Three-component Cyclocondensation Reaction Research Articles

Identification of imidazo[1,2-a]pyridines-pyrazole-pyran hybrids as potent glucose-6-phosphate dehydrogenase (G6PD) inhibitors: Synthesis, molecular docking, DFT studies and ADME prediction

In this study, we aimed to identify new anticancer agents by synthesizing a series of Imidazo[1,2-a]pyridines fused with pyrazole-pyran scaffolds 7a–g in good yields (75–85 %) under microwave irradiation. The synthesis was performed through a one-pot, three-component cyclocondensation reaction of 2-(p-substituted)imidazo[1,2-a]pyridine-3-carbaldehyde 4a-g, malononitrile 5, and 5-methyl-2,4-dihydro-3H-pyrazol-3-one 6 in the presence of triethylamine as a catalyst in acetonitrile. The characterization of all synthesized compounds was accomplished through various spectroscopic techniques. All the synthesized compounds were investigated for their anticancer potential in vitro, using an MTT-based assay against A549 lung cancer cell lines. Compounds 7b, 7e, and 7c demonstrated notable anti-proliferative activity against the A549 cell line, while compound 7e showed a significantly lower fluorescence generation (24-fold less) in the G6PD inhibition assay compared to the other compounds.

Biodegradable polyester copolymers: synthesis based on the Biginelli reaction, characterization, and evaluation of their application properties.

The Biginelli reaction, a three-component cyclocondensation reaction, is an important member of the multicomponent reaction (MCR) family. In this study, we conducted end-group modifications on a variety of biodegradable polyesters, including poly(1,4-butylene adipate) (PBA), poly(ε-caprolactone) (PCL), polylactic acid (PLA), and poly(p-dioxanone) (PPDO), based on the precursor polyethylene glycol (PEG). By combining two polymers through the Biginelli multi-component reaction, four new biodegradable polyester copolymers, namely DHPM-PBA, DHPM-PCL, DHPM-PLA, and DHPM-PPDO, were formed. These Biginelli reactions demonstrated exceptional completeness, validating the efficiency of the synthesis strategy. Although the introduction of various polyesters lead to different properties, such as crystallinity and cytotoxicity, the newly synthesized 3,4-dihydro-2(H)-pyrimidinone compounds (DHPMs) exhibit enhanced hydrophilicity and can self-assemble in water and N,N-dimethylformamide (DMF) solution to form micelles with a controllable size. Furthermore, DHPM-PPDO promotes cellular growth and has potential applications in wound healing and tissue engineering. In conclusion, this method demonstrates great universality and methodological significance and offers insights into the medical applications of polyethylene glycol.

Antimicrobial Potency and E. coli β-Carbonic Anhydrase Inhibition Efficacy of Phenazone-Based Molecules.

In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative 3. The as-prepared carbodithioate derivative 3 is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (4-9) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (10). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative (11) which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (12). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against E. coli β-carbonic anhydrase. The amount of cellular protein released by E. coli is directly correlated to the concentration of compound 9, which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound 9. This finding supports compound 9's antibacterial properties and explains how the formation of holes in the E. coli cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against E. coli β-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound (9) declared a greater activity than the other synthesized compounds.

Titanium tetrachloride immobilized on cross-linked poly(N-vinyl-2-pyrrolidone) as a recyclable heterogeneous catalyst for one-pot three component synthesis of 3, 4-dihydropyrimidin-2(1H)-ones/thiones

A new catalytic application of titanium tetrachloride immobilized on the cross-linked poly(N-vinyl-2-pyrrolidone) carrier as beads, TiCl4/PNVP, as a recoverable and heterogeneous macromolecular Lewis acidic catalyst is developed. This catalytic system allowed for the facile and cleaner synthesis of 3,4-dihydro pyrimidin-2(1H)-ones/thiones in high yields with TON up to 23.2 through the Biginelli three-component cyclocondensation reaction in ethanol. The reusability test ascertained that this heterogeneous titanium catalyst can be easily separated from the reaction mixture by simple filtration and reused several times with no great decline of activity.

New Strategy for Synthesis of Anticancer Active Piperastrol, Enastron Using Ammonium Sulfocyanate

This report describes an efficient and mild approach for the synthesis of Piperastrol and Enastron via a one-pot three-component cyclocondensation reaction employing ammonium sulfocyanate (NH4SCN) on gram scale in isopropyl alcohol–PEG 400 medium. In this reaction, ammonium sulfocyanate is not only the reacting component but also accelerates the rate of reaction to afford Biginelli compounds. High yields, short reaction time and easy workup procedure are the key advantages of the present protocol. Ammonium sulfocyanate is readily available, cheaper, safer and industrially acceptable inorganic salt.

Hantzsch reaction with bis-indole-2,3-diones: Synthesis of novel bis-spirocyclic oxindole incorporating acridine, dipyrazolo[3,4-b:4',3'-e]pyridine and pyrido[2,3-d:6,5-d']dipyrimidine

One-pot three-component cyclo-condensation reaction of bis(indole-2,3-diones) with dimedone, 3-methyl-1H-pyrazol-5(4H)-one, or 6-aminouracil in boiling acetic acid afforded bis-spirocyclic oxindoles linked to acridine, dipyrazolo[3,4-b:4',3'-e]pyridine, and pyrido[2,3-d:6,5-d']dipyrimidine, respectively.

An improved protocol for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones through L-valine-mediated domino three-component strategy

An expeditious, metal-free protocol has been demonstrated for the synthesis of isoxazolone derivatives using domino multi-component strategy. The envisaged methodology involves the L-valine promoted three-component cyclo-condensation reaction of alkylacetoacetates, hydroxylamine hydrochloride and aldehydes in ethanol under reflux. The reaction proceeded to deliver the desired products in good to excellent yields (74–97%), exhibited good functional group tolerance and completed in less than 4 min with most of the substrates. High yields, short reaction time, noncorrosive organocatalyst, mild reaction conditions, clean reaction profiles and the absence of any tedious workup or purification are the beneficial features of this process. Moreover, quantum computational study has been performed at B3LYP/6-311G++(d, p) level to investigate the various DFT based molecular descriptors, HOMO–LUMO energy gap and electrostatic potential surface properties of the synthesized product. An improved protocol for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones through L-valine-mediated domino three-component strategy

Computational investigation of catalytic effects of CX3COOH (X = F,Cl,H) on the three-component cyclocondensation reaction.

The mechanism of acetic acid (AA), trifluoroacetic acid (TFA), and trichloroacetic acid (TCA) catalyzed three-component cyclocondensation reaction to (4S,6S)-4,6-diphenyl-1,3,5-triazinane-2-thione was determined via density functional calculations. Based on the potential energy surface diagram, TCA was found to be a reasonable catalyst [energy span (δG) is 2kcalmol-1 less than TFA and AA] for the reaction. An energetic span model implies that TFA and AA show the same catalytic performance. The impact of the presence of halogen atoms in TFA and TCA catalysts is quantified via energy barriers. Graphical Abstract Ranking catalytic efficiency of OTC triazinane-2-thione formation Graphical Abstract contains poor quality and small text inside the artwork. Please do not re-use the file that we have rejected or attempt to increase its resolution and re-save. It is originally poor, therefore, increasing the resolution will not solve the quality problem. We suggest that you provide us the original format. We prefer replacement figures containing vector/editable objects rather than embedded images. Preferred file formats are eps, ai, tiff and pdf.It is attached as tiff format.

Efficient One-Pot Synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11-trione Derivatives Catalyzed by Y(OTf)3

In this study, substituted 2H-indazolo[2,1-b]phthalazine-1,6,11-triones, that may possess biological activity, have been synthesized via one-pot three-component cyclocondensation reaction of aromatic aldehydes, cyclic 1,3-dione and phthalhydrazide in ethanol catalyzed by Y(OTf)3 with good to excellent yields. The structures of all synthesized compounds, 3,4-dihydro-13-phenyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4a), 13-(4-cyanophenyl)-3,4-dihydro-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4b), 3,4-dihydro-3,3-dimethyl-13-(4-cyanophenyl)-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4c), 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4d), and 3,4-dihydro-13-(4-isopropylphenyl)-3,3-dimethyl-2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4e) have been elucidated from IR, NMR and mass spectral data.

Three VO2+ complexes of the pyridoxal-derived Schiff bases: Synthesis, experimental and theoretical characterizations, and catalytic activity in a cyclocondensation reaction

Three oxovanadium(IV) complexes of the pyridoxal Schiff bases have been newly synthesized and characterized. The used Schiff bases were N,N′-dipyridoxyl(ethylenediamine), N,N′-dipyridoxyl(1,3-propanediamine) and N,N′-dipyridoxyl(1,2-benzenediamine). Also, the optimized geometry, assignment of the IR bands and the Natural Bond Orbital (NBO) analysis of the complexes have been computed using the density functional theory (DFT) methods. Dianionic form of the Schiff bases (L2−) acts as a tetradentate N2O2 ligand. The coordinating atoms of the Schiff base are the phenolate oxygens and imine nitrogens, which occupy four base positions of the square-pyramidal geometry of the complexes. The oxo ligand occupies the apical position of the [VO(L)] complexes. In the optimized geometry of the complexes, the coordinated Schiff bases have more planar structure than their free form. Due to the high-energy gaps, all of the complexes are predicted to be stable. Good agreement between the experimental values and the DFT-computed results supports suitability of the optimized geometries for the complexes. The investigated complexes show high catalytic activities in synthesis of the tetrahydrobenzo[b]pyrans through a three-component cyclocondensation reaction of dimedone, malononitrile and some aromatic aldehydes. The complexes catalyzed the reaction in solvent free conditions and the catalysts were found to be reusable.

Ultrasound mediated, iodine catalyzed green synthesis of novel 2-amino-3-cyano-4H-pyran derivatives

An efficient synthesis of a novel series of twelve substituted 2-amino-3-cyano-4H-pyran derivatives was achieved by a one-pot three-component cyclocondensation reaction of heteroaryl aldehydes, malononitrile and active methylene compounds catalyzed by iodine in aqueous medium under ultrasound irradiation. In comparison with conventional methods, our protocol is convenient and offers several advantages, such as shorter reaction time, higher yields, milder conditions and environmental friendliness. We have herein successfully demonstrated the synergistic outcome of multi-component reaction (MCR) and sonication to offer a facile route for the design of these derivatives.

Efficient Three-Component Synthesis of 3,4-Disubstituted Isoxazol-5(4H)-Ones in Green Media

Several derivatives of 3,4-disubstituted isoxazol-5(4H)-ones were synthesized via a onepot, three-component cyclocondensation reaction of hydroxylamine hydrochloride, various aryl aldehydes and β-oxoesters. The process takes place in water at room temperature. Tetrabutylammonium perchlorate (TBAP), sodium oxalate or glycine act as catalysts in promoting this reaction. The merits of this method are its efficiency, simplicity, cleanness, greenness, easy work-up, high chemical yields, recyclability, avoidance of using organic solvents, as well as the relatively short reaction times.

Synthesis, characterization and pharmacological screening of some novel 5-imidazopyrazole incorporated polyhydroquinoline derivatives

A new category of polyhydroquinoline derivatives 8a–t were synthesized in moderate to good yield (64–85%) by one-pot three-component cyclocondensation reaction of 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 3 with various enaminones 6a–h and different active methylene compounds (malononitrile 7a, ethylcaynoacetate 7b and caynoacetamide 7c) in absolute ethanol. The newly synthesized compounds were evaluated for their in vitro antimalarial activity against Plasmodium falciparum, in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi and also for their antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Two of them (8n, 8t) exhibited excellent antimalarial activity. Some of them exhibited excellent antibacterial activity and moderate antituberculosis activity compared with the first line drugs.

Synthesis, characterization and biological screening of novel 5-imidazopyrazole incorporated fused pyran motifs under microwave irradiation

A novel combinatorial library of fused pyran derivatives has been designed and synthesized under microwave irradiation by one-pot three-component cyclocondensation reaction of 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde with two active methylene compounds and enolizable ketones/phenols in the presence of piperidine as a basic catalyst. All the newly synthesized compounds have been characterized by elemental analysis and various spectroscopic methods. All the final motifs have been screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, preliminary in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv and also for their antimalarial activity against Plasmodium falciparum.

InCl3-catalyzed green synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones under solvent-free conditions

Abstract A simple, efficient, and green practical approach to 1H-pyrazolo[1,2-b]phthalazine-5,10-diones from phthalhydrazide, aldehydes, and malononitrile/ethyl cyanoacetate has been developed that uses inexpensive and readily available InCl3 as a catalyst in solvent-free one-pot three-component cyclo condensation reaction. This method should provide high yields, shorter reaction time, easy work-up, purification of products by nonchromatographic method, and cleaner reaction. It is a new strategy for N-fused heterocycles synthesis, which haswider application in organic and medicinal chemistry.

Microwave-Assisted Synthesis of Spirofused Heterocycles Using Decatungstodivanadogermanic Heteropoly Acid as a Novel and Reusable Heterogeneous Catalyst under Solvent-Free Conditions

Decatungstodivanadogermanic acid (H6GeW10V2O40·22H2O) was synthesized and used as a novel, green heterogeneous catalyst for the synthesis of spirofused heterocycles from one-pot three-component cyclocondensation reaction of a cyclic ketone, aldehyde, and urea in high yields under solvent-free condition in microwave irradiation at 80°C. This catalyst is efficient not only for cyclic ketones, but also for cyclic β-diketones, β-diester, and β-diamide derivatives such as cyclohexanone, dimedone, and Meldrum's acid, or barbituric acid derivatives.

Nickel (II) Chloride Hexahydrate as an Efficient Catalyst for the Preparation of Highly Functionalised Piperidine Derivatives

Nickel (II) chloride hexahydrate (NiCl2.6H2O) has been employed for the efficient synthesis of highly functionalised piperidines via three-component cyclo-condensation reaction of aldehydes, aromatic amines and acetoacetic esters in ethanol under ambient condition. The key advantages of this procedure are high yields, easy work-up and purification of products by non-chromatographic methods.

An appropriate one-pot synthesis of dihydropyrimidinones catalyzed by heteropoly acid supported on zeolite: An efficient and reusable catalyst for the Biginelli reaction

Abstract A mild and efficient catalytic method has been developed for the synthesis of 3,4-dihydropyrimidin-2 (1 H )-ones (DHPM) by a one-pot three-component cyclocondensation reaction using molybdophosphoric acid (MPA) supported on Y zeolite in high to excellent yields. The reaction investigated in the presence of molybdophosphoric acid encapsulated in the supercage of zeolite for comparison. In the second method, no appreciable progress was observed due to large size of dihydropyrimidinone compounds towards the supercage dimension of Y zeolite. In addition, the catalyst was recovered and reused for several times without efficient loss in catalytic activity.

ZnO nanoparticles catalyzed efficient one-pot three-component synthesis of 2,3-disubstituted quinalolin-4(1H)-ones under solvent-free conditions

ZnO nanoparticles were prepared and applied as a favorable catalyst in three-component one-pot cyclocondensation reaction of isatoic anhydride with amines and aldehydes to afford the corresponding 2,3-disubstituted quinalolin-4(1H)-ones in good yields. Reactions occurred under solvent-free conditions in high atom economy.

Iodine-Catalyzed Versatile Synthesis of 4,6-Diarylpyrimidin-2(1H)-ones (DAPMs) via One-Pot, Multicomponent Reaction

An efficient, solvent-free, one-pot, three-component cyclocondensation reaction between aldehyde, ketone, and urea to give 4,6-diarylpyrimidin-2(1H)-ones (DAPMs) using iodine as catalyst is described. This new protocol provides a simple and environmentally benign route along with the associated advantages of good to excellent yield of the products (90–96%) and short reaction times (5–15 min) at 80 °C.