Indole derivatives

5-Substituted (butyl, phenyl)-5-skatyl(5-methoxyskatyl)barbituric acids were obtained by alkylation of the corresponding barbituric acids with gramine and 5-methoxygramine in dimethylformamide and dimethyl sulfoxide. 5,5-Dialkylation products were obtained in the alkylation of barbituric and thiobarbituric acids with gramine.     

Reaction of 4-acylaminomethylpyridine N-oxides with 5-monosubstituted barbituric acids in presence of acetic anhydride

The 5-alkyl-5-[(3,5-dimethylbenzoylamino)(4-pyridyl)methyl]barbituric acids are obtained in the title reactions, but they fail when barbituric or 5-phenylbarbituric acids are used. These results are explained by the pK_a values of barbituric acids.     

Ruthenium-catalyzed selective synthesis of monoalkylated barbituric acids through “borrowing hydrogen” methodology

An environmentally benign alkylation of barbituric acids via “borrowing hydrogen” process with ruthenium catalysis has been established. The corresponding 5-(alkyl)barubituric acids were obtained in good to excellent yields with low catalyst loading. Various substrates including aliphatic alcohols were tolerated in the present catalytic system. A novel method for construction of barbituric acid-fused benzopyrane derivatives was also demonstrated.     

5-(色酮基-3-次甲基)(硫代)巴比妥酸的合成

将巴比妥酸或硫代巴比妥酸、3-甲酰基色酮在乙酸-乙酸酐溶液(含乙酸酐10%)中进行缩合反应,制备了5-(色酮基-3-次甲基)(硫代)巴比妥酸.并经元素分析,IR,1H NMR及13C NMR确证了产物的结构.     

Reaction of Barbituric, 2-Thiobarbituric Acids and Their Derivatives with 2-Carboxybenzaldehyde and Opianic Acid: Synthesis and Tautomerism of 5-(3'-Oxo-1',3'-dihydroisobenzofuran-1'-yl)barbituric Acids and Their 2-Thio Analogs

The reaction of barbituric, N-alkylbarbituric acids, and their 2-thio analogs with carboxybenzaldehyde and 2-carboxy-3,4-dimethoxybenzaldehyde leads to the formation of the corresponding 5-(3'-oxo-1',3'-dihydroisobenzofuran-1'-yl)barbituric and 2-thiobarbituric acids, the structures of which were studied by ¹H and ¹³C NMR spectroscopy and mass spectrometry. In DMSO the derivatives of barbituric acid exist in the form of mixtures of the ketone and enol tautomers, while their 2-thio analogs exist in the enol form. In chloroform the tautomeric equilibrium is displaced fully toward the ketone form.     

Microtechniques for the gas chromatographic determination of barbiturates in small blood samples

A method for the determination of therapeutic levels of barbituric acids in 25 microliter of whole blood is described. After extraction and controlled concentration of the extract to a volume of 5 microliter, the barbituric acids are N,N'-dimethylated using a microrefluxer. Of the total extract 20-100% is injected into the gas chromatograph. Low blanks, recoveries of 70--80% and peak ratios that are comparable to those in calibration experiments are obtained provided the detailed working instructions are followed strictly. In addition, barbiturates were determined (1 ng in 25 microliter blood) using column-switching devices and nitrogen-sensitive detection.     

Azines and Azoles: CXX. Synthesis of Acyclic Analogs of N1-Ribosides of Barbituric Acid and Its 5-ylidene Derivatives

The reaction of 2,4,6-tris(trimethylsiloxy)pyrimidine with 2-oxabutane-1,4-diyl diacetate in methylene chloride in methylene chloride in the presence of SnCl₄ proceeds regioselectively to form 1-[(2-acetoxyethoxy)methyl]barbituric acid. The latter is readily deacetylated to a free acyclic analog of N-ribosides of barbituric acid. 1-[(2-Acetoxy- and 2-hydroxyethoxy)methyl]barbituric acids easily react with aromatic and heterocyclic aldehydes in water and organic solvents, forming 5-ylidenebarbituric acids. The structure of the products was proved by ¹H NMR and UV spectroscopy. Certain of the products exhibit a moderate antimicrobial and antiviral activity.     

Synthesis of derivatives of new heterocyclic system 5,7-dioxo(4h,6h)-1,3-dithiolo[4,5-d]pyrimidine on the basis of barbituric acid

The 5-phenyliodonium betaine of barbituric acid reacts with sodium diethyldithiocarbamate to form 5-(diethylaminothiocarbonylthio)barbituric acid, which is cyclized in concentrated H₂SO₄ solution to form the cation of 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidine, isolated in the form of the perchlorate and the chloride. These salts are split by sodium sulflde or selenide, forming 5-[diethylaminothio (seleno)carbonylthio]-4-thiobarbituric acids, which are cyclized by the action of concentrated HCl in an organic solvent to form 5,7-dioxo(4H,6H)-1,3-dithiolo[4,5-d]pyrimidinethione (selenone)-2. The thione and the selenone, as NH acids, form salts; alkylation of the tetrabutylammonium salt affords N₍₄₎-alkyl and N,N-dialkyl derivatives. The compounds that were obtained have been characterized by IR and PMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedenenii, No. 12, pp. 1667–1673, December, 1992.     

A malonic ester-type synthesis with 4-chloroquinoline utilizing highly acidic enols

A synthetic method of attaching carbon-chain substituents to the 4-position of the quinoline ring was developed. In our approach enolate anions were generated from highly acidic enols under conditions in which the 4-chloroquinoline can be N-acylated or N-protonated. Isopropylidene alkyl(4-quinolyl)malonates or 5-alkyl-5-(4-quinolyl)barbituric acids were obtained from the reaction of 4-chloroquinolines with isopropylidene alkylmalonates in acetic anhydride or with 5-alkylbarbituric acids by heating in the absence of solvent. Some of the products were hy-drolyzed and decarboxylated to give the corresponding 4-alkylated quinolines.     

Synthesis of 5-dialkylaminothiocarbonylthiobarbituric acids and 5-diethyiaminothiocarbonylthio-6-aminouracil

The title compounds are obtained by three different methods. The aminothiocarbonylthiolation of barbituric acids 1 and aminouracil ( 5 ) can be accomplished in one step by reaction with thiuram disulfides in the presence of potassium carbonate. On the other hand, compounds 4 can be obtained via the salt of chloro derivative 2 or the corresponding iodonium ylides 3 . The aminouracil derivative 7 was obtained in a similar fashion from 5 directly or via iodonium betaine 6 .     

Thiophene aldehyde and its derivatives. II

Condensation of thiophene-2-aldehyde with p-aminobenzoic and barbituric acids gives 2-thenylidene -p-aminobenzoic acid and 2-thenyl-idenebarbituric acid. Similarly, 5-nitro-thiophene-2-aldehyde gives 5-nitro-2-thenylidene-p-aminobenzoic acid and 5-nitro-2-thenyl-idenebarbituric acid. Condensation of thiophene-2-aldehyde with nitroethane gives 1-(2-thienyl)-2-nitroprop-1-ene; and 1-nitro-2-(2-thienyl-5-nitro) ethene is synthesized by nitrating thienylnitroethylene.     

Direct Synthesis of 5‐Aryl Barbituric Acids by Rhodium(II)‐Catalyzed Reactions of Arenes with Diazo Compounds

A commercially available rhodium(II) complex catalyzes the direct arylation of 5‐diazobarbituric acids with arenes, allowing straightforward access to 5‐aryl barbituric acids. Free N? H groups are tolerated on the barbituric acid, with no complications arising from N? H insertion processes. This method was applied to the concise synthesis of a potent matrix metalloproteinase (MMP) inhibitor.     

Syntheses on the basis of diethyl (2-morpholinoethyl)malonate

New functionally substituted butan-4-olides were synthesized by reactions of diethyl (2-morpholinoethyl) malonate with 2-(allyloxymethyl)oxirane, 4-(oxiran-2-ylmethyl)morpholine, N-ethyl-N-(oxiran-2-ylmethyl)aniline, and 1-chloro-2,3-epoxypropane. 5-[2-(Morpholino)ethyl]barbituric and -thiobarbituric acids were also synthesized.     

Preparation of Benzylidene Barbituric Acids Promoted by Infrared Irradiation in Absence of Solvent

Several benzaldehydes were condensed with barbituric acid under infrared irradiation, in absence of solvent, affording the corresponding 5-benzylidene barbituric acids.     

Synthesis of fused uracils: pyrano[2,3-d]pyrimidines and 1,4-bis(pyrano[2,3-d]pyrimidinyl)benzenes by domino Knoevenagel/Diels-Alder reactions

Abstract  

Knoevenagel condensation of barbituric acids with aromatic aldehydes containing one or two formyl groups was carried out. 5-Arylidenebarbituric acids underwent smooth hetero-Diels-Alder (HDA) reactions with enol ethers to afford cis and trans diastereoisomers of pyrano[2,3-d]pyrimidine-2,4-diones and 5,5′-(1,4-phenylene)bis[2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione] derivatives in excellent yields (75–88 %). Syntheses were realized by Knoevenagel condensation and HDA reaction in four different reaction conditions: Knoevenagel condensation in water and Diels-Alder reaction in methylene chloride solution, Knoevenagel condensation in water and Diels-Alder reaction without solvent, three-component one-pot reaction in methylene chloride solution, or three-component one-pot reaction in water. All reactions were carried out without catalyst at room temperature. The reactions of malononitrile with Knoevenagel condensation products of barbituric acids and heteroaromatic aldehydes or terephthalaldehyde were examined and did not provide corresponding pyranopyrimidines.     

Electrochemical oxidation of barbituric acids at low pH in the presence of chloride ion

Barbituric acid, 1-methylbarbituric acid and 1,3-dimethylbarbituric acid are electrochemically oxidized at the pyrolytic graphite electrode by way of a single voltammetric peak at pH 1 in the presence of chloride ion. At least four products are formed as a result of the reaction, the three major products, accounting for more than 80–90% of the oxidized barbituric acid, are the appropriately N-methylated 5,5′-dichlorohydurilic acids, 5,5-dichlorobarbituric acids and alloxans. The mechanism appears to proceed by an initial potential-controlling 1e/1H⁺ oxidation of the barbituric acids to give a barbituric acid radical. This can dimerize to hydurilic acid, which is then further electrochemically oxidized. However, this appears to be a minor route. The barbituric acid radical appears to be mainly further electrooxidized (1e) to a carbonium ion which further reacts with nucleophiles such as chloride ion to give 5-chlorobarbituric acid, or with water to give dialuric acid. Further electrochemical oxidation and chemical reactions of the latter species results in formation of the ultimate products.     

Three-component heterocyclization of 5-(arylmethylidene)pyrimidine-2,4,6(1<Emphasis Type="Italic">H</Emphasis>,3<Emphasis Type="Italic">H</Emphasis>,5<Emphasis Type="Italic">H</Emphasis>)-triones with aldehydes and amino acids

Previously unknown substituted 4-aryl-2,7,9-triazaspiro[4.5]decane-6,8,10-triones were synthesized in 50–70% yield by heating 5-(arylmethylidene)barbituric acids with N-methyl- or N-phenylglycine and para-formaldehyde or 4-methoxybenzaldehyde in boiling toluene for 14 h.     

A practical approach for spiro‐ and 5‐monoalkylated barbituric acids

The single step reactions of N,N′‐ substituted/‐unsubstituted barbituric acids with various alkyl dihalides under phase transfer catalytic conditions using DMF‐K₂CO₃ (base), TBAHSO₄ (catalyst) provide spirobarbituric acids in moderate to high yields. Irrespective of the existence of C₅‐monoalkylated compounds in the enolic form (confirmed by the isolation of some of its analogues), the second alkylation predominantly takes place at C₅. The underlying mechanism for the reaction is discussed. The 5,7‐dimethyl‐5,7‐diaza‐spiro[2.5]octane‐4,6,8‐trione undergoes ring opening with NaCN, PhSH, HS(CH₂)₂OH and Br₂ to provide 5‐monoalkylated barbiturates which are otherwise difficult to prepare by the usual alkylation of barbituric acids.     

微波辐射下吡啶[2,3-d]嘧啶衍生物的高效合成

本文以等摩尔的芳醛,巴比妥酸（或1,3-二甲基巴比妥酸）,5-氨基-2-甲基苯[d]噻唑为原料,以醋酸和乙二醇为溶剂,微波辐射下多组分一锅法合成了一系列新的吡啶[2,3-d]嘧啶衍生物。这种方法具有产率高,操作简便,反应时间短等优点。     

Chemical Modification of Plant Alkaloids. 2. Reaction of Cotarnine with Barbituric Acid Derivatives and Structure of 5-Dihydrocotarnylbarbituric Acids

The reaction of barbituric acid and its N-substituted derivatives and 2-thio analogs with cotarnine forms 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)barbituric acids, a new class of zwitter-ions, the structure of which was studied by ¹ H and ¹³ C NMR spectroscopy and mass spectrometry. The prepared compounds exist in solution as stable intermolecular associates and have a complicated H-bonded structure.