Multicomponent Condensation Reaction Research Articles

MOLECULAR IODINE CATALYZED SOLVENT FREE ONE POT SYNTHESIS, CHARACTERIZATION, INSILICO ADME, hERG ANALYSIS, MOLECULAR DOCKING STUDIES AND DFT ANALYSIS OF 2- SUBSTITUTED 4,5-DIPHENYL-1H-IMIDAZOLE DERIVATIVES

In the present investigation, a series of 2-substituted 4,5-Diphenyl-1H-imidazoles (3a-f) were prepared via one pot Debus-Radziszwski multicomponent condensation reaction using molecular iodine as a catalyst. Synthesis involves one pot reaction of benzil and substituted aromatic aldehydes (2a-e) in the presence of ammonium acetate and molecular iodine as catalyst under the solvent free grinding technique. The structures of the compounds were established based on multi nuclear NMR (1H 813C) spectral data and mass spectrometry. These compounds were subjected to in- silico ADMETox evaluation, hERG analysis, and molecular docking studies to evaluate their potency as antibacterial, antifungal, anti-inflammatory, and antimycobacterial. Molecular physicochemical properties were analyzed using density functional theory (DFT), molecular electrostatic potential (MEP) studies and reduced density gradient analysis.

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.

Efficient multicomponent processes for synthesis of novel poly-nuclear hetero aryl substituted terpyridine scaffolds: Single crystal XRD study

We studied the synthesis of novel terpyridine scaffolds from poly-nuclear and hetero-aryl aldehydes by the multicomponent condensation reactions with various acetyl pyridine derivatives in the presence of ammonium hydroxide. We have synthesised highly substituted pyridine scaffolds by different poly-nuclear and heterocyclic molecules that are not easily accessed by conventional methods. Comparative studies of two different processes catalysed by potassium hydroxide and pyrrolidine have been performed and presented in this report. The structures of all the newly prepared terpyridine molecules have been well established by preforming various spectral analysis and single crystal XRD studies for selected molecules. This approach addressed some structural miscellany concerns currently facing in photo-luminescent chemistry, and the derived hybrid pyridines could be used as suitable precursors for the synthesis of related photo-luminescent systems. The prepared scaffolds as such and their d-block or f-block metal complexes and coordination polymers may provide an efficient candidate for photo-luminescent chemistry.

Fe3O4@MCM‐41@ZrCl2: A novel magnetic mesoporous nanocomposite catalyst including zirconium nanoparticles for the synthesis of 1‐(benzothiazolylamino)phenylmethyl‐2‐naphthols

The present article reports the synthesis of a new magnetic mesoporous nanocomposite with core–shell structure, formulated as Fe3O4@MCM‐41@ZrCl2. The prepared reagent was successfully characterized using different types of methods. The combination of unique properties of MCM‐41 as an inimitable mesoporous compound, satisfying magnetic nature of the Fe3O4magnetic nanoparticles and substantial catalytical applications of zirconium, caused the favorable efficiency of the intended nanocomposite in the synthesis of 1‐(benzothiazolylamino)phenylmethyl‐2‐naphthols via a multicomponent condensation reaction of 2‐aminobenzothiazole, 2‐naphthol, and aromatic aldehydes in absence of solvent in good to high yields (70–90%). Green conditions of the reactions, easy separation, practicability, product purity, reusability of the catalyst, affordability, and environmentally profits are the considerable advantages of this protocol.

Study of supramolecular self-assembly of pyridone and dihydropyridone co-crystal: Synthesis, crystal structure, Hirshfeld surface, DFT and molecular docking studies

Dihydropyridone is synthesized by the multicomponent condensation reactions (MCRs), followed by three different oxidation methods to synthesize pyridone. The 3-D self-assemblies of both the compounds were determined using the single-crystal X-ray diffraction method. Dihydropyridone products are found as a racemic mixture in synthesis and crystalized as co-crystal. Similar structural conformations are observed in both the compounds but stabilized with different non-covalent interactions. Hirshfeld surface analysis is done to analyze the various intermolecular interactions in both the structure. This study gives the clue of driving force in the self-assembly of molecules in crystal lattices. The propensity of inter-molecular contacts to construct the supramolecular assembly was further studied using DFT. The geometrical optimizations of both the compounds were done by the electronic structure method using density functional theory (DFT) to identify the active sites and explore the molecules' chemically reactive parameters. Further, both compounds were docked with Survivin Protein and Kinesin Eg5 protein to analyze the binding affinity with targeted protein.

Bis-4-hydroxycoumarin Synthesis: A Simple Laboratory Experiment for Undergraduate Students

An undergraduate laboratory experiment for the synthesis of biologically significant bis-4-hydroxycoumarins using a new catalyst is described here. An experimental setup plan, monitoring the reaction by TLC, isolation of the product, safe laboratory handling procedures, and significance of data reproducibility of the result are the main learning outcomes of this work. The products are characterized by melting point, 1H nuclear magnetic resonance (NMR), 13C NMR, distortion enhancement by polarization transfer (DEPT) NMR, and Fourier transform infrared (FTIR) spectra. This simple and cost-effective experiment with wide substrate applicability also introduces the concept of research work on multicomponent condensation reaction among the students.

Design, synthesis and biological assessment of acridine derivatives containing 1,3,4-thiadiazole moiety as novel selective acetylcholinesterase inhibitors

A novel series of acridine derivatives containing substituted thiadiazol-2-amine moiety was synthesized via multi-component condensation reaction of dimedone, aromatic aldehyde and 5-aryl-1,3,4-thiadiazol-2-amines in the presence of LaCl3 as a catalyst under solvent-free conditions. Anticholinesterase (AChE and BuChE) activity evaluation of the derivatives showed that all the derivatives are capable of inhibiting both enzymes and are highly selective towards AChE. Among them, the ability of 4i and 4d with respective IC50 values of 0.002 and 0.006 µM to inhibit AChE was higher than the reference compound tacrine (IC50 = 0.016 µM). The kinetics studies demonstrated that 4i and 4d inhibit AChE through a competitive/non-competitive mixed mechanism. The HEPG2 cell viability assay evidenced that 4i and 4d significantly exhibit lower hepatotoxicity compared with tacrine. Blind docking experiments performed on TcAChE (PDB ID: 2ACE) indicated that an unknown site is preferred for binding by all the derivatives over classic binding site of the enzyme, site 1 (CAS/PAS). Identification of the residues by protein structure alignment confirmed that this site is site 2 which was recently recognized as a new allosteric site of hAChE. The binding modes of 4i and 4d were also investigated using local docking studies on site 1 and site 2.

Analysis of supramolecular self-assembly of two chromene derivatives: Synthesis, crystal structure, Hirshfeld surface, quantum computational and molecular docking studies

Two 4H-chromene derivatives (1C and 1F) were synthesized by the multicomponent condensation reactions (MCRs) and spectroscopically characterized. The 3-D structures of both the compounds were determined using single crystal X-ray diffraction method. The similar structural conformations are observed in both the compounds but they are stabilized with different packing modes. The supramolecular synthons constructed by strong hydrogen bond interactions plays a major role in the supramolecular self-assembly of molecules in the solid state. Hirshfeld surface analysis is used to assess the various intermolecular interactions in both the structure that driven the self-assembly of molecules in crystal lattices. The propensity of inter-molecular contacts to construct the supramolecular assembly were analyzed using enrichment ratios. The geometrical optimization of both the structures were done by electronic structure method using density functional theory (DFT) to identify the active sites and to explore the chemically reactive parameters of the molecules. Further, novel 1C and 1F compounds were docked with DNA gyrase protein of S. aureus to analyze the binding affinity with targeted protein.

New cage-fused polyaza polycyclic systems based on thioglycolurils and alkanediamines

New aspects of multicomponent condensation reactions of ethylene/propylenediamine, formaldehyde and unsubstituted and 1-methyl substituted semithio- and dithioglycolurils have been examined. Ethylene-linked 2,3a,4a,6,9,10a,11aheptaaza-6,9-methanobenzo[cd]cyclonona[gh]pentalene and 2,6:10,14-dimethano-2,6,7a,8a,10,14,15a,16a-octaazadicyclodeca[cd,gh]pentalene as well as their simpler analogues were synthesized, and their structures were proved by 1D and 2D NMR spectroscopy, HRMS and X-ray analysis.

MCM-BP as a Novel Nanomagnetic Reusable Basic Catalyst for the one Pot Solvent-Free Synthesis of Dihydropyridine, Polyhydroquinoline and Polyhydroacridine Derivatives via Hantzsch Multicomponent Condensation Reaction

By the immobilization of bipyridinium chloride onto mesoporous MCM-41encapsulated Fe3O4 nanoparticles via a simple post-synthesis method, a totally new organic-inorganic hybrid nanocomposite was formulated. The heterogeneous hybrid nanomagnetic composite was characterized by Fourier Transform InfraRed (FT-IR), X-Ray powder Diffraction (XRD), Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM), Vibrating Sample Magnetometer (VSM) and Thermal Gravimetric Analytical (TGA). The potential applications of this novel nanomagnetic and recyclable basic nanocomposite, Fe3O4@MCM-Bp , were also investigated for solvent-free synthesis of 1,4-dihydropyridine, polyhydroquinoline, and polyhydroacridine derivatives via Hantzsch multicomponent condensation reaction. High isolated yields, operational simplicity, clean reaction conditions and minimum pollution of the environment, makes the procedure a useful and appealing process in organic transformation.

Application of [Pyridine-1-SO3H-2-COOH]Cl as an efficient catalyst for the preparation of hexahyroquinolines

Pyridinium-1-sulfonic acid-2-carboxylic acid chloride {[Pyridine-1-SO3H-2-COOH]Cl} was synthesized and applied as a novel and efficient catalyst for the preparation of hexahydroquinolines by the one-pot multi-component condensation reaction of various aryl aldehydes with dimedone (5,5-dimethylcyclohexane-1,3-dione), β-ketoesters and ammonium acetate under mild and solvent-free conditions. Low cost, non toxic nature, simple work-up and excellent yields of products are the main advantages of this work.

Novel One‐Pot Access to Diastereoisomeric Tertiary Phospholanes Oxides by Using Enantiomerically Pure Phospholane Oxides Under Catalyst‐Free Conditions

AbstractFor the first time, enantiopure 1‐r‐oxo‐2‐c,5‐t‐diphenylphospholane was introduced as nucleophile in the multicomponent condensation reaction. Diastereoisomers of 2,5‐diphenyl‐1‐oxo‐1‐[alkylphenyl‐1‐(phenylamino) methyl] phospholane derivatives were synthesized by one‐pot process from aromatic aldehydes, anilines and enantiopure1‐r‐oxo‐2‐c,5‐t‐diphenylphospholane under green and eco‐compatible conditions. The reaction proceeds under catalyst‐free conditions at room temperature within very short time (3 min) in excellent yields (up to 95%). An X‐ray crystal structure has been obtained for 2,5‐diphenyl‐1‐oxo‐1‐[phenyl (phenylamino) methyl] phospholane.

Eco-friendly heteropoly acid supported on natural clay for the synthesis of calix[4]resorcinarene derivatives

The catalytic activity of green catalyst heteropoly-11-tungsto-1-vanadophosphoric acid, H4[PVW11O40] (HPV) supported on activated natural clay (HPVAC) has been tested towards the synthesis of calix[4]resorcinarene under solvent-free condition. It is a one-pot multi-component condensation reaction of four moles of aromatic aldehydes with four moles of resorcinol. The advantages of the protocol, solvent-free heterogeneous reaction condition, simple workup procedure, short reaction time, high yield of products and reusability of the catalyst make this method to declare as green approach for synthesis of calix[4]resorcinarene.

Polyethylene Glycol (PEG-400): A Green Reaction Medium for One-Pot, Three Component Synthesis of 3-Substituted Indoles under Catalyst Free Conditions

A catalyst-free, cost-effective and environmentally friendly protocol for the synthesis of 3-substituted indoles via a one-pot multicomponent condensation reaction of indole, C–H activated acids and aromatic aldehydes in polyethylene glycol 400 (PEG-400) as a reaction medium and reaction promoter has been developed. The most important feature of this protocol is selectivity in the formation of heterodimer products instead of homodimer adducts such as bisindole or xanthine.

Preparation of cationic poly(ionic liquids) functionalization of silica nanoparticles via multicomponent condensation reaction with significant enhancement of adsorption capacity

In this work, we present for the first time for surface functionalization of SiO2 nanoparticles with cationic poly(ionic liquids) through the Debus–Radziszewski condensation reaction. The resultant SiO2@PIL composites were further utilized for removal of Congo red (CR). Characterization results demonstrated that the cationic poly(ionic liquids) were successfully introduced on SiO2 nanoparticles. So as to assess the maximum adsorption capacity (Qmax) of SiO2@PIL for dyes, a batch of experiments were performed under different adsorption parameters. The SiO2@PIL adsorbents exhibited an excellent adsorptive capacity for CR, with the Qmax of 205.3 mg g−1, which is obvious greater than that of unmodified SiO2 nanoparticles (22.4 mg g−1). Experimental data described well with the pseudo-second order model. The adsorption isotherms indicate that the equilibrium data of adsorption process were better fitted by Freundlich model. The thermodynamics further indicated that the process for CR into SiO2@PIL composites was endothermic. The adsorption mechanism was proposed that include hydrogen bonding, electrostatic interactions between the positive charged imidazole ring of SiO2@PIL and anionic dyes. This method could be an interest and useful tool for fabrication of functional materials for various applications.

An efficient one‐pot synthesis of N‐(substituted phenyl)‐1,2,5‐thiadiazolidine‐2‐carboxamide 1,1‐dioxide derivatives

Abstract1,2,5‐Thiadiazolidine‐1,1‐dioxide carboxamide derivatives 3a‐3n are novel heterocyclic compounds synthesized by multicomponent condensation reaction in one pot of aniline, chlorosulfonyl isocyanate, and 2‐chloroethylamine hydrochloride which is used as a useful precursor under mild conditions. This reaction is realized with high atom economy, at room temperature and in a short reaction time. Series of these desired products are obtained from good to excellent yields within 2 hours in all cases. All the synthesized compounds are characterized by 1H, 13C NMR, MS, and HMBC/HSQC spectroscopy.

Multicomponent synthesis and molecular structure of 3-amino-2-aroyl(alkoxycarbonyl, arylcarbamoyl)-4-aryl(hetaryl)-5-arylcarbamoyl-6-methylthieno[2,3-b]pyridines

A new, effective method has been developed for the synthesis of functionalized thieno[2,3-b]pyridines by multicomponent condensation reactions of aromatic and heteroaromatic aldehydes, cyanothioacetamide, acetoacetanilides, and alkylating agents containing activated methylene groups. The structures of 3-amino-2-benzoyl-4-(furan-2-yl)-6-methyl-N-phenylthieno[2,3-b]pyridine-5-carboxamide, 3-amino-N2-(4-bromophenyl)-N5-(4-chlorophenyl)-6-methyl-4-(3-methylthiophen-2-yl)thieno[2,3-b]pyridine-2,5-dicarboxamide, and 3-amino- 4-(2-chlorophenyl)-N-(4-chlorophenyl)-6-methyl-2-(4-methylbenzoyl)thieno[2,3-b]pyridine-5-carboxamide were studied by X-ray structural analysis.

Sulfamic acid well dispersed in the micropores of Al-pillared α-ZrP as efficient heterogeneous catalyst for synthesis of structurally diverse 1,4-dihydropyridines under mild conditions

In this study, α-zirconium phosphate (α-ZrP) has been prepared via reflux method. The α-ZrP material was pillared with [Al13O4(OH)24(H2O)12]7+ polycations to improve its surface area and thermal stability. The aluminum oxyhydroxy clusters were synthesized by in situ partial base hydrolysis of the aluminum salt precursor using sodium hydroxide as base. The microporous inorganic matrix of Al-pillared α-ZrP (AZP) was used for molecular dispersion of sulfamic acid to prepare novel composite materials. The sulfamic acid modified AZP materials were characterized by using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM) and Brunauer–Emmett–Teller (BET) specific surface area analysis. XRD study indicated an expansion in the interlayer space as a result of bilayer intercalation of Al137+ pillaring species. The pillared interlayer space is retained in the composite material. FTIR study indicated the structural integrity of the sulfamic acid. The composite materials exhibited enhanced microporosity with surface area and pore volume in the range 80–120 m2/g and 0.1–0.2 cc/g. FESEM and HRTEM studies indicated morphological reorganization of α-ZrP particles as a result of pillaring and subsequent dispersion of sulfamic acid. Elemental mapping study suggested well dispersion of the sulfamic acid in the composite material without any sign of local agglomeration. The catalytic activity of sulfamic acid loaded AZP materials has been evaluated for the synthesis of 1,4-dihydropyridines by multi component condensation reaction of ethyl acetoacetate, arylaldehydes/chalones and ammonium acetate. The composite materials were highly active for synthesis of structurally diverse 1,4-dihydropyridines in high yield and purity under mild conditions.

An efficient and reusable nano catalyst for the synthesis of benzoxanthene and chromene derivatives

Potassium fluoride impregnated on clinoptilolite nanoparticles (KF/CP NPs) was investigated as an efficient solid base catalyst for multicomponent condensation reaction. A broad range of aromatic aldehydes and enolizable compounds were condensed with 2-naphthol or 4-hydroxycumarine. The reaction was carried out under a solvent-free condition to give the corresponding benzoxanthene and pyrano [3,2-c]chromene derivatives in high yields. The low cost and availability of catalyst, novel and green procedure makes this strategy more useful for the preparation of tetrahydrobenzo[a]-xanthene-11-one and pyrano [3,2-c]chromene derivatives.

SO3H-dendrimer functionalized magnetic nanoparticles (Fe3O4@D[sbnd]NH[sbnd](CH2)4[sbnd]SO3H): Synthesis, characterization and its application as a novel and heterogeneous catalyst for the one-pot synthesis of polyfunctionalized pyrans and polyhydroquinolines

In this study, novel SO3H-dendrimer functionalized magnetic nanoparticles (Fe3O4@DNH(CH2)4SO3H) were prepared and characterized by using FT-IR, X-ray diffraction patterns, scanning electron microscopy, transmission electron microscopy, thermogravimetry analysis, and energy-dispersive X-ray spectroscopy. The synthesized nanosized catalyst was successfully applied to the synthesis of highly substituted pyrans and polyhydroquinolines via a straightforward one-pot multicomponent condensation reaction. The key advantages are the short reaction time, high yields, simple workup, and purification of products by simple recrystallization from ethanol.