Three-component Reaction Of Isatins Research Articles

EnantioselectiveSynthesis ofspiro[indoline-3,4- pyrrolo [3,4-b]pyridines] via Organocatalysed Three-Component Cascade Reaction.

Asymmetric synthesis of spiro[indoline-3,4-pyrrolo [3,4-b]pyridines] derivatives was first developed through organocatalytic cascade Knoevenagel/Michael/cyclization reaction using a quinidine -derived squaramide. Under the optimized conditions, the three-component reaction of isatins, cyanoacetates, and 3-aminomaleimides yield the desired heterocycle-fused spirooxindoles in good yields (78-91%) with 53-99% enantiomer excess (ee). Notably, this reaction enabled a broad substrate scope under mild conditions, and provided a convenient method for enantioselective construction of diverse spirooxindoles combined with dihydropyridine and maleimide skeleton, which brought great potential to build new bioactive chemical entities.

One-pot synthesis, structural study, in silico and in vitro anticancer evaluation of spiropyrrolidine oxindoles obtained by the 3-CR of isatin, benzyl amine and a thiazolo[3,2-a]indole derivative

Stereoselective green synthesis of spiropyrrolidine oxindoles, in excellent yields, by the three-component reaction of isatins, benzyl amines and a thiazolo[3,2-a]indole derivative is reported here. In silico molecular docking studies of selected compounds in order to evaluate the MDM2 inhibition potential suggested that compound 4s was the best fit and further in vitro evaluation proved that 4s exhibited cell viability less than 80% with an effective dose of 25 µg/mL. Analysis of the single crystals of four derivatives showed that the S∙∙∙O chalcogen bond was a common feature which might be the reason for conformational locking and influence in the molecule's binding affinities to the biological target. QTAIM analysis revealed that two different modes of S∙∙∙O chalcogen bonds were present and Localized-Orbital Locator (LOL) plots suggested that the lone pairs on oxygen are oriented towards the sulphur atom supporting the S∙∙∙O interaction as a chalcogen bond of n→σ* type.

Application of novel Fe3O4/Zn-metal organic framework magnetic nanostructures as an antimicrobial agent and magnetic nanocatalyst in the synthesis of heterocyclic compounds.

Using the microwave-assisted method, novel Fe3O4/Zn-metal organic framework magnetic nanostructures were synthesized. The crystallinity, thermal stability, adsorption/desorption isotherms, morphology/size distribution, and magnetic hysteresis of synthesized Fe3O4/Zn-metal organic framework magnetic nanostructures were characterized by XRD patterns, TGA curve, BET adsorption/desorption technique, SEM image, and VSM curve, respectively. After confirming the Fe3O4/Zn-metal organic framework magnetic nanostructures, its antimicrobial properties against Gram-positive bacterial, Gram-negative bacterial, and fungal strains based on minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC) values were studied. The MIC values in antimicrobial activity for Gram-positive and Gram-negative bacterial strains, between 16–128 μg/ml, and for fungal strain, 128 μg/ml were observed. The results showed that the high specific surface area of Fe3O4/Zn-metal organic framework magnetic nanostructures caused the antimicrobial power of nanoparticles to be high, and the observed antimicrobial effects were higher than some known commercial antimicrobial drugs. Another advantage of the specific surface area of Fe3O4/Zn-metal organic framework magnetic nanostructures was its high catalytic properties in the three-component reaction of isatin, malononitrile, and dimedone. New spiro [indoline-pyranopyrimidines] derivatives were synthesized with high efficiency. The catalytic activity results of Fe3O4/Zn-metal organic framework magnetic nanostructures showed that, in addition to recyclability, derivatives could be synthesized in less time than previously reported methods. The results of investigating the catalytic activity of Fe3O4/Zn-metal organic framework magnetic nanostructures showed that the spiro [indoline-pyranopyrimidines] derivatives were synthesized in the time range of 10–20 min with an efficiency of over 85%. As a final result, it can be concluded that the microwave synthesis method improves the unique properties of magnetic nanostructures, especially its specific surface area, and has increased its efficiency.

Highly efficient endo’- selective synthesis of (dispiro 3,2′-pyrrolidinyl) bisoxindoles containing three contiguous chiral stereocenters with two contiguous quaternary spirostereocenters

An efficient, atom economical, one-pot synthesis of endo’- selective (dispiro 3,2′-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3-dicarbonyl compounds in water in the presence of L-proline. One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst have also been achieved in good yields. This new methodology offers many advantages of catalyst-free, mild reaction conditions, shorter reaction time, environmental friendliness, regio- and stereoselective processes in higher yields. Synopsis: One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst provides endo’- selective (dispiro 3,2′-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved in good yield. The reactions preceded under mild reaction conditions without any catalyst yields high regio- and stereoselective products up to 55–99%.

Eosin Y-catalyzed one-pot synthesis of spiro[4H-pyran-oxindole] under visible light irradiation

An efficient and simple synthetic approach has been developed for the preparation of biologically interesting spiro[oxindole-3,4’-(4′H-pyran)] derivatives via visible light-mediated one-pot, three-component reaction of isatins, 1,3-dicarbonyl compounds and malononitrile by using an inexpensive organic dye, Na2 eosin Y, as the photocatalyst in aqueous ethyl lactate at ambient temperature. The substrate scope of this three-component reaction is expanded to linear 1,3-dicarbonyl compounds as viable starting materials. All rights reserved.

Efficient Multicomponent Synthesis of Spirooxindole Derivatives Catalyzed by Copper Triflate

A simple and efficient method for the synthesis of spirooxindole derivatives via a three-component reaction of isatin, 5-aminopyrazole, and 1,3-dicarbonylcompounds (or β-​oxo-benzenepropanenitril​e) catalyzed by copper triflate in ethanol is described. The advantages of this method include high efficiency, mild reaction conditions, recoverable catalyst, and environmentally benign conditions.

The synthesis of spiro[indole-3,1’-pyrrolo[3,4 -c]pyrrole]- 2,4’,6’-trione derivatives, the study of their antimicrobial activity and the molecular docking on staphylococcal dehydrosqualene synthase

Aim. To synthesize the series of new spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-trione derivatives, study their physicochemical characteristics, antibacterial activity and precision of the molecular docking on the model of staphylococcal dehydrosqualene synthase. Materials and methods. The methods of organic synthesis, instrumental methods for analysis of organic compounds, as well as the molecular docking method in silico and agar diffusion method in vitro were used. Results and discussion. To synthesize new bis-derivatives of 3’a, 6’a-dihydro-3’H-spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-triones the three-component reaction of 1,6-maleimidamidohexane with L-amino acids and isatin was studied. New bis-spiro derivatives were isolated with a double excess of the corresponding isatin and L-amino acids. With the equimolar ratio of three reagents 6-N-maleimidohexyl derivatives spiro[indole-3,1’-pyrrolo[3,4-c] pyrrole]-2,4’,6’-triones were isolated with the yields of 30-90 %. To prove their reactivity two symmetrical bis-spirooxindoles were counter-synthesized by condensation of two 6-N-maleimidohexyl spiro-2-oxindole derivatives with isatin, L-phenylalanine or sarcosine with the yields of 35 and 38 %. In the microbiological screening it was found that some compounds revealed the activity against S. aureus at the level of cefalexin and against C. albicans fungi relative to fluconazole. The docking in silico identified a high ability of the compounds studied to interact with at least six key amino acid residues – Arg45, Asp48, Asp52, Gln165, Asn168 and Asp172 of the active center of S. aureus dehydrosqualene synthase (CrtM). Conclusions. It has been found that the one-pot three-component reaction of isatin, L-amino acids and 1,6-maleimidohexane as a function of the mole ratio of the reagents leads to both bis-derivatives of spiro[indole-3,1’-pyrrolo[3,4-c]pyrrole]-2,4’,6’-trione, and to the corresponding asymmetric 6-N-maleimidohexyl derivatives. The substances synthesized have predominantly shown the activity in relation to gram-positive bacteria and yeast-like fungi. For the first time it has been demonstrated by the molecular docking method that the compounds studied forming a complex with a high docking score are potential inhibitors of staphylococci CrtM.

Spirooxindole-fused pyrazolo pyridine derivatives: NiO–SiO2 catalyzed one-pot synthesis and antimicrobial activities

ABSTRACTWe describe here a one-pot synthesis of 13 spirooxindole-fused pyrazolo pyridine derivatives using NiO–SiO2 catalyst via three-component reaction of isatin, 5-amino-3-methylpyrazole, and malononitrile. This multicomponent one-pot protocol also features shorter reaction time, good yield, and simple work-up using a recoverable and reusable solid acid heterogeneous catalyst. The NiO–SiO2 catalyst was characterized using different instrumental techniques such as X-ray diffraction study, surface area analysis, transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, UV-DRS (diffuse reflectance spectroscopy), and energy dispersive X-ray analysis (EDX). The new compounds were tested for in-vitro anti-microbial activity.

Catalyst-Free, Visible-Light Promoted One-Pot Synthesis of Spirooxindole-Pyran Derivatives in Aqueous Ethyl Lactate

A highly efficient, eco-friendly protocol has been developed for synthesis of spirooxindole-pyran derivatives via one-pot, three-component reaction of isatins, malononitrile, and enolizable C–H activated compounds (2-hydroxynaphthalene-1,4-dione, 4-hydroxycoumarine and dimedone) under visible-light irradiation in water-ethyl lactate at room temperature. The reported approach shows significant advantages such as a high yield, mild and clean reaction conditions, the application of clean visible light as a source of energy, the absence of catalyst, the use of ethyl lactate/water as an environmentally friendly solvent, a one-pot multicomponent reaction at room temperature, no chromatographic separation, and applicability for large-scale synthesis.

ChemInform Abstract: Green Synthesis of Spiro[indoline‐3,4′‐pyrazolo[3,4‐b][1,6]naphthyridine]‐2,5′(1′H)‐diones Catalyzed by TsOH in Ionic Liquids.

A three-component reaction of isatin, 3-methyl-1-phenyl-1H-pyrazol-5-amine, and piperidine-2,4-dione was treated in ionic liquids catalyzed by TsOH and provided an efficient and green method for the synthesis of spiro[indoline-3,4′-pyrazolo[3, 4-b][1,6]naphthyridine]-2,5′(1′H)-dione derivatives in high yields.

Supported molybdenum on graphene oxide/Fe3O4: An efficient, magnetically separable catalyst for one-pot construction of spiro-oxindole dihydropyridines in deep eutectic solvent under microwave irradiation

Magnetically separable graphene oxide supported molybdenum (Fe3O4/GO-Mo) nanoparticles were prepared and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and vibrating sample magnetometry (VSM) techniques. The synthesized heterogeneous material was found to exhibit high catalytic activity in one-pot, three-component reaction of isatins, malononitrile and anilinolactones using choline chloride (ChCl)/urea as a green solvent under microwave irradiation. It provided an efficient method for the synthesis of spirooxindole dihydropyridines in high to excellent yields. The catalytic system can be successfully reused eight times with a small decrease of its catalytic performance.

Efficient One-Pot Three-Component Synthesis of Novel Spiro(Indoline-3,7′-Thiazolo[3,2-a]Pyrimidine) Derivatives

A practical, simple and efficient method for the synthesis of thiazolo[3,2- a]pyrimidine-fused spirooxindoles by a three-component reaction of isatins, malononitrile and 2-amino-2-thiazoline in the presence of Cul as catalyst in ethylene glycol is reported.

ChemInform Abstract: Combinatorial Synthesis of Spiro[indoline‐3,2′‐pyrrole] Derivatives via a Three‐Component Reaction under Catalyst‐Free Conditions.

Reported here is a convenient catalyst-free method for preparing a series of spiro[indoline-3,2′-pyrroles] from a three-component reaction of isatins, α-amino acid and phenylpropiolic acid esters in refluxing isopropanol with high regioselectivity and yields. A plausible mechanism for this process was proposed. In addition, this protocol permitted the facile construction of spiro[indoline-3,2′-pyrroles] through an expanded scope of substrates.

Bmim]OH: An efficient catalyst for the synthesis of mono and bis spirooxindole derivatives in ethanol at room temperature

A rapid and efficient, one pot synthesis of spirooxindole derivatives has been attempted by three-component reaction of isatin, malononitrile and carbonyl compound possessing a reactive α-methylene group by using task specific ionic liquid, 1-butyl-3-methyl imidazolium hydroxide [bmim]OH as a catalyst. The important features of this methodology are straight forward route in short reaction time at room temperature and avoid any hazardous organic solvent, toxic catalyst, tedious purification step. Interestingly, this protocol is not only limited to mono-systems but also to the synthesis of newer bis-spirooxindole system. The separation of the product and reusability of the catalyst are easy with excellent yield. The [bmim]OH catalyst system could be reused up to five recycles without appreciable loss of activity.

Combinatorial synthesis of spiro[indoline-3,2′-pyrrole] derivatives via a three-component reaction under catalyst-free conditions

Reported here is a convenient catalyst-free method for preparing a series of spiro[indoline-3,2′-pyrroles] from a three-component reaction of isatins, α-amino acid and phenylpropiolic acid esters in refluxing isopropanol with high regioselectivity and yields.

Silica sulfuric acid magnetic nanoparticle: an efficient and ecofriendly catalyst for synthesis of spiro[2-amino-4H-pyran-oxindole

Silica sulfuric acid magnetic nanoparticles efficiently catalyze the one-pot, three-component reaction of isatins and malononitrile with dimedone, 1,3-dimethylbarbituric acid or 4-hydroxycoumarin in EtOH–H2O to afford the corresponding spiro[2-amino-4H-pyran-oxindole] derivatives in high yields under ultrasound irradiation at 60 °C. The heterogeneous nanocatalyst could be recovered easily from the reaction mixture using an external magnet and reused many times without significant loss of its catalytic activity.

Synthesis of 2-(3-amino-2-oxoindolin-3-yl)-3-hydroxynaphthalene-1,4-dione derivatives via a one-pot, three-component reaction under catalyst-free conditions

A concise, facile and straightforward synthetic method has been described for the synthesis of 2-(3-amino-2-oxoindolin-3-yl)-3-hydroxynaphthalene-1,4-dione derivatives by a one-pot, three-component reaction of isatins, 2-hydroxy-1,4-naphthoquinone and ammonium acetate under catalyst-free conditions in ethanol. This protocol becomes highly efficient due to its mild reaction conditions, operational simplicity, and overall good to excellent yields (80–99%).

A Green, Facile Approach for the Multicomponent Synthesis of Bioactive Spiro[Indoline-3,7′-Pyrrolo[1,2-c]Imidazole] Derivatives

An efficient synthesis of spiro[indoline-3,7′-pyrrolo[1,2-c]imidazole] is achieved through a three-component reaction of isatins, malononitrile, and hydantoin/2-thiohydantoin in water catalysed by NaHCO3. All the target compounds were screened for the Cell Division Cycle 25 Phosphatase B (CDC25B) inhibitory activities.

DABCO-functionalized mesoporous SBA-15: an efficient and recyclable catalyst for the synthesis of spiro-pyranoxindoles as antioxidant agents

A series of spiro-pyranoxindole derivatives were prepared in good yields via a three-component reaction of isatins with activated methylene reagents and kojic acid using 1,4-diazabicyclo[2.2.2]octane (DABCO) immobilized on mesoporous SBA-15 as a heterogenized organocatalyst in aqueous media. The synthesized compounds were evaluated for their antioxidant activity by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay.

Synthesis of pyranocoumarin fused spirooxindoles via Knoevenagel/Michael/cyclization sequence: a regioselective organocatalyzed multicomponent reaction

Synthesis of pyranocoumarin fused spirooxindole derivatives from the three-component reaction of isatin, malononitrile, and 5,7-dihydroxy-4-methyl-2H-chromen-2-one using piperidine as organocatalyst has been reported. Replacing malononitrile by ethyl cyanoacetate and using methanol as solvent, the same protocol provides the corresponding transesterified products. The salient features of this protocol are metal-free reaction conditions, easy isolation of products, applicability to a wide range of isatins with good yields and formation of only one regioisomer among the three possible products.