One-pot Three-component Reaction Research Articles

High-performance modified LDH for green one-pot synthesis of pyrido[2,3-d]pyrimidines.

This study introduces a new nano catalyst tailored for the eco-friendly synthesis of pyrido[2,3-d]pyrimidine via a three-component one-pot reaction involving benzaldehydes, malononitrile, and uracil. To achieve this objective, we anchored copper acetate onto the surface of layered double hydroxides modified with 1,3‑benzenedisulfonyl amide (BDSA) (LDH@PTRMS@BDSA@Cu(NO3)2), which exhibited remarkable activity and selectivity. The main benefits of this method include high product yield, swift reaction times, straightforward purification, catalyst reusability, and the employment of a mild reaction process. Furthermore, the catalyst maintained its effectiveness even after being recycled four times without notable degradation in catalytic performance.

Discovery and Chemical Exploration of Spiro[Benzofuran-3,3'-Pyrroles] Derivatives as Innovative FLT3 Inhibitors for Targeting Acute Myeloid Leukemia.

This study aimed at the synthesis of several spiro[benzofuran-3,3'-pyrroles] derivatives by a three-component reaction conducted by mixing DMAD, N-bridgehead het-erocycles, and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. Moreover, in vitro evaluation of their cytotoxicity affinities against FMS-like tyrosine kinase 3 was carried out. The objective of this study was to use a one-pot, three-component reaction to synthesize a novel set of spiro[benzofuran-3,3'-pyrroles] derivatives. A novel set of spiro[benzofuran-3,3'-pyrroles] ((11-13)a-e) was synthesized by a one-pot three-component reaction involving dimethyl acetylenedicarboxylate, N-bridgehead heterocycles and benzofuran-2,3-diones in dichloromethane at room temperature for 24 h. The compounds were analyzed using NMR 1H, 13C, 2D-NMR (COSY, HMQC, HMBC), and HRMS. Docking simulations were conducted to elucidate the anticancer activity of synthe-sized compounds on FLT3 protein, with Gilteritinib as a reference for comparison. This study demonstrated the successful design, synthesis, and biological evaluation of spiro[benzofuran-3,3'-pyrroles] derivatives as FLT3 inhibitors for AML treatment. The synthesized compounds demonstrated promising binding affinities and significant inhibitory activity against FLT3 kinase. The inhibitors (11a, 11b, 11c, 12d, and 12e) exhibited excellent selectivity profiles against FLT3. Particularly, compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM). Fifteen new synthetic spiro[benzofuran-3,3'-pyrroles] were prepared, character-ized, and evaluated for cytotoxicity affinities against FMS-like tyrosine kinase 3. Compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM), making it a promising candidate for further development as a therapeutic option for AML treatment. These findings lay the groundwork for further optimization and development of spiro[benzo-furan-3,3'-pyrroles] derivatives as potential therapeutics for AML treatment. Further studies are needed to explore their efficacy and safety profiles in preclinical and clinical settings.

One-Pot Synthesis of β-Amino Carbonyl Compounds via the Mannich Reaction Using a Barium-Modified Bismuth-Phosphovanadate Catalyst: A Green and Eco-Friendly Approach

A simple and efficient one-pot three-component Mannich reaction for synthesizing β-amino ketones is developed, using barium-modified bismuth phosphovanadate as a catalyst under room temperature conditions. The catalyst, prepared by thermal synthesis, was characterized by FT-IR, SEM, EDS, and XRD. The reaction involves the formation of C-C and C-N bonds through an enolizable carbonyl compound and an imine intermediate, yielding high amounts of the desired product. The method features low catalyst loading, fast reaction times, excellent yields, recyclability, and a clean reaction profile without by-products.

Evaluation of Spirooxindole-3,3'-pyrrolines-incorporating Isoquinoline Motif as Antitumor, Anti-Inflammatory, Antibacterial, Antifungal, and Antioxidant Agents.

A series of novel 2-(isoquinolin-1-yl)-spiro[oxindole-3,3'-pyrrolines] were synthesized by a one-pot three-component reaction involving dimethyl acetylenedicarboxylate, 3- phenylimidazo[5,1-a]isoquinoline and N-alkylisatins in chloroform at ∼60 °C for 24 h. This study aimed at the synthesis of novel spirooxindole-3,3'-pyrrolines derivatives and in vitro evaluation of cytotoxicity affinities in cross-correlations with their antiinflammation and radical scavenging capacities. The objective of this study was to use a one-pot, three-component reaction to synthesize a novel set of spirooxindole-3,3'-pyrrolines derivatives. A novel set of spirooxindole-3,3'-pyrrolines (8a-i) was synthesized by a one-pot threecomponent reaction involving dimethyl acetylenedicarboxylate, 3-phenylimidazo[5,1-a]isoquinoline and N-alkylisatins in chloroform at ∼60 °C for 24 h. These new compounds were characterized by 1HNMR, 13C-NMR, and HRMS spectral data and screened for their antitumor, anti-inflammatory, antibacterial, antifungal, and antioxidant activities. The new synthetic spirooxindole-3,3'-pyrrolines (8a-i)-tested compounds displayed significant anti-inflammatory properties and were noncytotoxic on PDL fibroblasts. However, they lacked antioxidative-DPPH radical scavenging capabilities. Notably, Doxorubicin and cisplatin demonstrated antiproliferative effects on various cancer monolayers. Moreover, compounds 8b, 8d, 8f, 8h, and 8i exhibited pronounced viability reduction properties in colorectal and pancreatic cancer monolayers, as well as across skin, lung, prostate, and cervical adenocarcinomas, with higher cytotoxicity in mammary cancer cells MCF7 and T47D. None of the tested compounds had significant antibacterial activity against S. aureus or E. coli. However, compounds 8c, 8d, and 8f exhibited notable antifungal properties, indicating potential for further investigation. Eight new synthetic spiro[indoline-3,3-pyrroles] were prepared, characterized, and evaluated for their anti-inflammatory and cytotoxic properties. The compounds showed significant anti-inflammatory effects and promising cytotoxicity against various cancer monolayers, especially in colorectal and pancreatic cancers. Some compounds also exhibited antifungal properties. However, they did not exhibit significant antibacterial activity.

One-Pot Three-Component Access to Furan and Thiophene Derivatives

AbstractThe furan and thiophene skeleton structures are widely present in natural products and synthetic drugs, and display multiple bioactivities. An effective one-pot three-component reaction to access furan and thiophene derivatives from 2-bromo-5-(dichloromethyl)furan or -thiophene; cyanoacetate esters, cyanoacetamides, or malononitrile; and aliphatic secondary amines has been developed. The multicomponent reaction for the construction of new C–N and C–C bonds in one pot is simple, mild, and efficient, and the yield of the target product is as high as 96%.

Robust Organocatalytic Three-Component Approach to 1,3-Diarylallylidene Pyrazolones via Consecutive Double Condensation Reactions.

A robust pyrrolidine-BzOH salt-catalyzed one-pot three-component reaction involving 4-unsubstituted pyrazolones, aryl/heteroarylaldehydes, and aryl methyl ketones is reported for the first time. This catalytic process fortifies an efficient method, allowing for the practical synthesis of a wide array of synthetically useful 1,3-diarylallylidene pyrazolones in good to high yields exclusively in their single geometrical isomer forms. Furthermore, this catalyst facilitates a sequential double condensation reaction under thermal conditions, thereby enabling two consecutive C═C bonds through displacement of aryl groups. Moreover, this organocatalytic technique achieves a 100% carbon atom economy, marking a significant step forward toward efficient and sustainable synthesis.

Synthesis of Hetaryl Substituted Pyrazolo[3,4-b]Quinolinone Systems by Multicomponent Cyclocondensation Reaction

In this study, the synthesis of pyrazolo[3,4-b]quinolinone compounds was carried out via one-pot three-component reactions. These reactions proceed as domino processes, making them easier to occur than the conventional multistep organic reactions. By employing this method, new organic molecules can be synthesized in a single step, using minimal time and number of trials. In the first phase of this two-step study, heteroaromatic carbaldehydes (quinoline-8-carboxaldehyde and quinoline-4-carboxaldehyde) were prepared to be used as substrates in subsequent reactions by oxidation of 8-methylquinoline and 4-methylquinoline with selenium dioxide, a mild oxidant. In the second step, heteroaromatic carbaldehyde reacted with aminopyrazole and dimedone in anhydrous ethanol by one-pot multicomponent condensation method to synthesize six compounds with heteryl-substituted pyrazolo[3,4-b]quinolinone ring system. The crude products were obtained in excellent yields and further purified by crystallization. The structures of the compounds, which were found to be completely pure as a result of chromatographic studies, were elucidated by spectroscopic methods and elemental analysis.

Photocatalytic One-Pot Three-Component Reaction for the Regioselective Synthesis of Bromo-Substituted Pyrazoles.

A photocatalytic three-component cascade reaction of readily available enaminones, hydrazines, and CBr4 for the synthesis of bromo-substituted pyrazoles in one pot has been demonstrated. This strategy involves intermolecular C-N/C-Br bond formation and represents an efficient approach to the construction of 4-bromo-substituted pyrazoles with high regioselectivity, broad substrate scope, good functional group tolerance, convenient operation, and mild reaction conditions. Mechanistic investigations show that this reaction proceeds via intermolecular cyclization of enaminones with hydrazines, followed by a regioselective bromination of pyrazoles using CBr4 as a "Br" source.

Recent Progress in Synthetic Chemistry and Biological Activities of Pyrimido[ 4,5-b] Quinoline Derivatives (Part III)

Abstract: Amongst heterocyclic compounds, quinoline and pyrimidine are advantaged scaffolds that appear as significant assembly motifs for the development of new drug entities. Moreover, quinolinepyrimidine- inspired hybrids have a number of biological characteristics that are known. In addition, many pyrimido[4,5-b]quinoline ring systems (PyQs4,5-b), specifically concerning medicinal chemistry, have been reported over the past decade. The synthesis of (PyQs4,5-b) using barbituric acid, thiobarbituric acid, pyrimidine, and their derivatives is presented in this review. The preparation of PyQs4,5-b was clarified through the following chemical reactions: Friedländer, Vilsmeier-Haack formylation, Hantzsch-like reaction, and one-pot three-component reaction.

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.

Construction of pyrrolo[3,2-b]pyrrolyl-linked covalent organic polymers to promote continuous overall H2O2 production

Sacrificial agent-free, solar-driven photocatalytic oxygen reduction holds promise for hydrogen peroxide production. However, the rapid recombination of electron–hole pairs in catalysts and the slow diffusion rate of oxygen on the catalyst surfaces significantly hinder the efficiency of hydrogen peroxide production. To address these issues, we developed a novel class of pyrrolo[3,2-b]pyrrolyl-linked covalent organic polymers (COPs) combined with microreactor technology to enhance hydrogen peroxide synthesis. These structurally well-defined polymers feature photoactive pyrrolo[3,2-b]pyrrolyl units were assembled from aldehyde, aniline, and 2,3-butanedione through a one-pot three-component reaction. Integrating pyrrolo[3,2-b]pyrrolyl moieties into the COPs creates donor–acceptor structures that facilitate the separation of photogenerated electrons and holes. Among them, COP-2 achieved the highest H2O2 yield of 5446 μmol g−1 h−1. Furthermore, we designed a coiled tube photomicroreactor to improve mass transfer efficiency in the gas–liquid–solid triphase system, boosting the H2O2 yield to 20285 μmol g−1h−1 without the need for a sacrificial agent. This study offers new insights into integrating polymer photocatalysts with microflow technology, underscoring the potential for future green and continuous H2O2 production.

Marine-derived magnetic nanocatalyst in sustainable ultrasound-assisted synthesis of 2,3-diphenyl-2,3-Dihydroquinazolin-4(1H)-One derivatives

This research presents a sustainable approach to fabricate iron oxide nanoparticles by employing phytochemicals derived from marine grass extract as both reducing and stabilizing agents. Formation of magnetic nanoparticles (MNPs) initially confirmed by ultraviolet–visible spectroscopy (UV–vis) showing absorption peak at 370 nm. X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques unveiled magnetic iron oxide NPs with a rod shape, an average size of 21 nm, and an inverse spinel crystal structure. The participation of organic compounds in the production and stabilization of MNPs was evidenced through Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). A vibrating sample magnetometer (VSM) demonstrated the magnetic properties of iron oxide NPs showing a saturation magnetization value of 21.46 emu/g. The catalytic efficiency of these marine-assisted MNPs was evaluated in a one-pot three-component reaction involving isatoic anhydride, aromatic aldehydes, and amines under ultrasonic conditions. Under optimal conditions, a low dose of 1.5 mg of biobased magnetite nanoparticles yielded dihydroquinazolin-4(1H)-One products with up to 95 % efficiency in a brief duration of 15 min at an ultrasonic power intensity of 130 W. Different directing groups were investigated, and control experiments were carried out to enhance the understanding of the reaction mechanism. The obtained results highlight the synergistic effect of marine grass-mediated magnetic nanocatalysts combined with ultrasonic-assisted synthesis in developing sustainable green methodologies in organic synthesis.

One-pot Three-component Synthesis of Fully and Diversely Functionalized Pyrans and Spiropyrans Using Sodium Formate as Catalyst in Aqueous Ethanol at Room Temperature

Abstract: A convenient and general method has been developed for the synthesis of fully and diversely functionalized pyrans via one-pot three-component reactions of various aryl or heteroaryl aldehydes, malononitrile, and 1,3-dimethyl/1,3-diethyl-acetonedicarboxylates in the presence of a catalytic amount of sodium formate as an efficient organocatalyst in aqueous ethanol at room temperature. All the scaffolds were synthesized in excellent yields within 2.5 hours. Under the same reaction conditions, fully and diversely functionalized spiro-pyrans were also synthesized in excellent yields from the reaction of isatin, malononitrile, and 1,3-dimethyl/1,3-diethylacetonedicarboxylates. All the products were isolated pure just by simple filtration. Synthesis of fully and diversely functionalized biologically promising pyrans, excellent yields, use of organocatalyst, less toxic solvent, no column chromatographic purification, and energy efficiency are some of the major advantages of this newly developed protocol. method: In a clean test tube a magnetic stir bar, 0.5 mmol of aldehydes (1a-1i), 0.5 mmol of malononitrile (2; 0.033 g) and 0.5 mmol of 1,3-dimethylacetonedicarboxylate (3a; 0.087 g) or 1,3-diethylacetonedicarboxylate (3b; 0.101 g), 4 ml aqueous ethanol (1:1 v/v) and 20 mol% sodium formate were taken sequentially. The whole reaction mixture was stirred at room temperature for the time mentioned in Table 2. The progress of reaction was monitored by TLC. By using the same amount of catalyst and solvent the synthesis of methyl/ethyl-2'-amino-3'-cyano-6'-(2-meth/ethoxy-2-oxoethyl)-2-oxospiro[indoline-3,4'-pyran]-5'-carboxylate (6a/6b) was achieved from the reactions of 0.5 mmol of isatin (5; 0.0735 g), 0.5 mmol of malononitrile (2; 0.033 g) and 0.5 mmol of 1,3-dimethylacetonedicarboxylate (3a; 0.0871 g) or 1,3-diethylacetonedicarboxylate (3b; 0.1011 g). After the completion of each reaction, the desired products were isolated simply by filtration and subsiquent washing with aqueous ethanol (EtOH:H2O = 1:1).

MPC@But-SO3H a mesoporous heterogeneous organocatalyst in one-pot tandem synthesis of dihydroindeno[1,2-b]pyrrole derivatives

A sustainable, metal-free, and highly efficient protocol for the synthesis of dihydroindeno[1,2-b]pyrrole derivatives via a tandem one-pot three-component reaction in aqueous medium at room temperature using an effective and reusable mesoporous heterogeneous organocatalyst, MPC@But-SO3H has been developed. MPC@But-SO3H was easily synthesized using a melamine-based covalent organic polymer and 1,4-butane sultone. The organocatalyst was well characterized by numerous spectroscopic techniques such as Fourier Transform Infrared (FTIR), Brunauer-Emmett-Teller (BET), X-ray photoelectron spectroscopy (XPS), Powder X-ray diffraction (PXRD), Scanning Electron Microscope (SEM), Energy Dispersive X-ray (EDX), elemental mapping, and Thermal Gravimetric (TG) analyses. The catalyst displayed excellent catalytic potential, high thermochemical stability, and reusability for up to eight catalytic cycles. It offered the title compounds in excellent yields (˃90%) in a short reaction time (9-14 min). The synthesized compounds were characterized through FTIR, 1H, and 13C Nuclear Magnetic Resonance (NMR), and the molecular structure of 2-(benzylamino)-3a,8b-dihydroxy-1-methyl-3-nitro-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-one (4a) was confirmed by the Single Crystal XRD (SC-XRD) analysis. The key features of the present protocol include the use of water as a green solvent, zero involvement of any metal, sustainable reaction conditions, easy catalyst recovery, and a simple work-up procedure. The calculations for green metrics parameters further supported the greenness and sustainability of the protocol.

One-pot three-component synthesis of 2,4-dimethoxy-5,8,9,10-tetrahydropyrimido[4,5-b]quinolinone derivatives along with in silico and in vitro investigation of their antimalarial activity

Pyrimidoquinolinone-derived compounds have exhibited a broad spectrum of biological activities and have been acknowledged as a potential antimalarial scaffold through multiple conventional strategies. In the present study, a novel series of 2,4-dimethoxy-5,8,9,10-tetrahydropyrimido[4,5-b]quinolinones 4(a-m) were synthesized via a one-pot three-component reaction of cyclohexane-1,3‑dione, 4-amino-2,6-dimethoxypyrimidine and various aldehyde with l-proline as the catalyst and acetic acid as the solvent under reflux condition. In vitro antimalarial activity toward P. falciparum 3D7 strain cultures were investigated. Compounds 4b and 4m demonstrated significant efficacy against strains of P. falciparum, with IC50 values of 0.63 and 0.65 μg/mL, respectively. The results were also supported by molecular docking and ADME assays.

“In-Water” Three-Component One-Pot Reaction for the Facile Synthesis of Densely Functionalized 2,3-Dihydro-1H-pyrrol-2-ols and Mechanistic Insight

“In-Water” Three-Component One-Pot Reaction for the Facile Synthesis of Densely Functionalized 2,3-Dihydro-1<i>H</i>-pyrrol-2-ols and Mechanistic Insight

Rapid and selective detection of Gram-positive bacteria using new dual emissive and non-cytotoxic organoboron esters

In this work, we report the green synthesis of five emissive organoboron esters, obtained by a condensation reaction via one-pot three-component reaction under microwave irradiation in just 5 min, yielding quantitative yields. The molecular structure proposed in solution (1H, 11B and high-resolution mass spectrometry) was corroborated through X-ray diffraction analysis for 3c, where the boron ion resides in distorted tetrahedral geometry. The photophysical properties of organoboron esters were obtained in solution state, revealing that these molecular materials could be classified as semiconductors with a fluorescence quantum yield in the 0.70–32 % range. Furthermore, organoboron ester 3a demonstrated a non-hazardous selective fluorescent yellow stain against Staphylococcus aureus and Bacillus subtills strains. To the best of our knowledge, this is the first report of the use of a non-toxic organoboron ester compound as a selective fluorescent dye against Gram-positive bacterial.

Blue luminescent pyridine-tethered quinazoline framework: Highly selective and sensitive picric acid chemosensor

The microwave-assisted one-pot three-component reaction of 2-phenyl-7,8-dihydroquinazolin-5(6H)-one, 2-arylidenemalononitrile and ammonium acetate under solvent-free conditions occurred through a five-step multiple bond-forming transformation to afford 2-amino-8-phenyl-4-aryl-5,6-dihydropyrido[2,3-f]quinazoline-3-carbonitriles in excellent yields. All the quinazoline-3-carbonitriles exhibited bright blue fluorescence under a UV lamp and were found to be efficient chemosensors of picric acid with detection limits in the nano-molar range.

Multicomponent Synthesis of New Fluorescent Boron Complexes Derived from 3-Hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde.

Novel fluorescent pyrazole-containing boron (III) complexes were synthesized employing a one-pot three-component reaction of 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-aminobenzenecarboxylic acids, and boronic acids. The structures of the novel heterocyclic compounds were confirmed using 1H-, 13C-, 15N-, 19F-, and 11B-NMR, IR spectroscopy, HRMS, and single-crystal X-ray diffraction data. The photophysical properties of the obtained iminoboronates were investigated using spectroscopic techniques, such as UV-vis and fluorescence spectroscopies. Compounds display main UV-vis absorption maxima in the blue region, and fluorescence emission maxima are observed in the green region of the visible spectrum. It was revealed that compounds exhibit fluorescence quantum yield up to 4.3% in different solvents and demonstrate an aggregation-induced emission enhancement effect in mixed THF-water solutions.

One-step construction of indolo[2,1-a]isoquinolines using solid calcium carbide as an alternative to gaseous acetylene

An efficient method for the synthesis of indolo[2,1-a]isoquinolines using calcium carbide as an alkyne source, 2-(2-bromophenyl)-1H-indoles as starting materials, and copper as a catalyst is described. The target products are synthesized via Sonogashira cross-coupling/nucleophilic addition tandem reactions. The advantages of this protocol include the use of inexpensive and easy-to-handle solid alkyne source instead of flammable and explosive gaseous acetylene, cheap and readily available raw materials, wide range of substrates, and simple reaction procedure. The method can also be extended to gram scale. In addition, the desired product can also be obtained by one-pot three-component reaction of phenylhydrazine hydrochlorides, o-bromoacetophenones and calcium carbide.