Active Methylene Ketones Research Articles

Synthesis, Characterization and Antimicrobial and Anticancer Evaluations of Some Novel Heteroannulated Difuro[3,2-c:3',2'-g]Chromenes.

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3',2'-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6-8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds.

Design, Characterization and Antimicrobial Efficiency of Novel Annulated Furo[3'',2'':6',7']Chromeno[3',4':4,5]Furo [3,2-b]Pyridines

The principle approach of the present study is directed to find an appropriate technique to create a new category of multi-fused compounds including furo[3,2-g]chromenes. The novel 2-acetyl-3-amino-6,10-dimethoxy-4-oxo-4H-difuro[3,2-c:3′,2′-g]chromene (3) was efficiently synthesized and utilized as a key intermediate to build a new class of multi-fused compounds namely furo[3′′,2′′:6′,7′]chromeno[3′,4′:4,5]furo[3,2-b]pyridines. Reaction of precursor 3 with active methylene nitriles yielded 2-amino-3-substituted furo[3′′,2′′:6′,7′]chromeno[3′,4′:4,5]furo[3,2-b]pyridines 4–9. Also, Friedländer's reaction of precursor 3 with active methylene ketones produced hetero-annulated furochromenofuropyridines 10–13. The synthesized compounds showed high inhibition action when tested in vitro against fungal strains, whereas compounds 3 and 8 showed good inhibitory effects against all types of tested microorganisms. The structures of the novel annulated compounds were inferred using spectral and analytical results.

Visible-Light-Promoted C(sp3)–H Bond Functionalization toward Aminothiazole Skeletons from Active Methylene Ketones and Thioureas

AbstractA novel and efficient visible-light-induced method is developed for the one-pot synthesis of functionalized 2-aminothiazoles from easily accessible active methylene ketone derivatives and different thioureas at room temperature. The mild reaction conditions, green chemistry, straightforward work-up, and high yields of the products make this procedure useful for the construction of 2-aminothiazole derivatives.

Novel heteroannulated chromeno[3′,2′:5,6]pyrido[2,3-d]pyrido[2′,3′: 4,5][1,3]thiazolo[3,2-a]pyrimidines: synthesis, characterization and antimicrobial evaluation

The main aim of the current research is directed to find a suitable approach to construct a new annulated systems namely chromeno[3′,2′:5,6]pyrido[2,3-d]pyrido[2′,3′:4,5][1,3] thiazolo[3,2-a]pyrimidines. Treatment of 3-cyano-6,8-dimethylchromone with thiobarbituric acid gave chromeno[3′,2′:5,6]pyrido[2,3-d]pyrimidine, which upon treatment with chloroacetonitrile afforded 3-aminochromenopyridothiazolopyrimidine. Vilsmeier Haack formylation of the later compound produced the desired o-aminocarboxaldehyde derivative 4. Condensation of compound 4 with some active methylene nitriles namely malononitrile, cyanoacetamide, ethyl cyanoacetate, cyanoacetamide, N-phenyl-2-cyanoacetamide, 1H-benzimidazol-2-ylacetonitrile, and malononitrile dimer produced annulated compounds 5–10 (64–76% yields). Friedländer condensation of compound 4 with some active methylene ketones namely acetylacetone, ethyl cyanoacetate, diethyl malonate, and acetoacetanilide afforded annulated systems 12–15 (65–71% yields). During in vitro examination of the prepared compounds against antimicrobial activity, they appeared high activity against yeast, fungus strains and intermediate activity against all types of bacterial strains. The poly-functional product 10 exhibited notable efficiency against all types of the used microorganisms, while compound 4 present high activity against Gram-positive, yeast and fungus strains. Using spectral and analytical data, the structures of the newly synthesized products were inferred.

Recyclization Reactions of 2-Methylchromone-3-Carbonitrile with Active Methylene Nucleophiles: Synthesis and Reactions of 4-Methylchromeno[2,3-b]Pyridines

The chemical reactivity of 2-methylchromone-3-carbonitrile (1) was investigated toward a diversity of active methylene nucleophiles. Ring-opening followed by recyclization reactions of compound 1 with some active methylene nitriles afforded 2-amino-3-substituted-4-methylchromeno[2,3-b]pyridin-5-ones. Also, reactions of carbonitrile 1 with some active methylene ketones produced 2,4-dimethylchromeno [2,3-b]pyridin-5-ones. Annulated chromeno[2,3-b]pyrazolo[4,3-e]pyridine, chromeno[2,3-b][1,3]thiazolo[5,4-e]pyridine and chromeno[2,3-b]quinoline were efficiently synthesized from reaction of carbonitrile 1 with some cyclic methylene compounds. Heteroannulated chromeno[3′,2′:5,6]pyrido[2,3-d]pyrimidines and chromeno[2,3-b][1,8]naphthyridines were synthesized from reaction of compound 2 with formic acid, formamide, and malononitrile, cyanoacetamide, respectively. Chromeno[2′,3′:6,5]pyrido[2,3-b][1,8]naphthyridine 17 was synthesized from reaction of compound 2 with malononitrile dimer. Structures of the newly synthesized products were deduced based on their analytical and spectral data.

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH4I.

The electrochemical preparation of 2-aminothiazoles has been achieved by the reaction of active methylene ketones with thioureas assisted by ᴅʟ-alanine using NH4I as a redox mediator. The electrochemical protocol proceeds in an undivided cell equipped with graphite plate electrodes under constant current conditions. Various active methylene ketones, including β-keto ester, β-keto amide, β-keto nitrile, β-keto sulfone and 1,3-diketones, can be converted to the corresponding 2-aminothiazoles. Mechanistically, the in situ generated α-iodoketone was proposed to be the key active species.

Synthesis, characterization, DFT, QSAR, antimicrobial, and antitumor studies of some novel pyridopyrimidines

6-Amino-5-formyluracil (1) was efficiently utilized for construction of a variety of novel heteroannulated pyrimidines. Friedländer condensation reaction of compound 1 with some cyclic active methylene ketones including 1,3-cyclohexanedione, dimedone, 1,3-indanedione, substituted pyrazolones, 1,3-thiazolidine-2,4-dione and thiobarbituric acid gave a variety of heterocycles fused pyrido[2,3-d]pyrimidines. Compound 1 reacted with some cyclic enamines such as 5-amino-3-methyl-1H-pyrazole, 6-aminouracil and 6-amino-1,3-dimethyluracil yielded pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine and pyrimido[5′,4′:5,6]pyrido[2,3-d]pyrimidines. In addition, reaction of compound 1 with some heterocyclic enols namely 4-hydroxycoumarin, 1-ethyl-4-hydroxyquinolin-2(1H)-one and 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one produced a diversity of polyfused systems. On the basis of DFT, the molecular structural parameters as well as a variety of global reactivity descriptors were calculated to inspect the optimized structures of the synthesized compounds. The values of energy gap of the present compounds ranging from 3.75- 4.82 eV; where compound 16 has the lowest value of energy barrier. To investigate for electrophilic and nucleophilic reactivity, the molecular electrostatic potential (MEP) of each molecule was measured. The synthesized compounds were screened in vitro for their bioassays against fungal strains, gram-positive and gram-negative bacteria, showing moderate and high inhibitory action. Also, most of the present compounds revealed good to excellent activities against colon carcinoma cell lines (HCT-116) and human Hepatocellular carcinoma cell lines (HePG-2). Compounds 5 and 10-12 showed higher antiproliferative activity (from 2.68 to 16.82 µg/mL) against the two types of cancer cell lines as compared with the reference drug (5-fluoeouracil). Quantitative structure activity relationship (QSAR models) were created using a multiple linear regression analysis (MLR) procedures and were used to design the correlations between molecular descriptors and antitumor activity of the prepared compounds.

Synthesis of 1,2,3-Triazole Derivatives by Cyclocondensation of Alkyl Azides with Active Methylene Ketones in the System K2CO3/DMSO

Synthesis of 1,2,3-Triazole Derivatives by Cyclocondensation of Alkyl Azides with Active Methylene Ketones in the System K2CO3/DMSO

Synthesis and antimicrobial evaluation of the novel heteroannulated furo[3′,2′:6,7]chromeno[2,3‐b]pyridines: Part 1

AbstractThe chemical behavior of 4,9‐dimethoxy‐5‐oxo‐5H‐furo[3,2‐g]chromene‐6‐carbonitrile (1) was investigated toward some acyclic and cyclic active methylene ketones namely acetylacetone, ethyl acetoacetate, ethyl benzoylacetate, acetoacetanilide, dimedone, indanedione, pyrazolidine‐3,5‐dione and 5‐methyl‐2‐phenyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one, barbituric acid and 1‐allylthiobarbituric acid, and hippuric acid. A variety of novel heteroannulated furochromenopyridines were efficiently synthesized through a cascade reactions between 4,9‐dimethoxy‐5‐oxo‐5H‐furo[3,2‐g]chromene‐6‐carbonitrile (1) and the carbon nucleophilic reagents. Structures of the new products were inferred based on their analytical and spectral data.

The Chemical Behavior of (2E)-3-(4,9-Dimethoxy-5-Oxo-5H-Furo[3,2-g] Chromen-6-yl)Acrylonitrile Towards Some Carbon Nucleophiles

Some novel substituted benzofurans and annulated furochromenes were obtained through the treatment of the novel (2E)-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)acrylonitrile (2) by some active carbon nucleophiles such as active methylene ketones and methylene nitriles. Thus, the reaction of acrylonitrile 2 with acetylacetone, ethyl acetoacetate, diethylmalonate, and acetoacetanilide in ethanol containing piperidine produced efficiently the corresponding polyfunctionalized benzonitrile derivatives 3–5 and furochromeno-pyridine 6, respectively. Also, treatment of acrylonitrile 2 with some methylene nitriles such as malononitrile, ethyl cyanoacetate, and malononitrile dimer afforded the annulated furochromene derivatives 7–9. Furthermore, the pyrido[1,2-a] benzimidazole system 10 was furnished via reaction of acrylonitrile 2 with 2-(1 H-benzimidazol-2-yl)acetonitrile. These reactions took place through Michael addition, retro-Michael, and γ-pyrone ring opening followed by different types of recyclization. The chemical structures of the novel products were established on the basis of their spectral data and elemental analysis.

TBHP/AIBN-Mediated Synthesis of 2-Amino-thioazoles from Active Methylene Ketones and Thiourea under Metal-free Conditions

A new oxidative system of tert-butyl hydroperoxide (TBHP)/azodiisobutyronitrile (AIBN) has been used for the first time for a convenient, metal-free synthesis of substituted 2-aminothioazoles from active methylene ketone derivatives and thiourea. The reaction is postulated to proceed via an oxidative cyclization initiated by a radical process and followed by a condensation reaction.

Domino reactions between 3-(6-methylchromonyl)acrylonitrile and nucleophilic reagents

The chemical reactivity of electron deficient chromone–linked acrylonitrile [3-(6-methylchromonyl)acrylonitrile (1)] was studied towards some active methylene nitriles and active methylene ketones. Reaction of compound 1 with malononitrile, cyanoacetamide, ethyl cyanoacetate, malononitrile dimer and acetoacetanilide afforded 5-cyanomethylchromeno[4,3-b]pyridines 2–4 and 9. Compound 1 reacted with 1H-benzimidazol-2-ylacetonitrile producing pyrido[1,2-a]benzimidazole derivative 5. Benzonitrile derivatives 6–8 were efficiently synthesized from the reaction of compound 1 with acetylacetone, ethyl acetoacetate and diethylmalonate. In these reactions a diversity of products has been synthesized through a domino process, including Michael addition, retro-Michael with γ-pyrone ring opening followed by different types of recyclization (RORC). Structures of the new synthesized products were deduced on the basis of their analytical and spectral data, and the reaction mechanisms are discussed.

Organocatalyzed aerobic oxidative Robinson-type annulation of 2-isocyanochalcones: expedient synthesis of phenanthridines.

A DBU-catalyzed aerobic oxidative Robinson annulation of 2-isocyanochalcones with active methylene ketones was developed for the expedient synthesis of phenanthridines in high to excellent yields. This unprecedented multistep domino reaction represents a new strategy for the construction of this tricyclic scaffold by the sequential formation of two rings and three C-C bonds in a single operation at room temperature.

ChemInform Abstract: Fluorination of α‐Oxoketenedithioacetals: One‐Pot Four‐Component Synthesis of α‐Fluoro‐α‐oxoketenedithioacetals.

AbstractThe dithioacetals (IV) are prepared by two routes.

Fluorination of α-oxoketenedithioacetals: one-pot four-component synthesis of α-fluoro-α-oxoketenedithioacetals

The α-fluoro-α-oxoketenedithioacetals 3a–l have been synthesized by two routes. In Route 1 the pre-constructed α-oxoketenedithioacetals 1a–l are subjected to fluorination using selectfluor 2 to yield the corresponding stable α-fluoro-α-oxoketenedithioacetals 3a–l in 61–75% overall yields. In Route 2 a four-component one-pot protocol was followed involving addition of a mixture of active methylene ketone and carbon disulfide to sodium tert-butoxide suspended in tetrahydrofuran and dimethylformamide followed by addition of dimethyl sulfate and selectfluor sequentially to yield the corresponding 3a–l in an improved 79–87% overall yields.

ChemInform Abstract: Sequential One‐Pot Synthesis of Tri‐ and Tetrasubstituted Thiophenes and Fluorescent Push—Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push–pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

Sequential One-Pot Synthesis of Tri- and Tetrasubstituted Thiophenes and Fluorescent Push-Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push-pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

Synthesis of novel β-aryl-β-(methylthio)acroleins via Vilsmeier–Haack protocol as potential 1,3-dielectrophilic three-carbon building blocks

A new general route for the synthesis of novel β-aryl-β-(methylthio)acroleins, a class of stable potential 1,3-dielectrophilic synthons, has been reported. The overall protocol involves treatment of either β-chloroacroleins or their precursor iminium salts (generated in situ from the corresponding active methylene ketones under Vilsmeier–Haack reaction conditions) with S,S-dimethyldithiocarbonates (DDC)/aqueous KOH in either a one-pot or two-step process. The dimethyldithiocarbonate (DDC)/30% aqueous KOH has been shown to be an excellent source of methylthiolate anion.

One-pot three-component synthesis of substituted 2-(1,2,3-triazol-1-yl)pyrimidines from pyrimidin-2-yl sulfonates, sodium azide and active methylene ketones

Abstract New 2-(1,2,3-triazol-1-yl)pyrimidines were synthesized in good yields by the three-component reaction of pyrimidin-2-yl sulfonates, sodium azide and active methylene ketones in the presence of K2CO3 at room temperature. This procedure eliminates the need to handle organic azides in the synthesis of analogous compounds.

ChemInform Abstract: Novel Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles via a One‐Pot Three‐Component Reaction of Boronic Acids, Azide, and Active Methylene Ketones.

A series of 1-aryl-5-trifluoromethyl (or difluoromethyl)–1,4,5-trisubstituted 1,2,3-triazoles were synthesized in high yield by a novel one-pot three-component reaction of arylboronic acids, sodium azide, and active methylene ketones, such as ethyl 4,4-difluoroacetoacetate or ethyl 4,4,4-trifluoroacetoacetate in the presence of Cu(OAc)2 and piperidine using a DMSO/H2O (10/1) mixture as solvent.