Synthesis of 5,7‐Disubstituted 7H‐Pyrrolo[2,3‐d]Pyrimidin‐4(3H)‐ones and Their N‐Alkylation's under Phase Transfer Conditions

5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 were synthesized by the cyclocondensation of 1,4‐disubstituted 2‐amino‐3‐cyanopyrrole 1 with formic acid. When comparative study of N versus O alkylation of ambident 5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 was carried out under liquid–liquid PTC, solid–liquid PTC, and solid–liquid solvent free conditions using various alkylating agents 3 , the N‐alkylated product 4 were obtained selectively and exclusively.     

Synthesis of Novel Substituted 2‐Lactosylthiothieno[2,3‐d]pyrimidin‐4(3H)‐one Derivatives

The title compounds substituted 2‐lactosylthiothieno[2,3‐d]pyrimidin‐4‐ones 6 were synthesized by the glycosyl reaction and alcoholysis reaction of substituted 2‐thioxo‐thieno[2,3‐d]pyrimidin‐4‐ones 4 ,which is formed by the base catalytic and acetic acidify reaction of amino esters 2 with alkyl or arylisothiocyanates and hepta‐O‐acetyl‐lactosyl bromide in good yields. All of the compounds were confirmed by NMR, ESI‐MS, and elemental analysis.     

Efficient synthesis of 2‐substituted thieno[2,3‐d]pyrimidin‐4(3H)‐ones via an iminophosphorane

The carbodiimides 4 , obtained from reactions of iminophosphorane 3 with aromatic isocyanates, were reacted with secondary amines to give 2‐dialkylamino‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in the presence of catalytic amount of EtONa. Reactions of 4 with phenols or ROH in the presence of the catalytic amount of K2CO₃ or RONa gave 2‐aryloxy‐ or 2‐alkoxy‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in satisfactory yields. The effects of the nucleophiles on cyclization have been investigated. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:266–270, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20424     

A Convenient Synthesis and Biological Activity of Novel Pyrido[4,3‐d]pyrimidin‐4(3H)‐ones

Fifteen novel 2‐alkylamino‐3‐aryl‐8‐cyano‐5‐methyl‐7‐(methylthio)‐pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k , 6l , 6m , 6n , 6o were designed and have been successfully synthesized via tandem aza‐Wittig and annulation reactions with the corresponding iminophosphorances 4 , aryl isocyanate, and amines in good yields. Their structures were clearly verified by IR, ¹H NMR, EI‐MS spectroscopy and elemental analysis, and in the case of compound 6i , analyzed by single‐crystal X‐ray diffraction further. The preliminary results of an in vivo bioassay showed that some compounds display moderate antifungal activity.     

A Convenient Synthesis and Biological Activity of Novel Pyrido[4,3‐d]pyrimidin‐4(3H)‐ones

Fifteen novel 2‐alkylamino‐3‐aryl‐8‐cyano‐5‐methyl‐7‐(methylthio)‐pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k , 6l , 6m , 6n , 6o were designed and have been successfully synthesized via tandem aza‐Wittig and annulation reactions with the corresponding iminophosphoranes 4 , aryl isocyanate, and amines in good yields. Their structures were clearly verified by IR spectroscopy, ¹H‐NMR spectroscopy, EI‐MS, and elemental analysis, and in the case of compound 6i , further analyzed by single‐crystal X‐ray diffraction. The preliminary results of an in vivo bioassay showed that some compounds display moderate antifungal activity.     

Synthesis and Herbicidal Activity of Muti‐Substituted Pyrido[4,3‐d]pyrimidin‐4‐ones

A series of novel muti‐substituted pyrido[4,3‐d]pyrimidin‐4‐one derivatives 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l were designed and synthesized by the muti‐step reaction. N,S‐acetal 1 reacted with acetyl acetamide in the presence of zinc nitrate to obtain muti‐substituted pyridine 2 , which reacted with triethyl orthoformate to give 8‐cyano‐5‐methyl‐7‐methylthio‐pyrido[4,3‐d]pyrimidin‐4‐one 3 ; the target compounds 5 were obtained in good yields by the oxidation of 3 with H₂O₂ in a catalytic amount of sodium tungstate then by the substitution with various substituted phenols. Their structures were confirmed by IR, ¹H NMR, EI‐MS, and elemental analyses. The preliminary bioassay indicated that some of them displayed moderate herbicidal activity against dicotyledonous weed Brassica campestris L. at the concentration of 100 mg/L. For example, compounds 5a , 5f , and 5g possessed 76.0%, 62.7%, and 60.2% inhibition against B. campestris at the concentration of 100 mg/L. Moreover, 5a exhibited 58.2% inhibition against B. campestris at the concentration of 10 mg/L.     

[DBU‐H]+ and H2o as effective catalyst form for 2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones: A DFT Study

DFT investigations are carried out to explore the effective catalyst forms of DBU and H₂O and the mechanism for the formation of 2,3‐dihydropyrido[2,3‐d]‐pyrimidin‐4(1H)‐ones. Three main pathways are disclosed under unassisted, water‐catalyzed, DBU and water cocatalyzed conditions, which involves concerted nucleophilic addition and H‐transfer, concerted intramolecular cyclization and H‐transfer, and Dimroth rearrangement to form the product. The results indicated that the DBU and water cocatalyzed pathway is the most favored one as compared to the rest two pathways. The water donates one H to DBU and accepts H from 2‐amino‐nicotinonitrile ( 1 ), forming [DBU‐H]⁺‐H₂O as effective catalyst form in the proton migration transition state rather than [DBU‐H]⁺‐OH^?. The hydrogen bond between [DBU‐H]⁺···H₂O··· 1 ^? decreases the activation barrier of the rate‐determining step. Our calculated results open a new insight for the green catalyst model of DBU‐H₂O. © 2015 Wiley Periodicals, Inc.     

Molecular Iodine Promoted Synthesis of New Pyrido[2,3‐d]pyrimidin‐4‐ols

A highly ef?cient synthesis of novel pyrido[2,3‐d]pyrimidin‐4‐ols was developed via an iodine‐catalyzed tandem oxidative cyclization under focused microwave irradiation. Pyrido[2,3‐d]pyrimidin‐4‐ols were obtained from easily available 2‐amino‐4‐aryl‐6‐arylnicotinamides and benzylic amines with good to excellent yields.     

Synthesis and Bioassay of Novel Substituted Pyrano[2,3‐f]cinnoline‐2‐ones

A new series of 9‐substituted‐4,10‐dimethylpyrano[2,3‐f]cinnolin‐2‐ones ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m ) were synthesized via intramolecular cyclization of the respective acyl amidrazone derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ), catalyzed by polyphosphoric acid. Compounds ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m ) were synthesized through direct interaction of coumarin‐7‐yl hydrazonoyl chloride ( 3 ) with the corresponding cyclic sec‐amines in the presence of triethylamine. The structures of the new compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m was evaluated in vitro on breast cancer cell line (MCF‐7) by a cell viability assay utilizing the tetrazolium dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Among the compounds tested, compounds 5d , 5f , 5k , and 5h showed potential anti‐MCF‐7 activity and were able to reduce the viability after 72 h to less than 50%.     

A facile synthesis of 2‐substituted thieno[3′,2′‐5,6]‐pyrido[4,3‐d]pyrimidin‐4(3H)‐ones

The thienopyridine derivative 2 , obtained from reaction of acetoacetic ester with 1 in the presence of tin tetrachloride, was treated with triphenylphosphine in hexachloroethane and Et₃N to give iminophosphorane 3 . Iminophosphorane 3 reacted with phenyl isocyanate to give carbodiimide 4 , which was further treated with phenols or ethenol to produce 2‐substituted 5,8,9‐trimethyl‐3‐phenyl‐thieno[3′,2′‐5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 5 in presence of catalytic amount of K₂CO₃ or EtONa. The structures of compounds 5 were confirmed by ¹H NMR, IR, MS, and elemental analysis.     

Efficient Iminophosphorane‐Mediated Preparation of Benzofuro[3,2‐d]pyrimidin‐4(3H)‐ones and Unexpected Ring Opening Products

The carbodiimides 4 , obtained from aza‐Wittig reactions of iminophosphorane 3 with aromatic isocyanates, reacted with secondary amines, phenols or alcohols in the presence of catalytic amounts of K₂CO₃ or sodium alkoxide to give 2‐substituted benzofuro[3,2‐d]pyrimidin‐4(3H)‐ones 6 . However, when 2,2′‐iminobis[ethanol] was used, the unexpected ring opening product 7 was formed instead of 6 . Reaction of 4 with primary amines RNH₂ (R=Et, Pr, Bu, etc.) gave guanidine intermediates 8 , which were further treated with EtONa to give only one regioisomer 9 via a base catalyzed cyclization. However, another regioisomer 11 was obtained when NH₃ or ‘small’ amines RNH₂ (R=Me, NH₂) were used in the absence of EtONa via a spontaneous cyclization of 8 .     

A facile synthesis of novel thiazolo[4,5‐d]pyrimidin‐7‐ones

Sixteen 5‐alkylamino‐3,6‐diaryl‐2‐thioxo‐2,3,6,7‐tetrahydrothiazolo[4,5‐d]pyrimidin‐7‐ones 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m , 4n , 4o , 4p were designed and easily synthesized via a tandem aza‐Wittig reaction. The iminophosphorane 2 , obtained from reaction of 1 with triphenylphosphine, hexachloroethane and Et₃N, reacted with aromatic isocyanate to give carbodiimide 3 . carbodiimide 3 reacted with alkylamines to provide the title compounds in 45–61% isolated yields in presence of catalytic amount of ethoxide. The structures of compounds 4 were confirmed by ¹H NMR, IR, MS, and elemental analysis. J. Heterocyclic Chem., 2011.     

Efficient Synthesis of New Thieno[2,3‐d]pyrimidin‐4(3H)‐one Derivatives for Evaluation as Anticancer Agents

Thieno[2,3‐d]pyrimidinones were reported to act as potent anticancer agents; in this work, a series of new substituted thieno[2,3‐d]pyrimidinone ( 6 ) were synthesized via the aza‐Wittig reaction in satisfactory yields. The structures of these compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data, and compound 6h was further analyzed by single crystal X‐ray diffraction. Cytotoxic effect of all the compounds was carried out on human breast and lung cancer cell lines (MCF‐7 and SPC‐A‐1, A459). Compound 6f exhibited the best inhibition activities against A459 with IC₅₀ 4.1 μM.     

A Facile Synthesis of 2‐Substituted 2,3‐Dihydro‐4(1H)‐Azuleno[2,1‐d]Pyrimidinones

A facile, efficient, and novel approach to access 2‐substituted 2,3‐dihydro‐4(1H)‐azuleno[2,1‐d]pyrimidinones was developed by condensation of 2‐amino‐1‐carbamoyl‐3‐phenylazulene with ary1 aldehydes or ketones in ionic liquids by catalyzed p‐toluenesulfonic acid.     

Microwave‐assisted three‐component synthesis and in vitro antifungal evaluation of 6‐cyano‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐ones

The reaction of 6‐aminopyrimidin‐4‐ones 1 with benzaldehydes 2 and β‐aminocrotononitrile 3 or benzoylacetonitrile 4 under microwave irradiation in dry media yields the 6‐cyano‐5,8‐dihydropyrido[2,3‐d]‐pyrimidinones 5a‐t . The structure of the synthesized compounds was determined on the basis of nmr measurements, especially by ¹H,¹H?, ¹H,¹³C COSY, DEPT and NOESY experiments. In contrast with other pyrido‐[2,3‐d]pyrimidine derivatives, these compounds did not show any antifungal in vitro activity up to 250 μg/mL.