Synthesis of some new pyrido[2,3‐d]pyrimidines and their ribofuranosides as possible antimicrobial agents

The ribofuranosides, namely, 4‐amino‐5,7‐disubstituted‐1‐[2′,3′,5′‐tri‐O‐benzoyl‐α‐d ‐ribofuranosyl]pyrido‐[2,3‐d] pyrimidine‐2(1H)‐thiones, have been synthesized by the condensation of trimethylsilyl derivatives of 5,7‐disubstituted pyrido[2,3‐d]pyrimidine‐2(1H)‐thiones with β‐d ‐ribofuranose‐1‐acetate‐2,3,5‐tribenzoate in the presence of SnCl₄. The heterocyclic bases, namely, 4‐amino‐5,7‐disubstituted pyrido[2,3‐d]pyrimidine‐2(1H)‐thiones, were synthesized by the treatment of 2‐amino‐3‐cyano‐4,6‐disubstituted pyridines with thiourea. The structures of all the synthesized ribofuranosides and their precursors have been established by elemental analysis, IR, and ¹H NMR spectral data. The ¹³C NMR data of ribofuranosides has also been presented. All the synthesized heterocyclic bases and their ribofuranosides have been screened for their antibacterial and antifungal activities. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:52–56, 2001     

SYNTHESIS AND ANTIMICROBIAL SCREENING OF SOME NEW 4-IMINO-3,5,7-TRISUBSTITUTED PYRIDO[2,3-d]PYRIMIDINES AND THEIR RIBOFURANOSIDES AS POTENTIAL CHEMOTHERAPEUTIC AGENTS

Some new nucleosides, viz. 4-imino-3,5,7-trisubstituted-1-(2′,3′,5′-tri-O-kbenzyl–β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin/e–2(1H)-ones/ thiones(VII/VIII), have been synthesized by condensation of trimethylsilyl derivatives of 4-imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin/e-2(1H)-ones/thiones (III/IV) with β-D-ribofuranosyl1-acetate-2,3,5-tribenzoate. Compounds III/IV have been synthesized by refluxing 2-amino-3-cyano-4,6-disubstituted pyridine (II) with substituted an arylisocyanate or an isothiocyanate respectively. The structure of all the synthesized compounds have been established by IR and ¹H NMR studies. These compounds have been screened for antimicrobial activities in order evaluate. The possibility of the derivatives to be used as potential chemotherapeutic agents.     

Utility of Pyridine‐2(1H)‐thiones in the Synthesis of Novel Bis‐Thieno[2,3‐b]pyridines and Their Fused Azines

The starting materials pyridine‐2(1H)‐thiones are prepared and reacted with halogen‐containing reagents in ethanolic sodium acetate solution to give the corresponding 2‐S‐alkylpyridines, which cyclized upon their boiling in methanolic sodium methoxide solution at reflux to give the corresponding thieno[2,3‐b]pyridines in excellent yields. Bis (thieno[2,3‐b]pyridine‐2‐carboxamides), incorporating 2,6‐dibromophenoxy moiety, are prepared by the bis‐O‐alkylation of thieno[2,3‐b]pyridine‐2‐carboxamide derivatives. Two synthetic routes are designed to prepare the target molecules pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐ones, pyrido[3′,2′:4,5]thieno[3,2‐d][1,2,3]triazin‐4(3H)‐ones, and their bis‐analogues using thieno[2,3‐b]pyridine‐2‐carboxamides and their bis‐analogues. The structure of the target molecules is elucidated using elemental analyses as well as spectral data.     

Structural Elucidation and Antimicrobial Evaluation of Novel [1,2,4]Triazolo[4,3‐a]pyrimidines and Pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones

1,3‐Di(thiophen‐2‐yl)prop‐2‐en‐1‐one ( 1 ) was utilized in the synthesis of 4,6‐di(thiophen‐2‐yl)‐3,4‐dihydropyrimidine‐2(1H)‐thione ( 2 ) and 5,7‐di(thiophen‐2‐yl)‐2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐one ( 4 ). The latter thiones were used in the synthesis of two new series of [1,2,4]triazolo[4,3‐a]pyrimidines 10a – i and pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinones 5a – i via reaction with the appropriate hydrazonoyl halides using triethylamine as a basic catalyst in dioxane. The mechanism of formation of the synthesized compounds was discussed, and the assigned structure was established via microanalysis, spectral data (infrared, ¹H NMR, and Mass), and density functional calculations. Moreover, the newly synthesized products were evaluated for their antimicrobial activities, and the results show that some derivatives have been well with mild activities. Finally, quantum chemistry calculations confirmed the mechanism and structure of the products.     

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

The effect of conformational restriction of the C9‐N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6(5H,8H)‐one ( 4 ), 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐9‐hydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6‐(8H)‐one ( 5 ) and 1,3‐diamino‐(8H)‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidine ( 7 ) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclo‐condensation of the β‐keto ester 17 with 2,4,6‐triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.     

Synthesis of new thienotriazolopyrimidine and thienopyrimidotetrazine derivatives from bifunctional intermediates

New compounds containing the thienotriazolopyrimidine and thienopyrimidotetrazine skeleton are prepared from the bifunctional intermediates 2,3‐diamino‐5,6‐dimethylthieno[2,3‐d]pyrimidin‐4(3H)‐one derivatives 13–17 . The 2,3‐dihydro‐3‐substituted‐5,6‐dimethylthieno[2,3‐d]pyrimidin‐4(1H)‐one derivatives 8–12 are also prepared.     

A Convenient Synthetic Route of Diethyl (4‐Oxo‐chromeno[2,3‐d]pyrimidin‐2(5)‐yl)phosphonates

Novel diethyl (4‐oxo‐3,4‐dihydro‐2H‐chromeno[2,3‐d]pyrimidin‐2‐yl)phosphonate as two enantiomers and diethyl (4‐oxo‐1,5‐dihydro‐4H‐chromeno[2,3‐d]pyrimidin‐5‐yl) phosphonate were obtained in easy procedure via reaction of 2‐imino‐2H‐chromene‐3‐carboxamide, dimethylformamide dimethyl‐acetal, and diethyl phosphite in a simple one pot. Possible reaction mechanisms were proposed. The structures of the obtained products were confirmed by elemental analyses and spectral tools.     

Investigation into the reaction of 2‐amino‐4,5‐dimethylthiophene‐3‐carboxamide with iso(and isothio)cyanates under microwave irradiation

The reaction of 2‐amino‐4,5‐dimethyl‐ thiophene‐3‐carboxamide with iso(and isothio) cyanates for the synthesis of thieno[2,3‐d]pyrimidines has been investigated. The reactions under microwave irradiation in the presence of N,N‐dimethyl acetamide as solvent gave 5,6‐dimethylthieno[2,3‐d]pyrimidine‐2,4(1H,3H)‐dione, 5,6‐dimethyl‐2‐thioxo‐2,3‐dihy‐ drothieno[2,3‐d]pyrimidin‐4(1H)‐one, and 2‐aryla‐ mino‐5,6‐dimethylthieno[2,3‐d]pyrimidin‐4(3H)‐one derivatives. These reactions probably proceed through intermediates 4,5‐dimethyl‐2‐substitutedcarbamoth‐ ioylaminothiophene‐3‐carboxamides. Two of these intermediates were isolated. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:346–349, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20557     

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.     

Polycyclic N‐Heterocyclic Compounds,Part 72: Reaction of N‐([1]Benzofuro (or Benzothieno)[3,2‐d]pyrimidin‐4‐yl)formamidine and N‐(Pyrido[2,3‐d]pyrimidin‐4‐yl)formamidine Derivatives with Hydroxylamine Hydrochloride

The reactions of N‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide oximes. N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamidines and N‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave similar results.     

Folded conformations due to arene interactions in dissymmetric and symmetric butylidene‐linker models based on pyrazolo[3,4‐d]pyrimidine,purine and 7‐deazapurine

The butylidene‐linker models 1‐[2‐(2,6‐dimethylsulfanyl‐9H‐purin‐9‐yl)‐2‐methylidenepropyl]‐4,6‐bis(methylsulfanyl)‐1H‐pyrazolo[3,4‐d]pyrimidine, C₁₈H₂₀N₈S₄, (XI), 7,7′‐(2‐methylidenepropane‐1,3‐diyl)bis[3‐methyl‐2‐methylsulfanyl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4(7H)‐one], C₂₀H₂₂N₆O₂S₂, (XIV), and 7‐[2‐(4,6‐dimethylsulfanyl‐1H‐pyrazolo[3,4‐d]pyrimidin‐1‐yl)‐2‐methylidenepropyl]‐3‐methyl‐2‐methylsulfanyl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4(7H)‐one, C₁₉H₂₁N₇OS₃, (XV), show folded conformations in solution, as shown by ¹H NMR analysis. This folding carries over to the crystalline state. Intramolecular π–π interactions are observed in all three compounds, but only (XIV) shows additional intramolecular C—H...π interactions in the solid state. As far as can be established, this is the first report incorporating the pyrrolo[2,3‐d]pyrimidine nucleus for such a study. In addition to the π–π interactions, the crystal structures are also stabilized by other weak intermolecular C—H...S/N/O and/or S...N/S interactions.     

Multi‐component Reactions,Solvent‐free Synthesis of Substituted Pyrano‐pyridopyrimidine under Different Conditions Using ZnO Nanoparticles

2‐Amino‐4‐(4‐substitutedphenyl)‐5‐oxo‐4H,5H‐pyrano[2,3‐d]pyrido[1,2‐a]pyrimidine‐3‐carbonitrile‐derivatives 2–12 were synthesized via multi‐component condensation reactions of different aromatic aldehydes, 3H‐pyrido[1,2‐a]pyrimidine‐2,4‐dione 1 , and malononitrile by using ZnO nanoparticles as green chemistry, environmentally friendly catalyst under solvent‐free conditions. The present work creates a variety of biologically active heterocyclic compounds in excellent yield and a short time. The structures of all synthesized compounds were elucidated with the elemental analyses, IR, ¹H NMR, and mass spectral data.     

Synthesis of Novel Spiro Pyrano[2,3‐d]thiazolo[3,2‐a]pyrimidine via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The reaction involving 4‐phenyl‐octahydro‐pyrano[2,3‐d]pyrimidine‐2‐thione, ethyl chloroacetate and the appropriate aromatic aldehyde yielded 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones. The 1,3‐dipolar cycloaddition of 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones with azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone afforded 4′‐aryl‐1′‐methyl‐5″‐phenyl‐5a″,7″,8″,9a″‐tetrahydro‐2H,5″H,6″H‐dispiro[acenaphthylene‐1,2′‐pyrrolidine‐3′,2″‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine]‐2,3″‐diones in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis, and X‐ray crystallographic analysis.     

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.     

Synthesis and Structure of 2‐Substituted Thieno[3′,2′:5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one Derivatives

A series of new 2‐substituted 3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 8 were synthesized via an aza‐Wittig reaction. Phosphoranylideneamino derivatives 6a or 6b reacted with 4‐chlorophenyl isocyanate to give carbodiimide derivatives 7a or 7b , respectively, which were further treated with amines or phenols to give compounds 8 in the presence of a catalytic amount of EtONa or K₂CO₃. The structure of 2‐(4‐chlorophenoxy)‐3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one ( 8j ) was comfirmed by X‐ray analysis.     

Polycyclic N‐Heterocyclic Compounds. Part 84: Reaction of N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines or N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines with Hydroxylamine Hydrochloride

The reactions of nine N‐(pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4‐yl)amidines ( 3 ) with hydroxylamine hydrochloride produced new cyclization products. These were formed via ring cleavage of the pyrimidine component followed by a 1,2,4‐oxadiazole‐forming ring closure to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)thieno[2,3‐b]pyridin‐3‐yl]formamide oximes ( 11 ). Reaction of six N‐(pyrido[2′,3′:4,5]furo[3,2‐d]pyrimidin‐4‐yl)amidines ( 12 ) with hydroxylamine hydrochloride gave similar results. Effects of the newly synthesized compounds on pentosidine formation were also evaluated.     

Pyridopyrimidines. X. Synthesis of 3‐Substituted 2‐Thioxo‐5,7‐dimethylpyrido[2,3‐d] pyrimidin‐4(3H)‐ones and their S‐Alkylation Under Phase Transfer Conditions

2‐Thioxo‐5,7‐dimethylpyrido[2,3‐d]pyrimidin‐4(3H)‐ones 3 were synthesized by the cyclocondensation of 2‐amino‐3‐carbethoxy‐4,6‐dimethylpyridine 1 with methyl‐N‐aryldithiocarbamates 2 and compared with the condensation between 1 and aryl isothiocyanates 4. When a comparative study of N vs S alkylation of ambident 2‐thioxo‐5,7‐dimethylpyrido[2,3‐d]pyrimidin‐4(3H)‐ones 3 was carried out under liquid‐liquid and solid‐liquid phase transfer conditions using various alkylating agents 5 , the S‐alkylated products 6 were obtained exclusively and selectively.     

Facile Methods for the Synthesis of 5‐Aryl and 5‐Iodo Pyrrolo[2,3‐d]pyrimidines

An efficient and environmentally benign one‐pot method has been developed for the synthesis of 4‐amino‐5‐arylpyrrolo[2,3‐d]pyrimidines. Phthalimido acetophenones were reacted with cyanoacetamide to give 2‐amino‐4‐phenyl‐1H‐pyrrole‐3‐carboxamides, which were further converted to 5‐aryl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4‐ones. A novel method is also developed for the synthesis of 4‐amino‐5‐iodopyrrolo[2,3‐d]pyrimidines.     

An Expedient Synthesis of Novel Derivatives of Pyrido[2,3‐d]pyrimidines Using Magnetically Supported ZrO2 Nanocatalyst

An efficient synthesis of pyrido[2,3‐d]pyrimidine derivatives via one‐pot multicomponent reactions of 6‐amino‐2‐(alkylthio)pyrimidin‐4(3H)‐one, 3‐cyanoacetylindole and arylaldehydes using [Fe₃O₄@ZrO₂] as magnetically recyclable nanocatalyst is reported. This protocol furnished the desired products in good to excellent yields (70–93 %) and lower reaction times. The catalyst could be easily and efficiently separated from the final product solution by an external magnet and be reused in 5 consecutive runs without any significant activity decrease.     

Synthesis and interconversion of isomeric pyrrolotriazolopyrimidines

4‐Hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 were cyclocondensed with formic acid or triethyl orthoformate to give 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[1,5‐c]pyrimidines 6 and 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[4,3‐c]pyrimidines 7 , respectively. The [4,3‐c] isomers 7 were rearranged into thermodynamically more stable [1,5‐c] isomers 6 . The identical compounds 6 were prepared using another route by reacting 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 with formic acid or triethyl orthoformate. The reaction of 2‐amino‐3‐cyanopyrroles 1 with triethyl orthoformate gave N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 . Further reaction with an equivalent of hydrazine hydrate provided 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 , whereas treatment with excess of hydrazine hydrate, 3 rearranged to 4‐hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 . Compounds 4 were also obtained by the treatment of N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 in excess of hydrazine hydrate. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:265–273, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20295