Three-component Cyclocondensation 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.

Ceric ammonium nitrate catalyzed one-pot three-component microwave-assisted synthesis of indole-substituted fused pyrimidine and pyridine derivatives

The study investigates the synthesis of fused pyridine and pyrimidine derivatives known for their diverse biological activities and structural versatility which serve as pivotal building blocks in organic synthesis. A series of indole-substituted cyanamide derivatives were synthesized by one-pot three-component cyclo-condensation between Indole-3-carboxaldehyde, malononitrile, and electron-rich aromatic and heterocyclic amines by employing several methods such as grinding, microwave irradiation and conventional reflux in the presence of ceric ammonium nitrate and DMF. The nuclei differ concerning the heterocyclic amines such as pyridine, pyrimidine, pyrazine, thiazole, and tetrazole. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and Mass spectra. The reaction proceeds via Knoevenagel condensation, Michael addition, and intramolecular cyclization. The employed methodology offers the convenient advantages of cascade one-pot condensation, easy isolation, short reaction time, and excellent yield (83–95%).

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.

Green Synthesis of Arylideneisoxazol-5-Ones Catalyzed by Silicon Dioxide Nanoparticles

4-Arylideneisoxazol-5(4H)-ones were obtained via a simple and efficient one-pot, three-component cyclocondensation of diverse aldehydes with hydroxylamine hydrochloride and β-keto esters in water. This one-pot heterocyclization has been performed in the presence of catalytic amounts of silicon dioxide nanoparticles (SiO2 NPs) at room temperature. This approach is economical for the synthesis of potentially bioactive 4-arylideneisoxazol-5(4H)-one derivatives. The products were formed in 86–94% isolated reaction yields using 5 mol% nanocatalyst. The heterocyclization reactions were completed at room temperature under aqueous conditions. The significant features of the present procedure are uncomplicated product isolation, purification without chromatographic methods, great biocompatibility of SiO2 NPs, straightforward reaction conditions, easy workup, environmentally friendly, readily available starting materials, reusability of the catalyst, as well as inexpensive and green reaction medium.

Arylideneisoxazole-5(4H)-One Synthesis by Organocatalytic Three-Component Hetero-Cyclization

An expedient, green, practical, and vastly efficient three-component cyclo-condensation is catalyzed by triphenylphosphine. The 4-arylideneisoxazol-5(4H)-one heterocycles are generated in good to excellent isolated reaction yields. Experiments show that the best results were obtained using 15 mol% of the catalyst under aqueous conditions at room temperature. The sonochemical synthesis of 4-arylideneisoxazol-5(4H)-one derivatives were also performed by using 10 mol% of triphenylphosphine in water as an eco-friendly reaction medium. In the comparative method, ultrasonication showed shorter reaction times and also requires smaller amounts of catalyst. While aryl/heteroaryl aldehydes were used, the variation of β-keto-ester was also explored. The β-keto-esters (ethyl acetoacetate/ethyl 4-chloro-3-oxobutanoate/ethyl 3-oxohexanoate) under optimized reaction conditions reacted well and afforded the corresponding 4-arylideneisoxazol-5(4H)-ones in shorter reaction times. The approach is simple, approximately compatible with the pot-, atom-, and step-economy.

Plant-Based Bronsted Acidic Polyphenol Catalyzed Synthesis of 3'-Phenyl-1'H-Spiro[Cyclohexane-1,2'-Quinazolin]-4'(3'H)-Ones and 3'-Phenyl-1'H-Spiro[Cyclopentane-1,2'-Quinazolin]-4'(3'H)-One Derivatives

An efficient, metal-free method for the synthesis of 3'-phenyl-1'H-spiro[cyclohexane-1,2'-quinazolin]-4'(3'H)-ones, 4-(tert-butyl)-3'-phenyl-1'H-spiro[cyclohexane-1,2'-quinazolin]-4'(3'H)-ones and 3'-phenyl-1'H-spiro[cyclopentane-1,2'-quinazolin]-4'(3'H)-one derivatives was developed using isatoic anhydride, cycloalkanone and different anilines through one-pot three-component cyclocondensation by utilizing tannic acid(TA)—a weakly acidic natural polyphenol, as a novel inexpensive greener catalyst. The reaction allows rapid cyclocondensation (10–30 min) at reflux condition with 5 mol% of tannic acid to give diversely functionalized spiroquinazolinones in good to excellent yield. This green protocol is of big interest due to employing simple, nontoxic and inexpensive tannic acid as a catalyst and environmentally benign aqueous ethanol as green solvent without the use of any harmful mineral acid and toxic transition metal catalyst.

A catalytic three-component synthesis of isoxazol-5(4H)-ones under green conditions

The three-component cyclocondensation of various aryl/heteroaryl aldehydes, hydroxylamine hydrochloride, and ethyl acetoacetate/ ethyl 4-chloro-3-oxobutanoate have been established for the synthesis of isoxazol-5(4 H )-ones using sodium malonate as an efficient catalyst. This reaction has been performed in water as a green reaction medium at 25°C. Optimization of the reaction conditions show that the reaction performs better in aqueous medium, at room temperature, and in the presence of 10 mol% of the catalyst. This procedure has several unique features, including shorter reaction times, easy separation of pure products, avoiding the hazardous organic solvents, simplicity of experimental procedures, operationally simple, and eco-friendly.

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.

Synthesis of new bimetallic phosphate (Al/Ag3PO4) and study for its Catalytic performance in the synthesis of 1,2-dihydro-l-phenyl-3H-naphth [1,2-e]-[1,3] oxazin-3-one derivatives

<p>This work aims to prepare a new bimetallic phosphate catalyst using a new simple and effective method. This new catalyst was ready for the first time by a modification of Triple Super Phosphate (TSP) fertilizer with silver sulfate (AgSO<sub>4</sub>), followed by the impregnation of the aluminum atoms using aluminum nitrate (Al(NO<sub>3</sub>)<sub>3</sub>). The use of Al/Ag<sub>3</sub>PO<sub>4</sub>, for the first time as a heterogeneous catalyst in organic chemistry, offers a new, efficient, and green pathway for synthesizing 1,2-dihydro-l-phenyl-3H-naphth[1,2-e]-[1,3]oxazin-3-one derivatives by one-pot three-component cyclocondensation of b-naphthol, aryl aldehyde, and urea. The structure and the morphology of the prepared catalyst were characterized by spectroscopic methods such as X-Ray Diffraction (XRD), Fourier Transform Infrared spectroscopy (FT-IR), and dispersive X-ray spectrometry coupled with a scanning electron microscope (EDX-SEM). In addition, the optimization of the reaction parameters was carried out considering the effect of catalyst amount, the temperature, and the solvent. The procedure described herein allowed a comfortable preparation of oxazine derivatives with excellent yields, short reaction times, and in the absence of organic solvent.</p>

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.

Three-component Synthesis of 4-Arylidene-3-alkylisoxazol-5(4H)-ones in the Presence of Potassium 2,5-dioxoimidazolidin-1-ide

An efficient synthesis of 4-arylidene-3-alkylisoxazole-5(4H)-ones has been implemented via the three-component cyclocondensation of aryl(heteroaryl)aldehydes with hydroxylamine hydrochloride and β-ketoesters. The potassium 2,5-dioxoimidazolidin-1-ide has been introduced as the new organocatalyst to facilitate this heterocyclization. In the current process, three starting materials, including substituted benzaldehydes/heterocyclic aromatic aldehydes, hydroxylamine hydrochloride, and ethyl acetoacetate/propyl acetoacetate/butyryl acetoacetate have been successfully used to synthesize the number of substituted isoxazole- 5(4H)-ones in good to high yields in ethylene glycol as a green reaction medium at 80 ºC. The low catalyst loading is also a main advantage over some reported catalysts.

An efficient (TBA)2S2O8 catalyzed regioselective solvent-free one-pot synthesis of fully substituted pyrazoles

An efficient tetra-n-butyl ammonium peroxydisulphate (TBA)2S2O8 catalyzed a direct one-pot synthesis of fully substituted pyrazoles in excellent yields with high regioselectivity has been described via a three-component cyclocondensation of aldehydes, aryl hydrazines with β-diketones or β-keto esters under solvent-free conditions. The structure of the target compound 4 m was confirmed by X-ray diffraction.

An efficient one-pot three-component synthesis of 7-amino-2, 4-dioxo-5-aryl-1,3,4,5-tetrahydro-2 H-pyrano[2,3-d]pyrimidine-6-carbonitriles catalyzed by SnO2/SiO2 nanocomposite

We have developed a SnO2/SiO2 catalyzed efficient and rapid protocol for the synthesis of pyrano[2,3-d]pyrimidinone derivatives by the three-component cyclocondensation of aromatic benzaldehydes, malononitrile, and barbituric acid in ethanol at room temperature. Nanocomposite SnO2/SiO2 catalytic materials were synthesized using the sol–gel method. The synthesized catalytic materials were well characterized by using a transmission electron microscope, X-ray diffraction spectroscopy, scanning electron microscopy, energy dispersive spectroscopy, Fourier transform infrared spectroscopy, temperature-programmed desorption (NH3-TPD), and Brunauer–Emmett–Teller theory. This protocol has several advantages such as high yield, simple workup procedure, non-toxic, clean, and easy recovery and reusability of the catalytic system. An efficient catalytic system has been developed for the synthesis of pyrano[2,3-d]pyrimidinone derivatives from one-pot three-component cyclocondensation of aromatic benzaldehydes, malononitrile, and barbituric acid in ethanol at room temperature using 15 wt% SnO2/SiO2.

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

DBU catalysis in micellar medium: an environmentally benign synthetic approach for triheterocyclic 4H-pyrimido[2,1-b]benzothiazole derivatives

An efficient, simple, practical and scalable approach for the preparation of pharmaceutically important scaffold 4H-pyrimido[2,1-b]benzothiazoles using one-flask three-component cyclo-condensation of β-ketoester, substituted aromatic aldehydes and 2-aminobenzothiazole under micellar medium as an environmentally benign protocol is reported. The reaction is catalyzed by DBU and CPB as a green, easily available, cheap and sustainable catalyst. The product formation takes shorter duration with good to excellent yield of the products. The method is also demonstrated on multi-gram level. The Atom economy, environmentally benign, easy to work-up, no use of hazardous solvents, short reaction time are the most outstanding advantages of the developed methodology.

Silica chloride (SiO2-Cl) catalyzed one pot synthesis of 2,3-disubstituted-thiazolidin-4-one

In this paper, we report one-pot, three-component cyclo condensation of an aldehyde, an amine and thioglycolic acid to form 2,3-disubstituted-thiazolidin-4-one by using supported protic acid (Silica Chloride: SiO2-Cl) catalyst. The catalyst SiO2-Cl is compatible with a variety of aldehydes (aryl/heteroaryl) and the aromatic amines affording 2,3-disubstituted-thiazolidin-4-one analogs in 72–89% yields. Moreover, the supported catalyst was recycled several times without significant loss of catalytical activity

3,5-Bis(trifluoromethyl) Phenylammonium triflate(BFPAT) as a Novel Organocatalyst for the Efficient Synthesis of 2,3-dihydroquinazolin-4(1H)-one Derivatives.

A one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives by threecomponent cyclo-condensation of isatoic anhydride, aldehydes and amine or ammonium acetate has been developed using 3,5-Bis(trifluoromethyl) phenylammonium triflate (BFPAT) as a new organocatalyst. All of the obtained products are known compounds and identified by IR, 1HNMR, 13CNMR and melting points. A wide variety of structurally different aldehydes reacted easily and rapidly to result in the relating 2,3-dihydroquinazolin-4(1H)-ones in good to excellent yield. We have demonstrated an extremely effective and new process for synthesizing 2,3- dihydroquinazolin-4(1H)-ones employing BFPAT as a novel organocatalyst in one-pot fashion.

Antibacterial Evaluation of Some 3-Amino-1H-Pyrazolo[1,2-b]Phthalazine-2-Carboxamides by using Fish Scale Hydroxyapatite as a Heterogeneous Catalyst

Fish scale hydroxyapatite (FS-HAP) has been used as an efficient catalyst for the synthesis of 3-amino-1H-pyrazolo[1,2-b]phthalazine-2-carboxamide derivatives via the one-pot, three-component cyclocondensation reactions of aromatic aldehydes with cyanoacetamide and phthalhydrazide under solvent-free condition. FS-HAP has been characterized by FT-IR, XRD, SEM and EDS techniques. The synthesized compounds were evaluated for their in vitro antibacterial activity against gram-positive (Bacillus cereus, Bacillus aryabhattai, Bacillus megaterium, Staphylococcus aureus) and gram-negative (Serratia marcescens, Bacillus Pseudomonas putida, Escherichia coli, Enterobacter cloacae) bacteria. Tetracycline and erythromycin were used as standard antibiotics in this investigation. In the present protocol, we have achieved remarkable yields of the product in shorter reaction time and the catalyst was easily recovered and reused.