Active Methylene Compounds Research Articles

Copper‐Catalyzed C(sp3)− Functionalization and Annulation of 2‐Bromoaryl Oximes with Active Methylene Compounds towards Synthesis of Isoquinoline N‐Oxides

AbstractThe established process proceeds through copper (II)‐catalyzed C(sp3)− functionalization of β‐diketones/β‐ketoesters with 2‐bromobenzaldehyde oximes followed by the intramolecular cyclization of in situ generated acylated intermediates to deliver isoquinoline N‐oxides. The copper(II) acetate catalyzed C−H functionalization showed maximum efficacy at 60 °C in methanol/toluene as solvent. The described reaction conditions were applicable over a wide range of substrates with a variety of functional groups to yield isoquinoline N‐oxides in yields up to 85%. The developed approach was further elucidated by means of control experiments and DFT calculations.

Green and Benign Strategies for Synthesis of Biologically Active Compounds using Lipase as Biocatalyst

An efficient, feasible, mild, affordable, and environmentally friendly method has been developed for the synthesis of biologically active compound 3-methylene-indoline-2-one from Isatin and active methylene compounds using Lipase as a Green and Biocatalyst. Biological Processes are very important to optimization to increase and improve the efficiency of cost. In this project, Malononitrile, or Dimedone reacts with Isatin in presence of lipase. The essential features of this approach are metal-free reaction, high yield, nontoxic, and less hazardous. These reactions surpass metal-catalyzed processes because these reactions have violent reaction conditions, toxic, less yields, complex workups, and environmentally hazardous ingredients. This approach replaces hazardous chemicals with benign material during their design, manufacture, use and disposal. Designing of product is cost-effective and environmentally benign chemically products. It is completely followed to Green Approach. The entire given biologically active compound have shown biological activities such as Antiviral, Anti-HIV, Antibacterial, and Anticonvulsants.

Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines

Background: Hepatoprotectors, currently used in clinical practice, often show low efficacy. One of the promising goals in the therapy of liver diseases is the targeted synthesis of smallmolecule drugs with hepatoprotective activity. Some heterocycles, such as 1,4-dihydropyridines, are proven to be good hepatoprotectors. Objective: This study aimed to prepare and investigate the hepatoprotective effects of some dihydro- and tetrahydro pyridines using the experimental rat model of tetrachloromethane (CCl4)- induced acute liver damage. Methods: Several 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines were synthesized by the reaction of cyanothioacetamide with carbonyl compounds and active methylene compounds, such as Meldrum’s acid, ethyl cyanoacetate or β-keto esters, followed by S-alkylation of intermediate pyridine-2-thiolates. In silico prediction studies were performed to explore the possible protein targets. Using virtual bioscreening tools, we selected the six most promising compounds from the library of new partially saturated pyridines. Six novel compounds were characterized by IR, 1H, 13C DEPTQ NMR spectroscopy, 2D NMR experiments (1H–13C HSQC, 1H–13C HMBC), HRMS (ESI), and elemental analysis. The hepatoprotective effects were studied in vivo on eighty white rats with CCl4-induced liver damage. Biochemical studies, including thymol turbidity test and measurements of levels of bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in the blood of rats, were performed. Results: Five of six studied compounds showed a good hepatoprotective effect on a rat model of tetrachloromethane (CCl4)-induced acute hepatitis. The blood of rats in the experimental groups revealed significantly lower levels of total bilirubin, alanine aminotransferases, aspartate aminotransferases, thymol turbidity and alkaline phosphatase compared to the control group of rats with acute toxic tetrachloromethane hepatitis. Conclusion: Our results suggests that compound, (benzyl 4-(4-chlorophenyl)-5-cyano-6-({2-[(3,4- dimethylphenyl)amino]-2-oxoethyl}thio)-2-methyl-1,4-dihydropyridine-3-carboxylate), can be considered as candidate for further preclinical studies. Moreover, as per our knowledge, this is the first report on the hepatoprotective effects of the 1,2,3,4-tetrahydropyridine series.

Direct Organocatalytic Chemoselective Reductive Alkylation of Chiral 2-Aroylcyclopropanecarbaldehydes: Scope and Applications.

We developed a simple and practically feasible protocol for the chemoselective coupling of optically active functionally rich 2-aroylcyclopropanecarbaldehydes with various CH acids or active methylene compounds under 10 mol % of (s)-proline in the presence of Hantzsch ester as a hydrogen source through a three-component reductive alkylation reaction. The metal-free, organocatalytic selective reductive C-C coupling method has wide advantages/applications like no epimerization, no ring opening, high carbonyl control, and large substrate scope, generating only monoalkylated 2-aroylcyclopropanes, and the resulting chiral products can be synthons in medicinal to material chemistry. We have also shown the synthetic applications of chiral CH-acid-containing 2-aroylcyclopropanes 5 by transforming them into the interesting molecules of pyrimidine analogues 8, dimethyl cyclopropane-malonates 9, functionally rich dihydropyran 10, cyclopropane-alcohols 11, and cyclopropane-olefins 12/13. Many of these chiral products 5-13 can serve as excellent building blocks for the synthesis of value-added small molecules, natural products, pharmaceuticals, and their analogues.

Novel pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d] pyrimidine derivatives: Design, synthesis, and structure elucidation

ABSTRACT. A cyclo condensation reaction is an effective method for a two-component reaction of 2-amino-1,5-diphenyl-1H-pyrrole-3-carbonitrile 3a-c and active methylene compounds in acetic acid and catalytic hydrochloric acid to produce new substituted 1H-pyrrolo[2,3-b]pyridine 4a-c, 5a-c, and 6a-c have been established. Additionally, a new series of substituted 1H-pyrrolo[2,3-d]pyrimidines 7a-c and 8a-c could be synthesized utilizing a feasible and efficient approach, including urea and thiourea substrates. Spectroscopic data IR, MS, 1H, and 13C NMR, as well as elemental analyses, elucidated these compounds' structures.
 
 KEY WORDS: 1H-Pyrrolo[2,3-b]pyridine, 1H-Pyrrolo[2,3-d]pyrimidines, Active methylene compounds
 
 Bull. Chem. Soc. Ethiop. 2023, 37(4), 983-992. 
 DOI: https://dx.doi.org/10.4314/bcse.v37i4.14

Preparation of Alkyl Di(p-tolyl)sulfonium Salts and Their Application in Metal-Free C(sp3)-C(sp3) and C(sp3)-C(sp2) Bond Formations.

Alkyldiarylsulfonium salts were synthesized by a combination of active sulfonium species, prepared through the activation of diarylsulfoxide, and alkyl nucleophiles. The isolated sulfonium salts were subjected to the allylation and cyclopropanation of the active methylene compounds and metal-free C(sp3)-C(sp2) couplings via oxyallyl cation intermediates under mild conditions. The series of reactions included an umpolung strategy for the coupling of alkyl nucleophiles and metal-free C-C bond formation using sulfonium salts.

Catalytic role in Biginelli reaction: Synthesis and biological property studies of 2‐oxo/thioxo‐1,2,3,4‐tetrahydropyrimidines

The Biginelli reaction has received significant consideration in recent years due to its easily accessible aldehyde, urea/thiourea, and active methylene compounds. When it comes to pharmacological applications, the Biginelli reaction end-products, the 2-oxo-1,2,3,4-tetrahydropyrimidines, are vital in pharmacological applications. Due to the ease of carrying out the Biginelli reaction, it offers a number of exciting prospects in various fields. Catalysts, however, play an essential role in Biginelli's reaction. In the absence of a catalyst, it is difficult to form products with a good yield. Many catalysts have been used in search of efficientmethodologies, including biocatalysts, Brønsted/Lewis acids, heterogeneous catalysts, organocatalysts, and so on. Nanocatalysts are currently being applied in the Biginelli reaction to improve the environmental profile as well as speed up the reaction process. This review describes the catalytic role in the Biginelli reaction and pharmacological application of 2-oxo/thioxo-1,2,3,4-tetrahydropyrimidines. This study provides information that will facilitate the development of newer catalytic methods for the Biginelli reaction, by academics as well as industrialists. It also offers a broad scope for drug design strategies, which may enable the development of novel and highly effective bioactive molecules.

Construction of CF<sub>3</sub>-containing Tetrasubstituted Carbon Frameworks by Way of <i>p</i>-Quinone Methides

Development of a new synthetic method for the construction of quaternary carbon centers with a trifluoromethyl group was realized by way of smooth 1,6-addition of various active methylene compounds to highly reactive δ-trifluoromethylated p-quinone methides generated in situ only with a catalytic amount of a base. A variety of aldehydes also behaved as nice nucleophiles with the aid of a NHC catalyst and the resultant products were further converted to such congested structures as the consecutive quaternary-tetrasubstituted carbons in a highly stereoselective manner. This method was also extended for the incorporation of heteroatoms like nitrogen, oxygen, and sulfur atoms.

Synthesis of novel adamantane-containing dihydropyrimidines utilizing Biginelli condensation reaction

Novel dihydropyrimidines incorporating an adamantane motif have been synthesized using a three-component Biginelli reaction of adamantane-containing β-keto amide N-1-adamantyl acetoacetamide as active methylene compound, thiourea, and aromatic aldehydes in more convenient condition and high yields. The structures of the synthesized compounds were confirmed by spectral data.

Structural Analysis of Calcium Oxide Derived from Waste Egg’s Shells and their Application for Knoevenagel Condensation Reactions

The present study demonstrates the simple and easy synthesis of calcium oxide (CaO) from waste egg’s shells. Fine egg’s shells powder were calcinated at 500, 700 and 800 ºC. The structural and morphological evaluation of calcium oxide derived from waste egg’s shell were examined by using XRD, FT-IR, SEM, EDS and TEM techniques. The sintered calcium oxide was used as heterogeneous catalyst for the synthesis of 5-arylidene malononitrile and 5-arylidene barbituric acid derivatives by the condensation of various aromatic aldehyde and active methylene compounds via Knoevenagel condensations reaction under ultrasound irradiation method. The reaction completed within a very short reaction time with high yields of product. The present method describes easy synthesis of calcium oxide catalyst from the waste egg’s shells, short reaction times, simple product isolation, excellent yield and reusability of the catalyst.

Thiourea fused γ-amino alcohol organocatalysts for asymmetric Mannich reaction of β-keto active methylene compounds with imines.

Catalytic functionality of new optically active thiourea fused γ-amino alcohols was examined in the asymmetric Mannich reaction of β-keto active methylene compounds with imines to afford chiral Mannich products, β-amino keto compounds, with continuous chiral centers, that are versatile synthetic intermediates for deriving various biologically active compounds. In particular, the thiourea fused γ-amino alcohols showed satisfactory catalytic activity in this reaction and afforded chiral Mannich products in excellent chemical yield (up to 88%) and stereoselectivities (up to syn : anti/93 : 7 dr, up to 99% ee).

Chitosan as a sustainable heterogeneous catalyst for the preparation of functionalized α-diazo carbonyl compounds

The food industry generates vast amounts of waste and one of the most abundant is the biopolymer chitin, which is the main constituent of crustacean shells and insect exoskeletons. The alkaline deacetylation of the N-acetyl-d-glucosamino units of chitin leads to chitosan, a stable, inexpensive, non-toxic, biocompatible, and biodegradable material of basic properties due to the presence of free amino groups. In the present study, we report the catalytic activity of commercially available chitosan as a sustainable heterogeneous catalyst for the preparation of α-diazo carbonyl compounds through the diazo transfer reaction to active methylene compounds using a sulfonyl azide as the diazo transfer reagent. Thus, 17 α-diazo carbonyl compounds were readily prepared under mild conditions in 50–92% yield after a simple work-up consisting of vacuum filtration to separate the insoluble catalyst and the sulfonamide byproduct. This procedure was also adapted to aqueous medium, making the process more environmentally benign. The recovery and recyclability of the biocatalyst were also addressed, with the catalytic activity being slightly reduced after four reuses depending on the substrate used. The synthetic potential of diazo carbonyl compounds was further demonstrated through the rhodium-catalyzed O–H insertion reactions.

Silica-zinc chloride (SiO2-ZnCl2) catalyzed Michael addition reaction of active methylene compounds to β-nitrostyrenes: Synthesis of functionalized pyrazole derivatives

Under solvent-free conditions, a simple and efficient procedure has been developed for the Michael addition reaction of active methylene compounds to β-nitrostyrenes. The resulting Michael adducts are efficiently converted into functionalized pyrazole derivatives with hydrazine hydrate in excellent yields. All the compounds were well characterized by spectroscopic techniques.

New method for synthesis of 7-hydroxydibenzopyran-6-ones: Benzannulation of coumarins by three-component condensation

We have achieved a simple, facile and three-component synthesis of C8 and C9 alkyl/aryl C7-hydroxydibenzopyrans-6-ones involving C3-acyl coumarins, selective active methylene compounds and some methyl ketones (reagent/solvent) under basic (K2CO3) conditions. Overall, our method worked by benzannulation of the existing coumarins. In this work, we used the 2-NB group (2-NB = 2-nitrobenzyl) as a surrogate for C7–OH to engineer the construction of the ring C of the 3-hydroxydibenzopyran-6-ones. Subsequently, the photolabile 2-NB was removed under neutral conditions to reveal the C3–OH.

An efficient and practical synthesis of functionalized pyridines via recyclable copper-catalyzed three-component tandem cyclization

An efficient heterogeneous copper(I)-catalyzed three-component tandem cyclization of ketoxime acetates, aldehydes, and activated methylene compounds has been developed that proceeds smoothly in DMSO at 120 °C by using an 3-(2-aminoethylamino)propyl-modified MCM-41-bound copper(I) bromide [MCM-41-2N-CuBr] as the catalyst, delivering a variety of polysubstituted pyridines in good to high yields. The heterogenized copper(I) catalyst can be readily obtained via a simple preparative procedure from commercially available and inexpensive reagents, and reused more than seven times without any apparent drop in its catalytic efficiency.

Unprecedented C-C Bond Formation via Ipso Nucleophilic Substitution of 2,4-Dinitrobenzene Sulfonic Acid with Active Methylene Compounds.

The sulfonic acid functionalization of sufficiently electron-deficient benzene sulfonic acids undergoes ipso nucleophilic substitution with various active methylene compounds, leading to new C-C bond formation. Good to excellent yields are obtained under mild conditions without transition-metal (Pd or Cu) catalyst, PTC, and ligand. No solid waste is generated. It is a highly effective strategy for incorporating various active methylene compounds into the o-nitro-substituted benzene ring. This method has been applied not only for synthesizing APIs but also in materials chemistry. It shows a novel route for creating heavily crowded all-carbon quaternary centers. Carbon-carbon bond formation by substituting a sulfonic acid group was unknown.

Ionic Liquid Supported on Magnetic Graphene Oxide as a Highly Efficient and Stable Catalyst for the Synthesis of Triazolopyrimidines.

A novel sulfonic acid functionalized ionic liquid was prepared by anchoring 1-(propyl-3-sulfonate) vinylimidazolium hydrogen sulfate ([(CH2)3SO3HVIm]HSO4) on Fe3O4@GO. The prepared heterogeneous catalyst was characterized by XRD, FT-IR, EDX, SEM, VSM and TGA techniques. The results show that [(CH2)3SO3HVIm]HSO4 was successfully deposited on the surface of Fe3O4@GO and the prepared ionic liquid catalyst exhibited good thermal stability. The activity of the prepared catalyst was investigated in the synthesis of triazolo[1,5-a]pyrimidine derivatives by a one-pot three-component reaction of active methylene compound (malononitrile or ethyl cyanoacetate), 3-amine-1H-1,2,4-triazole and aryl aldehydes under solvent-free conditions. This catalyst could be rapidly separated by an external magnet and recycled seven times without significant loss of catalytic activity.

Stereoselective Knoevenagel reaction between pyrimidine carbaldehyde bearing an adjacent aryl group and active cyano-containing methylene compounds

The Knoevenagel reaction between cyanoacetic acid and 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarboxaldehyde (1), which contains an aryl group adjacent to the formyl group in the pyrimidine-5-carbaldehyde moiety, was found to proceed stereoselectively to give an alkene product bearing cyano and phenyl groups in a cis relationship. Similar selective reactions also occurred between 1 and several active methylene compounds bearing a cyano group. An X-ray structure analysis of the alkene products and molecular orbital calculations suggested that the attractive CN/π interaction between the cyano and 4-fluorophenyl groups of 1 plays an important role in the selectivity by stabilizing the carbocation intermediates.

Synthesis, DFT calculations, In silico studies, and biological evaluation of pyrano[2,3-c]pyrazole and pyrazolo[4′,3′:5,6]pyrano[2,3‐d]pyrimidine derivatives

An eco-friendly approach was conducted for synthesizing pyrano[2,3-c]pyrazoles M1-M25via a one-pot reaction of hydrazine hydrate 99%, ethyl acetoacetate or diethyl malonate, carbonyl group source, and active methylene compounds. Besides, pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidines M26-M31 was synthesized via intramolecular cyclization of M10 and M13. Thereafter, the antimicrobial, antioxidant, and anti-cancer activities of the titled compounds were evaluated utilizing an array of techniques. Fortunately, the vast majority of the compounds exhibited promising biological activities. Over and above, in silico study was employed to determine the expected mode of action of the synthesized compounds. M21 was the most promising anti-bacterial agent, while M5 was the most cytotoxic compound. Finally, DFT theoretical calculations were used to study the stability and structural parameters of the newly synthesized compounds. DFT calculations showed the energy gaps between the HOMO-LUMO with all the investigated compounds in a range of 4.04–5.66 eV allowing for easy exchange of electrons and the reactivity.

Synthesis of Diazo Compounds by Using NaN3 and Inexpensive SO2F2

AbstractA concise and efficient method was developed in which sodium azide (NaN3) and sulfuryl fluoride (SO2F2) were directly employed to synthesize diazo compounds with active methylene compounds. A variety of diazo compounds were produced in good to excellent yields. This protocol avoids the use of organosulfonyl azides, and features atom economy and mild reaction conditions. An alternate method for the synthesis of diazo compounds was provided.