One-pot Three-component Reaction Research Articles

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.

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.

1,2,4-Triazolo-quinazolinones as Effective Antifoulants: Molecular Design, Synthesis, and Biological Evaluation.

A series of 1,2,4-triazolo-quinazolinones and 1,2-benzisothiazolone derivatives (S1-S12) were successfully synthesized as environmentally friendly alternatives to copper-based antifouling paints using N-alkylation, cyclocondensation, and one-pot three-component and amide coupling reactions. The monoclinic structure of single-crystal 1,2,4-triazolo-quinazolin-acetic acid (S8) was confirmed by single-crystal X-ray diffraction analysis. All the synthesized molecules were studied for their in silico molecular docking interactions with three target proteins, namely, RbmA, ToxR, and Bap. Following that, the antialgal activity was assessed against two types of marine algae: Chlorella sp. and Chaetoceros curvisetus. The minimal inhibitory concentration and zone of inhibition have been used to evaluate the antibacterial activities of S1-S12 against both marine Gram-positive (Staphylococcus aureus) and Gram-negative (Vibrio parahemolyticus and Vibrio vulnificus) bacteria. Additionally, antifouling studies have been done on all the compounds, and among them, 1,2,4-triazolo-quinazolinyl-acetate (S7), 1,2,4-triazolo-quinazolinyl-acetic acid (S8), 1,2,4-triazolo-quinazolinyl-oxobutanoate (S9), benzo[d]isothiazolyl butanoate (S10), benzo[d]isothiazolyl-acetic acid (S11), and 1,2,4-triazolo-quinazolinyl-acetyl-benzo[d]isothiazolone (S12) exhibited good antialgal, antibacterial, and antifouling activities.

Natural product synthesis by a nanoporous In-MOF Catalyst: Crystallographic insight by incorporating substrate inside its nanopores

Metal-organic frameworks (MOFs) are promising candidates as nanoporous heterogeneous catalysts over other solid catalysts. Herein, utilizing a new tetra-acid ligand and employing high-valent Indium metal source we have strategically developed a 3D robust nanoporous framework, IITKGP-53, which retained its crystallinity over a wide range of pH solution (2–12). Considering the green synthesis approach IITKGP-53 was explored as a heterogeneous catalyst toward one-pot three-component Strecker reaction under solvent-free condition, with low catalyst loading for a broad range of substrates. Considering practical utility, biologically important natural product, Girgensohnine, was synthesized for the first time by using this catalyst with excellent conversion rate. The substrate binding sites inside the nanopores and host–guest interactions were verified crystallographically by obtaining a substrate inside nanopores of this MOF (aniline@IITKGP-53) and computational modeling. An in-depth theoretical investigation unveiled the most plausible transition states for the first time. This study inaugurates the usage of nanoporous MOFs as heterogeneous catalysts for natural product synthesis.

Synthesis and biological evaluation of 2-(2-hydrazinyl) thiazole derivatives with potential antibacterial and antioxidant activity

Heterocyclic systems containing 2-(2-hydrazinyl) thiazole moieties were synthesized by heterocyclization of thiosemicarbazones with arylglyoxals and Meldrum's acid in ethanol and water 1:1 (v/v) under reflux conditions. The paper reports an efficient, facile, and environmentally friendly protocol via a novel one-pot three-component reaction to access a broad range of 2-(2-Hydrazinyl) thiazole derivatives. Products were isolated by plate chromatography and their structures were established from their spectroscopic data, then the antibacterial and antioxidant activity of synthesized 2-(2-hydrazinyl) thiazole derivatives were evaluated, and demonstrated encouraging antibacterial activity against Staphylococcus aureus as a gram positive bacteria and Escherichia coli as a gram negative bacteria. Furthermore, when representative products were assessed for radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH0), high antioxidant effects were observed, indicating their potential safety for use in pharmacological studies.

Variation in Catalytic Efficacies of a 2D pH-Stable MOF by Altering Activation Methods.

Although it is well-known that the Lewis acidity of Metal-Organic Frameworks (MOFs) can effectively enhance their catalytic activity in organic transformations, access to these Lewis-acidic sites remains a key hurdle to widespread applications of Lewis-acidic catalysis by MOFs. Easy accessibility of strong Lewis acidic sites onto 2D MOFs by using proper activation methods can be a cornerstone in attaining desired catalytic performance. Herein, we report a new 2D chemically stable MOF, IITKGP-60, which displayed excellent framework robustness over a wide pH range (2-12). Benefiting from the abundant open metal sites (OMSs) and framework robustness, the catalytic activity of the developed material was explored in one-pot three-component Strecker reaction and Knoevenagel condensation reaction. Moreover, the developed catalyst is superior in catalyzing the reactions involving sterically hindered substrate (1-naphthaldehyde) with high turnover number. A comparative catalytic study was conducted using different activation methods (chloroform and methanol exchanged activated samples), highlighting the significant effect of activation methods on its catalytic performances. The sustainable synthetic pathway under solvent-free conditions for a broad scope of substrates using low catalyst loading and excellent recyclability made the developed pH-stable framework a promising heterogeneous catalyst.

One-Pot and Three-Component Coupling Synthesis of Novel p-[(Benzothiazolylamino)(aryl/heteroaryl)methyl]phenols and Its Corresponding O-Tosylates under Catalyst- and Solvent-Free Conditions

AbstractA catalyst- and solvent-free procedure has been developed for the synthesis of p-[( benzothiazolylamino)(aryl/heteroaryl)methyl]-functionalized phenols and its O-tosylates via one-pot three-component coupling reaction of thymol or carvacrol, aryl/heteroaryl aldehydes, and 2-aminobenzothiazoles with high selectivity. The present amino methylation process is convenient to perform even on large scale with a broad scope. The products were likely formed through the initial para attack of thymol on aldehydes to generate p-quinone methide intermediate and subsequent 1,6-aza-Michael addition of 2-aminobenzothiazoles on in-situ generated p-quinone methide intermediate.

Metal-Catalyzed Multi-Component Approach to Quinoline-Linked Covalent Organic Frameworks

The development of new reaction chemistry is highly desirable to construct new structural and functional covalent organic frameworks (COFs). Benefiting from the extremely large database of metal-catalyzed reaction database, we herein develop a new synthetic strategy that can generate quinoline-linked COFs via a silver-catalyzed three-component one-pot reaction and achieve functionalization by the simple replacement of alcohols. This metal-catalyzed approach to the construction of robust COF structures characterized by extended π-conjugation holds the potential to pave a novel pathway in the synthesis of COF materials endowed with both heightened stability and functionality.

Development of novel 9H-carbazole-4H-chromene hybrids as dual cholinesterase inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease affecting mental ability and neurocognitive functions. Cholinesterase enzymes affect concentration of acetylcholine in the brain, leading to dementia. Thus, there is an urgent need to develop novel dual cholinesterase inhibitors as possible anti-AD drugs. Herein, we have designed and synthesized a novel series of 9H-carbazole-4H-chromenes 4(a-l) through a one-pot three-component reaction of salicylaldehydes (1), hydroxycarbazole (2) and N-methyl-1-(methylthio)-2-nitroethenamine (3) using triethylamine as a catalyst in ethanol. Synthetic transformation involves the formation of two C-C bonds and one C-O bond in a single step to obtain desired analogs. The rapid one-pot reaction does not require chromatographic purification, proceeds under mild conditions, and exhibits good tolerance toward various functional groups with high synthetic yields. Synthesized compounds were screened for cytotoxicity using MTT assay in BV-2 microglial cells. These compounds were then in-vitro screened against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes. Most of these ligands have shown dual cholinesterase inhibitory activity compared to the standard drug. In-vitro results showed that the compounds 4a and 4d have promising anticholinesterase response against both cholinesterase enzymes (4a, AChE IC50: 5.76µM, BuChE IC50: 48.98µM; 4d, AChE IC50: 3.58µM, BuChE IC50: 42.73µM). In-vitro results were validated by molecular docking and dynamic simulation at 100ns. Molecular docking and molecular dynamics simulation study strongly supported structural features present in these analogs. Together, these analogs could be exploited to develop dual anti-cholinesterase candidates to treat AD in combination with other drugs.

One-Pot Three-Component Reaction for the Synthesis of 3,4-Dihydroquinazolines and Quinazolin-4(3H)-ones.

A highly efficient and straightforward one-pot synthesis of diversely substituted 3,4-dihydroquinazolines and quinazolin-4(3H)-ones has been achieved through a domino three-component assembly reaction of arenediazonium salts, nitriles, and bifunctional aniline derivatives. This new protocol involves three C-N bond formations through the initial formation of N-arylnitrilium intermediates from arenediazonium salts and nitriles, followed by the sequential nucleophilic addition and cyclization reactions with bifunctional anilines, leading to such N-heterocyclic compounds of biological and pharmacological importance. This method offers a simple, expedient, and robust approach with the use of amenable and easily accessible reactants/reagents under metal-free mild conditions, good functional group tolerance, and high efficiency. The synthetic applications were also demonstrated by derivatization of the products obtained from these processes and syntheses of a diverse range of valuable polycyclic N-heterocycles.

Synthesis of Unsymmetrical 1,6-Dicarbonyl Compounds through Photocatalytic One-Pot Tandem Three-Component Reaction.

Unsymmetrical 1,6-dicarbonyl compounds are useful building blocks in organic synthesis. However, the synthetic methods are limited. Herein we report a three-component one-pot reaction for the synthesis of unsymmetrical 1,6-diketones. This reaction utilizes sulfides as radical precursors and enol ethers as building blocks. It takes advantage of photocatalysis and Lewis acid catalysis. Its synthetic utility was demonstrated in the modification of biorelevant compounds.

Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells.

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87-18.5μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

Pyrimido[5,4-c]quinolines: Synthesis from 3,4-Di-functionallized Quinoline, Reactivity and Biological Activities.

Quinoline and pyrimidine moieties are ubiquitous components in both natural and synthetic compounds, showcasing diverse applications. The fusion of these well-known structures into hybrid molecules has garnered attention due to their intriguing biological properties. Particularly in the field of medicinal chemistry, numerous studies in the last decade have focused on pyrimido[5,4-c]quinoline ring systems (PyQs5,4-c). This review elucidates the synthesis of PyQs5,4-c and their derivatives using 3,4-difunctionalized quinoline as a key starting material. The preparation of PyQs5,4-c involves a series of chemical transformations, including the Friedländer, Ullmann and Biginelli reaction, Vilsmeier-Haack formylation, Suzuki coupling, and a one-pot three-component reaction. These synthetic routes not only offer access to diverse PyQs5,4-c derivatives.

GO@dopamine-Cu as a Green Nanocatalyst for the Efficient Synthesis of Fully Substituted Dihydrofuran-2(5H)-ones

A new nanocatalyst graphene oxide@dopamine-Cu was synthesized, and its structure was characterized by fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Energy Dispersive X-ray Spectrometry (EDX), and thermogravimetric analysis – differential thermal analysis (TGA-DTA) techniques. The three-component one-pot reaction between an arylamine, aromatic aldehyde, and acetylenic carboxylate was achieved and formed methyl 5-oxo-2-aryl-4-(arylamino)-2,5-dihydrofuran-3-carboxylate derivatives (4) in the presence of the catalytic amount of graphene oxide@dopamine-Cu nanocatalyst in high yield. Molecular structures of products were characterized by FT-IR, 1H, 13C nuclear magnetic resonance (NMR), and Mass spectroscopy techniques. Representatively, the mass fragmentation of 4a was discussed, and the structure was confirmed. Easy reaction, high performance, and easy catalyst recyclability are the main advantages of this work. This nanocatalyst is recycled up to five successive runs.

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.

Copper (II) complex supported on magnetic nanoparticles as a novel nanocatalyst for the synthesis of imidazo[1,2-a]pyridines.

Research on the synthesis of imidazo[1,2-a]pyridines has gained great importance among synthetic chemists because there have been numerous reports of their biological and medicinal activities. In this respect, we fabricated CuCl2 immobilized on Fe3O4 nanoparticles modified with 1,10-phenanthroline-5,6-diol [Fe3O4@Diol/Phen-CuCl2] and investigated its catalytic activity for the preparation of imidazo[1,2-a]pyridine derivatives through one-pot three-component reaction of 2-aminopyridines, aldehydes and terminal alkynes under ecofriendly conditions. FT-IR spectroscopy, EDX, SEM, TEM, XRD, TGA, VSM and ICP-OES techniques employed in order to identify the structure of the as-constructed Fe3O4@Diol/Phen-CuCl2 nanocatalyst. This catalytic system has a series of advantages such as the synthesis of imidazo[1,2-a]pyridine products with high yields in suitable time, performing the reactions in an environmentally friendly solvent (PEG), easy preparation of the catalyst with a simple method, and the recyclability of the Fe3O4@Diol/Phen-CuCl2 nanocatalyst.

Selective synthesis of thiadiazolo-2H-chromen-2-ones and chromeno-thiadiazolo-pyrimidines under thermal conditions and microwave irradiation catalyzed by calixarene-based ionic liquid immobilized on magnetic nanoparticles

In this research, a calixarene-based acidic ionic liquid immobilized on Fe3O4 magnetic nanoparticles coated with epoxy-functionalized silica (Calix-AIL-MN) was successfully synthesized and characterized by various spectroscopic and analytical techniques such as FT-IR, VSM, TEM, SEM, EDX, elemental-mapping, TGA, ICP and elemental analysis. This catalytic system showed excellent activity in the selective synthesis of 4-amino-1,3,4-thiadiazolo-2-yl-2H-chromen-2-ones and 6H,7H-chromeno[4,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidines through the one-pot three-component reaction of 4-aminocoumarin, aldehydes, and 2-amino-1,3,4-thiadiazoles under thermal conditions and microwave irradiation, respectively. Short reaction times, high to excellent yields, simple workup, easy recovery and reuse of the catalyst, and solvent-free conditions are the most prominent features of this method, which make it a green and sustainable process for the synthesis of these very important fused heterocycles.

Efficient synthesis of novel thiadiazolo[2,3-b]quinazolin-6-ones catalyzed by diphenhydramine hydrochloride-CoCl2⋅6H2O deep eutectic solvent

In this research, a new Lewis acid-based deep eutectic solvent (LA-DES) was synthesized using diphenhydramine hydrochloride and CoCl2·6H2O, (2[HDPH]:CoCl42−), and identified by FT-IR and 1HNMR techniques. The physicochemical properties of this LA-DES, such as thermal behavior, thermal stability, and solubility in common solvents were also investigated. The catalytic ability of 2[HDPH]:CoCl42− was ascertained in the efficient synthesis of a novel array of thiadiazolo[2,3-b]quinazolin-6-one scaffolds via a one-pot three-component reaction of dimedone/1,3-cyclohexanedione, aldehydes, and 5-aryl-1,3,4-thiadiazol-2-amines/3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one under solvent-free conditions. This catalyst was also successfully utilized for the synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehydes or bis-1,3,4-thiadiazol-2-amine. The simplicity of enforcement, short reaction time, avoidance of toxic organic solvents, scalability of the synthesis procedure, excellent atom economy, high reaction mass efficiency, and low E-factor are other outstanding advantages of this newly developed method. Furthermore, due to the convenient recovery and reuse of LA-DES, this protocol is economically justified and environmentally friendly.

Rhodium-Catalyzed [3+2]-Cycloaddition of in-situ Generated Nitrile Ylides with Nitrosoarenes.

Herein we report the rhodium-catalyzed one-pot three-component reaction of diazo compounds, nitriles, and nitrosoarenes to construct 2,5-dihydro-1,2,4-oxadiazole derivatives. Mechanistic studies indicate that the transformation may proceed through the formation of nitrile ylides intermediates, which then undergo [3+2]-cycloaddition with nitrosoarenes. The strategy exhibits several synthetic advantages, including operational simplicity, good functional group tolerance, and scalability.