Synthesis and in vitro Antibacterial Activities of 5‐(2,3,4,5‐Tetrahydro‐1H‐chromeno[2,3‐d]pyrimidin‐5‐yl)pyrimidione Derivatives

A series of novel 5‐(2,3,4,5‐tetrahydro‐1H‐chromeno[2,3‐d]pyrimidin‐5‐yl)pyrimidione derivatives have been synthesized from substituted salicylaldehydes and barbituric acid or 2‐thiobarbituric acid in water catalyzed by phase transfer catalysis of triethylbenzyl ammonium chloride (TEBA). Elemental analysis, IR, ¹H NMR, and ¹³C NMR elucidated the structures of all the newly synthesized compounds. In vitro antimicrobial activities of synthesized compounds have been investigated against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa. These newly synthesized derivatives exhibited significant in vitro antibacterial activity.     

1‐(4,6‐Diethoxy­pyrimidin‐2‐yl)‐2‐thioxo‐2,3‐dihydro­pyrido[2,3‐d]pyrimidin‐4(1H)‐one

In the title compound, C₁₅H₁₅N₅O₃S, two parallel inter­molecular N—H⋯S hydrogen bonds, forming an eight‐membered ring, link two mol­ecules into a dimer unit; these dimer units linked into a chain of edge‐fused rings by weak C—H⋯O hydrogen bonds.     

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.     

A New Multicomponent Synthetic Route to Hexahydropyrido[2,3‐d]pyrimidine Derivatives

A new one‐pot multicomponent reaction of equimolar amounts of malononitrile and benzaldehyde in ethanol for the synthesis of hexahydropyrido[2,3‐d]pyrimidine derivatives through a sequence of Knoevenagel condensation, Michael addition, and Addition of Nucleophile, Ring Opening, and Ring Closure process is described.     

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.     

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.     

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     

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.     

Bis(enaminones) as Versatile Precursors for Novel Bis([1,2,4]triazolo[1,5‐a]pyrimidines) and Bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones)

Novel bis([1,2,4]triazolo[1,5‐a]pyrimidines) and bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones) were prepared utilizing bis(enaminones) as precursors. The structures of the prepared compounds were elucidated by several spectral tools as well as elemental analyses.     

[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.     

A Convenient Synthetic Route to Spiro[indole‐3,4′‐piperidin]‐2‐ones

Starting from 1‐[(tert‐butoxy)carbonyl]piperidine‐4‐carboxylic acid and 2‐bromoaniline, the spiro[indole‐3,4′‐piperidin]‐2‐one system was obtained in three high‐yielding steps: anilide formation, N(1)‐protection, and intramolecular cyclization under Pd catalysis as the key reaction. The preparation of the corresponding 2‐bromoanilide was studied. In extension, the same sequence was developed with 4‐methyl‐ and 4‐nitro‐2‐bromoaniline. In the key step, the NO₂ group led to a rather diminished yield. The transformation of the protected spiro[indole‐3,4′‐piperidin]‐2‐one to the corresponding unprotected dihydroindoles is discussed.     

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.     

Synthetic approaches to bridgehead nitrogen methanesulfonamide derivatives of 3‐amino‐2‐thioxo‐2,3‐dihydrothieno[2,3‐d]pyrimidin‐4(1H)‐ones,potential cox‐2 selective inhibitors

Methane sulfonamide derivatives of 3‐amino‐2‐thioxo‐2,3‐dihydrothieno[2,3‐d]pyimidin‐4(1H)‐one, potential selective COX‐2 inhibitors, were synthesized and their structural elucidation is here reported. Some derivatives, at 10 μM concentration, showed a significant percentage of inhibition in some in vitro experiments.     

An efficient synthesis of new pyrido[4′,3′:4,5]thieno[2,3‐d]‐pyrimidin‐4(3H)‐one derivatives

The carbodiimides 5 , obtained from reactions of iminophosphorane 4 with aromatic isocyanates, reacted with amines, phenols or ROH to give 2‐substituted 5,6,7,8‐tetrahydropyrido[4′,3′:4,5]thieno[2,3‐d]‐pyrimidin‐4(3H)‐one 7 in the presence of catalytic amount of sodium alkoxide or solid potassium carbonate in satisfactory yields.     

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.     

2‐Hydroxyphenyl 2‐methylpyrazolo[1,5‐a]pyrimidin‐6‐yl ketone

The mol­ecules of the title compound, C₁₄H₁₁N₃O₂, form a three‐dimensional soft hydrogen‐bonded network involving C—H?N hydrogen bonds.     

Synthesis of New Furo[2,3‐d]pyrimidines and Pyrimido[4′,5′:4,5]furo[2,3‐d]pyrimidines

Sodium salt of 4‐hydroxy‐6‐methyl‐2‐phenylpyrimidine‐5‐carbonitrile ( 3 ) was subjected to alkylation with different a‐halo compounds, where the corresponding O‐alkylated products 4_a‐g were obtained. Ring closure of the O‐alkylated product 4_a‐c performed using sodium ethoxide in refluxing ethanol afforded furo[2,3‐d]pyrimidines 5_a‐c The latter compounds on reaction with a variety of reagents gave other new furopyrimidines as well as a number of furodipyrimidines.     

Synthesis of new benzo[h]‐ and benzo[f]chromeno[2,3‐b]‐pyridine‐5‐ones

A number of new benzo[h]‐ and benzo[f]chromeno[2,3‐b] pyridine‐5‐ones derivatives were synthesized from benzo[h]‐ and benzo[f]‐chromone‐carbonitriles and amino‐benzo[h]‐ and benzo[f]chromone‐carbaldehydes. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:2–7, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20152