Five-membered 2,3-dioxo heterocycles: LXIX. Direct heterocyclization of [3,4-dihydroisoquinolin-1(2H)-ylidene]-acetamides with 5-arylfuran-2,3-diones. Crystalline and molecular structure of (3E,5Z)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-5-(2-oxo-2-phenylethylidene)pyrrolidine-2,4-dione

5-Arylfuran-2,3-diones react with (Z)-2-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]acetamides to give (3E,5Z)-5-(2-aryl-2-oxoethylidene)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-pyrrolidine-2,4-diones. The crystalline and molecular structures of one of the products were determined by X-ray analysis.     

Aldimines of 5-aminouracil as reagents in 1,3-dipolar cycloaddition reaction

Abstract  

The condensation of 5-aminouracil with aromatic aldehydes gave the appropriate C-arylimines, which were used in [2+3] cycloaddition with nitrile oxides derived from 4-substituted benzaldoximes. As a result of the dipolar cycloaddition reaction several hitherto unknown 5-(3,5-diphenyl-1,2,4-oxadiazol-4(5H)-yl)pyrimidine-2,4(1H,3H)-diones have been obtained in satisfactory yields.     

Facile and efficient synthesis of quinazoline-2,4(1H,3H)-diones through sequential hydrogenation condensation

The heterocyclizations from various methyl (2-nitrobenzoyl)carbamates to substituted quinazoline-2,4(1H,3H)-diones under hydrogenation conditions were investigated in this study. In the presence of p-toluenesulfonic acid monohydrate in methanol, various quinazoline-2,4(1H, 3H)-diones were obtained in good to excellent yields within 12?h. The reaction was proposed to proceed through the cascade reactions of nitro reduction and condensation.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Synthesis of 5′-azido- and 5′-amino-2′,5′-dideoxynucleosides from quinazoline-2,4(1H,3H)-diones

Quinazoline-2,4(1H,3H)-diones 4 were silylated and condensed with methyl 5-azido-2,5-dideoxy-3-O-(4-methylbenzoyl)-α,β-D-erythro-pentofuranoside (3) using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as the catalyst to afford the corresponding 5′-azidonucleosides 5 . 1-(5-Azido-2,5-dideoxy-α-D-erythro-pentofuranosyl)quinazoline-2,4(1H,3H)-diones 6 and the corresponding β anomers were obtained by treating 5 with sodium methoxide in methanol at room temperature. 6-Methyl-1-(5-amino-2,5-dideoxy-β-D-erythro-pentofuranosyl)quinazoline-2,4(1H,3H)-dione (8) was obtained by treatment of the corresponding azido derivative 7 with triphenylphosphine in pyridine, followed by hydrolysis with ammonium hydroxide.     

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.     

Tetracarbonyl Systems: VII. Reactions of 1,3,4,6-Tetracarbonyl Compounds with o-Aminothiophenol in the Synthesis of Regioisomeric 3(2)-Aroylmethylene-1,4-benzothiazin-2(3)ones

In reaction of 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-diones with o-aminothiophenol (3Z)-3-aroylmethylene-3,4-dihydro-2H-1,4-benzothiazin-2-ones were obtained in a preparative yield. In solution of the latter compounds an enamine-imine tautomerism was observed. In reaction of ethyl esters or amides of 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acids with the o-aminothiophenol regioisomeric 2-aroylmethylene-2H-1,4-benzothiazin-3(4H)-ones were formed.     

A one-step preparation of pyrido[3,4-d]pyrimidine ring system by reaction of 5-formyl-1,3,6-trimethyl-pyrimidine-2,4(1H,3H)-dione with primary amines

6,7-Dihydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-diones were obtained in high yields from the reaction of 5-formyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione ( 1 ) and primary amines. For this pyridopyrimidine synthesis the following reaction pathway is proposed; the [1,5]-hydrogen shift of 1 gives a 5,6-dihydro-5,6-dimethylenepyrimidine-2,4(1H,3H)-dione intermediate. The cycloaddition reaction of the intermediate with aldimines from 1 and the primary amines affords 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(1H,3H)-diones, which are dehydrated to the final products.     

The first entry to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones

Wittig olefination of 3-aminoquinoline-2,4(1H,3H)-diones 1 with ethyl (triphenylphosphoranylidene)acetate (Ph₃PCHCO₂Et) afforded (E)-3-amino-4-ethoxycarbonylmethylene-1,2,3,4-tetrahydro-2-quinolones (E)-2 and pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3. An alternative approach for the synthesis of 3 via 3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7, their corresponding triphenylphosphonium salts 8, and ylides A that undergo intramolecular Wittig reaction, was investigated. Under the applied reaction conditions, the phosphonium salts 8 and ylides A are so unstable that they partly decompose to 3-acetamidoquinoline-2,4(1H,3H)-diones 9 during the synthesis of 3.     

Synthesis of novel 1,3-oxazino[6,5-b]indole-2,4-(3H,9H)-dione and 2H-1,3,5-oxadiazino[3,2-a]indole-2,4-(3H)-dione from oxindoles

Two novel tricyclic ring systems were designed as serine protease inhibitors and synthesized from oxindoles; the first series, 1,3-oxazino[6,5-b]indole-2,4-(3H,9H)-diones, were prepared from 2,3-dihydro-2-oxo-(1H)-indole-3-carboxamides and phosgene in tetrahydrofuran with triethylamine. The second, a 2H-1,3,5-oxadiazino[3,2-a]indole-2,4-(3H)-dione was made using a similar cyclization on 2,3-dihydro-2-oxo-N-phenyl-(1H)-indole-1-carboxamide.     

Alkylation of quinazoline-2,4(1H,3H)-diones with 1,4-dibromo-2-methylbut-2-ene under phase-transfer-catalysis

Quinazoline-2,4(1H,3H)-dione ( 1 ) was reacted with 1,4-dibromo-2-methylbut-2-ene ( 2 ) to give two dialkylated products and two monoalkylated products. The reaction of 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione ( 8 ) with 1,4-dibromo-2-methylbut-2-ene ( 2 ) resulted in the formation of three dialkylated products.     

Limitations of the Wittig-Horner-type annulation of fluorobutenolide moiety to 3-hydroxyquinoline-2,4(2H,3H)-diones. Novel modifications of the Perkow reaction including fluorinated acyloxy leaving groups

3-(Fluoroacyloxy)quinoline-2,4(1H,3H)-diones react with triethyl phosphite to afford either the product of the Perkow reaction or the corresponding 4-ethoxyquinolin-2(1H)-one. In both reactions, the fluorocarboxylate anion acts as the leaving group. For the corresponding 3-(fluoroiodoacetoxy) derivative this observation precludes the application of the intramolecular Wittig-Horner synthesis to modify quinoline-2,4(1H,3H)-diones by the annulation of a fluorinated but-2-enolide moiety.     

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.     

New [f]-fused xanthines: Synthesis of 1,3-dipropyl-1H,3H-pyrazino,pyrido, pyrimido and pyrrolo[2, 1-f]purine-2,4-diones

Synthesis of 1,3-dipropyl-1H,3H-pyrazino, pyrido, pyrimido and pyrrolo[2,1-f]purine-2,4-diones, starting from 5,6-diamino-1,3-dipropylpyrimidine-2,4-dione 1 and 6-chloro-1,3-dipropylpyrimidine-2,4-dione 14 is described. A new synthetic approach to 1,3-dipropyl-1H,3H-pyrido(or pyrazino)[1′,2′-1,2]pyrimido[4,5-d]pyrimidine-2,4,5-triones 19 e, f, h has been also developed.     

Heterocyclic analogs of prostaglandins: III. Synthesis of 10-oxa-13-aza, 11-oxa-13-aza, and 9-oxa-7-aza prostanoids from 3-acyl-and 3-(3-arylprop-2-enoyl)furan-2,4-diones

A number of new 10-oxa-13-aza, 11-oxa-13-aza, and 9-oxa-7-aza prostanoids belonging to the B series were synthesized on the basis of 3-acyl-and 3-(3-arylprop-2-enoyl)furan-2,4(3H,5H)-diones. The scheme of synthesis includes selective hydrogenation of the exocyclic carbonyl group and reduction of the conjugated double bond in the acyl fragment of 3-acyl-and 3-(3-arylprop-2-enoyl)furan-2,4(3H,5H)-diones to obtain 3-alkyl-and 3-(3-arylpropyl)furan-2,4(3H,5H)-diones, transformation of the latter into the corresponding regioisomeric enol ethers via regioselective O-alkylation, and treatment of the enol ethers with primary aliphatic amines.     

Synthesis of thietanyl-substituted pyrimidine-2,4(1H,3H)-dions

Reactions of 6-methylpyrimidine-2,4(1H,3H)-dione or 5-hydroxy-6-methyl-pyrimidine-2,4(1H,3H)-dione with 2-chloromethylthiirane afforded the corresponding substituted 1-(thietan-3-yl)pyrimidine-2,4(1H,3H)-diones. The calculations in the framework of approximations PBE/3z, B3LYP/6-31G++(d,p) and MP2/6-31G++(d,p) showed that the alkylation occurred at the atom N¹ of the pyrimidine ring.     

Synthesis of new thietanylpyrimidine and thietanylimidazole derivatives

New thietanyl-substituted derivatives of pyrimidine-2,4(1H,3H)-dione and imidazole were synthesized. The alkylation of 6-methylpyrimidine-2,4(1H,3H)-diones with 2-chloromethylthiirane in water involved the N¹ atom of the pyrimidine ring and afforded 6-methyl-1-(thietan-3-yl)-pyrimidine-2,4(1H,3H)-diones. Under analogous conditions 6-aminopyrimidine-2,4(1H,3H)-dione gave rise to 6-(thietan-3-ylamino)pyrimidine-2,4(1H,3H)-dione. Unsymmetrically substituted 2-methyl-4(5)-nitro- and 5(4)-bromo-2-methyl-4(5)-nitro-1H-imidazoles reacted with 2-chloromethylthiirane to produce mixtures of isomeric 2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles and 5(4)-bromo-2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles.     

Cesium carbonate catalyzed efficient synthesis of quinazoline-2,4(1H,3H)-diones using carbon dioxide and 2-aminobenzonitriles

Abstract

An efficient protocol for the synthesis of quinazoline-2,4(1H,3H)-diones derivatives from 2-aminobenzonitriles with carbon dioxide using catalytic amount of cesium carbonate has been developed. 6,7-Dimethoxyquinazoline-2,4(1H,3H)-dione, which is one of the key intermediate for the synthesis of several drugs (Prazosin, Bunazosin and Doxazosin) was synthesized. The effect of different reaction parameters like influences of bases, solvent, temperature, CO₂ pressure and reaction time were investigated for the title reaction.     

Retro-ene reactions in heterocyclic synthesis. IV. A new synthetic method for 6-hydroxypyrimidin-4(3H)-ones and 1,3,5-triazine-2,4(1H,3H)-diones

N-t-Butylbenzamidines 1 reacted with diphenyl phenylmalonate or diphenyl methylmalonate to give 6-hydroxypyrimidin-4(3H)-ones 4 or 5. Amidines 1 on reaction with diphenyl imidodicarboxylate afforded 1,3,5-triazine-2,4(1H, 3H)-diones 8.     

Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones using the Vilsmeier reaction

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives.