% of CT26 cells after treatment with tested 3-azaspiro[bicyclo [3.1.0]hexane-2,5'-pyrimidines]. We discovered that the number of HeLa cells with filopodium-like membrane protrusions was reduced significantly (from 91% in control cells to 35%) after treatment with the most active compounds. A decrease in cell motility was also noticed. Preliminary in vivo experiments on the impact of the studied compounds on the dynamics of CT26 tumor growth in Balb/C mice were also performed.

Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction.

In the present work, a novel heterocyclic hybrid of a spirooxindole system was synthesized via the attachment of ferrocene and triazole motifs into an azomethine ylide by [3 + 2] cycloaddition reaction protocol. The X-ray structure of the heterocyclic hybrid (1″R,2″S,3R)-2″-(1-(3-chloro-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carbonyl)-5-methyl-1″-(ferrocin-2-yl)-1″,2″,5″,6″,7″,7a″-hexahydrospiro[indoline-3,3″-pyrrolizin]-2-one revealed very well the expected structure, by using different analytical tools (FTIR and NMR spectroscopy). It crystallized in the triclinic-crystal system and the P-1-space group. The unit cell parameters are a = 9.1442(2) Å, b = 12.0872(3) Å, c = 14.1223(4) Å, α = 102.1700(10)°, ß = 97.4190(10)°, γ = 99.1600(10)°, and V = 1484.81(7) Å3. There are two molecules per unit cell and one formula unit per asymmetric unit. Hirshfeld analysis was used to study the molecular packing of the heterocyclic hybrid. H···H (50.8%), H···C (14.2%), Cl···H (8.9%), O···H (7.3%), and N···H (5.1%) are the most dominant intermolecular contacts in the crystal structure. O···H, N···H, H···C, F···H, F···C, and O···O are the only contacts that have the characteristic features of short and significant interactions. AIM study indicated predominant covalent characters for the Fe-C interactions. Also, the electron density (ρ(r)) at the bond critical point correlated inversely with the Fe-C distances.

exo'-Selective Construction of Spirobipyrrolidines by the Silver-catalyzed Asymmetric [3+2] Cycloaddition of Imino Esters with 4-Benzylidene-2,3-dioxopyrrolidines.

An unprecedented Ag-catalyzed exo'-selective [3+2] cycloaddition of imino esters with 4-benzylidene-2,3-dioxopyrrolidines is described. The reaction was efficiently catalyzed by Ag/(R, Sp )-ThioClickFerrophos (TCF) leading to the construction of the corresponding spirobipyrrolidine scaffolds in excellent enantio- and diastereoselectivities. This reaction is the first example of a silver-catalyzed exo'-selective asymmetric [3+2] cycloaddition, as well as the first exo'-selective spirobipyrrolidine construction via a [3+2] cycloaddition process using imino esters. The wide substrate scope of this reaction enabled the preparation of structurally diverse spirobipyrrolidine derivatives, which are attracting attention as targets for drug discovery. Mechanistic studies suggested that the unusual exo'-selectivity of this reaction is not due to epimerization following the common exo- or endo-selective cycloaddition, but instead is due to a stepwise Michael addition/Mannich sequence with bond rotation.

Synthesis of functionalized pyrrole derivatives via diverse cyclization of azomethine ylide and olefins.

The azomethine ylides are generally used in 1,3-dipolar cycloadditions with various dipolarophiles. In this work, a new and diverse route has been developed for the azomethine ylides, for synthesis of novel pyrrole derivatives. The azomethine ylide, produced via C-H activation of unreactive C(sp3)-H bond of 2-methylquinoline, by molecular iodine, in the presence of pyridine. Herein, we represent novel pyrrole derivatives, synthesized from the reaction of pyridinium ylide with olefins, which formed via a reaction of isatin, dialkyl acetylenedicarboxylate derivatives and pyridine as a base in moderate to excellent yields. Various features of this cyclization, discussed.