Reduction of 4,7-diphenyl-1,2,5-thia(oxa)diazolo[3,4-c]pyridines affording 2,5-diphenyl-3,4-diaminopyridines and ring closure of the diamines to fluorescent azaheterocycles

Reduction of 4,7-diphenyl-1,2,5-thia- ( 1a-i ) and 1,2,5-oxadiazolo[3,4-c]pyridines ( 3a and c-e ) gave 3,4-diamino-2,5-diphenylpyridines ( 2a-g ), which were converted into the fluorescent triazolo[4,5-c]-( 5 ), 1,2,5-selenadiazolo[3,4-c]- ( 6 ), imidazolo[4,5-c]pyridines ( 8 ), and pyrido[5,6-c]pyridines ( 11 ). In the reduction of 3a, c and e , 4,5-dihydro[1,2,5]oxadiazolo[3,4-c]pyridines ( 4a-c ) were obtained.     

Fused polycyclic nitrogen-containing heterocycles 20. Thiazolo[3,4-<Emphasis Type="Italic">a</Emphasis>]quinoxalines from 4-hydroxy-2-phenyliminothiazolidines and C-substituted 1,2-phenylenediamines

The condensation of 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine with 4,5-dimethyl-1,2-phenylenediamine affords 7,8-dimethyl-3-phenyl-1-phenyliminothiazolo[3,4-a]quinox-alin-4(5 H)- one; the condensation with 1,2-phenylenediamines containing different substituents at positions 4 and 5 gives both theoretically possible isomeric thiazolo[3,4-a]quinoxalines, which differ in the distribution of these substituents between positions 7 and 8 in the benzene ring of the quinoxaline system. 3a-Hydroxy-7,8-dimethyl-3-phenyl-l-phenylimino-3,3a-di-hydrothiazolo[3,4-a]quinoxalin4(5 H)- one was isolated and characterized as the intermediate of the reaction giving rise to thiazolo[3,4-a]quinoxaline from 4,5-dimethyl-1,2-phenylene-diamine. This intermediate is a covalent hydrate of the final product.     

4-Aminofurazan-3-carboxylic Acid Iminoester in Reactions with N,O-Nucleophiles

Reactions of 4-aminofurazan-3-carboxylic acid iminoester with o-aminophenol and ethylenediamine give rise respectively to 4-(1,3-benzoxazol-2-yl)- and 1-(4,5-dihydro-1H-imidazol-2-yl)-1,2,5-oxadiazol-3-amines, with aminoethanol arises 2-[(Z)-1-amino-1-(4-amino-1,2,5-oxadiazol-3-yl)methylideneamino]-1-ethanol. Treating of 3-amino-4-(1H-benzo[d]imidazol-2-yl)-1,2,5-oxadiazole with triethyl orthoformate in acetic anhydride yielded benzo[4,5]imidazo[1,2-c][1,2,5]oxadiazolo[3,4-e]pyrimidine, and alkylation with haloalkanes furnished 3-amino-4-(1-R-benzo[d]imidazol-2-yl)-1,2,5-oxadiazoles.     

A convenient synthesis for some new pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine derivatives with potential biological activity

Ready, convenient synthesis for 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-1,2,3,-4-tetrahydropyrido-[3′,2′:,4,5]thieno[3,2-d]pyrimidines 5 , 8-cyano-7-ethoxy-4-oxo-9-phenyl-2-substituted-3,4-dihydropyrido[3′,2-: 4,5]thieno[3,2-d]pyrimidines 6 , 4-chloro-8-cyano-7-ethoxy-9-phenyl-2-substitutedpyrido[3′,2′:4,5]thieno[3,2-4 -pyrimidines 7 and 8-cyano-7-ethoxy-2-(2′-nitrophenyl)-9-phenyl-4-substitutedpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidines 8-18 from 2-chloro-3,5-dicyano-6-ethoxy-4-phenylpyridine 1 via 3,5-dicyano-6-ethoxy-2-mercapto-4-phenylpyridine 2 and aminocarboxamide 4 are reported. In addition, the reaction of hydrazino derivative 12 with reagents such as formic acid and triethyl orthoformate yielded the fused tetraheterocyclic 8-cyano-9- ethoxy-5-(2′-nitrophenyl)- 7-phenylpyrido[3′,2′:4,5]thieno[2,3-e]-1, 2,4-triazolo[4,3-c]pyrimidine system 19 .     

Reactions of some pyranylidene esters with amines

The reactions of 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2,6-diphenyl-4H-pyran ( 1 ) with primary amines gave the corresponding 1-substituted 1,4-dihydropyridine derivatives. The related benzo derivative of 1 (12) and primary amines gave 3-substituted 3,4-dihydro-2-phenyl-5H-[1]benzopyrano[3,4-c] pyridine-4,5-dione derivatives. With secondary amines, 12 gave 2-phenyl-4H,5H-pyrano[3,4-c] [1]benzopyrane-4,5-dione, and with isopropylamine, N,N-dimethylhydra-zine, and methanolic potassium hydroxide, 12 gave 4-phenacylcoumarin. Some reaction intermediates were isolated which indicate probable reaction paths. The reactions with amines were extended to a naphtho derivative of 1 (19) and to a thia homolog of 12 (24).     

The synthesis of 3,5-dimethylpyrazol-1-yl-vl-v-triazolo[4,5-d]pyridazines and substituted 3,5-dimethylpyrazol-1 -ylimidazo[4,5-d]pyridazines

The synthesis of 4-(3,5-dimethylpyrazol-1-yl)-v-triazolo[4,5-d]pyridazine, 4-(3,5-dimethylpyrazol-1-yl)imid-azo[4,5-d]pyridazine and several S-substituted derivatives of 4-(3,5-dimethylpyrazol-1-yl)imidazo[4,5-d]pyrid-azine-2-thiol is reported. These syntheses were carried out to provide a variety of interesting compounds for biological screening.     

A new method for the synthesis of novel 6-quinoxalinylpyrazolo[5,1-c][1,2,4]triazines

The reaction of the quinoxaline 1 with 4-ethoxycarbonyl-1H-pyrazole-5-diazonium chloride 7 at room temperature gave 3-[α-(4-ethoxycarbonyl-1H-pyrazol-5-ylhydrazono)methoxycarbonylmethyl]-2-oxo-1,2-dihydroquinoxaline 8. The pmr spectrum of 8 in deuteriodimethylsulfoxide supported the presence of two tautomers 8-I and 8-II. Refluxing of 8 in N,N-dimethylformamide or acetic acid resulted in cyclization to afford 8-ethoxycarbonyl-4-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 9. Compound 9 was also obtained directly by the reaction of 1 with 7 under reflux in better yield. The reaction of 9 with hydrazine hydrate provided the hydrazinium salt 10 , while the reactions of 9 with triethyl and trimethyl orthoformates in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene produced 8-ethoxycarbonyl-4-ethoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11a and 8-ethoxycarbonyl-4-methoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11b , respectively. The chlorination of 11a with phosphoryl chloride gave 3-(3-chloroquinoxalin-2-yl)-8-ethoxycarbonyl-4-ethoxylpyrazolo[5,1-c]-[1,2,4]triazine 12 , whose reaction with morpholine afforded 8-ethoxycarbonyl-4-ethoxyl-3-[3-(morpholin-4-yl)-quinoxalin-2-yl]pyrazolo[5,1-c][1,2,4]triazine 13.     

Convenient construction of spiro[indoline-3,5'-pyrrolo[3,4-c]carbazole] and spiro[indene-2,5'-pyrrolo[3,4-c]carbazole] via acid-catalyzed Diels-Alder reaction

p-TsOH catalyzed Diels-Alder reaction of 3-(indol-3-yl)maleimides with 3-phenacylideneoxindoles in toluene at 80 °C for two hours afforded cis/trans isomers of 3a',4′,6′,10c'-tetrahydrospiro[indoline-3,5′-pyrrolo[3,4-c]carbazoles] in nearly comparable yields, which could be easily converted to the corresponding 4′,6′-dihydrospiro[indoline-3,5′-pyrrolo[3,4-c]carbazole] in high yields and with high diastereoselectivity by further DDQ oxidation. Additionally, the similar reaction of 3-(indol-3-yl)maleimides with 2-arylidene-1,3-indanediones in toluene 80 °C and sequential DDQ oxidation afforded functionalized dihydrospiro[indene-2,5′-pyrrolo[3,4-c]carbazoles] as major products.     

Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

Azolopyrimidines and pyrimidoquinazolines from 4-chloropyrimidines

5-Cyano-3,4-dihydro-6-phenyl-2-substitutedpyrimidin-4-ones 1a-c reacted with phosphorus oxychloride to give the corresponding 4-chloropyrimidine derivatives IIa-c . Compounds IIa-c reacted with aniline and hydrazine to yield the 4-anilino, IIIa,e , and 4-hydrazino, IIIb-d derivatives. The 4-hydrazino analogues IIIb,c could be converted into the triazolo[4,3-c] and tetrazolo[4,5-c]pyrimidines IV and V by the action of carbon disulphide and nitrous acid, respectively. The reaction of IIb,c with phenylhydrazine afforded directly the 5-amino-4,6-diphenyl-6H-2-substitutedpyrazolo[3,4-d]pyrimidines VIa,b . The 4-chloro derivative IIa reacted with antrhanilic acid to form the 5-cyano-2,4-diphenyl-6-(o-carboxyphenylamino)pyrimidine VIII , which could be cyclised into the 4-cyano-1,3-diphenyl-10H-pyrimido[6,1-b]quinazolin-10-one IX by heating with acetic anhydride.     

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.     

Polyazasteroids II.. 1,2,4-Triazolol[3′,4′:2,3]pyrimido[4,5-c]quinolin- 11(12H)ones,imidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3] pyrimido[4,5-c]quinolin-11(12H)ones

Starting with 2-substituted quinoline-3,4-dicarboxylic acids, a series of substituted 1,2,3,4-tetrahydropyrimido[4,5-c]quinolinone-3-thiones were obtained. The latter compounds were converted to the three novel polyazasteroid series: 1,2,4-Triazolo[3′,4′:2,3]pyrimido[4,5-c]-quinolin-11(12H)ones, imidazo[2′,1′:2,3]pyrimido[4,5c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones. The intermediate 3-hydrazino-1,2-dihydropyrimido[4,5-c]quinolinones and nitrous acid gave the 3-azido derivatives rather than the tetrazolo compounds.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

Reinvestigation of the reported preparation of 3-(4-nitrophenyl)thiazolo[2,3-c][1,2,4]triazepines

2-(1H-Pyrazol-1-yl)-4-(4-nitrophenyl)thiazoles 2a and 2b , resulting from the condensation of 2-hydrazino-4-(4-nitrophenyl)thiazole ( 1 ) and acetylacetone and dibenzoylmethane, respectively, were previously [4] misas-signed as 3-(4-nitrophenyl)thiazolo[2,3-c][1,2,4]triazepines 3a and 3b . The assignments were corrected by authentic syntheses of 2a and 2b from 2-chloro-5-(4-nitrophenyl)thiazole ( 6 ) and 3,5-dimethyl-1H-pyrazole and 3,5-diphenyl-1H-pyrazole, respectively. In addition, the mass spectrum of 2a is reported. An apparent ionmolecule reaction produces an ion of significant intensity at m/e 394.     

On the Chemistry of Cinnoline V [1]. Reactions of 4-Aminocinnolines with Amines

Summary. We describe the effect of the solvent during the intra-cyclization of the arylhydrazonomalononitrile to obtain new and useful substituted cinnolines, namely 4-amino-3-cyanocinnolines and (4-amino-cinnolin-3-yl)arylmethanones. 4-Amino-3-cyano-5,7-dimethyl-cinnoline was treated with n-hexylamine, cyclohexylamine, and isopropylamine to yield the corresponding cinnoline-3-carboxamidine derivatives. Furthermore, 4-amino-3-cyano-5,7-dimethylcinnoline was reacted with diaminoethane to give 4-amino-5,7-dimethyl-3-(4,5-dihydroimidazol-2-yl)cinnoline. Treatment of 4-amino-3-cyano-5,7-dimethylcinnoline with hydrazine hydrate provided 3-amino-7,9-dimethyl-1H-pyrazolo[4,3-c]cinnoline. Moreover, (4-aminocinnolin-3-yl)phenylmethanones were treated with hydrazine hydrate to give 3-phenyl-1H-pyrazolo[4,3-c]cinnolines. Finally, reactions of (4-aminocinnolin-3-yl)phenylmethanone with 3,5-dimethylaniline, phenyl hydrazine, hydroxylamine, and phenyl isothiocyanate are discussed. Chemical and spectroscopic evidence for the structures of the new compounds is presented.     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

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.     

Reformatsky Reaction of Methyl 1-Bromocycloalkanecarboxylates with α-Dicarbonyl Compounds

Reformatsky reactions of methyl 1-bromocyclohexanecarboxylate and methyl 1-bromocyclo-pentanecarboxylate with 2-aryl-2-oxoacetaldehydes involve both carbonyl groups of the latter and result in formation of 3a-aryl-3,3 : 6,6-bis(pentamethylene)- and 3a-aryl-3,3 : 6,6-bis(tetramethylene)tetrahydrofuro-[3,2-b]furan-2,5-diones. The reaction with 2-(2,4-dimethylphenyl)-2-oxoacetaldehyde gives acyclic products, methyl 1-[1-hydroxy-2-(2,4-dimethylphenyl)-2-oxoethyl]cyclohexanecarboxylate and methyl 1-[1-hydroxy-2-(2,4-dimethylphenyl)-2-oxoethyl]cyclopentanecarboxylate, while with benzil methyl 1-(4-hydroxy-1-oxo-3,4-diphenyl-2-oxaspiro[4.5]dec-3-yl)cyclohexanecarboxylate and methyl 1-(4-hydroxy-1-oxo-3,4-diphenyl-2-oxaspiro[4.4]non-3-yl)cyclopentanecarboxylate are obtained.     

The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido[4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido[5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido[4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido[4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido[5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido[5,4-c]pyridazin-8-one ( 38 ). Pyrimido[5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido[5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido[5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.