One-pot Multicomponent Reaction Research Articles

Thiol-Ene Click-Inspired Late-Stage Modification of Long-Chain Polyurethane Dendrimers

The construction of well-defined polyurethane dendrimers is challenging due to the high reactivity of externally added or in situ formed isocyanates leading to the formation of side products. With a primary focus of dendrimer research being the interaction of the periphery and the core, we report the synthesis of a common polyurethane dendron, which allows for the late-stage variation of both the periphery and the core. The periphery can be varied simply by installing a clickable unit in the dendron and then attaching to the core and vice-versa. Thus, a common dendron allows for varying periphery and core in the final two steps. To accomplish this, a protecting group-free, one-pot multicomponent Curtius reaction was utilized to afford a robust and versatile AB2 type polyurethane dendron employing commercially available simple molecules: 5-hydroxyisophthalic acid, 11-bromoundecanol, and 4-penten-1-ol. Subsequent late-stage modifications of either dendrons or dendrimers via a thiol-ene click reaction gave surface-functionalized alternating aromatic-aliphatic polyurethane homodendrimers to generation-three (G3). The dendrons and the dendrimers were characterized by NMR, mass spectrometry, and FT-IR analysis. A bifunctional AB2 type dendritic monomer demonstrated this approach’s versatility that can either undergo a thiol-ene click or attachment to the core. This approach enables the incorporation of functionalities at the periphery and the core that may not withstand the dendrimer growth for the synthesis of polyurethane dendrimers and other dendritic macromolecules.

Synthesis and Biological Evaluation of Novel Phenothiazine Derivatives as Potential Antitumor Agents

Phenothiazines ˗ Antipsychotic drugs, which have been studied from centuries and attracted researcher’s attention toward its antitumor activities apart from their fundamental neuroleptic properties. Hence, we have targeted different structures of phenothiazines to develop potent antitumor agents. In the present study, we have synthesized various heterocyclic derivatives incorporating phenothiazine compounds via one-pot multicomponent reaction by means of N-alkyl-3-formylphenothiazine under reflux/ultrasonic method and different spectral characterization techniques such as FT-IR, mass, 1H and 13C NMR spectroscopy were used to validate the molecular structures of the synthesized compounds. The antitumor properties of all the synthesized compounds were investigated using MTT and LDH assay against HeLa cell lines. The results shown that the compounds 4 b, 2a and 3a have maximum LDH release (57.69 ± 4.69, 57.7 ± 4.6 & 67.8 ± 4.9) at 1000 µg concentration.

Green Chemistry in the Synthesis of Pharmaceuticals.

The principles of green chemistry (GC) can be comprehensively implemented in green synthesis of pharmaceuticals by choosing no solvents or green solvents (preferably water), alternative reaction media, and consideration of one-pot synthesis, multicomponent reactions (MCRs), continuous processing, and process intensification approaches for atom economy and final waste reduction. The GC's execution in green synthesis can be performed using a holistic design of the active pharmaceutical ingredient's (API) life cycle, minimizing hazards and pollution, and capitalizing the resource efficiency in the synthesis technique. Thus, the presented review accounts for the comprehensive exploration of GC's principles and metrics, an appropriate implication of those ideas in each step of the reaction schemes, from raw material to an intermediate to the final product's synthesis, and the final execution of the synthesis into scalable industry-based production. For real-life examples, we have discussed the synthesis of a series of established generic pharmaceuticals, starting with the raw materials, and the intermediates of the corresponding pharmaceuticals. Researchers and industries have thoughtfully instigated a green synthesis process to control the atom economy and waste reduction to protect the environment. We have extensively discussed significant reactions relevant for green synthesis, one-pot cascade synthesis, MCRs, continuous processing, and process intensification, which may contribute to the future of green and sustainable synthesis of APIs.

Catalytic performance of copper(II) Schiff base complex immobilized on Fe3O4 nanoparticles in synthesis of 2-amino-4H-benzo[h] chromenes and reduction of 4-nitrophenol

A copper(II) Schiff base complex immobilized on the surface of Fe3O4 nanoparticles with a coating of silica shell (Fe3O4@SiO2CPS-CuL) have been synthesized as an effective nanocatalyst. The as‐synthesized Fe3O4@SiO2CPS-CuL and its precursors were well characterized using Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), inductively coupled plasma (ICP), scanning electron microscopy (SEM), energy‐dispersive X‐ray spectroscopy (EDX), vibrating sample magnetometry (VSM), and powder X‐ray diffraction (XRD). As a next step, the synthesized nanocatalyst was utilized for the preparation of 2-amino-4Hbenzo[h]chromenes through one-pot multicomponent reactions as well as efficient reduction of 4-nitrophenol to 4-aminophenol. High reaction conversion, short reaction time and simple procedure are some of advantages of this work. In addition, the nanocatalyst could be separated easily from the reaction mixture using an external magnet and reused several consecutive runs for both reactions with only low diminish of its catalytic efficiency.

Green Synthesis of Fused Chromeno-pyrazolo-phthalazine Derivatives with Silicasupported Bismuth Nitrate under Solvent-free Conditions.

The study aimed to synthesize chromeno-pyrazolo[1,2-b]phthalazine-6,9,14(7H)-trione analogs with the help of silica-supported bismuth nitrate catalyst. Nitrogen-containing heterocyclic compounds are widespread, and their applications to pharmaceuticals, agrochemicals, and functional materials are becoming more and more important. Pyrazoles are an important class of compounds for new drug development, as they are the core structure of numerous biologically active compounds, including blockbuster drugs such as celecoxib, viagra, pyrazofurine, and many others. Similarly, heterocycles containing a phthalazine moiety are of current interest due to their pharmacological and biological activities; for example, pyrazolo[1,2-b]phthalazinedione is described as an anti-inflammatory, analgesic, antihypoxic, and antipyretic agent. In continuation of our ongoing investigation for the synthesis of efficient and simple approaches for the preparation of heterogeneous catalysts, herein we wish to disclose a highly efficient, simple, and one-pot synthesis of chromeno-pyrazolo-phthalazine derivatives via a one-pot multi-component reaction between 4- hydroxycoumarin, aromatic/heterocyclic aldehydes and 2,3-dihydro-1,4-phthalazinedione using silica-supported bismuth nitrate as an inexpensive, environmentally friendly and reusable catalyst under solvent-free conditions. Microanalytical data (C, H, and N) were collected on Carlo Erba analyzer model 1108. The microwave synthesis was performed in Anton Paar, Monowave 300 microwave synthesizer. Melting points were measured in open glass capillaries in the Kofler apparatus and are uncorrected. Spectroscopic data were obtained using the following instruments: Fourier transform infrared spectra (KBr discs, 4000-400 cm-1) by Shimadzu IR-408 Perkin-Elmer 1800 instrument; 1H NMR and 13C NMR spectra by Bruker Avance-II 400 MHz using DMSO-d6 as a solvent containing TMS as the internal standard. Mass spectra were set down on a JEOL D-300 mass spectrometer. In continuation of our ongoing studies to synthesize heterocyclic and pharmaceutical compounds by mild, facile, and efficient protocols, herein we wish to report our experimental results of the synthesis of chromeno- pyrazolo-phthalazine derivatives under solvent-free condition derivatives, using various aromatic/heterocyclic aldehydes in the presence of silica-supported bismuth nitrate catalyst. The prepared catalyst was characterized by various physical and chemical techniques. We have demonstrated an efficient reaction path for the synthesis of new aryl and heteroaryl chromeno-pyrazolo[1,2-b]phthalazine-6,9,14(7H)-trione by one-pot three-component condensation of aryl/ heteroaryl aldehydes, 2,3-dihydro-1,4-phthalazinedione and 4-hydroxy coumarin using silica-supported bismuth nitrate (SSBN) under microwave irradiation. The scheme not only offers the use of microwave at low temperatures and significant yield of products but also affords mild reaction conditions, without harmful solvent, shorter reaction times, high purity, operational simplicity, and easy workup.

Multicomponent Synthesis and Investigations Fluorescence Activity of Chromenone-Pyrazole Compounds.

A synthetic method is described to produce some chromenone-pyrazole derivatives through a one-pot multicomponent reaction using SrFe12O19 as a magnetic catalyst. This method provides quite a few merits, including the use of an effective and easy separable nanocatalyst, high yields of products, short reaction time, and easy work-up. Two of the products showed fluorescence properties, which have detected mercury ions without any interference with other ions. They can detect a tiny amount of mercury ions, which were comparable with other chemosensors. The detection limit is 4 × 10-7 and 3 × 10-8M, respectively, for the compound I and II, respectively, which were considered very low amounts. The effect of mercury on health and environmental pollution is essential in medical science.

Design, synthesis and cytotoxic evaluation of 2-amino-4- aryl-6-substituted pyridine-3,5-dicarbonitrile derivatives

Purpose: To synthesize novel pyridine derivatives and evaluate their efficiency as potent inhibitors of cyclin dependent kinase 2 (CDK2) enzyme for cancer therapy.Methods: Pyridine scaffold were synthesized using one-pot multicomponent condensation reaction of arylidine with different primary amines. The cytotoxic potential of the new compounds was assessed using various cell lines. Furthermore, molecular docking studies based on the crystal structure of CDK2 was carried out to determine the possible binding modes that influence the anticancer activities.Results: The results indicate that one-pot multicomponent reaction generated a series of functionalized pyridines with good yield. In vitro cytotoxicity study revealed superior cytotoxicity of the designed compounds against prostate and cervical cancer cell lines compared to 5-fluorouracil (standard anticancer compound) with half-maximal inhibitory concentration (IC50) values of 0.1 – 0.85 and 1.2 –74.1 μM, respectively. Finally, molecular modeling simulation of the newly synthesized compounds showed that they fit well and are stabilized into CDK2 active site via hydrogen bonding and hydrophobic interactions.Conclusion: The results indicate that the newly synthesized pyridine can exert potent anticancer activity presumably via inhibition of CDK2. However, this will need to be confirmed in in vivo studies.

Diastereoselective synthesis and spectral characterization of trans-4,4a-dihydro-3H-benzo[4,5]oxazolo[3,2-a]pyridines

An efficient one-pot multi-component reaction for the diastereoselective synthesis of novel trans-4,4a-dihydro-3H-benzo[4,5]oxazolo[3,2-a]pyridines starting from readily available cinnamaldehydes, o-aminophenol and 1,3-dicarbonyl compounds/ ethyl propiolate catalysed by AcOH is described. The products could be obtained in 3 h under refluxing conditions with perfect diastereoselectivity. Single crystal X-ray analysis confirmed the trans-derivative as the only isomer. All the compounds were unequivocally confirmed by NMR, HRMS and XRD analysis. To discuss the special pattern of methylene protons (H8a: td and H8b: dt) on the NMR of the compound 4a, NMR spectra analysis (1D-NMR and 2D-NMR) was conducted in details by the chemical shifts, couplings and correlations. XRD analysis of 4a and 6a further aids to disclose the spatial effect of methyl group on the geometry of the tetrahydropyridine rings of the compounds.

Introduction of [2,2'-Bipyridine]-1,1'-Diium Perchlorate as a Novel and Highly Efficient Dicationic Brönsted Acidic Organic Salt for the Synthesis of 3-Methyl-4-Arylmethylene Isoxazole-5(4H)-One Derivatives in Water

In this work, a novel pyridinium-based dicationic organic salt, [H2-BiPyr][ClO4]2, was easily prepared and characterized by FT-IR and NMR spectroscopy. After characterization, it was used as the catalyst in a one-pot multi-component reaction of aromatic aldehydes, ethyl acetoacetate and hydroxylamine hydrochloride under aqueous conditions at reflux temperature leading to the formation of 3-methyl-4-arylmethylene isoxazole-5(4H)-one derivatives. Easy and low-cost preparation of the catalyst, high yields, short reaction times and acceptable reusability of the catalyst are the most important advantages of this method.

Tomato fruit extract: an environmentally benign catalytic medium for the synthesis of isoxazoles derivatives

One-pot multicomponent reaction between aromatic aldehyde, hydroxylamine hydrochloride and ethyl acetoacetate/methyl acetoacetate for the synthesis of isoxazoles derivatives by employing tomato fruit extract as a catalytic medium has been developed. Tomato fruit extract was found to be a favorable catalytic medium for the synthesis of titled compounds. Mild reaction condition, ease of separation, moderate to high yield of the product, and short reaction time makes this method more attractive over earlier reported methods for the synthesis of isoxazoles derivatives.

Ultrases Destekli 9-(Substitue heteroaril) akridindion Türevlerinin Tek Basamakta Sentezi

An efficient green approach for the synthesis of 9-heteroaryl-acridine-1,8-dione derivatives (3a-f) was accomplished via reactions of dimedone (1) with various heteroaromatic aldehydes (2a-f) and ammonium acetate through one-pot multicomponent reactions in water under mild conditions using ultrasound irradiation in excellent yields. Of the synthesized compounds, 3d-f were novel and this process presents the advantages of high yields and easy work-up procedures. Spectral analyses were accomplished by FTIR, 1H NMR, 13C NMR and LC-MS TOF analyses.

Synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives and exploring molecular and cytotoxic properties based on DFT and molecular docking studies

• Dicyclic 1,4-dihydropyran[2,3- c ]pyrazole-5-carbonitrile derivatives were synthesized as potential anticancer agents. • The cytotoxic activity was tested against PC-3, SKOV-3, HeLa and A549 cell lines. • The frontier molecular orbitals, electron affinity, ionization potential and molecular electrostatic potential (MEP) were studied. • The molecular docking was accomplished onto thymidylate synthase (TS) protein was discussed. One-pot multicomponent reaction of ethyl 3-oxobutanoate or ethyl 3-oxo-3-phenylpropanoate, hydrazine hydrate, malononitrile, various aldehydes in ethanolic piperidine solution under Microwave irradiation gave 6-amino-4-aryl/hetaryl-3-methyl/pheny-1,4-dihydropyran[2,3- c ]pyrazole-5-carbonitriles. The structures of these compounds were established on the basis of IR, 1 H NMR, 13 C NMR, 13 C NMR-APT, MS data and elemental analysis. Furthermore, the cytotoxic activity properties were evaluated against the human cancer cell lines PC-3, SKOV-3, HeLa and A549 in comparison to the positive controls Vinblastine and Doxorubicin, employing the viability assay. The obtained results confirmed that some of the tested molecules revealed strong and selective cytotoxic activities against the four cancer cell lines. Herein, frontier molecular orbitals (FMO), electron affinity (EA), ionization potential (IP) and molecular electrostatic potential (MEP) was carried out to understand the active sites and biological active nature of pyrano[2,3- c ]pyrazole synthesized compounds. A systematic study was performed then frontier molecular orbitals energies, active sites and molecular descriptors were compared with reference drug. The molecular docking was accomplished onto thymidylate synthase (TS) protein. The compounds with highest efficiency exhibited promising binding interactions and binding affinities into active site.

A one-pot synthesis of piperidinium spirooxindoline-pyridineolates and indole-substituted pyridones in aqueous or ethanol medium.

Piperidinium spirooxindoline-pyridineolate has been prepared via one-pot multicomponent reaction of isatin, malononitrile, cyanoacetohydrazide, and piperidine in water or ethanol medium at room temperature. In addition, the synthesis of two indole-substituted 2-pyridones from indole-3-carbaldehyde, malononitrile, and cyanoacetohydrazide in the presence of piperidine is described.

One Pot Unexpected Isocyanide-based Three-component Synthesis of Pyrrole-3-carboxamides Containing Ether Groups

One-pot multicomponent reactions (MCRs) have been the focus of much recent attention in organic chemistry due to their speed, converging features, efficiency, ready implementation, and cost effecti...

An efficient synthesis of novel functionalized benzo[h]pyrano[2,3-b]quinolines and pyrano[2,3-b]quinoline derivatives via one-pot multicomponent reactions

An efficient synthesis of novel functionalized benzo[h]pyrano[2,3-b]quinolines and pyrano[2,3-b]quinoline derivatives via one-pot multicomponent reactions

One-Pot Multicomponent Coupling Reaction of Catechols, Benzyl Alcohols/Benzyl Methyl Ethers, and Ammonium Acetate toward Synthesis of Benzoxazoles.

The multicomponent coupling reaction of catechol, ammonium acetate, and benzyl alcohol/benzyl methyl ether in the presence of a Fe(III) catalyst precursor afforded benzoxazole derivatives in good to excellent yields. The notable features of this protocol are abundant availability of the catalyst system, large-scale synthesis, high diversity, and high yields of products.

Synthesis, characterization, and physicochemical properties of three new nanostructured benzimidazole-based dicationic Brønsted acidic molten salts and comparison of their catalytic and antibacterial activities

In the present study, three novel dicationic Brønsted acidic molten salts based on benzimidazole were synthesized and characterized by FT-IR, 1HNMR, 13CNMR and FESEM techniques. Topological analysis of the atoms in molecules (AIM), electron localization function (ELF), Mayer bond index and local aromaticity analysis were applied to study the theoretical and electronic structure of the presented molten salts molecules, and the nature of C-N, N-H, N-S, O-H, and H-Cl bonding was investigated. Antibacterial activities of the molten salts were tested against the Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) by the agar well diffusion method. The catalytic activity of the novel salts was also assessed using two different one-pot multi-component reactions in two various media (in the presence and absence of solvent) for the promotion of the synthesis of pyrano[2,3-d]-pyrimidinone and polyhydroquinoline derivatives. In this study, also the acidity of molten salts (by determination of their Hammett acidity function (H0) and potentiometric titration method) and its effect on their catalytic activity was investigated. Easy preparation of the reagents, reusability, green process, simple work-up procedure, high yields, and short reaction times are the most important advantages of the application of these salts as catalysts.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 μM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.

One-Pot Multicomponent Synthesis of 3-Methyl-4-(Hetero)Arylmethylene Isoxazole-5(4H)-Ones Using Guanidine Hydrochloride as the Catalyst under Aqueous Conditions

Here, we have developed an expeditious and efficient protocol for the synthesis of isoxazole-5(4H)-ones derivatives using guanidine hydrochloride as a catalyst using water as a solvent. The one-pot multicomponent reaction of aldehydes, ethyl acetoacetate, and hydroxylamine hydrochloride at room temperature to give a 3-methyl-4-(hetero)arylmethylene isoxazole-5(4H)-ones derivatives in an excellent yield. The key advantages of the reported method are shorter reaction time, energy-efficient, easy work-up procedure, wide substrate scope tolerance, economical, etc. further the catalyst was recycled up to 5 times along with high product yield without significant loss of its catalytic activity.

Triethylammonium Hydrogen Sulfate [Et3NH][HSO4]-Catalyzed Rapid and Efficient Multicomponent Synthesis of Pyrido[2,3-d]pyrimidine and Pyrazolo[3,4-b]pyridine Hybrids.

An operationally simple, one-pot multicomponent reaction has been developed for the assembly of pyrido[2,3-d]pyrimidine and pyrazolo[3,4-b]pyridine derivatives (4a–4am) in excellent yields (92–94%) with high purity. The reactions were easy to perform simply by mixing of electron-rich amino heterocycles (including aminouracils and aminopyrazoles), aldehyde, and acyl acetonitrile in the presence of [Et3NH][HSO4] under solvent-free conditions. The remarkable feature of the present approach is that the ionic liquid possesses dual solvent-catalytic engineering capability. Results of this study revealed that 1 mmol of the ionic liquid catalyst under solvent-free conditions at 60 °C is the best reaction parameter for the construction of fused pyridine and pyrimidine derivatives in excellent yields. The present methodology showed good results under gram-scale conditions, thereby indicating its applicability in industrial as well as academic settings in the near future.