Active Methylene Compounds Research Articles

Natural Surfactant Mediated Synthesis of 4-Aryl Substituted 3,4-Dihydropyrimidinones

Present work describes the synthesis of 4-aryl substituted 3,4-dihydropyrimidinones (DHPMs) using aqueous extract of pericarp of Sapindus trifoliatus fruit as a green catalyst. The reaction is a one-pot reaction, similar to classical Biginelli reaction employing an aromatic aldehyde, urea and active methylene compound (ethyl acetoacetate) as substrates. Desired DHPMs were yielded within 2 h at room temperature. The key advantage of the present strategy was its low dependence on organic solvents as green synthesis.

Green Synthesis of Electrophilic Alkenes Using a Magnesium Catalyst under Aqueous Conditions and Mechanistic Insights by Density Functional Theory.

A green approach for the synthesis of electrophilic alkenes has been developed via Knoevenagel condensation between active methylene compounds and carbonyl compounds using Mg powder under aqueous conditions. In this strategy, Mg(OH)2 acts as a catalyst, which was generated in situ by the reaction between metallic Mg (20 mol %) and water. Mg was found to be an efficient, nontoxic, and inexpensive metal catalyst system for producing a range of electrophilic alkenes in excellent yields (≤98%). A gram-scale synthesis of electrophilic alkenes has been developed, and Mg metal was recovered and recycled up to three times without an appreciable loss of catalytic activity. A catalytic cycle was proposed, and the reaction mechanism was investigated using density functional theory. The key steps are enolization of ethyl cyanoacetate, C-C bond formation, and then regeneration of the catalyst via metathesis with H2O. The overall reaction occurs easily with a maximum ΔG°⧧ value of 7.9 kcal/mol for the rate-determining C-C bond formation step. Our protocol has several advantages and can be further extended to one-pot sequential Knoevenagel condensation and Michael addition, and one-pot sequential Knoevenagel condensation and chemoselective reduction can be used for the synthesis of valuable precursors of pharmaceutical products under green and aqueous conditions.

Synthesis of novel nitro functionalized 1,4-dihydropyridines under neat condition: Spectral characterization, crystallographic study and ADMET predictions

A cost-effective and sustainable protocol has been developed to synthesize novel nitro-functionalized N-methyl-1,4-dihydropyridines. This one-pot, three-component reaction was performed by using active methylene compounds with aromatic aldehydes and N-benzyl-N-methyl-2-nitroethene-1,1-diamine(nitroketene-N,N-acetal) in the presence of DMAP 10 mol% under neat conditions. Standard spectroscopic techniques like IR, 1H and 13C NMR, HRMS and elemental analysis are employed to characterize all synthesized compounds. The molecular structure of 2-amino-6-(benzylamino)-4-(4-chlorophenyl)-1-methyl-5-nitro-1,4-dihydropyridine-3-carbonitrile (4h) and 2-amino-6-(benzylamino)-1-methyl-5-nitro-4-(p-tolyl)-1,4-dihydropyridine-3-carbonitrile (4k) were confirmed by the single crystal XRD analysis. The spectral data is well correlated with the anticipated structure. The ADMET calculations of the prepared novel compounds were done, and vital pharmacokinetic properties were predicted. This solvent-free approach offers several distinguishing characteristic features including a short reaction time, low-cost solid catalyst, high yields, easy work-up, and no requirement for chromatography.

Cyclohexylamine – an efficient organocatalyst for the synthesis of 2-amino-4H-chromene derivatives by multicomponent reactions of salicylaldehydes, active methylene compounds and nitroalkanes

Cyclohexylamine – an efficient organocatalyst for the synthesis of 2-amino-4H-chromene derivatives by multicomponent reactions of salicylaldehydes, active methylene compounds and nitroalkanes

BaTiO3-xNy: Highly Basic Oxide Catalyst Exhibiting Coupling of Electrons at Oxygen Vacancies with Substituted Nitride Ions.

The base strength of oxide catalysts is controlled by the electron charge distribution between cations and anions, with unsaturated oxygen ions that have lone pair electrons typically acting as basic sites. Substitution of oxide ions with anions that have different valences, such as nitride and hydride ions, can often generate basic sites. It is plausible that electrons trapped at oxygen vacancy sites could provide increased electron density and shift the highest occupied molecular orbital energy levels of anions upward in the case that the oxygen vacancies couple with surface-substituted anions. The present work demonstrates that high catalytic basicity can be obtained via site-selective doping of anions at face-sharing Ti2O9 dimer sites with oxygen vacancies in BaTiO3-x. This improved basicity stems from the coupling of substituted nitride ions to electrons at oxygen vacancies. The oxynitride BaTiO3-xNy was found to contain nitride ions that have increased electronic charge density on the basis of such interactions. Enhanced surface basicity following doping with nitride ion was also confirmed by CO2 temperature-programmed desorption and infrared spectroscopy in conjunction with the adsorption of CHCl3. The strong Lewis base sites resulting from the formation of the oxynitride evidently facilitated the catalytic activation of C-H bonds to promote Knoevenagel condensation reactions between aldehydes and active methylene compounds with pKa values of up to 28.9.

Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds

Nerve growth factor (NGF) and its receptor, tropomyosin kinase receptor kinase type A (TrkA) is emerging as an important target for Glioblastoma (GBM) treatment. TrkA is the cancer biomarker majorly involved in tumor invasion and migration into nearby normal tissue. However, currently, available Trk inhibitors exhibit many adverse effects in cancer patients, thus demanding a novel class of ligands to regulate Trk signaling. Here, we exploited the role of TrkA (NTRK1) expression from the 651 datasets of brain tumors. RNA sequence analysis identified overexpression of NTRK1 in GBM, recurrent GBM as well in Oligoastrocytoma patients. Also, TrkA expression tends to increase over the higher grades of GBM. TrkA protein targeting hydrazone derivatives, R48, R142, and R234, were designed and their mode of interaction was studied using molecular docking and dynamic simulation studies. Ligands' stability and binding assessment reveals R48, 2 2-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene)-1-phenylbutane-1,3-dione, as a potent ligand that interacts well with TrkA's hydrophobic residues, Ile, Phe, Leu, Ala, and Val. R48- TrkA exhibits stable binding potentials with an average RMSD value <0.8 nm. R48 obeyed Lipinski's rule of five and possessed the best oral bioavailability, suggesting R48 as a potential compound with drug-likeness properties. In-vitro analysis also revealed that R48 exhibited a higher cytotoxicity effect for U87 GBM cells than TMZ with the IC50 value of 68.99 μM. It showed the lowest percentage of cytotoxicity to the non-cancerous TrkA expressing MEF cells. However, further SiRNA analysis validates the non-specific binding of R48, necessitating structural alteration for the development of R48-based TrkA inhibitor for GBM therapeutics.

Acid and base catalysis of SrTiO3 nanoparticles for C–C bond-forming reactions

The development of acid–base bifunctional catalysts is important because of their cooperative activation of a substrate to promote specific chemical transformations. We investigated two C–C bond-forming reactions—cyanosilylation and Knoevenagel condensation—over Ti-based perovskite oxides synthesized by a sol–gel method using water-soluble metal precursors and dl-malic acid. Among the tested catalysts, highly pure SrTiO3 nanoparticles (23 nm) with a high specific surface area (46 m2 g–1) exhibited the highest catalytic performance for the reactions, even when it was not subjected to a thermal pretreatment. The SrTiO3 catalyst could be easily recovered by simple filtration and reused two times without a substantial loss of its performance for the Knoevenagel condensation of benzaldehyde with phenylacetonitrile. Mechanistic studies—including studies of the effect of electron-withdrawing groups on the substrates, studies of the poisoning effect of acidic and basic additives for Knoevenagel condensation, and FT-IR measurements of probe molecules adsorbed onto the catalyst surface—revealed that acid and base sites on the catalyst surface cooperatively activate active methylene compounds with nitrile groups to promote the reactions effectively.

Base-Promoted [4 + 2] Annulation Reaction of In Situ-Generated Azadienes from N-Propargylamines with Active Methylene Compounds: Access to Highly Functionalized 2-Pyridones.

A facile and efficient synthesis of structurally diversified 2-pyridones is demonstrated using the [4 + 2] annulation of in situ generated azadienes from N-propargylamines and active methylene compounds. The reaction is promoted by an inorganic base giving moderate to good yields. The developed methodology is applicable for the direct and formal synthesis of various bioactive molecules. The synthetic utility of the protocol was also illustrated by late-stage functionalization of the products.

Photoinduced Efficient Catalytic α-Alkylation Reactions of Active Methylene and Methine Compounds with Nonactivated Alkenes.

In catalytic α-alkylation reactions of carbonyl compounds, although SN2-type substitution reactions of enolates with alkyl halides are a conventional methodology, addition reactions with alkenes are more desirable because of their atom-economical character; however, reactions with nonactivated alkenes are challenging. Here, we developed highly efficient catalytic α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes such as 1-decene using an organophotocatalyst and lithium thiophenoxide as a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalyst under blue-light irradiation. The reaction was also performed with a higher degree of efficiency under a continuous-flow system to obtain the products in multigram scales. The present reaction system enables highly efficient and practical α-alkylation reactions of active methylene and methine compounds to be achieved.

2+2+1+1] Cycloaddition Reaction of 1,3,5‐Triazinanes with Methylene Compounds: Approach to Hexahydropyrimidines

AbstractAn acetic acid‐catalyzed [2+2+1+1] cycloaddition of 1,3,5‐triazinanes with methylene compounds was developed. This protocol provides an access to hexahydropyrimidines (HHPs) (25 examples) in 35–99% yields under mild conditions in 2 hours. The potential application of this method was demonstrated by gram‐scale synthesis. Preliminary mechanistic investigation was conducted to elucidate the possible mechanism. This work represents the yet unknown example of [2+2+1+1] cycloaddition reaction between 1,3,5‐triazinanes and active methylene compounds.

One‐Pot Synthesis of β‐Ketoesters from Aryl Methyl Ketone via Ketene Dithioacetal

AbstractWe have discovered base‐mediated conversion of 3,3‐bis(methylthio)‐1‐arylprop‐2‐en‐1‐ones to versatile active methylene compounds (β‐keto esters). A series of products were isolated and characterized as a mixture of keto‐enol form. We have modified the method and synthesized the active methylene compounds (β‐keto esters) directly from aryl methyl ketone via ketene dithioacetal intermediate (not isolated) by stepwise reactions in one pot. Most of the one‐pot reactions also provided excellent yields. In addition to aryl methyl ketones, we also tested cyclopropyl methyl ketone as a source of an aliphatic ketone, and under similar reaction conditions, ethyl 3‐cyclopropyl‐3‐oxopropanoate was afforded.

Glycosyl Triazole Based Pyridinamide/CuI-Catalyzed Coupling of 2-Halobenzamides with Active Methylene Compounds

AbstractThis report describes a convenient method for the Cu(I)-catalyzed tandem synthesis of dihydrophenanthridinediones and substituted isoquinolinones with the assistance of efficient glycosyl 1,2,3-triazole-based pyridinamide ligands. The catalytic system effectively works for the coupling of N-substituted 2-halobenzamides with various active methylene compounds to form biologically relevant heterocyclic scaffolds in high to excellent yields. The consecutive path of the reaction including intermolecular C–C cross-coupling followed by intramolecular cyclization efficiently takes place at low catalytic loading. These glycosyl triazole-appended pyridinamides were synthesized in good yields by a CuI/DIPEA-mediated regioselective CuAAC click reaction. The notable features of the method include low catalytic loading, the use of cost-effective and biocompatible ligands, high reaction yield, and easily accessible starting materials that make the protocol more versatile.

Aqueous Extract of Musa Acuminata: An Ecofriendly Catalyst for Knoevenagel Condensation

AbstractAn efficient and greener approach for Knoevenagel condensation between substituted aldehydes and ketones with active methylene compound as starting substrate has been achieved using aqueous extract of Muca Acuminata as a neutral heterogeneous biocatalyst (Characterized by XRD, TEM, EDS, and ICP‐MS) at room temperature is reported. We found that this method is advantageous over the traditional methods that include refluxing, heating, use of toxic and highly expensive catalyst or solvents and also reduced the reaction time. It is ascertained that the reactions via this protocol are very clean and the isolated crude solid product is more than 95 % pure. The synthesized arylidene compounds exhibited great antioxidant potential and also acts as specific protein‐tyrosine kinase inhibitors and thus serves as an anticancer agent. The final product is separated by simple filtration and is characterized by various spectroscopic techniques like FT‐IR, 1H‐NMR, 13C‐NMR, 19F‐NMR and MS. The cheaper, simple and green approach suggests the possible use of this protocol for large scale preparations.

Quinoline- and Isoindoline-Integrated Polycyclic Compounds as Antioxidant, and Antidiabetic Agents Targeting the Dual Inhibition of α-Glycosidase and α-Amylase Enzymes.

Novel analogs of quinoline and isoindoline containing various heterocycles, such as tetrazole, triazole, pyrazole, and pyridine, were synthesized and characterized using FT-IR, NMR, and mass spectroscopy, and their antioxidant and antidiabetic activities were investigated. The previously synthesized compound 1 was utilized in conjugation with ketone-bearing tetrazole and isoindoline-1,3-dione to synthesize Schiff's bases 2 and 3. Furthermore, hydrazide 1 was treated with aryledines to provide pyrazoles 4a-c. Compound 5 was obtained by treating 1 with potassium thiocyanate, which was then cyclized in a basic solution to afford triazole 6. On the other hand, pyridine derivatives 7a-d and 8a-d were synthesized using 2-(4-acetylphenyl)isoindoline-1,3-dione via a one-pot condensation reaction with aryl aldehydes and active methylene compounds. From the antioxidant and antidiabetic studies, compound 7d showed significant antioxidant activity with an EC50 = 0.65, 0.52, and 0.93 mM in the free radical scavenging assays (DPPH, ABTS, and superoxide anion radicals). It also displayed noteworthy inhibitory activity against both enzymes α-glycosidase (IC50: 0.07 mM) and α-amylase (0.21 mM) compared to acarbose (0.09 mM α-glycosidase and 0.25 mM for α-amylase), and higher than in the other compounds. During in silico assays, compound 7d exhibited favorable binding affinities towards both α-glycosidase (-10.9 kcal/mol) and α-amylase (-9.0 kcal/mol) compared to acarbose (-8.6 kcal/mol for α-glycosidase and -6.0 kcal/mol for α-amylase). The stability of 7d was demonstrated by molecular dynamics simulations and estimations of the binding free energy throughout the simulation session (100 ns).

Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors.

The reaction of 4-azido-quinolin-2(1H)-ones 1a-e with the active methylene compounds pentane-2,4-dione (2a), 1,3-diphenylpropane-1,3-dione (2b), and K2CO3 was investigated in this study. This approach afforded 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones 3a-j in high yields and purity. All newly synthesized products' structures were identified. Compounds 3a-j were tested for antiproliferative activity against a panel of four cancer cell lines. In comparison to the reference erlotinib (GI50 = 33), compounds 3f-j were the most potent derivatives, with GI50 values ranging from 22 nM to 31 nM. The most effective antiproliferative derivatives, 3f-j, were subsequently investigated as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Compound 3h was the most potent inhibitor of the studied molecular targets, with IC50 values of 57 nM, 68 nM, and 9.70 nM, respectively. The apoptotic assay results demonstrated that compounds 3g and 3h function as caspase-3, 8, and Bax activators as well as down-regulators of the antiapoptotic Bcl2, and hence can be classified as apoptotic inducers. Finally, compounds 3g and 3h displayed promising antioxidant activity at 10 µM, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to Trolox (77.6%).

Photosensitized O2 enables intermolecular alkene cyclopropanation by active methylene compounds.

Cyclopropanes are key features in many preclinical, clinical, and commercial drugs, as well as natural products. The most prolific technique for their synthesis is the metal-catalyzed reaction of an alkene with a diazoalkane, a highly energetic reagent requiring stringent safety precautions. Discovery of alternative innocuous reagents remains an ongoing challenge. Herein, we report a simple photoredox-catalyzed intermolecular cyclopropanation of unactivated alkenes with active methylene compounds. The reaction proceeds in neutral solvent under air or dioxygen (O2) with a photoredox catalyst excited by blue light-emitting diode light and an iodine co-catalyst that is either added as molecular iodine or generated in situ from alkyl iodides. Mechanistic investigations indicate that photosensitized O2 plays a vital role in the generation of carbon-centered radicals for both the addition of active methylene compounds to alkenes and the ring closure.

Aqueous Phase Organocatalytic Multicomponent Green Synthesis of 2‐Amino‐4H‐Chromenes

AbstractAn efficient and green method for the synthesis of 4H‐chromenes via an organocatalytic three‐component one‐pot reaction between active methylene compound, aromatic aldehydes and resorcinol with high yields (upto 98 %) in water is reported. To the best of our knowledge, ours is the first report of study of MCR on resacetophenone for the synthesis of 2‐amino‐4H‐chromenes. The organo catalyst DMAP was recovered and reused for 6 times without substantial decrease in the yields, and the products were purified just by recrystallization from ethanol which avoids purification through column. This easy to handle method reduces the use of many hazardous catalysts and adverse reaction conditions and utilizes simple, readily accessible and recyclable catalyst. Single crystal X‐ray clearly confirms the structures of synthesized chromenes.

Synthesis of phthalazine-based derivatives as selective anti-breast cancer agents through EGFR-mediated apoptosis: in vitro and in silico studies

The parent 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-acetohydrazide (4) has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene compounds were produced by chemoselective N-alkylation of 4-Benzyl-2H-phthalazin-1-one (2) with ethyl chloroacetate to afford (4-benzyl-1-oxo-1H-phthalazin-2-yl) methyl acetate (3). The ester 3 was hydrazinolyzed to give hydrazide 4, then azide 5 coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetyl) glycinate (7a) was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(2-hydrazineyl-2-oxo ethyl) acetamide (8a). The hydrazide 8a under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide 8a was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds 11d, 12c and 12d exhibited potent cytotoxic activities with IC50 values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC50 = 1.02 μM). Interestingly compound 12d exhibited promising potent EGFR inhibition with an IC50 value 21.4 nM compared to Erlotinib (IC50 = 80 nM). For apoptosis, compound 12d induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound 12d towards EGFR protein. Hence, compound 12d may serve as a potential and selective anti-breast cancer agent.

Design and Synthesis of Pyridine and Thiazole Derivatives as Eco-friendly Insecticidal to Control Olive Pests.

Treatment of p-tosyloxybenzaldehyde (1) with ethyl cyanoacetate afforded ethyl 2-cyano-3-(4-{[(4-methylphenyl)sulfonyl]oxy}phenyl)acrylate (2) which reacted with some active methylene derivatives under microwave irradiation in presence of ammonium acetate yielded pyridine derivatives 3-7. On the other hand, when treatment of compound 1 with thiosemicarbazide gave 4-tosyloxybenzylidenethiosemicarbazone (8), which allowed to react with some active methylene compounds, such as: ethyl bromoacetate, chloroacetonitrile or phenacyl bromide derivatives gave thiazole derivatives 9-13. The structure of all products were confirmed by elemental and spectroscopic analyses such as IR, 1 H-NMR, 13 CNMR and mass spectra. The advanced of this method are short reaction time (3-7 min), excellent yield, pure products, and low-cost processing. In the final category, the toxicological characteristics of all compounds were tested towards Saissetia oleae (Olivier, 1791) (Hemiptera: Coccidae). With respect to the LC50 values. It has been found that compound 3 possesses the highest insecticidal bioefficacy compared with other products, with values of 0.502 and 1.009 ppm, for nymphs and adults female, respectively. This study paves the way towards discovering new materials for potential use as insecticidal active agents.

Nitrogen-Enriched Biguanidine-Functionalized Cobalt Ferrite Nanoparticles as a Heterogeneous Base Catalyst for Knoevenagel Condensation under Solvent-Free Conditions.

Designing efficient, economical heterogeneous catalysts for the Knoevenagel condensation reaction is highly significant owing to the importance of reaction products in industries as well as pharmaceutics. Herein, we have designed and synthesized biguanidine-functionalized basic magnetically retrievable cobalt ferrite nanoparticles (CFNPs) for the synthesis of Knoevenagel condensation products using benzaldehydes and active methylene compounds (malononitrile/ethyl cyanoacetate/cyanoacetamide). Several advanced techniques, such as Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibration sample magnetometry (VSM), were utilized to precisely characterize the catalyst. The robust features of the current approach involve outstanding catalytic performance, solvent-free reaction conditions, ease of catalyst retrievability, easy workup procedure, large substrate tolerance, high turnover frequency (TOF) values (up to 486.88 h-1), values of green chemistry metrics such as E-factor (0.15), reaction mass efficiency (RME) value (87.07%), carbon efficiency (93.4%), and atom economy (AE) value (88.10%) close to their ideal values, and recyclability up to eight runs without a considerable reduction in activity, boosting the appeal of this approach from a commercial and ecological point of view.