Three-component Condensation Reaction Research Articles

Comparative study of cerium-manganese ratios in the design of Ce-Mn-binuclear LDH-based Cu complex: a potent nanocatalyst for the green synthesis of spiro[acridine-9,3’-indole]triones

The Ce-Mn binuclear LDH was prepared at four different molar ratios of Ce to Mn (1:1, 1:2, 1:3, and 1:4), modified with both 3-chloropropyltrimethoxysilane (CPTMS) and N-amino-phthalimide (NAP), complexed with Cu(II), and characterized by the FT-IR, ICP, XPS, XRD, BET, UV/Vis, EDX, SEM, SEM-mapping, TEM, and TGA-DTA techniques. The ICP, XPS, BET, and UV-vis techniques showed that the 1:4 molar ratio of Ce to Mn is the best, therefore it was used as a heterogeneous nanocatalyst for the green synthesis of fourteen spiro[acridine-indole]triones from the three-component condensation reaction of isatin, aniline, and 1,3-diketone in mild reaction conditions. The advantages of this method include the absence of harmful organic solvents, easy separation of the catalyst and products, and rapid achievement of excellent yields. Furthermore, the activity of the catalyst was maintained even after four consecutive runs without a significant loss of activity.

One-pot synthesis of tricyclic pyrano[3.2-c]chromene derivatives and their evaluation through in vitro immunomodulatory activity against T cells; Molecular docking investigations and ADME-Tox prediction studies

The aim of this work is the in vitro determination of the immunomodulation effect of pyrano[3,2-c]chromenes on the proliferation of T lymphocyts. These tricyclic heterocycles were prepared at room temperature via a one-pot, three-component condensation reaction involving 4-hydroxy-2H-chromen-2-one, aromatic aldehydes, and malononitrile, using morpholine as a catalyst in a 1:1 ethanol/water mixture. This multicomponent reaction affords the product in high yields, in accordance with the criteria of green chemistry. The structure elucidation was accomplished by spectral data, IR, NMR (1H, 13C, 2D). We determined the in vitro effects of 2-amino-4-(3-hydroxy-5-methoxyphenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AC09) the 2-amino-5-oxo-4-(thiophen-2-yl)-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AC11) derivatives, on the proliferative responses of human T lymphocyts cells, cytokine secretion and intracellular redox status. The study revealed that compounds AC09 and AC11 are efficient immunostimulants in a dose-dependent manner.Human lymphocytes were less sensitive to AC11 at high concentrations compared to the potency of AC09. Human lymphocyte IL-2, IFNγ and IL-4 secretions were significantly enhanced by those pyrano[3,2-c]chromenes derivatives in a dose-dependent manner. The levels of intracellular lymphocytes glutathione (GSH), were unaffected by AC09 and AC11 at any concentrations. AC09 and AC11 induce a significant increase in hydroperoxide and carbonyl protein contents at high concentrations. Conversely, a computational study using molecular modelling revealed that compounds AC09 and AC11 exhibit a strong affinity for the active site residues of Interferon-γ (IFN-γ; PDB ID: 6E3K) target. This is confirmed by the low score energy value and the formation of different types of interactions such as: hydrogen bonds, hydrophobic interactions, and van der Waals forces. Moreover, all Drug likeness's rules were validated, and no toxicity is presented by these compounds. Finally, in vitro studies, molecular docking techniques and ADME-T (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluations were successfully conducted, aiding in the identification of new IFN-γ target inhibitors. A comparative analysis /or studies was then carried out to highlight the complementary effects of the two approaches.

Synthesis of Tryptamine-Thiazolidin-4-one Derivatives and the Combined In Silico and In Vitro Evaluation of their Biological Activity and Cytotoxicity.

Tryptamine, a monoamine alkaloid with an indole ring structure, is derived from the decarboxylation of the amino acid tryptophan, which is present in fungi, plants, and animals. Tryptamine analogues hold significant therapeutic potential due to their broad pharmacological activities, including roles as neurotransmitters and potential therapeutic agents for various diseases. Structural modifications of tryptamine enhance receptor selectivity and metabolic stability, improving therapeutic efficacy. These modifications are crucial for optimizing pharmacokinetic and pharmacodynamic properties, making the analogues more effective and safer for clinical use. In this study, novel tryptamine-thiazolidin-4-one (YS1-12) derivatives were synthesized via a one-pot three-component condensation reaction. The synthesized compounds are characterized by different spectroscopy techniques such as FT-IR, 1H NMR, 13C NMR, and HR-NMS. The synthesized compounds were subjected to binary QSAR disease models for bioactivity prediction and a target prediction model for target analysis. Potential targets were identified, and physics-based molecular simulations were conducted. Additionally, MM/GBSA binding free energy analysis was performed to calculate the average binding free energies of YS1-12 compared to reference molecules. Our computational results indicated promising biological activities for these new compounds. To further investigate these activities, the compounds were tested in vitro using two different cancer cell lines: YKG-1 glioblastoma and SH-SY5Y neuroblastoma cells. The results confirmed the potential activities of these novel compounds. Notably, compounds YS4 and YS10 exhibited favorable activities compared to the control compounds 5-FU and Temozolomide. YS4 demonstrated an IC50 value of 20 nM against YKG-1 cells, while YS10 exhibited an IC50 value of 0.44 nM against SH-SY5Y cells.

Synthesis and Characterization of a Hercynite-Supported Copper(II) Complex Based on 1,10-Phenanthroline-5,6-dione and Acetylacetone Building Blocks and Its Catalytic Application in Annulation Reactions.

In the present work, a novel Cu(II) complex containing 10-phenanthroline-5,6-dione (phen-dione) and acetylacetone (acac) was prepared via solid-phase synthesis on silica-modified hercynite magnetic nanoparticles (MNPs). The resulting structure underwent thorough structural analysis using diverse instrumental techniques. The catalytic potential of the synthesized Cu(II) complex was successfully demonstrated in the synthesis of 2-amino-3-cyano-4H-chromenes. This was accomplished via a one-pot, three-component condensation reaction involving lawsone, malononitrile, and aromatic aldehydes in ethanol under reflux conditions, leading to remarkably high yields and product purity. Several advantages stem from this investigation. Notably, the use of ethanol as a sustainable and environmentally friendly solvent highlights the ecoconscious approach of this research. Moreover, the reaction conditions were mild and the separation process was straightforward, resulting in reduced byproducts as well as time and cost savings. Furthermore, the catalyst's stability and reusability were studied under optimal conditions, revealing excellent reversibility for up to five cycles without any significant loss of activity. This excellent performance underscores the potential of the Cu(II) complex for sustainable catalytic applications.

Cu/N-doped carbon spheres derived from soybean flour as an active green nanocomposite for the synthesis of 1,4-disubstituted 1H-1,2,3-triazole derivatives

Cu immobilized onto N-doped carbon spheres (Cu/N-doped CS) derived from soybean flour was synthesized via the hydrothermal method and certified as a green high-efficiency catalyst for the regioselective synthesis of 1,4-disubstituted 1H-1,2,3-triazoles. The obtained N-doped carbon spheres from a combination of glucose and soy flour have a larger size and suitable affinity for load copper species. The morphology and structure of the as-prepared catalyst have been confirmed based on FT-IR, XRD, FE-SEM, EDX, BET, and ICP-OES characterizations. The catalytic performance of the Cu/N-doped carbon spheroids was investigated experimentally. It was found that the Cu/N-doped CS nanocomposite has a high efficiency and recyclability for 5 cycles without any appreciable loss in its catalytic activity in the synthesis of 1,4-disubstituted 1H-1,2,3-triazoles via the three-component condensation reaction of various epoxide/alkyl or aryl halides, sodium azide, and phenylacetylene in a water medium. Furthermore, significant advantages such as stability, ease of preparation, low cost of the carbon resource, high regioselectivity, and good product yield have been achieved in the heterogeneous catalyst system attractive for large-scale in many industrial products.

Solvent-free and efficient heterogeneous Biginelli reactions catalyzed by copper (II)-incorporated iminophenol-based porous organic polymer

The copper (II)-incorporated iminophenol containing porous polymer (Cu-TAzo-TAPB), which was reported to be a recyclable catalyst for click reactions, is now exploited as an efficient catalyst in the solvent-free one-pot process to make 3,4-dihydropyrimidinone derivatives (DHPMs) by a three-component condensation reaction of urea/thiourea, aldehydes, and active methylene compounds. Usually, these reactions are complicated to carry out in a neutral medium. We describe here an eco-friendly method to produce Biginelli products with 5 mol% catalyst loading with a simple isolation technique. The high product yields show the effective Biginelli reaction technique. The catalyst is highly stable and easily recoverable for reuse without significant loss of catalytic efficiency.

Синтез 5-амино-3-арил-1H-пиразол-4-карбонитрилов на основе гидразинов или бензгидразидов в условиях ультразвуковой активации

Pyrazoles containing amino and carbonitrile groups have a wide range of biological activities, including antimicrobial, antiinflammatory, antitumor, antioxidant, and are used to create pesticides and dyes. Also, these compounds are synthons for the preparation of various polyheterocyclic compounds. New potentially biologically active 5-amino-3-aryl-1H-pyrazole-4-carbonitriles containing pharmacophoric substituents have been obtained via three-component condensation reactions of malonic dinitrile with substituted aromatic aldehydes and benzhydrazides or hydrazines. This work considers the limits of applicability of hydrazines and hydrazides as weak nucleophiles in similar processes. The described target compounds have been synthesized using the «green chemistry» approach under ultrasonic activation in water or a mixture of water and isopropyl alcohol in the presence of triethylamine as base catalyst. The applicability of this environmentally friendly, economical and efficient approach for the synthesis of nitrogen-unsubstituted (7, 8) and N-aryl- (4, 6) or N-aroyl-substituted (1–3) pyrazole-4-carbonitriles has been demonstrated. The target pyrazole-4-carbonitrile (2) is formed and Schiff base (2’) is released as a by-product in the reaction of the weak binucleophile 3-nitrobenzhydrazide with 4-benzyloxy-3-methoxybenzaldehyde and malonic dinitrile. Step-by-step syntheses have shown that the initial reaction of a three-component interaction can be either croton condensation or the formation of a Schiff base. In any case, during subsequent heterocyclization, unstable substituted pyrazolines are formed, which aromatize to the target pyrazoles in the presence of atmospheric oxygen under synthesis conditions. The composition and structure of the products have been confirmed by elemental analysis, NMR 1H, 13C spectroscopy, HSQC, and HMBC heteronuclear correlations.

Synthesis and evaluation of novel sulfamethoxazole-containing 1,8-dioxo-decahydroacridine derivatives: Antimicrobial activity and emission properties

A straightforward and efficient method for synthesizing 1,8-dioxo-decahydroacridine derivatives is presented, utilizing a one-pot, three-component condensation reaction involving dimedone, sulfamethoxazole, and aromatic aldehydes. The primary objective of this synthesis is to incorporate the sulfamethoxazole ring into the acridine family structure and examine the antibacterial effects and fluorescence properties of the compounds. The antibacterial activity of the synthesized compounds was evaluated against various gram-positive and gram-negative microorganisms, as well as a fungal strain, using the disk diffusion method, minimum inhibitory concentration determination, and bactericidal assays. Notably, five compounds exhibited potent antibacterial activity against both strains of Bacillus cereus. Furthermore, the influence of pH on the fluorescence emission intensity and absorption spectrum of the synthesized compounds was investigated, revealing that all products displayed fluorescence radiation.

A Chemically Robust 2D Ni-MOF as an Efficient Heterogeneous Catalyst for One-Pot Synthesis of Therapeutic and Bioactive 2-Amino-3-Cyano-4H-Pyran Derivatives.

Despite possessing numerous catalytic advantages of MOFs, developing 2D frameworks having excellent chemical stability along with new catalytic properties, remains a grand challenge. Herein, by employing a mixed ligand synthetic approach, we have constructed a 2D Ni-MOF, IITKGP-52, which exhibits excellent framework robustness in open air, water, as well as over a wide range of pH solutions (2-12). Benefitting from its robustness and abundant Lewis acidic open metal sites, IITKGP-52 is explored in catalyzing the heterogeneous three-component condensation reaction for the tandem synthesis of bioactive 2-amino-3-cyano-4H-pyran derivatives with low catalytic loading, greater compatibility for a wide range of substrates, excellent recyclability and superior catalytic efficiency than the previously employed homo and heterogeneous systems. IITKGP-52inaugurates the employment of MOF-based catalysts for one-pot synthesis of therapeutic and bioactive 2-amino-3-cyano-4H-pyran derivatives.

Design, Green Synthesis and in silico Studies of New Substituted Naphtho[1,2-e][1,3]Oxazines as Potential Acetylcholinesterase Inhibitors.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors as the primary pharmacotherapy for numerous neurodegenerative conditions, leveraging their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, oxazine and its derivatives have brought worthy synthetic interest due to their extensive biological activities including, anti-acetylcholinesterase, anti-oxidant, anti-pyretic, anti-tubercular, anti-convulsant, anti-microbial, anti-malarial, and anti-cancer activities. In this study, a series of novel naphtho[1,2-e][1,3]oxazine derivatives has been designed and synthesized with potential of acetylcholinesterase (AChE) inhibition. The target products have been prepared by a one-pot and three-component condensation reaction of 2-naphthol, various aromatic aldehydes, and arylmethanimine in the presence of 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl) as an effective and recyclable ionic liquid catalyst under microwave irradiation solvent-free condition. The chemical structures of all resulting products were confirmed by spectroscopic methods (IR, 1H-NMR, 13C NMR) as well as elemental analysis. The molecular docking studies has also been performed to investigate the synthetic compounds in the the AChE active site gorge. The results showed that all these derivatives interact with the enzymes with high affinity in binding pocket. The MM-GBSA studies were performed for all synthesized derivatives and among them, compound 3-(4-Chlorophenyl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine 5f, showed the lowest the binding free energy (-48.04 kcal mol-1). In general, oxazine derivatives could be proposed as the strong AChE inhibitors.

One-pot Multicomponent Synthesis of Hydrazinyl Thiazoles Bearing an Isatin Moiety in Aqueous Medium

Abstract: Isatin-derivatives are an important class of nitrogen-containing heterocyclic compounds in organic synthesis. On the other hand, 1,3-thiazoles are 5-membered heterocyclic compounds containing nitrogen and sulphur atoms. Hydrazinyl thiazoles are often prepared through the classical condensation of aldehydes or ketones with thiosemicarbazide to yield thiosemicarbazones, which will then undergo heterocyclization with phenylacyl bromides to give the corresponding hydrazinyl thiazoles. Nowadays, multi-component reactions (MCRs) are considered the most powerful tool in organic synthesis. The use of water as a green solvent in organic synthesis is one of the goals of green chemistry. In this study, a series of new hydrazinyl thiazoles 3a-3u bearing an isatin moiety were synthesized in good yield via a one-pot three-component condensation reaction of isatins with thiosemicarbazide and phenyl acyl bromides in water under reflux condition. All the synthesized compounds were characterized by IR, 1D-NMR, 2D-NMR and LC/MS spectral data.

Synthesis of a Series of 4H-Pyran Derivatives with Multicomponent Reaction in DBSA/H2O Microemulsion System

A series of 4H-pyran derivatives were synthesized through a three-component condensation reaction in a pot using aromatic aldehyde, cyclohexanedione, and malononitrile in the dodecyl benzenesulfonic acid/H2O microemulsion system. This protocol is attractive because dodecyl benzenesulfonic acid microemulsion is superior for organic reaction due to its dual catalysis. On the one hand, dodecyl benzenesulfonic acid acts as a Brønsted acid to catalyze the reaction; on the other hand, it can form a microemulsion as surfactant to enlarge the boundary area and entrap water produced during esterification reaction. In addition, the reaction process is simple, with high liaison formation efficiency, good yields, and environmentally harmless reaction conditions. The dodecyl benzenesulfonic acid/H2O microemulsion system was equally effective when used in consecutive reactions.

One-Step, Low-Cost, Operator-Friendly, and Scalable Procedure to Synthetize Novel Tetrazolopyrimidinylbenzopyran-2-ones by Benign Protocol

Abstract: New coumarin chalcones 3j–p were conveniently obtained in high yields via Claisen-Schmidt condensation reaction, when acetyl coumarin 1 reacted with 3-aryl-1-phenyl pyrazole-4-carbaldehydes 2j–p in boiling ethanol in the presence of triethyl amine as a catalyst. Also, two synthetic pathways were afforded for the synthesis of novel tetrazolo[1,5-a]pyrimidinyl-2H-chromen-2-ones 5a-p. The first pathway is a multistep process including formation and separation of chalcones, which then were allowed to react with 5-aminotetrazole 4. While, the second pathway is a highly efficient one-pot three-component condensation reaction of 3-acetyl coumarin 1, aromatic aldehydes 2a-p and 5-aminotetrazole 4 under green and mild reaction conditions by using acetic acid (AcOH) as a catalyst and solvent. The molecular structure of products was established on the basis of their NMRs, IR and elemental analysis data. Solvent optimization was carried out in the reaction producing 3-(5-Phenyl-4,5-dihydrotetrazolo[1,5-a]pyrimidin-7-yl)-2H-chromen-2-one (5a). The advantages to using environmental-friendly acetic acid are simple operation, short reaction time, high efficient (97%), operationally facile and wide tolerance of starting materials. objective: The advantages of using environmental-friendly AcOH are simple operation, short reaction time, high efficient (97%), operationally facile and wide tolerance of starting materials.

Synthetic Methods of 1H-Pyrazolo[1,2-b]Phthalazine Derivatives

Abstract: This review deals with the synthetic methods of pyrazolo[1,2-b]phthalazine derivatives using one-pot multi-component reactions via modern and traditional methods. The synthetic methods are subdivided into groups according to the type of reactants e.g (1) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and acetonitriles; (2) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and aroyl acetonitriles; (3) one-pot three-component reaction of 2,3-dihydrophthalazine-1,4-dione, aldehydes and acetylacetone or 4-hydroxy-2H-chromen-2-one or acetylene derivatives; (4) one-pot four-component condensation reaction of phthalimide, hydrazine hydrate, aldehydes and acetonitriles; (5) one-pot four-component reaction of phthalic acid, hydrazine hydrate, indole-3- carbaldehyde and acetonitriles; and (6) one-pot three-component condensation reaction of 2,3- dihydrophthalazine-1,4-dione, aldehyde, and dimedone derivatives. Moreover, the various methods were reported.

The gentisic acid-based deep eutectic solvent mediated green synthesis of acridines

A novel gentisic acid-based deep eutectic solvent (ETPPBr/GA-DES) was prepared by mixing of ethyltriphenylphosphonium bromide (ETPPBr) and gentisic acid (GA = 2,5-dihydroxy-benzoic acid), and its structure fully investigated by using the FT-IR, TGA/DTA, densitometer and 1HNMR techniques. Different mole ration of ETPPBr to GA were examined and the eutectic point phase diagram showed that the best ratio for the synthesis of a novel gentisic acid-based DES is the one-to-one mole ratio of the two starting materials (ETPPBr and GA).Then, ETPPBr/GA-DES was used as a novel and capable catalyst for the green synthesis of diverse N-substituted decahydroacridine-1,8-diones a(1−12) from the three-component condensation reaction of aromatic aldehyde, aromatic amine and dimedone in solvent-free conditions at 80 °C.

Eco-friendly synthesis of various tri-substituted imidazole derivatives by using a novel functionalized NCP@SiO3PrNHPrSiO3TiO2 under solvent-free conditions

In this research, a novel NCP@SiO3PrNHPrSiO3TiO2 nano catalyst has been designed, synthesized and fully characterized using various analytical techniques such as; XRD, FT-IR, SEM, EDS, BET and TG analyses. The catalytic activity of NCP@SiO3PrNHPrSiO3TiO2 was also employed for the synthesis of tri-substituted imidazoles via three-component condensation reactions of aldehydes, benzyl and NH4OAc under solvent-free conditions. This synthesis features environmentally benign, short reaction time, efficiency, and feasibility of large-scale synthesis compared to classical reactions.

Novel UiO-NH2-like Zr-Based MOF (Basu-DPU) as an Excellent Catalyst for Preparation of New 6H-Chromeno[4,3-b]quinolin-6-ones.

A new two-fold interpenetrated pillar-layered metal-organic framework (MOF) was designed and synthesized based on zirconium cations, an amine-functionalized ligand, and a linear exo-bidentate bis-pyridine ligand. The structure of the prepared framework was evaluated using various techniques, such as Fourier transform infrared (FTIR), 13C NMR, energy-dispersive X-ray (EDX), elemental mapping analysis, scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis/differential thermal analysis (TGA/DTA), and Brunauer-Emmett-Teller (BET). Then, catalytic application of the prepared zirconium-based MOF was successfully explored in the synthesis of novel 6H-chromeno[4,3-b]quinolin-6-ones 4(a-l) through a one-pot three-component condensation reaction of 4-hydroxycumarine, 1-naphthylamine, and aromatic aldehydes under solvent-free conditions at 110 °C. The pure products were obtained with high atom efficiency (AE) and short reaction times and characterized by FTIR, NMR, and mass spectrometry techniques.

Lanthanum triflate as a capable catalyst for the synthesis of xanthenediones

The main purpose of this work was proposing a versatile and capable method for the synthesis of diverse xanthenediones from the three-component condensation reaction of two moles of dimedone and one mole of various aldehydes by the lanthanum triflate catalyst in solvent-free conditions at 60 °C. The products were characterized by comparison of their melting points, IR, and NMR spectra with authentic samples.

Synthesis, virtual screening, and computational approach of 6-(4-metoxyphenyl)-4-phenyl-1,2-dihydropyrimidin-2-one as a potential target for thioredoxin glutathione reductase (TGR)

The three-component condensation reaction of 4-methoxybenzaldehyde with acetophenone and urea in the presence of CF3COOH was investigated and as a result, 6-(4-methoxyphenyl)-4-phenyl-1,2-dihydropyrimidine-2-one was synthesized. The structure of the synthesized compound was confirmed by the X-ray method. Both the DFT and TD-DFT computations for comprehensive analysis of spectral data, and electronic parameters were carried out as an add-on to synthetic research and well corroborated with the experimental results. NBO, NLO, and Hirshfeld surface and energy framework analysis were also used to segregate the different intermolecular hydrogen bonds involved in the molecular packing strength. All DFT findings imply that the synthesized molecule has enhanced non-linear optical properties increased charge transfer and is a highly stable, and proactive candidate for drugs. Furthermore, molecular docking studies were carried out to investigate the binding mechanism between 6-(4-metoxyphenyl)-4-phenyl-1,2-dihydropyrimidin-2-one and the thioredoxin glutathione reductase (TGR) complex. ADMET parameter analysis was also carried out for the compound to understand the compound's safety and compound efficiency for the drug candidate.

Synthesis of 1,2,4,5-oxadiazaboroles by three-component condensations of hydroxylamines, nitriles, and diarylborinic acids

A method for the synthesis of substituted 1,2,4,5-oxadiazaboroles is described, in which hydroxylamines, nitriles, and diarylborinic acids engage in a three-component condensation reaction. The protocol provides access to a substitution pattern that is not readily available through other methods—namely, 2,3-disubstitution, with a tetracoordinate boron center. Structures of representative members of this class of heterocycles were determined by single crystal X-ray diffraction analysis.