Pyrrolopyrimidines. 5. Reaction of 6-Amino-1,3-dimethylpyrrolo[3,4-d]pyrimidine-2,4(1H,3H)-diones with 1,3-Diketones

The reaction of 6-amino-1,3-dimethylpyrrolo[3,4-d]pyrimidine-2,4-dione with 1,3-diketones leads to formation of predominantly pyrimido[4',5':3,4]pyrrolo[1,2-b]pyridazine-2,4(1H,3H)-diones and, to a lesser extent, pyrimido[5',4':3,4]pyrrolo[1,2-b]pyridazine-1,3(2H,4H)-diones. The ease and direction of the cyclization reaction suggests a very -electron rich pyrrole ring in the initial state, especially in the position 7.     

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.     

Synthesis and reactions of 1,2-fused 3-cyanoindolizines

With the intention that annulation of carbo- or heteroaromatic rings at the 1,2-positions can activate 3-cyanoindolizines as 1,3-dipolar species, 6-cyanobenz[a]indolizines, pyridazino[4,5-a]indolizines and 5-cyano-1,3-diphenylthiopheno[3,4-a]indolizine were prepared. 6-Cyanobenz[a]indolizines smoothly -underwent 1,3-dipolar cycloaddition on to dibenzoylacetylene and diacetylacetylene to afford the corresponding indolizino[3,4,5-ab]isoindoles, whereas 5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine reacted with dimethyl acetylenedicarboxylate to give the 1:2 adduct. Only a 3% yield of 5-cyano-1,3-diphenylthiopheno[3,4-a]indolizine formed upon phosphorus pentasulfide treatment of 1,2-dibenzoyl-3-cyanoindolizine.     

Bis-Pyrazolones as azodienophiles

Lead tetraacetate oxidations of 2,3,3a,4,6,7,7a,8-octahydrobenzo[1,2-c:4,5-c']dipyrazolo-3,7-dione and 2,3,3a,4,5,5a,6,7-octahydrobenzo[2,1-c:3,4-c']dipyrazolo-3,6-dione in the presence of 1,3-cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene or 1,4-diphenyl-1,3-butadiene have yielded octahydrodipyridazino[1,2-a:1,2-a']benzo[1,2-c:4,5-c']dipyrazolo-6,14-diones and octahydrodipyridazino[1,2-a:1,2-a']benzo[2,1-c:3,4-c']dipyrazolo-6,9-diones. In one of the eight Diels-Alder reactions two isomeric products were isolated.     

The synthesis and properties of pyridazino[4,3-e] -as-triazines and pyridazino[4,5-e] -as-triazines,two novel condensed pyridazine ring systems

The compounds prepared in the novel pyridazino[4,3-e]-as-triazine ring system are: 8-chloro-4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 21 ), 8-chloro-2,4-dimethyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 23 ), 8-chloro-2-ethyl-4-methyl-3,4-dihydropyridazino[4,3-e]-as- triazine ( 24 ), 4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine-8-thione ( 25 ), 4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 26 ), 2,4-dimethyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 27 ), and 2-ethyl-4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 28 ). In the novel pyridazino[4,5-e]-as-triazine ring system the following compounds were prepared: 1,2-dihydropyridazino[4,5-e]-as-triazine ( 31 ), 3-methyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 32 ), 3-ethyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 33 ), and 1-methyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 35 ). The preparation of a number of previously unreported intermediates and compounds for structure proof are also described.     

Synthesis of Precursors of Heterocyclic cis-β-Amino Alcohols by Intramolecular Amidoalkylation of 4-Hydroxyoxazolidin-2-ones

The reaction of intramolecular amidoalkylation of 4-hydroxyoxazolidin-2-ones leads to formation of novel and rare heterocyclic systems: substituted 1,5,6,10b-tetrahydro[1,3]oxazolo[4,3-a]isoquinolin-3-ones, 3a,4,5,10b-tetrahydro[1,3]dioxolo[4',5':6,7]naphtho[1,2-d][1,3]oxazol-2(1H)-ones, and 5,6,10,10a-tetrahydro-1H-di[1,3]oxazolo[3,4-d:4,3-g][1,4]diazepine-3,8-diones. Mild reaction conditions and the simplicity of isolation of the compounds formed make it possible to obtain the indicated heterocycles in high yields.     

On Condensation Reactions of Aceanthrene Quinone: Novel Heterocycles

Summary.  It was found that aceanthrene quinone can be condensed with ethylenediamine, 1,2-diaminobenzene, 4-nitro-1,2-diaminobenzene, 1,2-diaminoanthrene quinone, and 4,5,6-triaminopyrimidine derivatives to give aceanthryleno[1,2-b]pyrazine and aceanthryleno[1,2-g]pteridine derivatives. Condensation of aceanthrene quinone with 2-aminoguanidine, semicarbazide, and thiosemicarbazide yielded aceanthryleno[1,2-e]triazines, condensation with 6-hydrazinopyrimidine derivatives gave 3,4-aceanthrylenopyrimido[4,5-c]pyridazines. Reaction of aceanthrene quinone with 2-cyanoethanoic acid hydrazide afforded 10,11-dihydro-10-oxo-aceanthryleno[1,2-c]pyridazine-9-carbonitrile. Treatment of aceanthrene quinone with malononitrile and hydrazine hydrate resulted in 10-aminoaceanthryleno[1,2-c]pyridazine-9-carbonitrile. The antibacterial effects of the prepared compounds were tested. Three of the compounds were tested against 60 cancer types. Received May 6, 2001. Accepted June 5, 2001     

Stereoselectivity in the Addition of 1,3-Dipolarophiles to 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes

Thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of N-arylmaleimides having a substituent in the ortho position of the aromatic ring leads to predominant formation of the corresponding trans-9-arylperhydropyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-diones. 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes react with fumaric acid derivatives in a stereoselective fashion, affording perhydropyrazolo[1,2-a]pyrazoles with a trans,trans configuration.     

Purines,pyrimidines, and related fused systems. 19. Use of S N H methodology for the synthesis of a new heterocyclic system,pyrrolo[3",2":3,4]pyrimido[4,5-c]pyridazine

Sonogashira cross-coupling of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with terminal alkynes afforded the corresponding 3-(alkyn-1-yl) derivatives. Oxidative amination of the latter compounds with primary alkylamines was accompanied by heterocyclization to give 6,8-dimethylpyrrolo[3",2":3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

Purines, pyrimidines, and related fused systems. 21. Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione

Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with primary alkylamines and potassium amide in liquid ammonia gives rise to the corresponding 4-amino derivatives as the major products. The reactions with acyclic secondary amines are accompanied by annelation of the pyrrole moiety to the starting heterosystem to form 1-R-3-R"-6,8-dimethylpyrrolo[2",3";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones. The reaction with piperidine as the aminating agent occurs exclusively as aminodehalogenation. The Sonogashira cross-coupling of 4-amino-3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with terminal alkynes affords 1-R-2-R"-6,8-dimethylpyrrolo[3",2";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

Condensation of 2-Alkylcyclohexane-1,3-diones with Cyclic Azomethines

Reaction of 2-acylcyclohexane-1,3-diones with 5- and 6-membered cyclic azomethines (3,4-dihydro-2H-pyrrole and 2,3,4,5-tetrahydropyridine) furnished derivatives of 2,3,3a;,4,8,9-hexahydropyrrolo[1,2-a]quinoline-5,6(1H,5aH)-dione and 3,4,4a,5,9,10-hexahydro-1H-pyrido[1,2-a]quinoline-6,7(2H,8H)-dione respectively. In reaction with 7-membered 3,4,5,6-tetrahydro-2H-azepine we failed to isolate polycyclic nitrogen-containing products.     

Quino[1,2-c]quinazolines. I. Synthesis of quino[1,2-c]quinazolinium derivatives and the related indazolo[2,3-a]quinoline derivatives as analogs of the antitumor benzo[c]phenanthridine alkaloids

9,10-Dimethoxy-1,2,3,4,12,13-hexahydro-1-oxoquino[1,2-c]quinazolinium perchlorate, 1,2,3,4,13,24-hexahydro-1-oxo[1,3]dioxolo[4,5-g]quino[1,2-c]quinazolinium perchlorate, 6-methyl-2,3,9,10-tetramethoxyquino-[1,2-c]quinazolinium perchlorate and 2,3-dimethoxy-13-methyl[1,3]dioxolo[4′,5′:6,7]quino[1,2-c]quinazolinium perchlorate were synthesized as analogs of the potent antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine. The related 2,3,8,9-tetramethoxyindazolo[2,3-a]quinoline and 2,3-dimethoxy[1,3]dioxolo-[4,5-g]indazolo[2,3-a]quinoline were also synthesized. Further, the novel formation of 6,7-dimethoxy-2-(2-ethylamino-4,5-dimethoxyphenyl)quinoline via reductive alkylation with Raney nickel in refluxing ethanol is also reported.     

Angular polycyclic thiophenes containing two thiophene rings. I

We describe the synthesis of thieno[2,3-c]dibenzothiophene ( 6 ), thieno[3,2-c]dibenzothiophene ( 10 ), thieno-[3,2-a]dibenzothiophene ( 14 ), thieno[2,3-a]dibenzothiophene ( 16 ), benzo[1,2-b:4,3-b]bisbenzo[b]thiophene ( 18 ), benzo[1,2--6:3,4-b]bisbenzo[b]thiophene ( 20 ), benzo[2,1--6:3,4-b]bisbenzo[b]thiophene ( 22 ), benzo[1,2-b:3,4-g]bisbenzo[b]thiophene ( 27 ), benzo[1,2-b:4,3-e]bisbenzo[b]thiophene ( 29 ), benzo[2,1--6:3,4-g]bisbenzo[b]thiophene ( 36 ), benzo[2,1--6:4,3-e]bisbenzo[b]thiophene ( 38 ), benzo[1,2--6:4,3-g]bisbenzo[b]thiophene ( 41 ), benzo[1,2-b:4,5-g]bisbenzo[b]thiophene ( 42 ), benzo[1,2-b:3,4-e]bisbenzo[b]thiophene ( 44 ) and benzo-[1,2-b:5,4-e]bisbenzo[b]thiophene ( 45 ).     

[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.     

The Use of 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one as “Masked” α-Bromo-α'-Hydroxy Ketone in the Synthesis of Heterocyclic Systems

4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one was obtained on the basis of the readily obtainable 4-methylene-5,5-dimethyl-1,3-dioxolan-2-one. It forms 2-imidazo[1,2-a]pyridin-2-yl-2-propanol with 2-aminopyridine, 11a-hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide with 2-(aminomethyl)pyridine, and the corresponding derivative of 4-hydroxyoxazolidin-2-one with 2-(3,4-dimethoxyphenyl)ethylamine. The last product was converted by intramolecular amidoalkylation without isolation into 10b-(bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10b-tetrahydro[1,3]oxazolo[3,4-a]isoquinolin-3-one.     

Synthesis of novel pyridazino[3,4-b]quinoxalines

The pyridazino[3,4-b]quinoxaline 12 was synthesized by the cyclization of the α-arylhydrazonoacyl-hydrazide 11. The reaction of compound 12 with phosphoryl chloride gave pyridazino[3,4-b]quinoxaline 13, whose reactions with sodium azide or cyclic secondary amines provided pyridazino[3,4-b]quinoxalines 14,17 and 18, respectively. The acylhydrazide 15 was also cyclized to pyridazino[3,4-b]quinoxaline 16.     

[1,3,5]Triazino[1,2-a] azepines: A new ring system

The reaction of 2-pyrrolidino-1-aza-1-cycloheptene with aryl isocyanates leads, via 1,4-dipolar cycloaddition, to 1,3-diaryl-10a-pyrrolidinoperhydro[1,3,5]triazino[1,2-a]azepine-2,4-diones. The reaction provides a facile route to the novel [1,3,5]triazino[1,2-a]azepine ring system.     

Five-Membered 2,3-Dioxo Heterocycles: L. Synthesis and Thermolysis of 3-Aroyl- and 3-Hetaroyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalin-1,2,4-triones

(Z)-3-Phenacylidene- and (Z)-3-hetaroylmethylidene-1-phenyl-1,2,3,4-tetrahydroquinoxalin-2-ones react with oxalyl chloride to give 3-acyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Thermolysis of the latter generates acyl(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)ketenes which are stabilized via [4 + 2]-cyclodimerization followed by [1,3]-acylotropic shift to afford 4-acyl-3-acyloxy-2-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-2-yl)-6-phenyl-5,6-dihydro-1H-pyrido[1,2-a]quinoxaline-1,5-diones.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 7, 2005, pp. 1101–1108.Original Russian Text Copyright © 2005 by Bozdyreva, Smirnova, Maslivets.