Ethoxymethylene Malononitrile Research Articles

A new route to produce chitosan derivatives: nucleophilic vinylic substitution with ethoxymethylenemalononitrile

AbstractChitosan (Ch) is a polysaccharide obtained from chitin: a renewable, nontoxic, biocompatible biomolecule that constitutes the second most abundant natural polymer on the planet. The presence of amino groups in the chitosan polymer chains allows one to change the physicochemical properties of the natural polymer. In this work, we prepared a chitosan derivative (ChMM) with ethoxymethylenemalononitrile (EMM) through a nucleophilic vinylic substitution (SNV), changing the experimental conditions of stoichiometry, solvent (ethanol, dimethylsulfoxide (DMSO)) and reaction time (3 and 6 h). ChMM was characterized by Fourier transform infrared spectroscopy (FTIR), solid‐state 13C NMR, elemental analysis (EA), thermogravimetry (TG), scanning electron microscopy (SEM) and X‐ray diffraction (XRD). The FTIR and 13C NMR results confirm the success of the reaction, showing a sharp peak at 2213 cm−1 corresponding to the stretching of the C–N bond and additional signals at 52 and 166 ppm, respectively. The degree of substitution (DS) was calculated from EA and the results obtained show that sample modified with a [Ch]/[EMM] molar ratio of 1:2 over 3 h in DMSO presented the better result (DS = 0.91). ChMM did not show a considerable change in morphology (SEM) and thermal stability (TG). The insertion of methylenemalononitrile groups led to a decrease in the crystallinity index of chitosan derivatives (XRD). ChMM showed good ability to remove dyes in acidic and basic media (pH 5, 7, 9), and for crystal violet and safranin dyes the removal percentage surpassed 70%. © 2022 Society of Industrial Chemistry.

Synthesis, In-vitro Antioxidant, Anti-diabetic Evaluation and Docking Studies of Newly Synthesized Benzoxazole Derivatives

In the present study, a set of different benzoxazole derivatives has been synthesized from ethyl acetoacetate, ethoxymethylene malononitrile, NaNO2, and organic acids. Analytical instruments like proton NMR (1H), carbon NMR (13C), infrared spectroscopy (IR), and LC-MS mass spectrometry were used for structural characterization. Synthesized molecules were evaluated for In-vitro antioxidant property (DPPH assay, Total antioxidant & reducing power method) and anti-diabetic property (alpha-amylase & alpha-glucosidase assay). In silico, studies against Human pancreatic alpha-amylase (PDB ID: 3BAW) have been carried out to get the binding approach of the ligand towards the protein. The results demonstrated that compounds namely 5b, 6b, 3b and 4b had potent antioxidant and anti-diabetic activity compared with ascorbic acid and acarbose. HIGHLIGHTS Anti-oxidant (DPPH assay, Total antioxidant and Reducing power) and Anti-diabetic (alpha-amylase & alpha-glucosidase assay) activities performed for synthesized molecules Sulfonamide substitutions are more potent towards biological activities In silico docking studies correlate with in vitro studies The small three-dimensional, stable structure and its ability to form hydrogen bonding the molecules show good activity towards antioxidant and anti-diabetic GRAPHICAL ABSTRACT

Facile and expedient synthesis and anti-proliferative activity of diversely pyrrolones bearing 1,3-diphenylpyrazole moiety

A series of some pyrrolone derivatives were synthesized from the acid hydrazide, derived from a pyrazolyl-2(3H)-furanone, through treating with some carbonyl reagents such as 1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carbaldehyde, formic acid, lauroyl chloride, succinoyl chloride, propionic anhydride, as well as, ethoxymethylene malononitrile. All compounds were obtained in good yields and characterized by their microanalytical and spectral data. The synthesized products were evaluated for their in vitro antitumor activity against two human carcinoma cell lines (HCT-116 and MCF7) using doxorubicin as a reference drug by MTT assay. The results revealed that some compounds exhibited significant potency. Noteworthy, the N-propionyl hydrazide derivative was the most potent against both cell lines.

New 1,3,4‐Thiadiazole Derivatives: Synthesis, Characterization, and Antimicrobial Activity

In the present study, 2,5‐bis(mercapto‐acetichydrazide)‐1,3,4‐thiadiazole (1) was utilized by different reagents, namely, ethoxymethylene malononitrile, ethoxymethylene ethyl cyanoacetate, triethyl orthoformate, phenyl isothiocyanate, carbon disulfide, isatin, acetophenone, cyclohexanone, different aldehydes, and different anhydrides, to yield a new series of 2,5‐disubstituted‐1,3,4‐thiadiazoles 2–18. The chemical structure of these products was characterized by the spectral data IR, 1H‐NMR, 13C‐NMR, MS, and elemental analysis. All the synthesized compounds were screened for their antibacterial activity.

Synthesis, Reactions, and Pharmacological Evaluations of Some Novel Pyridazolopyridiazine Candidates

Herein, we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted pyrazolopyridazine derivatives. Compound 1 was reacted with ethoxymethylene malononitrile 2 in refluxing ethanol to give the corresponding compound 3, which was treated with hydrazine hydrate or formamide to give pyrazolo[3,4‐c]pyrazole 4 and pyrazolo pyrimidine 5 derivatives, respectively. Also, compound 3 was reacted with NH4SCN or carbon disulphide or ethyl acetoacetate to yield the corresponding pyrazolo derivatives 6, 7, 8, respectively. Additionally, compound 3 was reacted with triethyl orthoformat in acetic anhydride to give 9, which was treated with hydrazine hydrate to give hydrazino derivative 10. The latter compound transformed into the pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]‐pyrimidine 11 via refluxing with acetic anhydride. Finally, compound 9 was reacted with benzoic acid hydrazide or mercapto acetic acid to give compounds 12 and 13, respectively. The latter compound was treated with refluxing ethanolic sodium ethoxide solution to afford the pyrazolothiazolopyrimidine 14. Some of the compounds exhibited better activities as anti‐inflammatory and antimicrobial agents than the reference controls. The detailed synthesis, spectroscopic data, anti‐inflammatory, and antimicrobial activities of the synthesized compounds was reported.

Synthesis and Spectral Characterisation of Some Phthalazinone Derivatives

1,2,4-Triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3-dioxoisoindolin-2-yl, 1 H-pyrazol-4-yl, phthalazin-1(2 H)one, 5 H-2,3-benzodi-azepine-1,4-dione and pyridazine-1,4-dione derivatives were prepared via the reaction of the readily obtainable starting material 1-oxo-1,2-dihydrophthalazin-4-carbohydrazide with one carbon donor like phenyl isothiocyanate, phenyl isocyanate, triethylorthoformate, formic acid and different electrophilic reagents such as anhydrides, chromen-1,3-dione, chloroacetyl chloride, acetic anhydride, arylidene malononitrile, ethoxymethylene malononitrile and ethyl acetoacetate.

Immunomodulatory and Anticancer Activities of Some Novel 2‐Substituted‐6‐bromo‐3‐methylthiazolo[3,2‐a]benzimidazole Derivatives

Ethyl 6-bromo-3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 2 was prepared by the ambient temperature bromination of ethyl 3-methyl-1,3-thiazolo[3,2-a]benzimidazole-2-carboxylate 1. The acid hydrazide 4 was obtained by the reaction of ester 2 with hydrazine hydrate. Treatment of compound 4 with benzaldehyde or 2-thiophenaldehyde yielded the corresponding hydrazones 6a and 6b, respectively, while the reaction of acid hydrazide 4 with ethoxymethylene malononitrile (7a) or with ethyl ethoxymethylene cyanoacetate (7b) in refluxing ethanol afforded pyrazole derivatives 9a and 9b, respectively. Taken together, from the biological investigations compounds 9a and 9b were the most significant inhibitors of LPS-stimulated NO generation from Raw murine macrophage 264.7, and, as another result, compounds 2 and 4 had a weak radical scavenging activity against DPPH radicals. Moreover, 2, 4, and 9a had a concomitant strong cytotoxicity against both colon carcinoma cells (HCT-116) and hepatocellular carcinoma cells (Hep-G2) while 9b showed specific cytotoxicity only against colon carcinoma cells.

Fatty acid hydrazides in heterocyclic synthesis: Synthesis of 1,2‐diazepine and pyridazine derivatives

Abstract1,2‐Diazepinone derivatives 6a–d, 8a,b, and 10a–c were synthesized from the reaction of olefines carrying EWG as ethoxymethylene malononitrile, ethoxymethylene cyanoacetate, and tetracyanoethylene with 1a–f respectively. Also, 5‐alkyl‐6‐oxotetrahydropyridazine‐4,4‐dicarboxylate derivatives 12a–c were afforded via the reaction of 1d–f with diethyl ethoxymethylene malonate. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:259–264, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20294

Microwave‐Assisted Synthesis of Substituted Pyrazoles and Pyrazolo[3,4‐d]thiopyrimidines.

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Microwave-Assisted Synthesis of Substituted Pyrazoles and Pyrazolo [3, 4-d]thiopyrimidines

Ethyl(ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile were synthesized from the reaction of malononitrile or ethylcyanoacetate with triethyl orthoformate or orthoacetate in N, N-dimethylacetamide under microwave irradiation. In a similar manner, substituted pyrazoles were synthesized from the reaction of ethyl (ethoxymethylene)cyanoacetate and ethoxymethylene malononitrile with phenylhydrazine. These pyrazoles were converted to pyrazolo[3, 4-d]thiopyrimidines upon treatment with arylisothiocyanate and thiourea under microwave irradiation.

A nucleophilic reaction of acetylacetonatocobalt(III) complexes with nitriles in Lewis acidic conditions

Under Lewis acidic conditions, tris(acetylacetonato)cobalt( Co(acac) 3) reacted with ethoxymethylenemalononitrile ( ETMN), analogous derivatives and general aliphatic nitriles to give a new type of β-imino–cobalt(III) complexes. A possible mechanism for this reaction is proposed. In the case of ethyl acetocyanoacetate, an acylated γ-acetylimino–cobalt(III) complex was isolated. The structure of the complex was explained supporting the proposed mechanism. The crystal structures of several complexes were determined by X-ray diffraction. One of the complexes showed prominent crystal dichroic properties in the first absorption band region. Benzoyl cyanide and phthalonitrile did not react with Co(acac) 3 under the same conditions.

An Aminoimidazole and Its Utility in Heterocyclic Synthesis.

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An aminoimidazole and its utility in heterocyclic synthesis

AbstractAminoacetonitrile (1) reacted with acetamidinium chloride to give 4‐aminoimidazole (4), which reacted with DMFDMA to yield imidazole derivative 7 and with benzylidinemalononitrile and ethoxymethylene malononitrile to give imidazo[1,5‐a]pyrimidine derivatives 12 and 15. Compound 1 reacted with β‐crotononitrile to yield pyridine derivative 20. Imidazo[1,2‐a]pyridine derivative 23 could be obtained via the reaction of 20 with DMFDMA. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:503–508, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10178

Synthesis of Pyridine-stretched 2′-Deoxynucleosides

Synthesis of novel pyridine-stretched nucleoside (PSN) analogues of adenine (strA) (1), 2,6-diaminopurine (strD) (15) and hypoxanthine (strH) (17) from 4(5)-nitroimidazole has been achieved. Glycosylation of 4(5)-nitroimidazole was optimized to give consistently good yields (>70%) of the desired analytically pure 5-nitro-1′-β isomer 8 which on hydrogenation, C-addition of ethoxymethylene malononitrile (EMMN) and cyclisation provides the key intermediate 14 for PSN synthesis.

A facile method for the synthesis of novel fluorinated pyrido [2′,3′:3,4] pyrazolo [1,5-a] pyrimidines

The reaction of 3-amino-4-trifluoromethyl-6-substituted pyrazolo [3,4-b] pyridines ( 1) with active methylene compounds, such as ethoxy methylene malononitrile, ethyl-(ethoxymethylene)cyanoacetate and 1,3-diketones gave exclusively pyrido [2′,3′:3,4] pyrazolo [1,5-a] pyrimidines ( 2) and ( 5), respectively in high yields. When compound ( 1) was reacted with ethoxy methylene diethyl malonate (EMME), intermediate 3-amino (methylenediethylmalonate)-4-trifluoromethyl-6-substituted pyrazolo [3,4-b] pyridines ( 3) are obtained. The intermediates are further cyclized to give product ( 4).

Studies on aminopyrazoles: antibacterial activity of some novel pyrazolo[1,5- a]pyrimidines containing sulfonamido moieties

Hydrazones 2a– d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a– d were obtained by refluxing of 2a– d with hydrazine hydrate in ethanol. [Bis(methylthio)methylene]malononitrile ( 4) was reacted with aminopyrazoles 3a– d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5- a]pyrimidines 6a– d. The anilino derivatives 8a– h were obtained by fusion of compounds 6a– d with aromatic amines. When compounds 6a, c, d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a– c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5- a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some Gram positive and Gram negative bacteria.

SYNTHESIS OF POLYFUSED THIENO(2,3-b)THIOPHENES PART 1: SYNTHESIS OF THIENOPYRIMIDINE DERIVATIVES

3,4-Diamino-2,5-dicarbethoxythieno(2.3-b)thiophene 1 reacted with malononitrile or ethyl cyanoacetate to afford bis(thienopyrimidin-4-one) derivatives 2a.b The reaction of compound 1 with o-aminothiophenol, o-aminophenol or o-phenylenediamine gave benzothiazolyl-, benzoxazolyl-, benzoimidazolylthienothiophene 3a-c, Chloroacetylation of compound 1 and reacting the resulting compound 4 with malononitrile furnished thienopyrolopyrimidine 6. Fusion of compound 1 with formamide yielded bis(thienopyrimidine) 7 which reacted with POCI3/PCl5 to yield the corresponding chloro derivative 8 which was converted into the corresponding hydrazine derivative 9. Treatment of compound 1 with CS2, NaOH and 1,2 dibromoethane produced the corresponding 1.3 dithiolane 11 which also treated with chloroacetyl chloride or ethyl mercaptoacetate to get the corresponding β-lactame 12 or thiazolidinone 13. On reacting compound 1 with CS2, NaOH and (CH3)2S04 produced the corresponding bi(dithiocarbamate methyl ester) 14 which treated with hydrazine hydrate to yield the corresponding bis(thienopyrimidine) derivative 15. This compound reacted with Lawesson's reagent (LR) to give the desired compounds 16 and 17. While its reaction with (CH3)2 SO4 and NaOH furnished the corresponding methyl derivative 18. Fusion of compound 18 with aniline afforded compound 19. Compound 19 was allowed to react with ethyl acetoacetate, acetylacetone, α-oxoketene dithioacetal, ethoxymethylene malononitrile or LR to get the described compounds 2Oa.b-24 respectively.

Novel C-alkylation Reaction of Condensed Thiophenes with Enaminones, Enaminonitriles, Ethoxymethylene Malononitrile, Aryl Vinyl Ketones and ω-Nitrostyrenes

While the thienocoumarin 1 reacts with aryl vinyl ketones, ω-nitrostyrene and ethoxymethylene malononitrile to yield only C-1 alkylation products, it reacts with enaminones (3a–c) to yield either N-alkylated derivatives (4a–c) or a mixture of 4a–c and α,β-unsaturated ketones (9a–c), the former rearranged into the latter on prolonged boiling under reflux in 1,4-dioxane solution in the presence of diethylamine.

Novel C-alkylation Reaction of Condensed Thiophenes with Enaminones, Enaminonitriles, Ethoxymethylene Malononitrile, Aryl Vinyl Ketones and ω-Nitrostyrenes

While the thienocoumarin 1 reacts with aryl vinyl ketones, ω-nitrostyrene and ethoxymethylene malononitrile to yield only C-1 alkylation products, it reacts with enaminones (3a–c) to yield either N-alkylated derivatives (4a–c) or a mixture of 4a–c and α,β-unsaturated ketones (9a–c), the former rearranged into the latter on prolonged boiling under reflux in 1,4-dioxane solution in the presence of diethylamine.

Possible Rearrangements During the Synthesesof Di- and Trisubstituted Pyrazoles

The reaction of ethoxymethylene malononitrile and ethoxymethylene cyanoacetic acid ethylester with substituted hydrazines to substituted 5-aminopyrazoles is described. The influence of different substituents on possible migrations during the ring closure was studied..