Synthesis of Certain 3-Aminopyrazolo[5,4-b]pyridine and 3,4-Substituted Pyrido[2′,3′：3,4]pyrazolo[5,1-c][1,2,4]triazine Derivatives

2-Thioxo-1,2-dihydropyridine derivatives 2a, 2b were reacted with methyl iodide to give 2-methylthiopyridines 3a, 3b, which were reacted with hydrazine hydrate to produce 3-aminopyrazolo[5,4-b]pyridines 4a, 4b. Compounds 4a, 4b were diazotized to afford the corresponding diazonium salts 5a, 5b, which were reacted with some active methylene compounds 6a-6h to give the corresponding pyrido[2′,3′ ： 3,4]pyrazole[5,1-c][1,2,4]triazines 7-14.     

Synthesis,Reactions, Characterization and Biological Evaluation of 2,3′‐Bipyridine Derivatives (III)

1‐Pyridin‐3‐yl‐3‐(2‐thienyl of 2‐furyl)prop‐2‐en‐1‐ones 1a , 1b reacted with 2‐cyanoethanethioamide 2 to afford the corresponding 4‐(thiophen‐2‐yl or furan‐2‐yl)‐6‐sulfanyl‐2,3′‐bipyridine‐5‐carbonitriles 3a , 3b . The synthetic potentiality of compounds 3a , 3b were investigated in the present study via their reactions with several active halogen containing compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 5 , 5a , 5b . Our aim here is the synthesis of 4‐(2‐thienyl or 2‐furyl)‐6‐pyridin‐3‐ylthieno[2,3‐b]pyridin‐3‐amines 6a , 6b , 6c , 6d , 6e , 6g , 6h , 6i , 6j , 6k , 6l , 6m , 6n ,via 6‐(alkyl‐thio)‐4‐(2‐thienyl or 2‐furyl)‐2,3′‐bipyridine‐5‐carbonitriles 5a , 5b , 5c , 5d , 5e , 5i , 5j , 5k , 5l , 5m . The structures of all newly synthesized heterocyclic compounds were elucidated by considering the data of IR, ¹H‐NMR, mass spectra, as well as that of elemental analyses. Anti‐cancer, anti‐Alzheimer, and anti‐COX‐2 activities were investigated for all the newly synthesized heterocyclic compounds.     

Cyanothioacetamide in Heterocyclic Chemistry: Synthesis of Piperidine-3-carbonitrile,Pyrazolopyridine, Thiinopyridine-3-carbonitrile Derivatives,and Their Theoretical Calculations

Cyanothioacetamide ( 1 ) reacted with acrylonitrile ( 2 ) to afford the corresponding 6-oxo-2-sulfanylpiperidine-3-carbonitrile ( 6 ), which oxidized to give compounds 7 and 8 under different conditions. Moreover, compound 6 was used as a starting material to synthesize 12a-c , 16a-d , 26a-c , 27a-c , and 30a-c via reactions with aromatic aldehydes 9a-c , diazonium chlorides 13a-d , and 3-arylpropennitrile derivatives 18a-i respectively. Considering the data of IR, 1 H NMR, mass spectra, elemental analyses, and theoretical calculations, all the structures of the newly synthesized heterocyclic compounds were elucidated.     

Synthesis,Reactions, and Characterization of 6-Amino-4-(Benzo[b]Thiophen-2-YL)-2-Thioxo-1, 2-Dihydropyridine-3, 5-Dicarbonitrile

Abstract

Benzothiophene -2- carbaldehyde 1 reacted with 2-cyanoethanethioamide 2 in 1:2 molar ratios to give the corresponding 6-amino-4-(benzo[b]thiophen-2-yl)-2-thioxo-1, 2-dihydropyridine-3,5-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents to afford the corresponding thieno[2,3-b]pyridine derivatives 11a,b, 14, 16, and 19. Also, compound 6 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 21. Compound 21 condensed with 4-(2-thienyl)benzaldehyde to afford pyrazolo[3,4-b]pyridine derivative 23. Structural elucidation of all the newly synthesized heterocyclic compounds was based on elemental analyses, IR, ¹H NMR, and mass spectra.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Synthesis of 5‐Cyano‐2‐Carbethoxythieno[2,3‐b]thiophenyl‐3,4‐Diisothiocyanates and Its Utility IN Heterocyclic Synthesis under Phase Transfer Catalytic Technique

Regarding to the importance of thieno[2,3‐b]thiophens and isothiocyanaetes reactiveties in the physical, chemical and pharmaceutical fields, this study has been undertaken to prepare the target compound 5‐cyano‐2‐carbethoxythieno[2,3‐b]thiophenyl‐3,4‐diisothiocyanates via a safe method. The formed isothiocyanates derivative was reacted with aromatic amines, acid hydrazied and some active methylene groups, followed by cyclization reaction for the formed intermediates to give new series of heterocyclic compounds     

Microwave‐induced Stereoselectivity in Synthesis of trans‐4‐Aryl‐3‐methyl‐6‐oxo‐4,5,6,7‐tetrahydro‐2H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitriles

A facile synthesis of trans isomers of 4‐aryl‐3‐methyl‐6‐oxo‐4,5,6,7‐tetrahydro ‐ 2H ‐ pyrazolo[3,4‐b]pyridine‐5‐carbonitriles via three‐component condensation reaction of an aldehyde, 3‐amino‐5‐methylpyrazole and ethyl cyanoacetate in acetonitrile has been developed under microwave irradiation. This one‐pot reaction proceeds without any catalyst in short times and gives the product in high selectivities and high yields.     

Synthesis of Polyfunctionally Substituted Pyrazolonaphthyridine,Pentaazanaphthalene, and Heptaazaphenanthrene Derivatives

6-aminopyrazolo[3,4-b]pyridine-5-carbonitrile (2) was used as a precursor for the synthesis of a variety of pyrazolo[3,4-b][1,8]naphthyridines (3, 4) and pentaazacyclopenta[b]naphthalenes (5–10, 13, 14) via the initial addition to either the cyano or amino group followed by cyclization. Also, a series of heptaazadicyclopenta[a,g]naphthalenes (15–17) and heptaazacyclopenta[b]phenanthrenes (18, 19) were obtained via the interaction of 4-(dibenzothiophen-2-yl)-1,5-dihydro-5-imino-3-methyl-1-phenyl-1,2,6,8,9-pentaazacyclopenta[b]naphthalen-6-ylamine (14) with different reagents. The structures of the synthesized compounds were established by elemental and spectral analyses.     

A new nano‐Fe3O4‐supported organocatalyst based on 3,4‐dihydroxypyridine: an efficient heterogeneous nanocatalyst for one‐pot synthesis of pyrazolo[3,4‐b]pyridines and pyrano[2,3‐d]pyrimidines

A simple and practical strategy for the synthesis of a novel nano‐Fe₃O₄‐supported organocatalyst system based on 3,4‐dihydroxypyridine (Fe₃O₄/Py) has been developed. The prepared catalyst was characterized using Fourier transform infrared spectroscopy, transmission and scanning electron microscopies, X‐ray diffraction, vibrating sample magnetometry and energy‐dispersive X‐ray analysis. Accordingly, the Fe₃O₄/Py nanoparticles show a superparamagnetic property with a saturation magnetization of 61 emu g^?1, indicating potential application in magnetic separation technology. Our experimental results reveal that the pyridine‐functionalized Fe₃O₄ nanoparticles are an efficient base catalyst for the domino condensation of various aromatic aldehydes, Meldrum's acid and 5‐methylpyrazol‐3‐amine under very mild reaction condition and in the presence of ethanol solvent. Moreover, the synthesized catalyst was used for one‐pot, three‐component condensation of aromatic aldehydes with barbituric acid and malononitrile to produce 7‐amino‐2,4‐dioxo‐5‐phenyl‐2,3,4,5‐tetrahydro‐1H‐pyrano[2,3‐d]pyrimidine‐6‐carbonitriles. All reactions are completed in short times and all products are obtained in good to excellent yields. Also, notably, the catalyst was reused five times without significant degradation in catalytic activity and performance. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4‐b]Pyridines Based on 5‐Amino‐3‐Methyl‐1‐Phenylpyrazole

The reaction of the aminopyrazole 1 with benzenesulfonyl chloride, arenediazonium salt, chloroacetyl chloride, ethoxy methyleneamlononitrile and with ethyl 2‐cyano‐3‐ethoxyacrylate gave the substituted 3‐methyl‐1‐phenylpyrazole 2–5a,b . Compound 5b was cyclized to 6 and to 7 by treating it with AlCl₃ and with POCl₃, respectively. Compound 6 converted to 7 by boiling it in POCl₃/PCl₅. Compound 10b was produced through reaction of 9 with acetophenone. Reaction of 1 with benzylidinemalononitrile afforded 11 . New methods for preparation of 15 and 16 are described. The reaction of 8 with malononitrile, thiosemicarbazide, phenyl hydrazine and acetophenone afforded compounds 18–21 . The reaction of 21 with malononitrile gave 22 . Compounds 23–26 were produced upon reaction of 10a with malononitrile, phenyl hydrazine, thiosemicarbazide, semicarbazide and with benzaldehyde, respectively.     

Synthesis and Fungicidal Activity of (E)‐5‐[1‐(2‐Oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐4‐one Derivatives

The novel fungicidal agents, (E )‐5‐[1‐(2‐oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐ 4‐one derivatives, were designed and synthesized in moderate to excellent yields in four steps using α ‐hydroxyketone and diketene as raw materials and characterized by HR‐ESI‐MS , ¹H NMR and X‐ray diffraction. The preliminary bioassay showed that some of these compounds, such as 5e , 6a , 6e , and 7 h exhibit 87.8%, 91.3%, 89.9% and 87.8% inhibition rates against Sclerotinia scleotiorum , 3b , 3c , 4c and 7 h exhibit 96.4%, 92.5%, 90.3% and 76.9% inhibition rates against Phytophthora capsici at the concentration of 50 µg/mL , respectively. These compounds exhibited significant fungicidal activities against S. scleotiorum and P. capsici with EC₅₀ values of 2.56–11.60 µg/mL , and compounds 6e and 7 h exhibited weak inhibition against the spore germination of S. scleotiorum , while the spore germination of P. capsici was strongly inhibited by compound 7 h solution. Scanning electron microscopy (SEM ) and transmission electron microscopy (TEM ) observation indicated that compound 7 h had a significant impact on the structure and function of the hyphal cell wall of P. capsici mycelium.     

Synthesis of 2,3‐Diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ol Derivatives by the Reaction of Aryl(3‐isocyanopyridin‐4‐yl)methanones with Aryl Grignard Reagents

The reaction of aryl(3‐isocyanopyridin‐4‐yl)methanones 1 , easily prepared from commercially available pyridin‐3‐amine, with aryl Grignard reagents gave, after aqueous workup, 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ols 2 . These rather unstable alcohols were O‐acylated with Ac₂O in pyridine in the presence of a catalytic amount of 4‐(dimethylamino)pyridine (DMAP) to afford the corresponding 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐yl acetates 3 in relatively good yields.     

One‐pot Three‐component Synthesis of Spiro[pyrazolo[3,4‐b]pyridine‐4,3′‐indoline] Derivatives Catalyzed by Melamine Trisulfonic Acid

Novel spiro[pyrazolo[3,4‐b]pyridine‐4,3′‐indoline] derivatives were prepared by the three‐component reaction of isatins 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐amine and Meldrum's acid in the presence of a catalytic amount of melamine trisulfonic acid. This protocol provides a simple one‐step procedure with the advantages of easy work‐up, mild reaction conditions and environmentally benign.     

Synthesis and Characterization of α-Bromo Chalcone Derivatives

α-Bromo chalcones containing 2-thiene ring were prepared in good yields by the condensation of 1-(thien-3-yl)ethanone with aromatic aldehydes, followed by bromination with bromine and selective dehydrobromination with triethyl amine at room temperature.     

Highly Efficient Synthesis of Thieno[2,3‐b]indole Derivatives

Thieno[2,3‐b]indole derivatives were efficiently prepared via the reaction of 1,3‐dihydro‐2H‐indole‐2‐thiones with α‐bromo‐substituted ketones or aldehydes and in the presence of Et₃N (Scheme 2 and Table). The reaction took place under very mild conditions and in short times with good to excellent yields.     

Discovery of New Pyrazolopyridine,Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design,Synthesis, Docking Studies,and Anti-Proliferative Activity

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-⁻C² functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C²-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC₅₀ values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC₅₀ 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC₅₀ ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC₅₀ 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.     

A Novel and Efficient Synthesis of 3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐ones (=3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐1‐benzopyran‐2‐ones)

An efficient one‐pot synthesis of 3‐[(4,5‐dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐one (=3‐[(4,5‐dihydro‐1H‐pyrrol‐3yl)carbonyl]‐2H‐1‐benzopyran‐2‐one) derivatives 4 by a four‐component reaction of a salicylaldehyde 1 , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one, a benzylamine 2 , and a diaroylacetylene (=1,4‐diarylbut‐2‐yne‐1,4‐dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H‐1‐benzopyran‐2‐one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Synthesis and Structure of Novel Thieno[2, 3‐d]Pyrimidine Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

The reaction of 5‐(1‐pyrrolyl)‐4‐methyl‐2‐phenylthieno[2, 3‐d]pyrimidine carbohydrazide 5 with CS₂ in the presence of pyridine afforded the 6‐(2, 3‐dihydro‐2‐mercapto‐1, 3, 4‐oxadiazol‐5‐yl)‐4‐methyl‐5‐(1‐pyrrolyl)‐2‐phenylthieno[2, 3‐d]pyrimidine 6 , which reacted with methyl iodide in the presence of sodium methoxide to yield the 6‐(2‐methylthio‐1, 3, 4‐oxadiazol‐5‐yl)‐4‐methyl‐5‐(1‐pyrrolyl)‐2‐phenyl‐thieno[2, 3‐d]pyrimidine 7. The 6‐(2‐substituted‐1, 3, 4‐oxadiazol‐5‐yl)‐2‐phenylthieno[2, 3‐d]pyrimidine derivatives 9, 11 and 13 were obtained by the condensation of 6‐(2‐methylthio‐1, 3, 4‐oxadiazol‐5‐yl)‐2‐phenylthieno[2, 3‐d]pyrimidine 7 with appropriate secondary amines. The structure of the new compounds was substantiated from their IR, UV‐vis spectroscopy, ¹H NMR, mass spectra, elemental analysis and X‐ray crystal analysis.     

Selective Synthesis of 1,2‐Diarylpyrrolo[3,4‐b]pyridine‐5,7‐diones via Cyclization Reaction of β‐Enamino Imides with Cinnamaldehydes

The novel 1,2‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones were selectively synthesized in high yields by the base catalyzed cyclization reaction of 3‐arylamino‐1‐methyl‐1H‐pyrrole‐2,5‐diones with cinnamaldehyde and its derivatives in acetonitrile at room temperature. However, when piperidinium trifluoroacetate was employed as catalyst, the reaction afforded a mixture of 1,2‐diaryl and 1,4‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones in comparable yields.     

Synthesis of Furo[2,3‐d]pyridazin‐4(5H)‐one and Its N(5)‐Substituted Derivatives

We report the efficient preparation of furo[2,3‐d]pyridazin‐4(5H)‐one and its N‐substituted derivatives starting from methyl 2‐methylfuran‐3‐carboxylate. The Me group was converted to the aldehyde group, which was then condensed with hydrazine derivatives. Then, the ester functionalities were hydrolyzed to the corresponding acids, followed by treatment with SOCl₂ to give N‐substituted furopyridazinone derivatives.     

One‐pot Combinatorial Synthesis of Benzo[4,5]imidazo‐[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one Derivatives

A series of novel fused tetracyclic benzo[4,5]imidazo[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one derivatives were synthesized via the reaction of aryl aldehyde, 2H‐thiopyran‐3,5(4H,6H)‐dione, and 1H‐benzo[d]imidazol‐2‐amine in glacial acetic acid. This protocol features mild reaction conditions, high yields and short reaction time.