SYNTHESIS OF 15H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]QUINAZOLINE-7,13,15-TRIONES AND 14H-ISOQUINO[2′,3′:3,4]IMIDAZO[2,1-B]BENZO[G]QUINAZOLINE-8,14,16-TRIONE AS NEW POLYCYCLIC FUSED-RING SYSTEMS

3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (3) and 2-sub-stituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones (4a–l) were prepared from the reaction of 2-thiohydantoin (2) and 3-substituted 2-thiohydantoin (5a–l) with 2-formyl benzoic acid (1). Alkylation of 3 under an anhydrous basic conditions afforded 4a–i. The alkylation of 3 in aqueous basic solution afforded 3-(alkylmercapto)imidazo[1,5-b]isoquinoline-1,5-diones (7a,b). Reactions of the aromatic amino acids 9a,b and 12 with 7a afforded 2-(2H-1,5 dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)benzoic acids (10a, b) and 3-(2H-1,5-dioxoimidazo[1,5-b]isoquinazolin-3-ylideneamino)2-naphthalenecarboxylic acid (13), which were then cyclyzed by heating in acetic anhydride to afford 15H-isoquino[2′,3′ :3,4] imidazo[2,1-b]quinazoline-7,13,15-triones (11a,b) and 14H-isoquino[2′,3′:3,4]imidazo[2,1-b]benzo[g]quinazoline-8,14,16-trione (14). Some of the new compounds were tested for their antitumor activities.     

Nitrogen bridgehead compounds. Part 88. Synthesis of 3H, 7H-[1,4]diazepino[3,4-b]quinazoline-3,7-diones

3H,7H-[1,4]Diazepino[3,4-b]quinazolone-3,7-diones 9, 11 were synthesized starting from 2-(1-bromo-ethyl)quinazolin-4(3H)-ones 3 and 17 via 2-[1-(4-methoxyphenylamino)ethyl]quinazolin-4(3H)-ones 4 and 18. Cyclization of 3-[2-(1-bromoethyl)-4-oxo-3,4-dihydroquinazolin-3-yl)propionic acid 14 by the action of triethylamine provided the first representative of the tricyclic 7H-[1,4]oxazepino[3,4-b]quinazoline-3,7-dione system, compound 15. The new tricyclic derivatives 9, 11 and 15 are characterized by uv, ir and ¹H nmr spectroscopy.     

Synthesis of 12-aryl-1-oxo-1,2,3,4,5,12-hexahydroindolo-[2,1-b]quinazoline-6-carbonitriles by recyclization of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles

A general and convenient method for the synthesis of 12-aryl-1-oxo-1,2,3,4,5,12-hexahydroindolo[2,1-b]quinazoline-6-carbonitriles was proposed. The method is based on the recyclization of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles. The structure of 12-(3-methoxyphenyl)-8-methyl-1-oxo-1,2,3,4,5,12-hexahydroindolo[2,1-b]quinazoline-6-carbonitrile was studied by X-ray diffraction analysis.     

The synthesis of lin-benzoreumycin,lin-benzo-1-methylxanthine,and lin-benzo-1,9-dimethylxanthine

Commencing with 7-chloro-3-methylquinazoline-2,4(1H,3H)-dione ( 9a ), a five step synthesis of 7-methylpyrimido[5,4-g]-1,2,4-benzotriazine-6,8(7H,9H)-dione (lin-benzoreumycin, 6 ) has been accomplished. A synthesis of 1,7-dimethylpyrimido[5,4-g]-1,2,4-benzotriazine-6,8(1H,7H)-dione (lin-benzotoxoflavin, 5 ) employing an intermediate from the preparation of 6 (i.e., 7-chloro-3-methyl-6-nitroquinazoline-2,4(1H,3H)-dione, 9b ) was attempted but could not be accomplished beyond the dihydro precursor of 5 (i.e., 12 ). Compound 9b did lead to successful preparations of 7-methylimidazo[4,5-g]quinazoline-6,8(5H,7H)-dione (lin-benzo-1-methylxanthine, 7 ) and 3,7-dimethylimidazo[4,5-g]quinazoline-6,8(5H,7H)-dione (lin-benzo-1,9-dimethylxanthine, 8 ) by first reacting 9b with ammonia (for 7) or methylamine (for 8 ) followed by reductive cyclization in formic acid.     

The synthesis of two novel fused thienopyridopyridazines

Two previously unknown thienopyridopyridazine ring systems, thieno[2′,3′:5,6]pyrido[2,3-d]pyridazine-5,8,9(4H,6H,7H)-trione ( 4 ) and thieno[3′,2′:5,6]pyrido[2,3-d]pyridazine-4,5,8(6H,7H,9H)-trione ( 10 ) were synthesized and their chlorination reactions with phosphorus oxychloride were investigated.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

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.     

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.     

Synthetic transformations of methylenelactones of eudesmanic type. Behavior of isoalantolactone under the conitions of heck reaction

By Heck reaction of isoalantolactone with aryl bromides or aryl iodides (3aR,4aS, 8aR,9aR,E)-3-arylmethylidene-8a-methyl-5-methylidenedecahydronaphtho[2,3-b]furan-2(3H)-ones and (4aS,8aR,9aS)-3-arylmethyl-8a-methyl-5-methylidene-4a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(4H)-ones, products of the double bond shift, were synthesized. The yields of the arylation products depend on the nature of the catalytic system and on the structure of the aryl halide. The structures of (3aR,4aS,8aR,9aR,E)-3-(3,4-dimethoxybenzylidene)-8amethyl-5-methylidenedecahydronaphtho[2,3-b]furan-2(3H)-one and (4aS,8aR,9aS)-3-(2-methylsulfanylbenzyl)-8amethyl-5-methylidene-4a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(4H)-one were proved by XRD analysis.     

[3,4]-annulated pyrroles 1. Polynuclear heterocyclic systems based on pyrrolo[3,4-d]pyrimidine-2,4-dione

The intramolecular electrophilic substitution in 6-functionalized 1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-diones was used for the synthesis of pyrimido[4′,5′:3,4]-pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione, pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,2,4]benzo-triazine-8,10(7H,9H)-dione, and 2H-pyrimido[4′,5′:3,4]pyrrolo[1,2-a]indole-2,4,11(1H, 3H)-trione derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2180–2185, December, 2006.     

3-Methyl[1,3,4]thiadiazino[2,3-b]quinazolin-6-ones

4H,6H-[1,3,4]Thiadiazino[2,3-b]quinazolin-6-one with a methyl group in position 3 (6a) has been synthesised by the condensation of 3-amino-2-mercapto-3H-quinazolin-4-one (1) with allyl bromide (2) followed by treatment with bromine and subsequent dehydrohalogenation of the brominated product (4) with ethanolic sodium hydroxide. Its isomeric 3-methyl-2H,6H-[1,3,4]thiadiazino[2,3-b]quinazolin-6-one (6b) has also been obtained by condensation of1 and bromoacetone (7) followed by cyclisation of the intermediates (8 or9) with hydrobromic acid or with concentrated sulphuric acid. The structures have been established on the basis of IR and PMR data.

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3-Methyl[1,3,4]thiadiazino[2,3-b]chinazolin-6-one

Zusammenfassung Zur Synthese von 4H,6H-[1,3,4]thiadiazino[2,3-b]chinazolin-6-on (6a) wurde die Kondensation von 3-Amino-2-mercapto-3H-chinazolin-4-on (1) mit Allylbromid mit nachfolgender Behandlung mit Brom und Dehydrohalogenierung des bromierten Produktes4 mit ethanolischer Natronlauge herangezogen. Das zu6a isomere 2H,6H-Produkt6b wurde ebenfalls durch Kondensation von1 mit Bromaceton und nachfolgender Cyclisierung der Zwischenprodukte8 bzw.9 mit HBr oder H₂SO₄ erhalten. Die Strukturen wurden mittels IR und NMR abgesichert.

     

One-pot synthesis of chromeno[2,3-b]isoindolo[1,2-e]pyrrole-12,13-dione derivatives by sequential reaction of ninhydrin, 2-aminochromen-4-ones and arylamines

Stirring an equimolar mixture of ninhydrin 1 and 2-aminochromen-4-ones 2 in CH₃COOH at room temperature produced 6a,11a-dihydroxy-6H-chromeno[2,3-b]indeno[2,1-d]pyrrole-11,12(6aH,11aH)-diones 3, which on heating with aromatic amines 6 in acetic acid produced 11b-hydroxy-7-N-arylimino-6H-chromeno[2,3-b]isoindolo[1,2-e]pyrrole-12,13(11bH)-diones 7.     

Synthesis of structurally constrained 4-quinazolinone derivatives with a tetrahedral C-2 atom present in three rings

The reaction of 2-aminobenzamides with 2-oxocyclopentane-, 2-oxocyclohexane-, and 2-oxocycloheptaneacetic acids esters was found to give 7a,8,9,10-tetrahydrocyclopenta[2,3]pyrrolo[1,2-a]quinazoline-6,12(7H,11H)-diones, 7,7a,8,9,10,11-hexahydro-6H-indolo[1,7a-a]quinazoline-6,13(12H)-diones, and 7a,8,9,10,11,12-hexahydrocyclohepta[2,3]pyrrolo[1,2-a]quinazoline-6,14(7H,13H)-diones, respectively. The relative configuration with the cis-fused butyrolactam and cycloalkane rings was assigned to the prepared compounds on the basis of an X-ray crystallographic study.     

Isatins 3-C annulation vs ring-opening: Two different pathways for synthesis of spiro compounds via multicomponent reactions

An efficient synthesis of spiro compounds via two different pathways from the reactions of isatins, 3-phenylisoxazol-5(4H)-one (3-ethylisoxazol-5(4H)-one), and pyrazol-5-amine (6-aminopyrimidine-2,4(1H,3H)-dione) were reported. The catalyst Amberlyst-15 could be easy recycled and reused for many time without any appreciable loss in catalytic activity. The new type spiro compounds were gained through the ring-opening of isatins process. The structures of spiro[indoline-3,4′-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo[5,4-b]quino line-4,5′-pyrrolo[2,3-d]pyrimidine]-2′,4′,6′(1′H,3′H,7′H)-trione, and spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(5′H)-dione were successfully confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray crystal diffraction analysis.     

Brønsted acidic ionic liquids catalyzed the preparation of 13-aryl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraones and 3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-triones

An environmentally green method for the synthesis of 13-aryl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraone and 3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-trione derivatives using Brønsted acidic ionic liquids, 3-methyl-1-sulfonic acid imidazolium chloride, 1-H-3-methyl-imidazolium hydrogensulfate, triethylamine-bonded sulfonic acid, and triethylammonium hydrogensulfate as reusable catalysts under thermal solvent-free conditions is described.     

Pyridazines. XXXV. Preparation of some novel pyrimido[4,5-c]pyridazine derivatives from 3-alkylamino- and 3-arylamino-4-pyridazinecarboxamides

Facile syntheses of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones 4 , pyrimido[4,5-c]pyridazin-5(8H)-ones 7–10 , and dihydropyrimido[4,5-c]pyridazin-5(6H)ones 5,6 starting from 3-chloro-4-pyridazinecarbonitrile 1 via aminocarbonitriles 2 and aminocarboxamides 3 are described. In addition, a convenient access to the new aminopyridazinecarbonitrile 11 from the chloronitrile 1, employing the tetrazolo[1,5-b]pyridazine 12 as the key intermediate, is reported.     

Transaminations of enaminones:A Synthesis of tricyclic,N-aryl, 1,2,3-triazole-fused pyridones

1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions. The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[6]-1,2,3-triazolo[4,5-e]pyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazolo[4,5-b]quinolin-9(4H)-ones. Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno[3,4-e]-1,2,3-triazolo[4,5-b]pyridin-4-ones. Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[b]-1,2,3-triazolo[4,5-e]pyridines and 4-aryl-5,6,7,8-tetrahydro-3H,2,3-triazolo[4,5-b]quinoline-9-(4H)-ones. The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded. Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.     

Tetrahydropyridoazepines and tetrahydropyridoazepinones from the corresponding dihydroquinolones

The p-toluenesulfonate of 7,8-dihydro-5(6H)quinoloneoxime( 3 ) was subjected of a Beckmann rearràngement. The resulting 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one ( 4 ) was reduced with lithium aluminum hydride affording 2,3,4,5-tetrahydro-1H-pyrido[3,2-b] azepine ( 5 ). 5,6-l)ihydro-8(7H)quinolone ( 7 ), obtained by oxidation of 5,6,7,8-tetrahydro-8-quinolinol ( 6 ), was converted into the p-toluenesulfonate of 5,6-dihydro-8(7H)quinolone oxitne ( 9 ). Similarly the latter compound could be rearranged into 2,3,4,5-letrahydro-1H-pyrido [2,3-b] azepin-2-one ( 10 ) which on reduction produced 2,3,4,5-tetrahydro-1H-pyrido [2,3-b] azepine ( 11 ).     

Pyrimidines. 21. Novel reactions of 5-cyano-1,3-dimethyluracil with carbon nucleophiles. A facile preparation of certain pyrido[2,3-d]pyrimidines

Treatment of 5-cyano-1,3-dimethyluracil ( 8 ) with an activated acetonitrile, such as malononitrile, ethyl cyanoacetate or cyanoacetamide, in base afforded 7-amino-6-cyano-, 7-amino-6-ethoxycarbonyl-, and 7-amino-6-aminocarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18b, 18c and 18d , respectively) in high yields. On the other hand, reaction of 8 with acetonitrile in base gave the Michael adduct, 5-cyano-6-cyanomethyl-5,6-dihydrouracil ( 15 , R = H), and the hydrated product, 1,3-dimethyluracil-5-carboxamide ( 9 ) as the major products, and 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18a ) in only very low yield. Similar reaction with butanone gave 7-ethyl-1,3-dimethyl- and 1,3,6,7-tetramethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 10b and 10c ) in low yields. When 8 was treated with diethylmalonate in base, only a small amount of 6-ethoxycarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione ( 19 ) was obtained together with 1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 20 ) and 18c (also in low yields). Treatment of 8 in ethanolic sodium ethoxide without added carbon nucleophile gave significant amounts (14%) of 20 and a small amount of 18c .     

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.