Reaction of 3-aminoquinoline-2,4-diones with nitrourea. Synthetic route to novel 3-ureidoquinoline-2,4-diones and imidazo[4,5-c]quinoline-2,4-diones

1-Unsubstituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with 1-substituted and 1,1-disubstituted ureas in boiling acetic acid to give 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones. In contrast, the reaction of these amines with nitrourea in dioxane affords novel 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones or 9b-hydroxy-3a-alkyl/aryl-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones, which can smoothly be dehydrated to 3a-alkyl/aryl-3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. All three types of products can be converted to 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones by refluxing in acetic acid.     

Reaction of 3-aminoquinoline-2,4-diones with isothiocyanic acid—an easy pathway to thioxo derivatives of imidazo[1,5-c]quinazolin-5-ones and imidazo[4,5-c]quinolin-4-ones

3-Amino-1H,3H-quinoline-2,4-diones react with thiourea or potassium thiocyanate in boiling acetic acid to give novel 2,3-dihydro-3-thioxoimidazo[1,5-c]quinazolin-5(6H)-ones in high yields. However, if the starting compounds are substituted with a benzyl group at position 3, a C-debenzylation proceeds to give 2,3-dihydro-2-thioxo-1H-imidazo[4,5-c]quinolin-4(5H)-ones. According to a proposed reaction mechanism, a molecular rearrangement of the primarily formed mono-substituted thiourea takes place. All compounds were characterized by ¹H, ¹³C and ¹⁵N NMR and IR spectroscopy as well as by mass spectrometry.     

Reaction of 3-chloroquinoline-2,4-diones with ethanolamine and rearrangement of the reaction products

The reaction of tertiary α-chloroketones with ethanolamine has not been hitherto described in the literature. Herein, we describe the reaction of tertiary 3-chloroquinoline-2,4-diones with ethanolamine to give novel 3-(2-hydroxyethylamino)quinoline-2,4-diones. These compounds provide 3-(2-oxooxazolidin-3-yl)quinoline-2,4(1H,3H)-diones and new compounds with dimeric character after reaction with triphosgene. Molecular rearrangement proceeds during the reaction of 3-(2-hydroxyethylamino)quinoline-2,4-diones with isocyanic acid. Three types of reaction products arise: 2-(2-hydroxyethyl)imidazo[1,5-c]quinazoline-3,5-diones, 3-(2-hydroxyethyl)-3,3a-dihydro-2H-imidazo[4,5-]quinoline-4(5H)diones and primarily 5-hydroxy-1-(hydroxyethyl)-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones. The reaction mechanism and product stereochemistry are discussed. The ¹H, ¹³C and ¹⁵N NMR spectra of the prepared compounds were measured, and all resonances were assigned from appropriate two-dimensional experiments.     

Reaction of 1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones with urea. Synthetic route to novel 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones, 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones, and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones

1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in position 3 give 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react according to the character of the other substituent in position 3. If there is a hydrogen atom α to the carbon atom C(3), 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by their ¹H, ¹³C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by ¹⁵N NMR data.     

Rearrangement of furo[2,3-c]quinoline-2,4(3aH,5H)-diones to furo[3,4-c]quinoline-3,4(1H,5H)-diones

Thermally assisted base-catalyzed rearrangement of furo[2,3-c]quinoline-2,4(3aH,5H)-diones 1 to the corresponding furo[3,4-c]quinoline-3,4(1H,5H)-diones 2 is reported, and a mechanism of the transformation is proposed.     

Reaction of 1-substituted 3-aminoquinoline-2,4-diones with isothiocyanates. An easy pathway to generate novel 2-thioxo-1′H-spiro[imidazoline-5,3′-indole]-2,2′-diones

3-Butyl-3-amino-1H,3H-quinoline-2,4-diones react with isothiocyanates to give novel 3a-butyl-9b-hydroxy-2-thioxo-1,2,3,3a,5,9b-hexahydro-imidazo[4,5-c]quinolin-2-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric acid to give (E)- and/or (Z)-4-butylidene-2-thioxo-1′H-spiro[imidazoline-5,3′-indole]-2,2′-diones. All compounds were characterized by their ¹H, ¹³C, IR and MS spectra, and some of them also by ¹⁵N NMR. The structure of one compound was investigated by single-crystal X-ray diffraction.     

Molecular rearrangement of 1-substituted 9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones—an unexpected pathway to new indole and imidazolinone derivatives

1-Substituted 3a-alkyl/aryl-9b-hydroxy-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones and 3′-substituted 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones react in boiling acetic acid to give 2-alkyl/aryl-1H-indol-3-yl-ureas and/or 1,3-bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)-phenyl]-ureas. By the action of hydrochloric acid, the first of them rearrange to give 4-(2-aminophenyl)-1,3-dihydroimidazol-2-ones. The structure of 1,3-bis[2-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)-phenyl]-ureas was confirmed by their synthesis. All compounds were characteried by their ¹H NMR, ¹³C NMR, IR spectra, atmospheric pressure chemical ioniation mass spectra, and some of them also by ¹⁵N NMR spectroscopic data.     

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.     

Regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by radical cyclization

5-Hydroxy uracils or 4-hydroxy[1]benzopyran-2-ones were refluxed with 2-bromobenzyl bromides in acetone in the presence of anhydrous potassium carbonate to afford a number of 5-(2′-bromobenzyloxy) pyrimidine-2,4-dione (80-92%) or 4-(2′-bromobenzyloxy) benzopyran-7-ones (70-82%) respectively. These were then refluxed with tri-n-butyltin chloride and sodium cyanoborohydride in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) for 3-4 h to give 1H,3H,6H [2]benzopyrano[4,3-d]pyrimidine-2,4-diones (75-85%) or 12H-benzopyrano[3,2-c][1]benzopyran-5-ones (70-85%) respectively.     

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.     

Reaction of 3-phenyl-3-aminoquinoline-2,4-diones with isothiocyanates. Facile access to novel spiro-linked 2-thioxoimidazolidine-oxindoles and imidazoline-2-thiones

3-Phenyl-3-amino-1H,3H-quinoline-2,4-diones (1) react with alkyl or aryl isothiocyanates to give novel 9b-hydroxy-3a-phenyl-1,2,3,3a-tetrahydro-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concentrated hydrochloric acid to give novel 5-phenyl-2-thioxospiro[4H-imidazol-4,3′-[3H]indol]-2′(1′H,3H)-ones, 5-hydroxy-5-phenyl-2-thioxospiro[imidazolidine-4,3′-[3H]indol]-2′-ones and (2-methylaminophenyl)-5-phenyl-1H-imidazole-2(3H)-thiones. All compounds were characterized by their ¹H, ¹³C, IR and MS data, and in some cases also by ¹⁵N NMR data. The structures and compositions of four compounds were confirmed by single crystal X-ray diffraction.     

Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.     

Synthesis of 2-thioxoimidazolines via reaction of 1-unsubstituted 3-aminoquinoline-2,4-diones with isothiocyanates

3-Alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with alkyl/aryl isothiocyanates to give 3a-alkyl/aryl-1,2,3,3a-tetrahydro-9b-hydroxy-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric acid to give novel 4-(2-aminophenyl)-1H-imidazole-2(3H)-thiones, 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phenyl)ureas and minor N-(2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenyl)acetamides. In the presence of ethanol, the starting compounds rearrange in boiling acetic acid to give ethyl 2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenylcarbamates. All compounds were characterized by their ¹H, ¹³C, IR and MS spectra and some of them also by ¹⁵N NMR data. The structures of two compounds were supported by single-crystal X-ray diffraction.     

Chemical fixation of CO2: efficient synthesis of quinazoline-2,4(1H, 3H)-diones catalyzed by guanidines under solvent-free conditions

Guanidines were proved to be efficient catalysts for the chemical fixation of carbon dioxide with 2-aminobenzonitriles under solvent-free conditions. Notably, the catalysts with low loading worked well for a variety of 2-aminobenzonitriles. As a result, quinazoline-2,4(1H, 3H)-diones by employing present protocol were obtained in good yields under mild conditions. This process represents an alternative approach for the greener chemical fixation of CO₂ to afford valuable compounds.     

An efficient ionic liquid mediated synthesis of substituted 5H[1,3]-thiazolo[2,3-b]quinazoline-3,5-(2H)-dione and 5H-thiazolo[2,3-b]quinazolin-5-one

A new, environmentally benign two-step synthesis of 5H[1,3]-thiazolo[2,3-b]quinazoline-3,5-(2H)-dione and 5H-thiazolo[2,3-b]quinazolin-5-one derivatives has been accomplished stepwise. The substituted 2-aminobenzoic acid upon condensation with thiourea in 1-butyl-3-methylimidazolium bromide at moderate temperature under nitrogen atmosphere yielded 2-thioxo-1H-4-quinazolinones. The resulting intermediate 2-thioxo-1H-4-quinazolinones, when reacted with 2-chloroethanoic acid/2-chloropropanal underwent cyclization to yield the desired product in excellent yields.     

One-pot synthesis of novel 1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-diones

A facile synthesis of novel 1,2,6,7-tetrahydro-3H-pyrazolo[4,3-c]pyridine-3,4(5H)-diones has been achieved. The operationally simple procedure, using readily available intermediates, allows for rapid derivatisation of the pharmacophore with alkyl, aryl and heteroaryl substituents.     

Zinc triflate-catalyzed synthesis of pyrazino[2,1-b]quinazoline-3,6-diones

Using zinc triflate, the direct one-pot double cyclodehydration of linear tripeptides to the total synthesis of pyrazino[2,1-b]quinazoline-3,6-diones (1a-l) on solid support was achieved with good overall yields in short reaction time. These syntheses of the pyrazino[2,1-b]quinazoline-3,6-diones were conveniently achieved in only three steps, starting from the amino acid-bound Wang resin.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

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.