Cyanoacetamide in heterocyclic chemistry: Synthesis,antitumor and antioxidant activities of some new benzothiophenes

Cyanoacylation of 2‐amino‐tetrahydrobenzothiophene‐3‐carboxylate ethyl ester with 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile afforded cyanoacetamide 2 . The later was utilized as key intermediate for the synthesis of 3‐substituted 2‐iminocoumarins 3 , 4 , 5 , 6 and acrylamides 7a , b via Knoevenagel condensation with 2‐hydroxy‐1‐naphthaldehyde; 2‐hydroxybenzaldehyde; 1‐nitrosonaphthalen‐2‐ol; 7‐hydroxy‐5‐methoxy‐2‐methyl‐4‐oxo‐4H‐chromene‐6‐carbaldehyde; 4‐dimethylamino‐benzaldehyde; and 4‐piperidin‐1‐yl‐benzaldehyde in EtOH/piperidine. The derivatives 7a , b did not afford the pyrazoles 8a , b upon treating with phenyl hydrazine. Furthermore, coupling of 2 with 4‐amino‐1,5‐dimethyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐one and 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine afforded the hydrazone derivatives 9 and 10 , respectively. The later derivative 10 was cyclized in acetic acid to afford the pyridopyrazolotriazine 11 . Finally, 2 was treated with dimethylformamide‐dimethylacetal (DMF‐DMA) to afford the dimethylaminoacrylamide 12 which underwent transamination with 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine to afford the pyrazole 13 . Cyclization of compound 13 in acetic acid or pyridine was unsuccessful. The antitumor and antioxidant activities of the synthesized products were evaluated; several were found to exhibit promising antioxidant activities. J. Heterocyclic Chem., (2011).     

Synthesis and Antimicrobial Evaluation of Some Chalcones and Their Derived Pyrazoles, Pyrazolines, Isoxazolines, and 5,6-Dihydropyrimidine-2-(1 H )-thiones

Chalcones were synthesized by a base catalyzed Claisen-Schmidt condensation reaction. Bromination of chalcones afforded the dibromo derivatives. Monobromo derivatives could be obtained by treating the corresponding dibromochalcones with dry benzene in the presence of triethylamine. Pyrazole derivatives were obtained by refluxing of dibromochalcones with phenylhydrazine or 2,4-dinitrophenylhydrazine in dry pyridine. Chalcones were treated with hydrazine hydrate or phenyl hydrazine in ethanol to afford Δ ²-pyrazolines and N-phenyl-Δ ²-pyrazolines. Condensation of chalcones with hydroxylamine hydrochloride or thiourea in ethanolic sodium hydroxide solution gave 4,5-dihydroisoxazoles and 5,6-dihydropyrimidine-2-(1H)-thiones. The prepared compounds were tested for antimicrobial activity against four different bacterial species displaying different degrees of antibacterial activities or inhibitory actions.     

Synthesis and Antimicrobial Evaluation of Some Chalcones and Their Derived Pyrazoles,Pyrazolines, Isoxazolines,and 5,6-Dihydropyrimidine-2-(1<Emphasis Type="Italic">H</Emphasis>)-thiones

Summary. Chalcones were synthesized by a base catalyzed Claisen-Schmidt condensation reaction. Bromination of chalcones afforded the dibromo derivatives. Monobromo derivatives could be obtained by treating the corresponding dibromochalcones with dry benzene in the presence of triethylamine. Pyrazole derivatives were obtained by refluxing of dibromochalcones with phenylhydrazine or 2,4-dinitrophenylhydrazine in dry pyridine. Chalcones were treated with hydrazine hydrate or phenyl hydrazine in ethanol to afford Δ ²-pyrazolines and N-phenyl-Δ ²-pyrazolines. Condensation of chalcones with hydroxylamine hydrochloride or thiourea in ethanolic sodium hydroxide solution gave 4,5-dihydroisoxazoles and 5,6-dihydropyrimidine-2-(1H)-thiones. The prepared compounds were tested for antimicrobial activity against four different bacterial species displaying different degrees of antibacterial activities or inhibitory actions.     

A Facile One Pot Synthesis of 2-Aryl-4-[2H-2-oxo-[1]benzopyran-3-yl] 2,3-dihydro and 2,5-Dihydro-1,5-benzothiazepines

3-acetyl coumarins on condensation with various aromatic aldehydes in the presence of piperidine gave corresponding chalcones in a solid state under solvent free conditions. These chalcones are isolated and characterized. The in-situ-formed chalcones (1) are also converted into corresponding 2-aryl-4-[2H-2-oxo[1]benzopyran-3-yl]-2,3-dihydro (3) and 2,5-dihydro-1,5-benzothiazepines (4) in one step by interacting with orthoamino thiophenol. Both the 2,3-dihydro (3) and 2,5-dihydrobenzothiazepines (4) have been converted into same tetrahydrobenzothiazepine (5). Finally, the tetrahydrobenzo thiazepine (5) is converted into its acetyl derivative (11). The structures of the title compounds have been confirmed on the basis of their microanalytical, IR, ¹ H NMR, and mass spectral data.     

Derivatives of 1-azabicyelo[4.3.1]decane

1-Azabicyclo[4.3.1]decan-3-one has been synthesized via Dieckmann condensation and converted to the corresponding hydroxy and chloro derivatives.     

Synthesis and antioxidant screening of new 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl amide derivatives and some pyrazole-based heterocycles

Abstract

The high functionality compound namely 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl chloride (1) was utilized as a building block synthon via reactions with some nitrogen and sulfur nucleophilic reagents. The present work was planned to study the effect of 2-cyano group on the reactivity and stability of C₂–C₃ double bond toward different strong-to-weak nucleophiles, in addition to its facility of nucleophilic addition at C₂–C₃ double bond to construct new heterocyclic derivatives. The proclivity toward some mono-, 1,2-, 1,3-, 1,4-, and 1,5-binucleophiles was investigated. The reaction with 2-cyanoacetohydrazide was mainly dependent on the reaction conditions. Some new heterocycles integrated with pyrazole scaffold were successfully synthesized, such as benzoxazinone, indoline, isoindoline, pyrazolone, chromene, and pyrimidopyrimidine derivatives. Some of the newly synthesized compounds were screened for their antioxidant activity using ABTS method, and the results revealed that some compounds exhibited promising inhibitory antioxidant activity.     

Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol

A series of 2-isobornylphenol derivatives containing aminomethyl groups either at ortho-(monoderivatives) or ortho- and para-positions (bis-derivatives) relative to the hydroxy group of phenol moiety was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro models. It was demonstrated that Mannich bases containing an n-octylaminomethyl group are significantly exceeding both starting 2-isobornylphenol and the standard antioxidant, 2,6-di-tert-butyl-4-methylphenol, by their ability to inhibit H₂O₂-induced erythrocyte hemolysis.

     

The molecular structure and chemical reactivities of the condensation products of o-substituted benzylidenacetylacetone with hydrazine dihydrochloride

Reaction of o-nitrobenzylideneacetylacetone ( 1a ) with hydrazine dihydrochloride in methanol gave 4-(α-methoxy-o-nitrobenzyl)-3,5-dimethylpyrazole hydrochloride ( 4a ), whose structure was unambigously confirmed by an X-ray crystallographic analysis, via 4-(o-nitrobenzylidene)-3,5-dimethylisopyrazole ( 2a ). Compound 2a was synthesized by condensation of 1a with hydrazine dihydrochloride in acetonitrile. Analogously the corresponding o-chloro derivatives ( 2b, 4b ) were obtained. These were converted to N-methyl ( 6b ) and N-acetyl ( 7a,b ) derivatives and the behaviors on bromination and pyrolysis were investigated.     

E-5-(2-溴乙烯基)-2'-脱氧尿嘧啶的简便合成方法研究

以2'-脱氧尿嘧啶为原料, 在糖苷羟基未保护情况下, 经过羟甲基化、选择性氧化、Knoevenagel缩合和Hunsdiecker反应等4步反应, 简便地合成了抗病毒药物E-5-(2-溴乙烯基)-2'-脱氧尿嘧啶, 为工业化生产提供了可靠的依据.     

Synthesis and evaluation of the antioxidant properties for some novel aminomethyl derivatives of 2,6-diisobornylphenol bearing a pinane moiety

Some new derivatives based on 2,6-diisobornylphenol and containing amine moieties of the pinane structure at the para-position relative to the phenolic hydroxy group were synthesized. The antioxidant properties of the obtained compounds were estimated using various in vitro models. The introduction of diamine moiety into a starting molecule led to a significant increase in the radical scavenging activity and the ability to chelate Fe²⁺ ions.

     

Synthesis of Some New Benzo[b][1,4]diazepine Based Heterocycles

Preparation of 4‐chloro‐3H‐benzo[b][1,4]diazepine‐2‐carbaldehyde 5 , which is used as a key intermediate in the synthesis of chalcones derivatives, via its condensation with some aromatic acetophenone derivatives under ethanol piperidine condition was described. Also illustrated was the reaction of such chalcones with available nucleophilics and reagents of active methylene group to afford new series of fused and isolated pyrazoles, isoxazolines pyrimidines, pyridines, triazolo[1,5‐a]pyrimidines, benzo[1,4]oxa(thia)zepines, and pyrido[1,2‐a]benzimidazoles incorporating 4‐chloro‐3H‐benzo[b][1,4]diazepine moiety, which have a potential pharmaceutical interest. Furthermore, condensation reaction of 4‐chloro‐3H‐benzo[b][1,4]diazepine‐2‐carbaldehyde with aromatic amine derivatives to afford the Schiff's bases was described. The C═N double bond of the latter compounds has been reacted with chloroketene to give β‐lactams and with sulfanylacetic acid to give the 2‐(4‐oxo‐1,3‐thiazolidinyl)‐substituted derivative. The structures of the newly prepared compounds were established by elemental analysis, IR, MS, and ¹H NMR spectral analysis.     

Efficient Synthesis of 3‐Methyl‐Flavanones and Evaluation of Their Anti‐Bacterial Activity

A series of 2‐phenyl‐2,3‐dihydrochromon‐4‐one derivatives (flavanone derivatives) were synthesized by silica gel assisted isomerization of several α‐methyl‐2′‐hydroxy chalcones in 74%–88% yield. These flavanones were further oxidized to 3‐methyl flavones by using iodine in dimethyl sulphoxide at 60°C in presence of acid. The newly synthesized derivatives were evaluated for in vitro study against Staphylococcus aureus, Micrococcus luteus and Staphylococcus epidermis.     

Pyrazoles and Pyrazolines as Anti-Inflammatory Agents

The five-membered heterocyclic group of pyrazoles/pyrazolines plays important role in drug discovery. Pyrazoles and pyrazolines present a wide range of biological activities. The synthesis of the pyrazolines and pyrazole derivatives was accomplished via the condensation of the appropriate substituted aldehydes and acetophenones, suitable chalcones and hydrazine hydrate in absolute ethanol in the presence of drops of glacial acetic acid. The compounds are obtained in good yields 68–99% and their structure was confirmed using IR, ¹H-NMR, ¹³C-NMR and elemental analysis. The novel derivatives were studied in vitro for their antioxidant, anti-lipid peroxidation (AAPH) activities and inhibitory activity of lipoxygenase. Both classes strongly inhibit lipid peroxidation. Compound 2g was the most potent lipoxygenase inhibitor (IC₅₀ = 80 µM). The inhibition of the carrageenin-induced paw edema (CPE) and nociception was also determined, with compounds 2d and 2e being the most potent. Compound 2e inhibited nociception higher than 2d. Pyrazoline 2d was found to be active in a preliminary test, for the investigation of anti-adjuvant-induced disease (AID) activity. Pyrazoline derivatives were found to be more potent than pyrazoles. Docking studies of the most potent LOX inhibitor 2g highlight hydrophobic interactions with VAL126, PHE143, VAL520 and LYS526 and a halogen bond between the chlorine atom and ARG182.     

Synthesis of New 1,4-Benzodioxanуl-1,2,4-triazole Derivatives

The reaction of 5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol with N-substituted chloroacetic acid amides obtained by condensation of chloroacetyl chloride with various primary amines furnished a series of S-amidomethyl derivatives. The corresponding thiazolotriazolone prepared from 2-[5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazol-3-ylthio]acetic acid reacted with aromatic aldehydes to form arylidene derivatives.

     

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

A series of chalcones and their derivatives have been synthesized. Chalcones, 1-(1,3-benzodioxol-5-yl)-3-(aryl)-prop-2-en-1-ones were prepared by the aldol condensation of 1-(1,3-benzodioxol-5-yl)ethanones and aryl aldehydes. Based-catalyzed condensation of 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones with ethyl acetoacetate yields corresponding ethyl 4-(1,3-benzodioxol-5-yl)-6-(aryl)-2-oxocyclohex-3-ene-1-carboxylates. Some of the synthesized chalcones were reported in the literature; the newly synthesized compounds were characterized by single crystal X-ray studies, IR, ¹H-NMR and LCMS mass spectral analysis.     

Synthesis and Antimicrobial Activity of Some New 5-(3-Chloro-1-Benzothiophen-2-YL)-1,3,4-Oxadiazole-2-Thiol and Their Derivatives

Abstract

3-Chloro-1-benzothiophene-2-carbonylchloride 1 was made to reacts with hydrazine hydrate afforded 3-chloro-1-benothiophene-2-carbohydrazide 2 in good yield. 5-(3-chloro-1-benzothiophen-2-yl)-1,3,4-oxadiazole-2-thiol 4 was synthesized from 3-chloro-1-benzothiophene-2-carbohydrazide 2. Mannich bases, alkyl halide, and acid chlorides derivatives were then prepared. Compound 4 on condensation with chloroacetone in the presence of NaOH as base and ethanol as solvent gave 1-{[5-(3-chloro-1-benzo[b]thiophen-2-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}propan-2-on 6. Condensation of compound 6 with various aromatic aldehydes afforded a series of chalcones 7a–h. The structures of all the synthesized compounds were confirmed by spectral data and have been screened for antibacterial activity.

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GRAPHICAL ABSTRACT      

Synthesis of Coumarin Derivatives as Inhibitors of Platelet Aggregation

In a search for the inhibitors of platelet aggregation, certain coumarin derivatives were synthesized and evaluated for antiplatelet activity against thrombin(Thr)-, arachidonic acid(AA)-, collagen(Col)-, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 4-hydroxycoumarin ( 1 ) or naphthalen-1-ol via alkylation and Reformatsky-type condensation (Schemes 1–3). Among them, 4-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]-2H-1-benzopyran-2-one ( 6b ) showed potent antiplatelet effects on AA- and PAF-induced aggregation with IC₅₀ values of 8.21 and 103.67 m?M , respectively (see Tables 1 and 2). The antiplatelet potency of 6b against PAF-induced aggregation could be further improved by introducing a proper substituent at the 2-phenyl group of the lactone ring.     

Design,synthesis and evaluation of the antioxidant and neuroprotective properties of alkyl- and terpenylphenolchlorin conjugates

The new amide conjugates were synthesized from methyl pheophorbide a and its carboxyl derivatives by reactions with aminomethyl derivatives of 2,4-dimethylphenol, 2-isocamphyl-4- methylphenol, 2-bornyl-4-methylphenol, and 2-isobornyl-4-methylphenol. The antioxidant activity of some conjugates was established by investigation of their ability to inhibit the accumulation of secondary products of lipid peroxidation in a brain of laboratory mice in vitro. The neuroprotective properties of porphyrin and terpenylphenol conjugates have been studied on the model of H₂O₂-induced oxidative stress in SH-SY5Y cells (neuroblastoma).

     

Design and characterization of Dendrimer of MNPs as a novel,heterogeneous and reusable nanomagnetic organometallic catalyst for one‐pot synthesis of hydroxyl naphthalene‐1,4‐dione derivatives under solvent‐free conditions

A novel super acidic magnetic nanoparticle as catalyst was successfully synthesized. The preparation of this dendrimer sulfonic acid functionalized γ‐Fe₂O₃ magnetic core‐shell silica nanoparticles as a new recoverable and heterogeneous nanocatalyst was described. The new catalyst was characterized using various techniques such as scanning electron microscopy (SEM), energy dispersive spectrum (EDS), and thermo gravimetric synthesis (TGA). Moreover, we have examined the catalytic activity of the catalyst for one‐pot, efficient and facile synthesis of 2‐hydroxy‐1,4‐naphthoquinone derivatives via a three‐component condensation reaction of 2‐hydroxynaphthalene‐1,4‐dione, aromatic aldehydes and aniline derivatives. High yields of products, short reaction times, waste‐free, mild, ambient and solvent‐free reaction conditions are advantages of this protocol. Also, the catalyst can be easily recovered by an external magnetic and reused several times without significant loss of its catalytic activity.     

Synthesis of piperidine analogs of 1-(3-chlorophenyl)piperazine,a well known serotonin ligand

Synthesis of arylpiperideines 3a-3d and arylpiperidines 4a-4d as analogs of a well known serotonin ligand 1-(3-chlorophenyl)piperazine is reported. Starting aryllithium derivatives were treated with 1-methyl-piperdin-4-one to provide the corresponding hydroxy derivatives 6a and 6b. N-Methylpiperideine derivatives 3a and 3c were obtained by their dehydration while the corresponding N-unsubstituted compounds 3b and 3d were prepared indirectly by a three-step procedure. Hydrogenation of piperideine 3a provided the corresponding piperidine derivative 4a which after demethylation yielded 4b. Similar 4-pyridyl derivatives 4c and 4d were prepared by a similar strategy via the corresponding methoxy derivatives.