One-Pot Synthesis of Novel Spiro Pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine Derivatives

In a one-pot synthesis, 1′-methyl-2,3″-dioxo-5″-aryl-1,2,5a″,7″,8″,9a″-hexahydro-5″H,6″H-dispiro[indole-3,2′-pyrrolidine-3′,2″-pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine]-4′-carboxylic acid methyl ester was prepared via the sequential reaction of 4-aryl-octahydro-pyrano[2,3-d]pyrimidine-2-thione, dimethyl acetylenedicarboxylate (DMAD), and a mixture of isatin and sarcosine. All the novel spiro compounds, in moderate yields, were characterized thoroughly by infrared, NMR, mass spectromentry, and elemental analysis together with x-ray crystallographic analysis.     

A NOVEL SYNTHESIS OF 2-SUBSTITUTED-4H-THIENO [2,3-d][1,3] OXAZIN-4-ONE AND 2,3-DISUBSTITUTED THIENO [2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Abstract

The synthesis of acetic 2-{[1-methyl-2-(4-oxo-5,6,7,8-tetrahydro-4H-benzo [4,5]-thieno [2,3-d] [1,3-oxazin-2-yl)ethylidene]amino}-4,5,6,7-tetrahydrohenzo[b]thiophene ?3-carboxylic acid anhydride 5 and 2-(oxopropyl)-5,6,7,8-tetrahydro-4H-benzo-[4,5] thieno[2,3-d][1,3]oxazin-4-one 7, has been achieved in three steps from ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b]thiophene-3-carboxlate 1 via the reaction with ethyl acetoacetate followed by hydrolysis and acetic anhydride-induced cyclization. The 2-substituent in compound 5 has two functional groups i.e. active methylene and acid anhydride which are suitably located for intramolecular transformation. Thermal and/or base catalyzed intramolecular cyclization of 5 afforded 2-(4-acetoxy-(hydroxyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-b]pyridin-3-yl)-5,6,7,8- tetrahydro-4H-benzo[4,5]thieno[2,3-d] [1,3]oxazin-4-one 10 and 9 respectively. Treatment of 5 with hydrazine hydrate, aromatic and/or heterocyclic amines induced the same intramolecular cyclization with a concomitant oxazine-pyrimidine interconversion to give 3-amino(aryl or heteryl)-2-(4-hydroxy-5,6,7,8-tetrdhydrobenzo-[4,5]thieno[2,3-b]pyridin-3-yl)-3,4,5,6,7,8-hexahydrobenzo[4,5] thieno[2,3-d] pyrimid in-4-one 11–14 respectively.     

Synthesis and Biological Activity of a Series of New Thieno[2,3-d]Pyrimidines

Ethyl 2-amino-5-ethylthiophene-3- carboxylate 1, obtained from the reaction of butyraldehyde, ethyl cyanoacetate, sulfur, and triethylamine, reacted with benzoylisothiocyanate to give the corresponding ureido derivatives 2 in a high yield. Further reactions of the compound 2 with an aqueous-alcohol solution of potassium hydroxide and then with hydrochloric acid gave the 2-thio-thieno[2,3-d]pyrimidine-4-ones 3, which were reacted with RX to give novel compounds 4a–4i. Treating the compound 3 with dibromoalkane led to the formation of triacylic compounds 5j–5m. Their structures were clearly verified by IR, ¹H NMR, EI-MS spectroscopy, and elemental analysis. The results of a preliminary bioassay indicated that some compounds possess excellent inhibitory activities against the root and the stalk of Brassica napus (rape) and Echinochloa crusgalli (barnyard grass) at a dosage of 100 mg/L.

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 and Antimicrobial,Anticancer and Anti-Oxidant Activities of Novel 2,3-Dihydropyrido[2,3-d]pyrimidine-4-one and Pyrrolo[2,1-b][1,3]benzothiazole Derivatives via Microwave-Assisted Synthesis

In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a–e and pyrrolo[2,1-b][1,3]benzothiazoles 9a–e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile (5a–e) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a–e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a–e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a,d, and 9a,d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a, d, and 9a,d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.     

Synthesis of 5-glycopyranosylamino-pyrano[2,3-d]pyrimidin-2-one derivatives

Summary Three series of 3-substituted 5-glycopyranosylamino pyrano[2,3-d]pyrimidin-2-one derivatives,3 a–c,4 a–c, and5 a–c have been prepared by treatment of the corresponding 1,4-dihydro-6-glycopyranosylamino pyrimidin-4-ones1 a–c with malonic, methyl malonic and ethyl malonic acids, respectively.

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Synthese von Derivaten des 5-Glucopyranosylaminopyrano[2,3-d]pyrimidin-2-on

Zusammenfassung Es wurden drei Serien von 3-substituierten 5-Glucopyranosylaminopyrano[2,3-d]pyrimidin-2-onen (3 a–c,4 a–c und5 a–c) mittels Behandlung der entsprechenden 1,4-Dihydro-6-glucopyranosylamino-pyrimidin-4-one (1 a–c) mit Malon-, Methylmalon- bzw. Ethylmalonsäure dargestellt.

     

Synthesis of New 3-Carboxamidine Iminocoumarins and Benzopyrano[2,3-d]pyrimidines

A new approach to synthesis of a series of 3-carboxamidine iminocoumarins derivatives and substituted benzopyrano[2,3-d]pyrimidines was developed. The chemical structure of all the compounds was investigated by infrared, ¹H NMR, ¹³C NMR, mass, and elemental analysis. The anticholinesterase activity of compound 12 was evaluated according to the modified Ellman’s method.     

Synthesis of 2-Arylthiopyrano[2, 3-d]Pyrimidines and Thieno[2, 3-D]Pyrimidines

Diethyl thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylates 2a, b ; thiopyrano[23-d]pyrimidines 3a-c and 4a-c thieno[2,3-d]pyrimidine-6-carbonitriles 5a-c and thieno[2, 3-d]pyrimidine-6-carboxamides 5d-f have been prepared.     

Synthesis and Characterization of [1,2,4,6]Thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one and [1,3,5]Thiadiazino[3,4-a][1,3]benzimidazol-2-imine

Abstract

The reaction of thionyl chloride with amidines 2, derived from N-benzimidazol-2-yl imidates 1, leads to [1,2,4,6]thiatriazino[2,3-a][1,3]benzimidazol-1(2H)-one 3 in good yields. [1,3,5]Thiadiazino[3,4-a][1,3]benzimidazol-2-imine 4 was prepared by condensation of NaSCN with benzimidazol-2-yl imidate 1. The isolated compounds 3 and 4 were identified by spectroscopic methods including IR, ¹H NMR, and ¹³C NMR as well as elemental analyses and MS of 3d and 4b.

GRAPHICAL ABSTRACT      

Synthesis of a New Series of Imidazo[1,5-d]pyrido[2,3-b][1,4]thiazines as Potential Ligands for the GABA Receptor Complex

Summary.  Starting from 2-chloro-3-nitropyridine, 1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to give the intermediate 1H-pyrido[2,3-b][1,4]thiazin-2-ylphosphate derivative, which in turn afforded the 1,2,4-oxadiazolylimidazo[1,5-d]pyrido[2,3-b]pyrazine derivatives. The title compounds are potential ligands for the γ-aminobutyric acid A/benzodiazepine receptor complex. Corresponding author. E-mail: thomas.erker@univie.ac.at Received February 22, 2002. Accepted March 6, 2002     

Reaction of 6-glycopyranosylaminopyrimidin-4-ones with malonic acids. Synthesis of 8-glycopyranosylpyrido[2,3-d]pyrimidin-4-one derivatives

Summary Reactions of 6-glycopyranosylaminopyrimidin-4-ones1 a–d with malonic, methyl malonic and ethyl malonic acids are discussed in this paper. These reactions have been carried out in acetic anhydride at 100°C affording the 8-glycopyranosylpyrido[2,3-d]pyrimidin-4-ones2 a–d,3 c–d and the 5-acyl-6-glycopyranosylaminopyrimidin-6-ones4 a–d,5 a–d.

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Reaktion von 6-Glycopyranosylaminopyrimidin-4-onen mit Malonsäuren. Synthese von 8-Glycopyranosylpyrido[2,3-d]pyrimidin-4-on-Dervaten

Zusammenfassung Es werden Reaktionen der 6-Glycopyranosylaminopyrimidin-4-one1 a–d mit Malonsäure, Methylmalonsäure und Ethylmalonsäure diskutiert. Die Reaktionen wurden in Essigsäureanhydrid bei 100°C ausgeführt und ergaben 8-Glycopyranosylpyrido[2,3-d]pyrimidin-4-one2 a–d,3 c–d und die 5-Acyl-6-glycopyranosylaminopyrimidin-6-one4 a–d und5 a–d.

     

Synthesis and Antimicrobial Activities of Some Novel Pyrido[2,3- d ]pyrimidine Derivatives

2-Amino-(6-phenoxathiin-2-yl)-4-phenyl-nicotinonitrile has been synthesized and used as a starting material to construct a novel series of annulated and substituted pyrido[2,3-d]pyrimidine systems. Antibacterial and antifungal activities of some synthesized compounds were evaluated and reported.     

Heteroaromatization with Sulfonamido Phenyl Ethanone,Part I: Synthesis of Novel Pyrrolo[2,3-D]Pyrimidine and Pyrrolo[3,2-E][1,2,4]Triazolo[1,5-C]Pyrimidine Derivatives Containing Dimethylsulfonamide Moiety

4-(5-Amino-4-cyano-1-p-tolyl-1H-pyrrol-3-yl)-N,N-dimethyl-benzenesulfonamide (4) was prepared and converted to several pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethyl-benzenesulfonamide derivatives (5,7,9, and 13). Cyclocondensation of 13 with different electrophilic carbon reagents afforded several 4-(N,N-dimethylaminosulfonylphenyl)]pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]-pyrimidine derivatives (14–17,19, and 20); IR, ¹HNMR, and mass spectra of the newly synthesized compounds were recorded. Most of the obtained compounds were screened against Gram-positive and Gram-negative bacteria and fungi, for which some of these derivatives gave promising results.     

Efficient One-Pot Synthesis of Substituted Pyrido[2,3-d]pyrimidines from Vinamidinium and Chloropropeniminium Salts

A novel and efficient one-pot preparation of 6-substituted pyrido-[2,3-d]pyrimidines by cyclocondensation of 6-amino-1,3-dimethyluracil with symmetrical vinamidinium salts under basic conditions has been developed. Regioselectivity was observed with an unsymmetrical chloropropeniminium salt.     

Radioprotective and Antitumor Activity of Some Novel Amino Acids and Imidazoles Containing Thieno[2,3-d]pyrimidine Moiety

A variety of novel thieno[2,3-d]pyrimidine derivatives, comprising amino acids 3a–l, imidazothieno-pyrimidines 4A, 4b–h, and 7, were obtained via the reaction of 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine 1 with a variety of reagents. The structures of these compounds were confirmed by microanalysis, IR, ¹H NMR, and mass spectrometry. Some of the obtained compounds showed promising radioprotective and antitumor activities.     

Acetylenic chemistry,part 20: Ring opening of 3-azaisatoic anhydride with acetylenic amines: Synthesis of pyrido[2,3-d]pyrimidinones

Summary Ring opening of 3-azaisatoic anhydride with acetylenic amine gave the nicotinamides3 a–c. The reaction of triphosgene with the nicotinamides3 a–c yielded the pyrido[2,3-d]pyrimidinones4a,5b,5c, and7b.

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Acetylenchemie, 20. Mitt.: Ringöffnung von 3-Azaisatosäureanhydrid mit Acetylenaminen: Synthese von Pyrido[2,3-d]pyrimidinonen

Zusammenfassung Bei Ringöffnung von 3-Azaisatosäureanhydrid mit Acetylenaminen entstehen die Nicotinamide3 a–c. Die Reaktion von Triphosgen mit den Nicotinamiden3 a–c führt zu den Pyrido[2,3-d]pyrimidinonen4a,5b,5c und7b.

     

New Facile Route to Synthesize Furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine and Furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives

A new facile route for synthesis of 3-(aryl)-8,9-diphenylfuro[3,2-e][1,2,4]triazolo pyrimidines derivative from the same starting material, 2-amino-4,5-diphenylfuran-3-carbonitrile, has been developed through heterocyclization of the corresponding arylidene-hydrazono-5,6-diphenylfuro[2,3-d]pyrimidine and N-(arylmethylene)-4-imino-5,6-diphenylfuro[2,3-d]pyrimidin-3(4H)-amine under refluxing condition with acetic anhydride followed by air oxidation. The products were obtained in good yield with an easy workup along with the purification of products by a nonchromatographic method. This general synthetic procedure can be extended to the preparation of a wide range of isomeric triazoles using 2-amino 3-carbonitrile bifunctional derivatives.     

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.     

Novel Synthesis of N-Arylpyrrole,Pyrrolo[1,2-a]quinazoline,and Pyrrolo[3,4-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a,b react with dimethyl formamide dimethyl acetal (DMFDMA) in refluxing toluene to afford the enaminones 2a,b respectively. Compounds 2a and 2b react with the aromatic amines (aniline, p-toluidine, p-anisidine) in refluxing ethanol to afford the pyrroles 4a–f and with anthranilonitrile and methyl anthranilate to afford the pyrrolo[1,2-a]quinazolines 5a,b and 6a,b respectively. The pyrrole derivatives 4a–f react with hydrazine hydrate and phenyl hydrazine in refluxing ethanol to afford the pyrrolo[3,4-d] pyridazine derivatives 7a–f and 8a–f respectively.     

Regioselective Synthesis of 2-Substituted [1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones by Heteropolyacids

2-Substituted [1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones 3 were synthesized via regioselective cyclization of 4H-[1,2,4]triazol-3-ylsulfanyl-acrylic acids 2 in the presence of catalytic amounts of heteropolyacids at room temperature in very good yields and rates.     

新型2-氧代-1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂类稠杂环的合成

将取代色满酮(1)与芳肼反应生成的腙与HNCO发生[3+2]环加成反应,加成产物(2)经氧化得到偕偶氮异氰酸酯(3).化合物3在HBF4的催化下发生环化-重排反应,得到新颖的三环系2-氧代-1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂化合物5a～5g.