Reaction of 6-amino-1,3-dimethyluracil with hexafluoroacetone and ethyl trifluoropyruvate benzoylimines

Heating of 6-amino-1,3-dimethyluracil with hexafluoroacetone and ethyl trifluoropyruvate benzoylimines in DMF in the presence of Et₃N results in 1,3-dimethyl-7-phenyl-5,5-bis(trifluoromethyl)-1,2,3,4,5,8-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione and 5-benzoylamido-1,3-dimethyl-5-trifluoromethyl-1,2,3,4,5,6-hexahydropyrrolo[2,3-d]pyrimidine-2,4,6-trione, respectively.     

Reaction of 8-chloro-5,7-dinitroquinoline with β-dicarbonyl compounds

3-(5,7-Dinitroquinolin-8-yl)pentane-2,4-dione, 5-(5,7-dinitroquinolin-8-yl)pyrimidine-2,4,6-trione, and 5-(5,7-dinitroquinolin-8-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione cesium salts have been synthesized by a simple and efficient procedure via C-arylation of the corresponding β-dicarbonyl compounds with 8-chloro-5,7-dinitroquinoline.     

An expedient cyclization of polyfunctional (aryl)(pyrimidinyl)(pyranyl)methanes into spiro[furo[3,2-c]pyran-2,5’-pyrimidine] scaffold

Spirocyclization of morpholinium 3-[(aryl)(1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)methyl]-6-methyl-2-oxo-2H-pyran-4-olate by the action of sodium acetate-N-bromosuccinimide system in ethanol at room temperature results in spiro[furo[3,2-c]pyran-2,5’-pyrimidine] derivatives in 92–98% yields, the protocol allowing to avoid column chromatography purification. This new highly efficient and facile procedure is a convenient way to substituted unsymmetrical spiro scaffold containing pyrimidine-2,4,6-trione and 2,3-dihydro-4H-furo[3,2-c]pyran-4-one fragments promising for biomedical applications.     

Murexide reaction of caffeine with hydrogen peroxide and hydrochloric acid. II

In continuation of the study on the murexide reaction of caffeine with 3% hydrogen peroxide/hydrochloric acid and then with ammonia giving a purple coloration, we investigated the oxidation reaction of caffeine with 6% hydrogen peroxide/hydrochloric acid to isolate ten reaction products, 3-hydroxy-4,6-dimethyloxazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H)-trione 1 , 1,3-dimethylalloxan 2 , murexoin 3 , 1,3,7-trimethyl-2,6,8-trioxo-9-hydroxy-1H,3H,7H-xanthine 5 , 1,3,7-trimethyl-2,6,8-trioxo-1H,3H,7H-xanthine 6 , 1,3,7-trimethyl-2,6-dioxo-8-chloro-1H,3H,7H-xanthine 7, 5-(1,3-dimethyl-1,2,3,4,5,6-hexahydro-2,4,6-trioxopyrimidin-5-yl)-aminomethylene-1,3-dimethyl-1,2,3,4,5,6-hexahydro-2,4,6-trioxopyrimidine ammonium salt 9 , 1,3-dimethylpalabanic acid 10 , 1-methyl-2,4,5-trioxoimidazole 11 , 3-hydroxy-5,7-dimethyloxazolo[5,4-d]pyrimidine-2,4,6(3H,5H,7H)-trione 12 and 4,6,8-trimethyl-1,2,4-dioxazino[6,5-d]pyrimidine-3,5,7(4H,6H,8H)-trione 13 . The oxidation reaction using 6% hydrogen peroxide/hydrochloric acid was found to produce a similar purple coloration to that of the murexide reaction despite no subsequent addition of ammonia, indicating the liberation of ammonia by the oxidation of caffeine. Among the above compounds, the purple colored substance murexoin 3 and the yellow colored compound 9 were both ammonium salts, and compound 5 was the red colored substance. In the present investigation, these three compounds were found to contribute to the coloration.     

Carbohydrate-protein interactions at interfaces: synthesis of thiolactosyl glycolipids and design of a working model for surface plasmon resonance

Thiolactosyl lipids designed for carbohydrate-protein binding studies have been synthesised. One representative was selected for binding studies with a plant lectin RCA120, the agglutinin from Ricinus communis. The interactions were measured quantitatively in real time using a BIAcore surface plasmon resonance instrument. Removal of much of the galactose from the thiolactosyl lipid in situ with beta-galactosidase showed that the lectin binding was highly specific. A dissociation constant KD = 8.77 x 10(-8) M was measured for 1-[2-[2-(2-[beta-D-galactopyranosyl-(1-->4)-1-thio-beta-D -glucopyranosyl]ethoxy)ethoxy]ethoxy]octadecane 30 which is four orders of magnitude greater than that determined for binding to lactose in solution. A concentration of lactose of > 80 mM was required to block the lectin binding to thiolactosyl lipid in a neomembrane.     

Proton-acceptor properties of azahomofullerene and fullerenoaziridine containing a cyanuric acid fragment

¹³C and ¹H NMR and UV spectral studies on 1,3-diallyl-5-[4-(azahomo[60]fullereno)butyl]hexahydro-1,3,5-triazine-2,4,6-trione ([5,6]-open isomer) and 1,3-diallyl-5-[4-(aziridino[60]fullereno)butyl]hexahydro-1,3,5-triazine-2,4,6-trione ([6,6]-closed isomer), as well as quantum-chemical calculations, showed that only the latter possesses weakly basic properties.     

Novel synthesis, properties, and NAD+-NADH type redox ability of 1,3-dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine- 2,4(1,3h)-dionylium ions annulated with additional pyrrolo[2,3-d]pyrimidine-1,3(2,4h)-dione and furan analogue, and their hydride adducts

[reaction: see text] A convenient preparation of novel cations 11a,b+ x BF4(-) and 12a,b+ x BF4(-), which are derived from annulation of the 1,3-dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium ion with additional pyrrolo[2,3-d]pyrimidine-1,3(2,4H)-dione and a furan analogue, was accomplished by a novel oxidative cyclization of 1,7-dihydro-7-[1',3'-dimethyl-2',4'(1',3'H)-dioxo-6'-(phenylamino)-pyrimidin-5'-yl]-1,3-dimethyl-10-phenylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dione 9 and its furan-analogue by using DDQ or photoirradiation under aerobic conditions. Structural characteristics of 11a,b+ and 12a,b+ were clarified on inspection of the UV-vis and NMR spectral data as well as X-ray crystal analyses. The stability of cations 11a,b+ and 12a,b+ is expressed by the pK(R+) values that were determined spectrophotometrically to be 10.7-12.6. The electrochemical reduction of 11a,b+ x BF4(-) and 12a,b+ x BF4(-) exhibited reduction potential at -0.93 to -1.00 (V vs Ag/AgNO3). The first reduction potential of 11a+ was reversible due to steric hindrance of two phenyl groups. The photoinduced oxidation reaction of 11a,b+ x BF4(-) and 12a,b+ x BF4(-) toward some amines under aerobic conditions was carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling numbers of 0.6-30.3. Furthermore, as an example of the NAD+-NADH models, the reduction of a pyruvate analogue and some carbonyl compounds with the hydride-adduct of 11a+ x BF4(-) was accomplished for the first time to give the corresponding alcohol derivatives.     

Synthesis and Pharmacological Screening of Pyridopyrimidines as Effective Anti-Diarrheal Agents through the Suppression of Cyclic Nucleotide Accumulation

The increased levels of cyclic nucleotides (cGMP and cAMP) in enterocytes trigger intracellular mechanisms of ion and fluid secretion into the lumen, causing secretory diarrhea. Twelve novel pyridopyrimidines derived from 5-(3,5-bistrifluoromethylphenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2,1 : 5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (FPIPP) were synthesized and evaluated on intracellular cyclic nucleotide accumulation. All compounds had no effect on either cyclic nucleotide basal levels or on pre-contracted aortic rings. The metabolic activity and viability in T84 cells, assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and the LDH (lactate dehydrogenase) assays, respectively, were not affected by incubation with the compounds (50 μM). Compound VI almost abolished cGMP accumulation (94 % inhibition) induced by STa toxin in T834 cells and significantly reduced (69 %) forskolin-induced cAMP accumulation in Jurkat cells. Compound VI was active in an in vivo model for diarrhea in rabbits. These results prompted us to perform a microscopic histopathological analysis of intestinal tissues, showing that only compound VI preserves the intestine without significant pathological changes and with a decreased inflammatory pattern in comparison to FPIPP. In vitro stability test revealed that compound VI is resistant to oxidation promoted by atmospheric oxygen.     

Dynamic 1H NMR Study of Aryl-Nitrogen Single Bond and Carbon-Carbon Double Bond Rotational Energy Barriers in Two Highly Functionalized Pyranopyrimidines

 The reactive 1:1 intermediate produced in the reaction between 2,6-dimethylphenyl isocyanide and dimethyl acetylenedicarboxylate was trapped by N,N′ -dimethylbarbituric acid to yield the isomeric products dimethyl 7-(2,6-dimethylphenylamino)-1,3-dimethyl-2,4-dioxo-4H-pyrano[3,2-d]pyrimidine-5,6-dicarboxylate and dimethyl (E)-2-((2,6-dimethylphenylamino)-(1,3-dimethyl-2,4,6-trioxo-pyrimidine-5-ylidene)-methyl)-but-2-enedioate in a nearly 1:1 ratio and an overall yield of 85%. Dynamic effects were observed in the ¹H NMR spectra of these compounds and were attributed to restricted rotation around the aryl-nitrogen single bonds and the polarized carbon-carbon double bond.     

Coordination compounds of some d metals with nitrophenylhydrazone oxopyridine (pyrimidine) derivatives: Crystal and molecular structure of C10H9N5O6

Twelve new d-metal complexes with 5-[(4-nitrophenyl)hydrazo]pyrimidine-2,4,6-trione (HL¹) and 4-methyl-5-[4-nitrophenylhydrazo]-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitryl (HL²) have been synthesized and separated out in the crystalline state. The crystal and molecular structures of HL¹ have been solved by X-ray diffraction analysis. The organic molecule exists in the crystalline state as a planar hydrazo tautomer stabilized by intramolecular hydrogen bonds. Metal coordination is bidentate chelate. The acid-base equilibria and complexation of the ligands in solutions have been studied, and the complexation constants have been found.     

Efficient one-pot synthesis of novel 6′,9′-dihydro-2H,7′H-spiro[pyrimidine-5,8′-[1,3]dioxolo[4,5-f]quinoline]-2,4,6(1H,3H)-trione derivatives under mild and “green” reaction conditions

In this paper, an efficient method is introduced for the synthesis of 7′,9′-disubstituted 6′,9′-dihydro-2H,7′H-spiro[pyrimidine-5,8′-[1,3]dioxolo[4,5-f]quinoline]-2,4,6(1H,3H)-trione derivatives under mild and “green” reaction conditions. The method is based on one-pot multicomponent reaction of an aldehyde, barbituric acid, and benzo[d][1,3]dioxol-5-amine in ethanol as a green and environmentally friendly solvent. The reaction has given the products in the highest isolated yield in the presence of acetic acid as catalyst under reflux conditions. Various aldehydes, bearing electron-donating or -withdrawing functionalities have been used under the optimized conditions and successfully gave the desired products (13 examples) in high isolated yields.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

6-Methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazolyl)-pyrimidin-4(1H)-one as CH acid in Michael reaction

Addition of 6-methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-yl)pyrimidin-4(1H)-one, a compound with two CH-acidic centers, to 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione proceeds with the participation of the atom C⁵ of pyrimidine ring. Under the realized reaction conditions the latter possesses a greater nucleophilicity as a result of the priority ionization. The obtained Michael adduct is unstable in the neutral aqueous medium and is decomposed into initial oxopyrazolylpyrimidinone, pyrimidine-2,4,6-(1H,3H,5H)-trione, and benzaldehyde.     

One-Step Synthesis of Furo[2,3-d]Pyrimidine-2,4(1H,3H)-Diones Using the Can-Mediated Furan Ring Formation

The reaction of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione with various alkenes or terminal alkynes in the presence of cerium(IV) ammonium nitrate (CAN) afforded the corresponding 5,6-dihydrofuro[2,3-d]pyrimidine-2,4(1H,3H)-diones or furo[2,3-d]pyrimidine-2,4(1H,3H)-diones in moderate to good yields.     

Dynamic 1H NMR Study of Aryl-Nitrogen Single Bond and Carbon-Carbon Double Bond Rotational Energy Barriers in Two Highly Functionalized Pyranopyrimidines

Summary.  The reactive 1:1 intermediate produced in the reaction between 2,6-dimethylphenyl isocyanide and dimethyl acetylenedicarboxylate was trapped by N,N′ -dimethylbarbituric acid to yield the isomeric products dimethyl 7-(2,6-dimethylphenylamino)-1,3-dimethyl-2,4-dioxo-4H-pyrano[3,2-d]pyrimidine-5,6-dicarboxylate and dimethyl (E)-2-((2,6-dimethylphenylamino)-(1,3-dimethyl-2,4,6-trioxo-pyrimidine-5-ylidene)-methyl)-but-2-enedioate in a nearly 1:1 ratio and an overall yield of 85%. Dynamic effects were observed in the ¹H NMR spectra of these compounds and were attributed to restricted rotation around the aryl-nitrogen single bonds and the polarized carbon-carbon double bond. Received September 18, 2000. Accepted (revised) November 22, 2000     

Synthesis of 4- and 6-methyl derivatives of 5,7-dioxo(4h,6h)-1,3-dithiolo[4,5-d]pyrimidine based on methylbarbituric acids,spectroscopic characteristics and acidity constants

We have obtained previously unknown 1-methyl- and 1,3-dimethyl-5-diethylaminothiocarbonylthiobarbituric acids by reaction of sodium diethyldithiocarbamate with 5-phenyliodonium betaines of 1-methyl- and 1,3-dimethylbarbituric acids. Cyclization of these compounds upon heating in conc. H₂SO₄ gives methyl-substituted 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-diethylimmonium hydrosulfates; the derivative of 1-methylbarbituric acid forms a mixture of 4-methyl- and 6-methyl-substituted compounds (21). We isolated perchlorates of 4-methyl- and 4,6-dimethyl-substituted derivatives in pure form. By treatment of the immonium salt with sodium sulfide or selenide, we obtained 4-methyl- and 4,6-dimethyl-5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine-2-thiones and 4-methyl-, 6-methyl-, and 4,6-dimethyl-2-selenones. We characterized the isomeric 4- and 6-methyl-substituted selenones by electronic absorption spectra and ionization constants (7.65 and 4.0). The differences in the pK values and in the electronic absorption spectra makes it possible to distinguish the substitution site in N-mono-substituted derivatives of 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1526–1533, November, 1993.     

New,convenient synthesis of 2-alkyl- and 2-vinylpyrazolo[3,4-d]-pyrimidine derivatives

Treatment of 1,3-dimethyl-6-hydrazinouracil with the appropriate dimethylformamide dialkylacetal afforded the, corresponding 2-alkyl-5,7-dimethylpyrazolo[3,4-d]pyrimidine-4,6-(5H,7H)diones. The reaction of 1,3-dimethyl-6-(α-methylbenzylidenehydrazino)uracils with dimethylformamide dimethylacetal or triethyl orthoformate gave the corresponding 5,7-dimethyl-2-vinylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)diones, respectively. Similarly, treatment of 1,3-dimethyl-6-(α-methylbenzylidenehydrazino)uraeils with triethyl orthopropionate yielded the corresponding 5,7-dimethyl-3-ethyl-2-vinylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)diones.     

A convenient one-pot synthesis of substituted 2-pyrone derivatives

2-Pyrone derivatives were prepared in a one step procedure from readily available (chlorocarbonyl)phenyl ketene and 1,3-diketones such as 2,4-pentanedione, 1,3-diphenyl-1,3-propanedione, 1-phenyl-1,3-butanedione, 1,3-cyclohexanedione, 5,5-dimethyl-1,3-cyclohexanedione, 1,3-dimethyl-pyrimidine-2,4,6-trione and ethyl 2,4-dioxopentanoate. A mechanism is presented to account for the formation of the products. This method provides an easy route to prepare 3,4,5,6-tetrasubstituted 2-pyrones in good to excellent yields and in a short experimental time.     

Synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides

The method for the synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones is described. It is shown that the reaction of phosphorus trichloride, 2-pyrrolidones and 6-aminopyrimidines brings to condensation producing 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides. The reaction of 6-imino-1,3-dimethyl-5-tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinedione with benzoyl chloride produces 10-benzoyl-2,4-dimethyl-6-phenyl-1,2,3,4,8,9-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]pyrimidine-1,3-dione. A method for the selective reduction of the carbomethoxy group of methyl 5-(4-imino-1,3-dimethyl-2,6-dioxohexahydro-5-pyrimidinyliden)-2-pyrrolidine carboxylate by system NaBH₄/1,4dioxane/CoCl₂/PEG-400 is described.     

Design and the synthesis of 1-heteroaryl-1,2,3-triazoles connected to coumarins via ether linker

In this paper, we report an efficient and versatile methodology for the synthesis of a series of novel heteroaryl-1,2,3-triazoles connected to 4-methylcoumarin (4-methyl-2H-chromen-2-one) via oxymethylene linker. The desired molecules were accessed by both two-step synthesis and the one-pot copper catalyzed cycloaddition reaction of heteroaromatic azides with coumarin containing acetylenes. The developed protocol was found to be facile and effective for preparing a series of novel heteroaryl-1,2,3-triazole-coumarin conjugates in excellent yields. Practical utility of one-pot protocol has been confirmed by the successful gram-scale synthesis of 1,3-Dimethyl-6-(4-[([4-methyl-2-oxo-2H-chromen-7-yl]oxy)methyl]-1H-1,2,3-triazol-1-yl)pyrimidine-2,4(1H,3H)-dione.