Active Methylene Research Articles

Highly Active Copper(I)-Chalcogenone Catalyzed Knoevenagel Condensation Reaction Using Various Aldehydes and Active Methylene Compounds

Highly Active Copper(I)-Chalcogenone Catalyzed Knoevenagel Condensation Reaction Using Various Aldehydes and Active Methylene Compounds

Synthesis of novel bisazo disperse dyes: Spectroscopic characterization, DFT study and dyeing of polyester

A series of bis azo disperse dyes were synthesized starting from benzidine and four couplers contain active methylene group, namely; thiobarbituric acid, barbituric acid, dimedone and thiohydantoin, to give 3 a-c and 4, respectively. The dye products were identified by UV–visible, FT-IR, 1H NMR and 13C NMR spectroscopy. The electronic absorptions of the synthesized dyes indicated that the λmax are slightly dependent on the coupler moieties and quite sensitive to pH change. Dyeing of polyester yarn(PE-Y) was done in DMF, whereas, polyester fabric (PE-F) was dyed in water using dispersing agent DYEWELL-002. Fastness properties of bis azo dyes 3a-c and 4 on PE-F are better than those of PE-Y. The summation of color strength (K/Ssum) values of PE-F followed the order 3c > 4 > 3a >3b. The DFT method was used to calculate the chemical descriptor parameters of the protonated form of bis azo dyes 3a-c and 4, using B3LYP/6-31G(d,p) level for investigation of dyeing efficiencies as well as to predict the mechanism of dyeing process. The computed results point out that dye 3a has the highest dyeing strength based on EHOMO, ELUMO, ΔE, η and S parameters while dye 4 is the highest depending on χ and μ eV parameters. The correlation results of the computed parameter with color strength (K/S) and Exhaustion (%E) in case of PE-Y indicated that they depend mainly on the effect of electronegativity χ with correlation coefficient 0.993 and 0.877, respectively. In a similar way, the PE-F exhibits very good effect of color strength with dipole moment (R2 = 0.899). The protonated dyes 3a-c and 4 can adsorbed on the PE surface either by hydrogen bond or/and electrostatic attraction.

Highly Selective Monoalkylation of Active Methylene and Related Derivatives using Alkylsilyl Peroxides by a Catalytic CuI‐DMAP System

AbstractA new approach for highly selective monoalkylation of active methylene and related derivatives using various types of alkylsilyl peroxides in the presence of copper catalysts under mild conditions has been developed to a synthetically useful level. This approach has a wide substrate scope in terms of both active methylene compounds and alkylsilyl peroxides. In addition, nitroalkanes can also be employed for a copper‐catalyzed selective monoalkylation with alkylsilyl peroxides. The participation of radical species was proposed in the present monoalkylation reactions by the mechanistic study.

An effective green one-pot synthesis of some novel 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)pyrano[2,3-c]pyrazoles and 6-(thiophene-2-carbonyl)-7-(trifluoromethyl)pyrano[2,3-d]pyrimidines bearing chromone ring as anticancer agents

An effective green one-pot and catalyst-free synthesis of a series of novel 5-(thiophene-2-carbonyl)-6-(trifluoromethyl)pyrano[2,3-c]pyrazoles and 6-(thiophene-2-carbonyl)-7-(trifluoromethyl)pyrano[2,3-d]pyrimidines bearing chromone ring was achieved. The method depended on a one-pot three-component reaction of readily available starting materials 4-oxo-4H-chromene-3-carboxaldehyde, 2-thenoyltrifluoroacetone, and cyclic active methylene compounds in water as solvent. The targeted compounds were assessed for their in vitro anticancer activity against mammary gland breast cancer cell line (MCF-7), liver cancer (HepG-2), and human colon cancer (HCT-116) by using sulphorhodamine B assay (SRB) method, while doxorubicin, was utilized as standard reference drug. Compounds 4a, 4c, and 6b exhibited excellent anticancer activity versus all cancer cell lines with IC50 values ranging from 1.7 to 9.9 μg/mL.

Condensation of Active Methylene and Substituted Aldehydes over Mesoporous Nickel Oxides Nanostructures: A Combined Experimental and DFT Study

AbstractMesoporous NiO nanoarchitectures (NAs) with controlled hexagonal platelet‐ and flower‐like morphology were synthesized using facile hydrothermal methods in different reaction conditions. The NiO NAs were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption /desorption isotherms, and wide‐angle X‐ray diffraction. It was found that controlled morphology, large surface areas, and high crystallinity of NiO NAs offered high catalytic reactivity toward Knoevenagel condensation reactions. Large reaction yields in an aqueous media and easy separation of the NiO NAs without losing the catalytic activity were observed. Further, the formation mechanism of bonds over NiO NAs surface was explored by density functional theory (DFT). These findings open a new avenue for efficient bonds formation using reusable NiO NAs catalyst without using any expensive solvents.

Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12–0.25 µM) compared to Vancomycin (1–2 µM), and MBC values ranging from (0.5–1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.

ZnO Nanoparticles Embedded on a Reduced Graphene Oxide Nanosheet (ZnO−NPs@r‐GO) as a Proficient Heterogeneous Catalyst for a One‐Pot A3‐Coupling Reaction

AbstractThis study reports a simple and facile route for the synthesis of ZnO nanoparticles (ZnO−NPs) decorated on reduced graphene oxide nanosheet (ZnO−NPs@r‐GO) as a heterogeneous catalyst and tested over multicomponent one‐pot A3‐coupling reaction. The reduction of graphene oxide with the anchoring of ZnO−NPs on the r‐GO nanosheet was observed through the X‐ray diffraction patterns, Raman, FTIR, and XPS results of the ZnO−NPs@r‐GO sample. ZnO−NPs (average particle size of 3.4±1.5 nm) with uniform size distribution over r‐GO nanosheet were substantiated through HRTEM analysis. Impressively, ZnO−NPs@r‐GO significantly used for A3‐coupling reaction with different aromatic aldehydes, active methylene compounds, and urea and under the optimized reaction conditions gave exceptional activity to produce synthetically valuable 3,4‐dihydropyrimidinones products (possessing diverse therapeutic and pharmacological properties) i. e. 97 % isolated yield of the product. In addition, excellent reusability up to 4 repeated cycles are the key advantages of the present catalyst used for this multicomponent A3‐coupling reaction.

A review on recent trends in synthesis and applications of 1,4-dihydropyridines

1,4-dihydropyridinesbeing significant classes of nitrogen-containing heterocyclic compounds. These compounds have been utilized as a main skeleton in many drugs and starting material in synthetic organic chemistry due to their existence in biological applications. Recently, numerous researchers suggested many pathways to target the main skeleton in complex organic compounds but atom economy reactions are efficient and environmentally benign for the synthesis of bioactive 1,4-dihydropyridines. In this review, the authors made an efforts to illustrate all the recent methodologies adopted for the synthesis of 1,4-dihydropyridnes via multi-component reactions and concluded that mainly all the 1,4-DHPs were prepared by Hantzsch Condensation reaction. The future scope of this study is that all the active methylene groups used for 1,4-DHPs can also be further used to prepare more biologically active compounds by comparing their SARS activity.

One‐Step Method for Alicyclic Ring‐Fused Pyrimidine‐2,4‐diones

AbstractOne‐step method for the synthesis of alicyclic ring‐fused pyrimidine‐2,4‐diones is proposed. The method is based on the reaction of cyclic imidates with carbonylaminopropionic acid derivatives using an excess cyclic imidate as a base. It was shown that the first step is the condensation of a cyclic imidate and a carbonylaminopropionic acid derivative via an active methylene group. Various derivatives of alicyclic ring‐fused pyrimidine‐2,4‐diones bearing at the C5 position of the starting pyrimidine ring hydrogen, carboxylic, nitrile, methoxycarbonyl, and bromo groups were prepared. It was shown that methylation proceeded readily affording 3‐methyl‐5‐bromo‐ alicyclic ring‐fused pyrimidine‐2,4‐diones in good yield.

Synthesis, molecular docking, DFT study, and in vitro antimicrobial activity of some 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives.

The evolution of microbial resistance necessitates the development of new antimicrobial drugs that are more effective than those currently on the market. To address this problem, we have prepared a series of novel 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives via Hantzsch reaction using nine different compounds containing active methylene group. IR, NMR, and mass spectra were used to determine the structures. Using ampicillin and griseofulvin as standards, the titled compounds were investigated for their antibacterial activity against different bacteria and fungi. Compounds 1f, 1g, 2f, and 2g have the best antibacterial activity against Gram-negative bacteria (minimum inhibitory concentration = 50 μg/ml), while 1f, 1h, 2g, and 2h have high antifungal activity against Candida albicans (minimum inhibitory concentration = 100 μg/ml). To gain a better understanding of the binding process and affinity for the bacterial Staphylococcus epidermidis protein, researchers used molecular docking and molecular mechanics, as well as the generalized Born model and solvent accessibility-based binding free energy. The active compounds 1g, 1h, and 2f have good docking scores of -5.575, -5.949, and -5.234, respectively, whereas compound 2c has the greatest docking score (-6.23). The HOMO-LUMO energy gap and molecular electrostatic potential were used to evaluate the reactivity of promising compounds, which were then associated with antibacterial efficacy.

A Comparison of Clinical Efficiency of Photodynamic Therapy and Topical Corticosteroid in Treatment of Oral Lichen Planus: A Split-Mouth Randomised Controlled Study.

Background: The aim of the study was to compare the effectiveness of photodynamic therapy (PDT) to steroid therapy in the treatment of oral lichen planus (OLP). Due to the lack of commercially available drug carriers, innovative proprietary solutions were used for both the photosensitiser and the steroid carrier—in the first case to shorten and in the second to extend the contact of the active substance with the mucosa. Methods: A prospective, randomised, single-blind, 12-week full contralateral split-mouth clinical trial of 30 patients with bilateral oral lichen planus was conducted. The prepared matrices were incorporated with active substances methylene blue 5% and 0,05% triamcinolone. The size of lesions, Thongprasom, ABISIS, and VAS scale were evaluated. Results: Relatively high rates of complete remission of lichen were demonstrated: immediately after treatment, 33.3% with PDT and 22.2% with triamcinolone (TA), and after 3 months, 54.2% with PDT and 62.9% with TA. After 3 months of treatment, a reduction in the area of evaluated lesions of 52.7% for PDT and 41.7% for TA was achieved. Conclusion: In situations of topical or general contraindications to oral corticosteroids, resistance to them, or the need for repeated treatment in a short period of time, PDT appears to be a very promising treatment option.

Diastereoselective Synthesis of Densely Functionalized 3a,8a-Dihydro-8H-furo[3,2-a]pyrrolizines through One-Pot Three-Component Assembly.

A new domino mode of assembly was discovered from the one-pot three-component reactions of pyrrole derivatives, active methylene compounds (malononitrile, methyl cyanoacetate, or ethyl cyanoacetate), and sodium cyanide in the presence of piperidinium acetate in EtOH at room temperature, leading to a novel tricyclic skeleton in excellent yield under mild and eco-friendly conditions. This well-choreographed domino process enabled formation of multiple bonds (three C-C and one C-O) for consecutive construction of two rings (pyrrolidine and dihydrofuran) in a diastereoselective manner.

Stereoselective Synthesis of Tri- and Tetrasubstituted Olefins via 1,6-Additions of Diazo Compounds and Their Precursors to p-Quinone Methides.

Reactions of para-quinone methides (p-QMs) with α-diazo-β-ketosulfones and their corresponding esters as well as simple β-dicarbonyl compounds and β-ketosulfones have been carried out under basic conditions. While the reaction of diazosulfone with p-QMs afforded trisubstituted olefins via deacylative 1,6-addition and elimination, α-diazo-β-ketoesters and various active methylene compounds such as 1,3-dicarbonyls and β-ketosulfones afforded tetrasubstituted olefins via 1,6-addition and aerial oxidation. These simple, environmentally benign, and mechanistically diverse protocols provided the products in moderate to excellent yields and selectivities.

Construction of Indoline-Fused Tetrahydroisoquinolines through a Domino Coupling Reaction Catalyzed by CuCoFe Layered Double Hydroxide.

A convenient catalytic protocol for efficiently constructing indoline-fused tetrahydroisoquinolines based on CuCoFe layered double hydroxide (LDH) has been described. Preliminary mechanistic studies show that indoline-fused tetrahydroisoquinolines are produced via domino coupling/cyclization reactions between tetrahydroisoquinolines and active methylene compounds, including malononitrile, malonates, and analogues. CuCoFe-LDH can accelerate the Csp3-Csp3 and Csp3-Csp2 formation reactions in a single step. The research thus presents a unique opportunity to develop a synthetic methodology for N-containing polycyclic compounds.

Ethylene Glycol: Urea: NH4Cl Low Melting Mixture‐Assisted Reactions between Aromatic Aldehydes and Active Methylene Compounds

AbstractSustainable reaction processes have become a subject of high priority in the previous decade. Low melting mixtures play a great role in building up greener pathways for organic reactions. The easiness in preparation, low toxicity, non‐metallic behaviour, recyclability, low cost and biodegradability have made the low melting mixtures important. In this article, we explore the behaviour of the reaction between different active methylene compounds and aldehydes. A low melting mixture can act as solvent, catalyst and reactant when the reaction between aromatic aldehydes and active methylene groups are conducted. Ethylene Glycol: Urea: NH4Cl mixture was used as catalyst and solvent to get α‐β unsaturated products, while it behaved as catalyst, solvent and reactant to get dihydropyrimidinones. All the reactions were done at 30 °C which was the least reported in reactions with low melting mixtures. The physical properties such as solubility in organic solvents, density, acidity, viscosity, surface tension, refractive index, glass transition temperature, thermal stability, polarity, IR spectra and cytotoxicity of the mixture was studied. The α‐β unsaturated products and dihydropyrimidinones were characterized using GC‐MS, 1H NMR and 13C NMR spectroscopic techniques.

Design, synthesis, molecular docking and in silico ADMET profile of pyrano[2,3-d]pyrimidine derivatives as antimicrobial and anticancer agents

Pyrano[2,3-d]pyrimidine derivatives were synthesized by treating cyclic compounds containing active methylene group with aldehyde and malononitrile in butanol. The behavior of pyrano[2,3-d]pyrimidine towards some electrophlies namely triethylorthoformate followed by nitrogen nucleophiles as isobutylamine, urea, phenylthiourea, p-toluidine, o-phenylenediamine, o-aminophenol, 2-amino-4-methyl-pyridine and acetic acid with the aim of obtaining some interesting non-mixed heterocyclic compounds. All synthesized compounds to some extent have shown good antimicrobial activity against different microbial strains that had been extracted by inhibiting cell wall synthesis. Compound 5b showed the highest antibacterial activities against B. subtilis, S. aureus and E. coli. On the other hand compound 5 g exhibited the highest antibacterial and antifungal activities against P. aeruginosa and A. niger respectively. In addition, they explore cytotoxic potentialities against different cell lines via DNA intercalation and Top-II inhibition. The cytotoxic activities clarify the strong inhibitory activity of derivative 5a against HepG2 cells with IC50 = 2.09 μM, while HCT-116 cells were highly susceptible to derivative 5c with IC50 = 2.61 μM, in the meantime, derivative 5f showed pronounced negative impact against MCF-7 (IC50 = 2.43 μM) when compared with other prepared compounds. All derivatives exhibited higher anticancer activities than doxorubicin against the three cell lines except compound 2 against both HepG2 and MCF-7 and compound 5e against HepG2 cell lines. Compounds 5a, 5c and 5f potently intercalate DNA at IC50 values of 26.96, 27.13 and 29.86 µM respectively, which were more potent than doxorubicin (IC50 value of 31.27 µM). Moreover, compounds 5a, 5c and 5f exhibited very good Topoisomerase II inhibitory activities with IC50 values of 0.752, 0.791 and 0.776 µM respectively, that were more potent than that of doxorubicin (IC50 = 0.94 µM). For a great extent, the molecular modeling studies were in agreement with that of in vitro cytotoxicity activity, DNA binding and Top-II inhibition results.

Solvent Synthons: DMSO as an Active Methylene to Synthesize of Benzoxazines from Phenols and Nitriles

Solvent Synthons: DMSO as an Active Methylene to Synthesize of Benzoxazines from Phenols and Nitriles

A concise, facile and MCR-GAP chemistry strategy for the synthesis of spiro[benzo[4,5]thiazolo[3,2-a]pyrano[2,3-d]pyrimidine-4,3′-indoline] derivatives as fluorescent cellular imaging agents

In this research, polyheterocycles containing spirooxindole, pyran, and thiazolopyrimidines rings have been synthesized via one-pot three-component reactions of isatins, active methylene compounds and 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones in the presence of the catalytic amount of NEt3 (2 drops) in ethanol at 70 °C. The photophysical properties of the synthesized fluorophores were investigated against 36 different ions, and compound 4a as a model was successfully used in MCF-7 cell line staining.

Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells

Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.

Reactions under increased pressure: The reactivity of functionally substituted 3-oxo-2-arylhydrazones toward active methylene reagents in Q-tube

A one-pot two-component reaction of 3-oxo-2-arylhydrazones with active methylene nitriles under high pressure in a Q-tube safe reactor was reported. Comparison between conventional and Q-tube safe reactor-assisted synthesis of organic compounds was done by comparing total reaction time and percentage yield. The results show that the compound 5-cyano-6-oxo-1,4-diphenyl-1,6-dihydro-pyridazine-3-carboxylic acid ethyl ester (3) was synthesized within 2 h in a yield of 97%. In addition, the pyrazolo[3,4-c]pyridines 5b and 5c were obtained in yields of 93 and 95% within 1 h reaction time, respectively. The obtained results suggest that Q-tube safe reactor-assisted syntheses were led to higher product yields within very short reaction times.