One-pot Four-component Reaction Research Articles

Perfluoroalkyl-Decorated Noble-Metal-Free MOFs for the Highly Efficient One-Pot Four-Component Coupling between Aldehydes, Amines, Alkynes, and Flue Gas CO2.

The non-noble-metal catalysed-multicomponent reactions between flue gas CO2 and cheap industrial raw stocks into high value-added fine chemicals is a promising manner for the ideal CO2 utilization route. To achieve this, the key fundamental challenge is the rational development of highly efficient and facile reaction pathway while establishing compatible catalytic system. Herein, through the stepwise solvent-assisted linker installation, post-synthetic fluorination and metalation, we report the construction of a series of perfluoroalkyl-decorated noble-metal-free metal-organic frameworks (MOFs) PCN-(BPY-CuI)-(TPDC-Fx ) [BPY=2,2'-bipyridine-5,5'-dicarboxylate, TPDC-NH2 =2'-amino-[1,1':4',1''-terphenyl]-4,4''-dicarboxylic acid] that can catalyze the one-pot four-component reaction between alkyne, aldehyde, amine and flue gas CO2 for the preparation of 2-oxazolidinones. Such assembly endows the MOFs with superhydrophobic microenvironment, superior water resistance and highly stable catalytic site, leading to 21 times higher turnover numbers than that of homogeneous counterparts. Mechanism investigation implied that the substrates can be efficiently enriched by the MOF wall and then the adsorbed amine species act as an extrinsic binding site towards dilute CO2 through their strong preferential formation to carbamate acid. Moreover, density functional theory calculations suggest the tetrahedral geometry of Cu in MOF offers special resistance towards amine poisoning, thus maintaining its high efficiency during the catalytic process.

Novel carbazolyl-thiazolyl-chromone and carbazolyl-thiazolyl-pyrazole hybrids: synthesis, cytotoxicity evaluation and molecular docking studies.

A simple synthetic method was performed to design a novel series of polycyclic systems consisting of carbazole-thiazolidinone-chromone hybrids 4a-e and carbazole-thiazolidinone-pyrazole hybrids 5a-e in excellent yields. The methodology depended on the one-pot four-component reaction of 3-amino-9-ethylcarbazole, substituted isothiocyanates, ethyl bromoacetate and 6-methyl-3-formylchromone in ethanol under ultrasound waves at 50 °C to give the carbazole-thiazolidinone-chromone hybrids 4a-e. The latter isolated products were treated with hydrazine hydrate in ethanol under ultrasound waves at 50 °C affording the corresponding carbazole-thiazolidinone-pyrazole hybrids 5a-e. Spectral and analytical data confirmed the structures of all the synthesized compounds. The target compounds were screened for their in vitro anticancer activities against HCT116, PC3 and HepG2 cancer cell lines using the standard SRB method. Fortunately, both compounds 5dand5e were the most active against all cancer cell lines compared with doxorubicin and can be promising anticancer agents. Both bioactive products 5band5e were studied by the molecular docking to see how they bind with VEGFR-2 receptor. The results indicated that those compounds exhibited high affinities towards VEGFR-2 and established remarkably similar interactions to those of the powerful VEGFR-2-KDR.

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.

A facile access to the synthesis of highly functionalized novel 4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine hybrid via one-pot four-component domino reaction

A facile one-pot four-component domino protocol has been successfully developed for the combinatorial synthesis of novel N-methyl-3-nitro-4-aryl-4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine-2-amine 7 and 2-amino-4-aryl-4H-pyrano[2′,3′:4,5]imidazo[1,2-a]pyridine-3-carbonitrile 8. The protocol employs readily available starting materials, leading to high yields of the products (83–89%). The transformation involves a domino Knoevenagel-intramolecular Michael reaction sequence, enabling the formation of three new bonds (two CC, two CN, and one CO) and two rings in a single step. Notably, this reaction exhibits several remarkable features, including short reaction time, eliminating the need for extensive workup and column chromatographic purification. Additionally, the reaction demonstrates good scalability, producing satisfactory yields even on a gram-scale.

The Novel Catalyst (Hypogallic Acid-Based Deep Eutectic Solvent) for Preparation of the New Compounds (Pyrano[2,3-d]Pyrimidines)

A novel Deep Eutectic Solvent (MTPPBr/HGA-DES) was prepared by a mixture of methyl triphenylphosphonium bromide (MTPPBr) and hypogallic acid (HGA: 2,3-dihydroxybenzoic acid). The eutectic point phase diagram showed that the one mole of MTPPBr to two moles of HGA is the best mole ratio for the synthesis of a novel DES. Then, MTPPBr/HGA-DES was characterized by the FT-IR, TGA/DTA, densitometer, eutectic points, and 1H NMR techniques, and used as a novel catalyst for the green synthesis of new pyrano[2,3-d]pyrimidines 2(a-j) via a one-pot four-component condensation reaction of 4-hydroxycoumarin, barbituric acid, morpholine and benzaldehydes at 80 °C in solvent-free conditions.

One-Pot Multi-Component Synthesis of Polysubstituted Pyridines Using DBU-SiO2 as a Robust Recyclable Catalyst

We report an efficient novel route for the synthesis of polysubstituted pyridine derivatives with DBU-SiO2 catalyzed one-pot four-component reaction. This protocol offers a mild condition that which affords a series of new polysubstituted pyridine derivatives with good yields. A plausible mechanism for this process is proposed.

One-pot synthesis of novel poly-substituted 3-cyanopyridines: Molecular docking, antimicrobial, cytotoxicity, and DFT/TD-DFT studies

Novel pyridine-3-carbonitrile derivatives, denoted as (4a-j), were synthesized using a convergent synthetic approach that involved a one-pot four-component reaction. This was achieved by utilizing a combination of various aromatic aldehydes, acetophenone derivatives, malononitrile, and four different sodium alkoxide solutions. The synthesized compounds were characterized using various spectroscopic techniques such as IR, 1HNMR , 13CNMR , and elemental analysis. Molecular docking simulations were employed to investigate the binding affinity of compounds (4a-j) towards two proteins, DHFR and HT-hTS. The results revealed that 4-(4-chlorophenyl)-2-ethoxy-6-phenyl-pyridine-3-carbonitrile (4a) compound exhibited the highest binding affinity score (ΔG = -8.06 Kcal/mol) upon docking into the active site of DHFR, while 2-(4-nitrophenyl)-6-(4-chlorophenyl)-4-ethoxy-pyridine-3-carbonitrile (4d) compound displayed the strongest binding affinity score (ΔG = -4.17 Kcal/mol) when docked to the active site of HT-hTS. These results were supported by the cytotoxic activity of selected compounds (4a, 4b, 4e, and 4 h) against human cancer cell lines (MCF7, HT29, and A2780) as well as normal human fetal lung fibroblast (MRC5) using MTT assay. The cytotoxicity analyses revealed that compound (4a) displayed cytotoxic activity against all cancer cell lines, particularly human colorectal carcinoma (HT29) with an IC50 value of 2.243±0.217 μM, which is lower than that of the reference drug (Doxorubicin) with an IC50 value of 3.964±0.360 μM. Furthermore, compound (4a) exhibited a lower cytotoxic effect on normal human fetal lung fibroblast (MRC5) with an IC50 value of 2.222±0.137 μM, as compared to the IC50 value of the reference drug (Doxorubicin) which was 2.476±0.033 μM. The antimicrobial activity of selected compounds such as (4a, 4c, and 4f) was also evaluated against a panel of microorganisms, including two gram-positive strains (Staphylococcus aureus and Enterococcus faecalis) and two gram-negative strains (Escherichia coli and Pseudomonas aeruginosa). The zone of inhibition and minimum inhibition concentration (MIC) demonstrated the potency of these compounds. Specifically, compounds 4-(4-chlorophenyl)-2-ethoxy-6-phenyl-pyridine-3-carbonitrile (4a) and 4-(4-methoxyphenyl)-2‑methoxy-6-(4-nitrophenyl)-pyridine-3-carbonitrile (4f) exhibited MIC of 0.013 µM against E. coli strains, which is comparable to that of the reference drug amoxicillin (MIC=0.01 µM). Finally, Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) studies were performed on compounds (4a-j) to obtain a more comprehensive understanding of the structure-activity relationship and solvatochromic behavior of these molecules. Overall, the results suggest that compound (4a) could potentially serve as a promising cytotoxic and antibacterial agent with a better safety profile and reduced side effects on normal cells.

Synthesis, crystal structure, Hirshfeld surface, biological evaluation, DFT and molecular docking studies of unsymmetrical 3-allyl-5-ethyl-1,4-dihydro-2,6-dimethyl-4-phenyl pyridine-3,5-dicarboxylate derivatives

By employing ceric ammonium nitrate as an effective catalyst in the one-pot four-component Hantzsch reaction, a new series of unsymmetrical 1, 4-dihydropyridines were synthesised. The synthesised compounds were identified using spectral methods and the structure of the compound 3-allyl-5-ethyl-4(3-fluorophenyl)-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (5f) was confirmed by single crystal XRD analysis. Optimised bond parameters were calculated using DFT /B3LYP/6-311++(d,p) basis set and also compared with single crystal XRD data. The calculated hyperpolarisability may be attractive for further studies on the material's NLO properties. NBO analysis was used to examine the stability of the molecule resulting from the hyper conjugative interaction and charge delocalisation. The eventual charge transfer interactions that occur within the molecule are explained by HOMO–LUMO analysis. MEP reveals the electrophilic and nucleophilic reactive sites of the molecule. According to the Hirshfeld surface analysis, the intermolecular stabilisation in the crystal is mostly caused by hydrogen bond interactions between H … H, C–H … C, C–H … N, and particularly C–H–O. It was discovered that the chemicals 5d and 5i were effective antimicrobials activity. Molecular docking studies were employed to identify the primary binding site of piperidine to receptors. These results indicate that the target molecules may be considered for further drug design endeavours. Research highlights Compound synthesised by the one-pot four component Hantzsch method. Single crystal of 3-allyl-5-ethyl-4(3-fluorophenyl)−1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate(5f) was obtained by slow evaporation method. Hirshfeld analysis and fingerprint plots were performed to confirm the intermolecular interactions in the crystal structure. The stability and reactivities of 5f was achieved from DFT calculation. The antimicrobial studies showed that compounds have promising antimicrobial properties. Molecular docking studies were employed to identify the primary binding site of piperidine to receptors.

HDBU]Br@P-DD as Porous Organic Polymer-Supported Ionic Liquid Catalysts for Chemical Fixation of CO2 into Cyclic Carbonates

The chemical fixation of CO2 into high value-added cyclic carbonates is of significant potential and sustainability to address the energy and ecological issues. [HDBU]Br@P-DD-m/n, a series of porous organic polymer-supported ionic liquids (PSILs), were fabricated in this work through a one-pot four-component reaction of DMAEMA, DVB, 4-bromobutyric acid, and DBU. The formation of [HDBU]Br and construction of the P-DD polymer network proceeded concurrently with the support of the in situ-formed IL being achieved simultaneously. Characterization of the PSILs by IR, ICP, BET, SEM, and TGA etc. showed that the as-prepared catalysts possessed versatile hierarchical porosity with varying ionic densities and excellent thermostability. The porosity of the copolymer skeleton was found to be affected by the accompanying formation of [HDBU]Br. The PSILs were then evaluated as catalysts for the cycloaddition reaction of CO2 with epoxides, among which [HDBU]Br@P-DD-4/1 showed the optimal performance under atmospheric pressure and solvent-/cocatalyst-free conditions (95% yield and 99% selectivity for CO2 cycloaddition with epichlorohydrin). By correlating the performance and structures of the catalysts, the synergistic effect of the tertiary amine, [HDBU]Br, and pore distribution was demonstrated. In addition, the catalyst was found to be applicable in synthesizing a range of differently substituted carbonates in good to excellent yields. Finally, the catalyst could be recovered readily and good catalytic activity was still observed after use for 6 runs. The work not only provided an active, reusable, and metal-free heterogeneous catalyst for the fixation of CO2 into cyclic carbonates but also developed a facile one-step multicomponent strategy for constructing PSIL catalysts, which would be promising to find wide applications in catalysis and organic synthesis field.

MIL-101(Cr)-Functionalized TEDA-BAIL: An Efficient and Recyclable Catalyst for the Synthesis of Pyrimido[4,5-b]quinolinetrione Derivatives

Background: In this study, a heterogeneous catalyst containing MIL-101(Cr) functionalized TEDA-BAIL was used to carry out an efficient four-component reaction between aromatic aldehydes, barbituric acid, dimedone, and aryl amines, resulting in the synthesis of a new class of pyrimido[ 4,5-b]quinolinetrione derivatives. Methods: Pyrimido[4,5-b]quinolinetrione derivatives were synthesized through a one-pot fourcomponent reaction between aromatic aldehydes, barbituric acid, dimedone, and aryl amines, in the presence of triethylenediamine-based ionic liquid@MIL-101(Cr) composite as a catalyst under reflux conditions. The TEDA-BAIL@MIL-101(Cr), which is a recyclable catalyst, was fully characterized by Fourier transform infrared spectrophotometry (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX) thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET) and Transmission electron microscopy (TEM). Results: Four-component synthesis of pyrimido[4,5-b]quinolinetriones was catalyzed by TEDABAIL@ MIL-101(Cr) with aromatic aldehydes, barbituric acid, dimedone, and aryl amines under reflux conditions. The obtained experimental results revealed that the employed synthesis approach is a simple method that offers several advantages, including sustainability, facile separation from the reaction medium, and reusability of the catalyst after six consecutive runs without loss of activity. Conclusion: The presented method is an efficient synthesis route for the synthesis of pyrimido[4,5- b]quinolinetriones in the presence of TEDA-BAIL@MIL-101(Cr) under reflux conditions. This procedure provides multiple advantages, such as ease of execution, high yield, clean reaction conditions, shorter reaction time, and catalyst sustainability.

Synthesis and characterization of Se doped Fe3O4 nanoparticles for catalytic and biological properties

In this study, Se-doped Fe3O4 with antibacterial properties was synthesized using by a coprecipitation method. The chemistry and morphology of the Se doped Fe3O4 nanocomposite were characterized by energy-dispersive X-ray spectroscopy, field-emission scanning electron microscopy, X-ray diffraction, vibrating sample magnetometry, and Brunauer–Emmett–Teller spectroscopy. The antibacterial activity of the Fe3O4/Se nanocomposite was examined against G+ (Gram-positive) and G− (Gram-negative) bacteria, in the order Staphylococcusaureus, Staphylococcussaprophyticus, Pseudomonasaeruginosa, Klebsiellapneumonia, and Escherichiacoli, which are the most harmful and dangerous bacteria. Fe3O4/Se, as a heterogeneous catalyst, was successfully applied to the synthesis of pyrazolopyridine and its derivatives via a one-pot four-component reaction of ethyl acetoacetate, hydrazine hydrate, ammonium acetate, and various aromatic aldehydes. Fe3O4/Se was easily separated from the bacteria-containing solution using a magnet. Its admissible magnetic properties, crystalline structure, antibacterial activity, mild reaction conditions, and green synthesis are specific features that have led to the recommendation of the use of Fe3O4/Se in the water treatment field and medical applications. Direct Se doping of Fe3O4 was successfully realized without additional complicated procedures.

Lipase-catalyzed one-pot four-component reaction in water: green construction of substituted 2,3-dihydrothiophenes

A green and efficient method for the construction of functionalized 2,3-dihydrothiophene derivatives in water was reported.

An Efficient and Green Synthesis of New 6-Iodo- Pyrano[2,3-d] Pyrimidine-4-Ones via a One-Pot Four-Component Reaction Followed by Iodocyclization in Water

Eco-friendly one-pot synthesis of new 6-iodo-4H-pyrano[2,3-d]pyrimidin-4-ones via the condensation of pyrimidine-4,6-diol, aldehydes, phenylacetylene, and iodine has been reported in water at 60 °C. To obtain the optimal reaction conditions, the effects of reaction temperature, bases and solvents were investigated. Under the optimal condition, formaldehyde and different aromatic aldehydes bearing both electron-donating and withdrawing groups underwent the reaction to give the corresponding 6-iodo-5,7-disubstituted-3H-pyrano[2,3-d] pyrimidin-4(5H)-one derivatives in high to excellent (90–97%) yields. This transformation generates 6-iodo-4H-pyrano[2,3-d]pyrimidin-4-one derivatives using a domino reaction involving Knoevenagel condensation and iodocyclization in the absence of metal or acidic/basic catalysts. The prepared products were characterized using FT-IR, 1HNMR, 13CNMR, and Mass spectroscopies.

Design, synthesis, docking studies and anticancer evaluation of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives on MIN-6 cancer cell line

A series of spiro[indoline-3,4′-pyrano[2,3-c]pyrazoles] were synthesized by a one-pot four-component reaction of ethyl acetoacetate, hydrazine hydrate, malononitrile, and isatin catalyzed by new polymer-supported ionic liquid (PSIL) catalyst in an aqueous solution at ambient conditions. Newly synthesized compounds were fully characterized by FT-IR, 1H and 13C NMR, and mass spectrometry. The pharmacokinetic properties were screened and followed by molecular docking on COX-2 to check the in silico potency. Cytotoxicity of 5a-j molecules was evaluated against the Min-6 pancreatic cancer cell line. The 5a-j molecules have been found to have a good drugable profile and good binding affinity with the COX-2 enzyme. In addition, the in vitro cytotoxic potential of the synthesized compounds showed promising inhibition potential against cancer cell lines. The most promising compounds, 5e (IC50 11.33) and 5g (IC50 17.30) show the most remarkable cytotoxic activity as compared to other analogues. The results convey that the designed molecules are promising products for level-up biological evaluation.

The regioselective one-pot four-component synthesis of novel functionalized 4H-pyrano[2, 3-b]quinoline derivatives using DABCO as a homogeneous organocatalyst.

This study deals with the synthesis of the regioselective and facile domino one-pot four-component reaction of 2-chloroquinoline-3-carbaldehydes, 1, 3-cyclodione compounds (as cyclic active methylene), ethyl acetoacetate (as β-keto ester), and hydrazine hydrate in the presence of DABCO as a homogeneous organocatalyst yielding a novel series of 4H-pyrano[2, 3-b]quinolones. This multicomponent reaction has some advantages; the significant one is C-O bond formation under metal-free conditions. Other benefits include simple procedure, mild and green condition, high yield, easy purification, and excellent regioselectivity. All polycyclic products (7a-k, 11 new compounds) were characterized by IR, 1H NMR, 13C NMR, and mass spectra.

Design, preparation and application of the semicarbazide-pyridoyl-sulfonic acid-based nanocatalyst for the synthesis of pyranopyrazoles

A novel, efficient, and recoverable nanomagnetic catalyst bearing the semicarbazide linkers, namely, Fe3O4@SiO2@OSi(CH2)3-N(3-pyridoyl sulfonic acid)semicarbazide (FSiPSS) was designed, synthesized and characterized by the use of various techniques such as FT‐IR, EDX, elemental mapping analysis, XRD, SEM, TEM, TGA/DTA, BET, and VSM. Then, the catalytic capability of the novel prepared nanomagnetic FSiPSS catalyst was successfully investigated in the synthesis of diverse pyranopyrazoles through a one-pot four-component condensation reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes, and malononitrile or ethyl cyano-acetate by the help of ultrasonication in very short reaction time, good to high yields and easy work-up (Fig. 1).Figure 1Synthesis of diverse pyranopyrazoles by the FSiPSS nano-catalyst.

Concise One-Pot Multicomponent Reaction Approach to Mono­fluo­rinated Spiro-pyrazole-pyridine Derivatives without Additional Catalyst

AbstractMonofluorinated bis-heterocyclic spirocycles: functionalized ethyl 9-fluoro-8-methyl-1,4-dioxo-2,3,6,10-tetraphenyl-2,3,7-triazaspiro[4.5]dec-7-ene-9-carboxylate derivatives were efficiently synthesized from readily available 1,2-diphenylpyrazolidine-3,5-dione, ethyl 2-fluoroacetoacetate, aromatic aldehydes, and ammonium acetate via one-pot four-component reactions in the absence of additional catalyst. In the protocols, ammonium acetate serves not only as the fourth component but also as the catalyst.

Eco-friendly design of TiO2 nanoparticles supported on Fe3O4 coated carbon-based biochar substrate for the synthesis of pyrano-[2, 3-c]-pyrazole derivatives

The novel naturally based magnetic biochar/Fe3O4–TiO2 nanocatalyst was developed, characterised, and used to manufacture biologically active dihydropyrano-[2,3-c]-pyrazole [DHPP] derivatives. The one-pot four-component reaction between hydrazine hydrate, malononitrile, ethyl acetoacetate, and various aromatic aldehydes was carried out to synthesize the DHPP. The reaction was carried out in the presence of H2O:EtOH (1:1) as solvent at 60 °C with excellent yield (91–98%). This operationally simple approach has numerous benefits, including a green and clean reaction profile, easy workup and purification methods, a very fast reaction time, high atom efficiency, and low cost as well as magnetically separable nanocatalyst. XRD, FT-IR, TGA, HR-TEM, FE-SEM, EDAX, VSM were used to characterize the nanocatalyst and 13C NMR, 1H NMR, and mass spectrometry were investigate to studies the structure of products. Antimicrobial activity was tested on the resulting products (5a-5l). According to the data, the synthesized compounds were found to have substantial antimicrobial activities against the Gram-positive bacteria S. aureus and S. phyogens, Gram-negative bacteria E. coli and P. aeruginosa, and fungi Candida albicans.

Ionic Liquid [(EMIM)Ac] Catalyzed Green and Efficient Synthesis of Pyrano[2,3-c]Pyrazole Derivatives

A Green, efficient and clean route for synthesis of biologically potent pyrano[2,3-c]pyrazole derivatives has been developed in excellent yield, by using biodegradable ionic liquid 1-ethyl 3-methyl imidazolium acetate [(EMIM)Ac)] as a green catalyst via one-pot four-component condensation reaction of ethyl-acetoacetate, hydrazine-hydrate, malononitrile and carbonyl compounds at reflux condition in ethanol. The striking features of the protocol are a cleaner reaction profile, mild experimental procedure, applicable to extensive range of substrates and short reaction time.

Expeditious microwavable one-pot synthesis and biological exploration of spiro[indoline-3,4′-pyrazolo[3,4-b] pyridine derivatives

A rapid and efficient microwave-promoted one-pot strategy has been utilized to synthesize differentially functionalized spiro[indoline-3,4′-pyrazolo[3,4-b] pyridine derivatives. Different optimized reaction conditions have been exploited when one-pot four-component (hydrazines, 1,3-dicarbonyl compounds, isatin, and malononitrile) reactions took place to afford satisfying yields of compounds [5–28]. Among different methodologies, the catalyst-free microwave-assisted fusion process has been proved to be the strategy with desirable traits to give good-to-excellent yields of the target compounds. Structural features of the obtained compounds were confirmed by the basis of elemental analyses, mass, 1H-NMR, and 13C-NMR spectrometry.