A Convenient Synthesis of 1-Amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta[a]fluoren-5-ones and Some New 2,3-Dihydro-1,3,4-thiadiazoles

1-amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta-[a]fluoren-5-one and 6-methyl-6H-,9H-thia-4b,6,9,11,12-pentaazaindeno[1,2-a]-fluorene-5,8-dione derivatives were prepared from 2-methyl-1-oxo-3-thioxo-2,4,9b-trihydropyrimidino[1,6-a] benzimidazole-4-carbonitrile. Also, 2,3-dihydro-1,3,4-thidazoles were synthesized via a reaction of hydrazonoyl chlorides with 3-(methylamino)-2-substituted 3-thioxopropanenitrile. Structures of newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative methods synthesis whenever possible.     

Beiträge zur Chemie schwefelhaltiger Heterocyclen, 4. Mitt.: 6H-Benz[b]indeno[1,2-d]thiophen und 10H-Benz[b]indeno-[2,1-d]thiophen

Zusammenfassung Intramolekulare Cyclisierungsreaktionen von 3-Phenyl-benzo[b]thiophen-2-carbonsäurechlorid und von 2-Phenyl-benzo[b]thiophen-3-carbonsäurechlorid lieferten 6-Oxo-6H-benz[b]indeno[1,2-d]thiophen bzw. 10-Oxo-10H-benz[b]indeno[2,1-d]thiophen.

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Contributions to the chemistry of sulfur containing heterocycles, IV.: 6H-Benzo[b]indeno[1,2-d]thiophene and 10H-benzo-[b]indeno[1,2-d]thiophene

Intramolecular cyclization reactions of 3-phenyl-benzo[b]thiophene-2-carbonyl chloride and of 2-phenyl-benzo[b]-thiophene-3-carbonyl chloride gave 6-oxo-6H-benz[b]indeno-[1,2-d]thiophene and 10-oxo-10H-benz[b]indeno[2,1-d]thiophene, respectively.

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3. Mitt.:F. Sauter, Mh. Chem.99, 2100 (1968).     

Molecular structure of 3,7-dimethyl-9-thia-3,7-diazabicyclo[3.3.1]nonane-9,9-dioxide

By a single crystal X-ray diffraction study the molecular structure of 3,7-dimethyl-9-thia-3,7-diazabicyclo[3.3.1]nonane-9,9-dioxide having a chair-chair conformation with a diequatorial arrangement of methyl groups at nitrogen atoms is determined. Compound 1 C₈H₁₆N₂O₂S crystallizes in the space group Pnma with the following cell parameters: a = 11.0262(3) Å, b = 14.4490(3) Å, c = 6.1780(3) Å.     

Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide

The synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide ( 5 ), a novel sulfur-containing tetracyclic benzodiazepine, is reported starting from pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-diox-ide ( 6 ) by cycloaddition of tosylmethyl isocyanide to the azomethine double bond. Pyrrolobenzothiadiazepine 6 was obtained by iron powder/acetic acid reduction of 1-(2-nitrobenzenefulfonyl)pyrrole-2-carboxaldehyde ( 7 ) and subsequent ring closure of intermediate aminoaldehyde or by cyclization of 1-(2-formamidobenzene-sulfonyl)pyrrole ( 8 ) with phosphorus oxychloride via a Bischler-Napieralski reaction. Formylation of 1-(2-ami-nobenzenesulfonyl)pyrrole with acetic-formic anhydride gave 8. The structure of 5 was confirmed by oxidation with activated manganese dioxide of dihydro derivative 9 , obtained through cyclization of 11-amino-methyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide ( 10 ) with triethyl orthoformate. The last compound was prepared alternatively by catalytic reduction of nitro derivative 11 , obtained by addition of nitromethane to pyrrolobenzothiadiazepine 6 , or by lithium aluminum hydride/sulfuric acid reduction of amide 13 , synthesized starting from ethyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-carboxyl-ate 5,5-dioxide.     

Electron transfer from dibenzo[b,f]-1-azapentalene dianion: Attempted synthesis of dibenzo[b,f]-1-azapentalene

When dibenzo[b,f]-1-azapentalene dianion (3) was allowed to react with either iron (III) chloride or ethylene bromide, a one-electron transfer from3 took place readily to give the radical anion11. Further electron transfer from11 did not occur presumably due to the antiaromatic character of dibenzo[b,f]-1-azapentalene (1) that would have resulted. The radical anion11 underwent further transformation by hydrogen abstraction from the solvent to give 5,10-dihydroindeno[1,2-b]indole (2) and by dimerization to themeso and (R,S) isomers of 5,5,10,10-tetrahydro-10,10-biindeno[1,2-b]indole (4 a and4 b) respectively.

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Elektronentransfer von Dibenzo[b,f]-1-azapentalen-Dianion: Ein Versuch zur Synthese von Dibenzo[b,f]-1-azapentalen

Zusammenfassung Die Reaktion von Dibenzo[b,f]-1-azapentalen-Dianion (3) mit Eisen (III) oder Ethylenbromid ergab einen Ein-Elektronentransfer zum Radikalanion11. Ein weiterer Elektronentransfer fand nicht statt, vermutlich wegen des antiaromatischen Charakters von Dibenzo[b,f]-1-azapentalen (1), das dabei entstehen müßte. Das Radikalanion11 ergab unter Wasserstoffentzug aus dem Lösungsmittel 5,10-Dihydroindeno[1,2-b]indol (2), das weiter zummeso- bzw. (R,S)-5,5,10,10-tetrahydro-10,10-biindeno[1,2-b]indol (4 a bzw.4 b) dimerisierte.

     

Novel Synthesis of N-Arylpyrrole,Pyrrolo[1,2-a]quinazoline,and Pyrrolo[3,4-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a,b react with dimethyl formamide dimethyl acetal (DMFDMA) in refluxing toluene to afford the enaminones 2a,b respectively. Compounds 2a and 2b react with the aromatic amines (aniline, p-toluidine, p-anisidine) in refluxing ethanol to afford the pyrroles 4a–f and with anthranilonitrile and methyl anthranilate to afford the pyrrolo[1,2-a]quinazolines 5a,b and 6a,b respectively. The pyrrole derivatives 4a–f react with hydrazine hydrate and phenyl hydrazine in refluxing ethanol to afford the pyrrolo[3,4-d] pyridazine derivatives 7a–f and 8a–f respectively.     

Syntheses of Benzo[b]furan-6-carbonitrile and 6-Cyanobenzo[b]furan-2-boronic Acid Pinacol Ester

6-Cyanobenzo[b]furan-2-boronic acid pinacol ester (10) is a potentially useful two-point scaffold for the construction of specific compounds or compound libraries with benzofuran cores. Using a per-iodination/de-iodination strategy coupled with Sonogashira alkynylation and Cu-catalyzed heteroannulation, we have developed a procedure that allows the preparation of benzo[b]furan-6-carbonitrile (9) and 6-cyanobenzo[b]furan-2-boronic acid pinacol ester (10) in gram quantities.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Pyrido[2,3-d]pyrimidines,II. One step synthesis of pyrido[2,3-d]pyrimidines and pyrimido[4,5-b]quinolines from 6-amino uracils

Summary Reduction of 6-azidouracils2 with hydrogen palladium or sodium dithionite afforded the corresponding 6-aminouracils5 which could also be obtained by reaction of2 with triphenylphosphanevia phosphazenes and subsequent hydrolysis (Staudinger reaction). The use of trimethylphosphite instead of phosphanes yields with2b the expected trimethoxyphosphazene3c, whereas2a reacts to the phosphonoaminopyrimidine4. The syntheses of 5-hydroxy pyrido[2,3-d]pryimidine-2,4,7-triones6, pyrido[2,3-d]pyrimidine-2,4,5-triones8, cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-triones7a,c, and tetrahydro-pyrimido[4,5-b]quinolin-2,4,5-triones7b,d by condensation of 6-aminouracils5 with malonates, ethylaceto/benzoylacetate, ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate, respectively, are described.

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Pyrido[2,3-d]pyrimidine, 2. Mitt. Einstufige Synthese von Pyrido[2,3-d]pyrimidinen und Pyrimido[4,5-b]chinolinen aus 6-Aminouracilen

Zusammenfassung Reduktion der 6-Azidouracile2 mit Wasserstoff/Palladium oder Natriumdithionit ergibt die entsprechenden 6-Aminouracile5, die auch durch Reaktion von2 mit Triphenylphosphin und anschließende Hydrolyse erhalten werden können (Staudinger-Reaktion). Die Verwendung von Trimethylphosphit anstelle von von Trimethylphosphin ergibt mit2b das erwartete Trimethoxyphosphazin3c, während2a zum Phosphonoaminopyrimidin4 reagiert. Die Synthesen der 5-Hydroxy-pyrido[2,3-d]pyrimidin-2,4,7-trione6, der Pyrido[2,3-d]pyrimidin-2,4,5-trione8, der Cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-trione7a,c und der Tetrahydro-pyrimido[4,5-b]chinolin-2,4,5-trione7b,d durch Kondensation der 6-Aminouracile5 mit Malonat, Acetat, Ethyl-2-oxocyclopentancarboxylat und Ethylcyclohexancarboxylat werden beschrieben.

     

Synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline and related compounds

This paper describes the synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline ( 10 ), tetrazolo[4,3-b]pyridazino[4,5-b]quinoxaline ( 11 ) and some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 . Starting with 2-ethoxycarbonyl-3-methylquinoxaline 1,4-dioxide ( 1 ), 1,2-dihydro-1-oxopyridazino[4,5-b]quinoxaline ( 5 ) was prepared by three different ways: (a) chlorination of 1 in acetic acid gave 2-ethoxycarbonyl-3-dichloromethylquinoxaline 1,4-dioxide, which reacts with an excess of hydrazine to give about 60% of 5 ; (b) oxidation of 1 with selenium dioxide gave 90% of 2-ethoxycarbonyl-3-formylquinoxaline 1,4-dioxide ( 3 ), which reacts with hydrazine to give 5 (63%); (c) compound 3 was treated with hydrazine to give 1,2-dihydro-1-oxopyridazino-[4,5-b]quinoxaline 1,4-dioxide ( 4 ) (70%), which by reduction with sodium dithionite gave 5 (80%). Compound 5 reacts with phosphorus pentasulfide or the Lawesson reagent to give 1,2-dihydro-1-thiocarbonylpyridazino[4,5-b]quinoxaline ( 9 ), which treated with hydrazine gave 5 (80%). This last compound reacts with nitrous acid to give 11 . Some hydrazones 12 from 10 are described. Heating the aldehyde hydrazones 12a,c,d with dimethylsulfoxide some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 were obtained. Compound 13a was also obtained in the reaction of 10 with benzoyl chloride. Reaction of 3 with phenylhydrazine gave 1,2-dihydro-1-oxo-2-phenylpyridazino[4,5-b]quinoxaline ( 6 ). Reactions of 5 with acetic anhydride and dimethylsulfate gave, respectively, 1-acetoxypyridazino[4,5-b]quinoxaline ( 8 ) and 1,2-dihydro-1-oxo-2-methylpyridazino-[4,5-b]quinoxaline ( 7 ). All the compounds were characterized by elemental analysis and ¹H-nmr spectra. Compounds 5 and 10 showed antihypertensive activity in rats.     

Synthesis and in vitro anticancer activity of pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-d][1,2,3]triazines

A novel series of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazolo[1,5-a]quinazolines 18a, b were synthesized via condensation of 5-amino-1H-pyrazoles 10a, b with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones 11a–e and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (15), respectively, in glacial acetic acid. Finally, treatment of 10a, b with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-d]triazines 20a, b. Structures of compounds were confirmed by their spectral data. These compounds were screened for their in vitro cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results reveal that, the compounds 14b and 14h were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.     

The synthesis of benzo[b]phenanthro[d]thiophenes and anthra[b]benzo[d]thiophenes

The synthesis of benzo[b]phenanthro[2, 3-d]thiophene ( 5 ), benzo[b]phenanthro[4, 3-d]thiophene ( 6 ), benzo-[b]phenanthro[2, 1-d]thiophene ( 9 ), benzo[b]phenanthro[3, 2-d]thiophene ( 14a ), anthra[1, 2-b]benzo[d]thiophene ( 24 ), anthra[2, 3-b]benzo[d]thiophene ( 29 ) and anthra[2, 1-b]benzo[d]thiophene ( 30 ) is described as well as the preparation of 13-methylbenzo[b]phenanthro[3, 2-d]thiophene ( 14b ).     

Syntheses of 4-(benzo[b]furan-2 or 3-yl)- and 4-(benzo[b]-thiophen-3-yl)piperidines with 5-HT2 antagonist activity

The syntheses of 4-(benzo[b]furan-3-yl)piperidines, 4-(benzo[b]furan-2-yl)piperidines and 4-(benzo[b]thiophen-3-yl)piperidines with 5-HT₂ antagonist activity are described. Reaction of 1-acetyl-4-(2,4-difluorobenzo-yl)piperidine 2 with methyl glycolate gave methyl 6-fluoro-3-(1-acetylpiperidin-4-yl)benzo[b]furan-2-carboxylate 3 , which was converted to 2-[2-[4-(benzo[b]furan-3-yi)piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyridin-3(2H)-one hydrochloride 9 . Analogous benzo[b]furans 17a-d and benzo[b]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4-fluoro-2-(4-pyridinylmethoxy)acetophenones 20a,b afforded 4-(benzo[b]furan-2-yl)pyridines 21a,b , which were converted to 2-[2-[4-(benzo[b]furan-2-yl)-piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochlorides 24a,b. Among them, benzo[b]furans 9 and 17a,d and benzo[b]thiophenes 10 and 18a showed potent 5-HT₂ antagonist activity in vitro.     

[4 + 2]-Cycloadditionen von α, β- ungesättigten hydrazonen. Teil3. Isothiazolo[4,5-b]pyridin-3(2H)-on-1,1-dioxide (= 4-azasaccharine)

[4 + 2] Cycloaddition of α, β-Unsaturated Hydrazones: Isothlazolo[4,5-b]pyridin-3(2H)-on 1,1-Dioxides (= 4-Azasaccharine Derivatives) The [4 + 2] cycloaddition of α, β -unsaturated hydrazones of type 1 (1-azabuta-1,3-dienes) with isothiazol-3(2H)-on 1,1-dioxide derivatives 10 affords, depending on the solvent used, picolinamides 15 or 17 , 4,7-dihydro-4-azasaccharine 14 or 4-azasaccharine derivatives 16 (Scheme 4). The course of the reaction is mainly influenced by the substituent R of the dienophile 10 .     

Synthese von [1]Benzothieno[2,3—c]pyrazol-Derivaten

Derivatives of [1]benzothieno[2.3-c]pyrazole, a new heterocyclic ring system, were synthesized by 1.3-dipolar cycloadditions: benzo[b]thiophene-1.1-dioxide and derivatives thereof reacted with diazomethane and diazoethane to yield substituted [1]benzothieno[2.3-c]pyrazolines. A similar reaction with ethyl diazoacetate gave the corresponding cyclopropa[b][1]benzothiophene-2.2-dioxide derivative.     

The syntheses of 4b,5a-dihydro-5H-benzo[3,4]-phenanthro[1,2-b]azirine and 1a,11b-dihydro-6,11-dimethyl-1H-benz[3,4]anthra[1,2-b]azirine

The syntheses of the K-imine derivatives of carcinogenic benzo[c]phenanthrene and 7,12-dimethylbenz-[a]anthracene are described. Treatment of trans-5-azido-5,6-dihydrobenzo[c]phenanthren-6-ol ( 3 ) and trans-6-azido-5,6-dihydrobenzo[c]phenanthren-5-ol ( 5 ) with thionyl chloride yielded the corresponding β-chloro azides, which in turn, were reacted with lithium aluminium hydride to give 4b,5a-dihydro-5H-benzo[3,4]-phenanthro[1,2-b]azirine ( 2 ). In a similar manner trans-5-azido-5,6-dihydro-7,12-dimethylbenz[a]anthracen-6-ol ( 11 ) and trans-6-azido-5,6-dihydro-7,12-dimethylbenz[a]anthracen-5-ol ( 13 ) were transformed to the respective chloro azides and, converted into 1a,11b-dihydro-6,11-dimethyl-1H-benz[3,4]anthra[1,2-b]azirine ( 10 ).     

A facile synthesis of 2-phenylbenzo[b]thiophene-3-amine and the corresponding S-oxides

A rapid synthesis of 2-phenylbenzo[b]thiophene-3-amine and its S-oxides from o-nitrobenzonitrile is described. Also reported is the preparation of 2-phenylbenzo[b]thiophene-3-(2H)one, 1,1-dioxide from methyl o-nitrobenzoate.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza-naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring transformation of suitably functionalized 2H-pyran-2-one with α-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles) followed by their photocyclization either in CHCl₃ or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.     

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 some novel pyrazolo[1,5-a]quinazolines and their fused derivatives

New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid. Condensation of compounds 4a,b with various aromatic aldehydes furnished the corresponding arylidene derivatives 6a–j. On the other hand, condensation of 4a,b with o-hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a–h. Coupling of compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono derivatives 12a–h. Also, reaction of compounds 4a,b with phenyl isothiocyanate, followed by addition of ethyl chloroacetate and chloroacetonitrile, afforded the polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of hydrazine hydrate and guanidine hydrochloride afforded pyrazolo[4″,3″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and pyrimido[5″,4″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b, respectively. The structures of all the newly synthesized compounds were elucidated by elemental analyses and spectral data. The plausible mechanisms have been postulated to account for their formation.