4-Azapteridines. I. Covalent addition products of the pyrazino[2,3-e]-as-triazine ring system

Ring closure of 5, 6-diamino-3-methylthio-as-triazine with 40% aqueous glyoxal provided the 6, 7-dihydrate of the pyrazino[2, 3-e]-as-triazine (4-azapteridine) ring system. The C7 hydroxy group of this dihydrate underwent exchange in methanol or ethanol affording the 7-alkoxy, 6-hydroxy derivatives.     

Condensed as-triazines. Synthesis of 7-aryl-8H-[1,4]thiazino[2,3-e]-1,2,4-triazin-3(2H)-one

Ring closure of 6-amino-3-oxo-as-triazine-5-thione with α-haloketones provides the thiazino[2,3-e]-1,2,4-triazines which dehydrate via an unusual pathway to give 7-aryl-8H[1,4]thiazino[2,3-e]-1,2,4-triazin-3(2H)-ones.     

Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

Diazo-, azo-, and azidoazoles. VII. Imidazo[1,2-b]- versus imidazo[2,1-c]benzo-as-triazines

Treatment of 3-aminobenzo-as-triazines with bromoacetaldehyde ethylene acetal give linear tricyclic imidazobenzo-as-triazines, where 3-amino-7-methylbenzo-as-triazine 1-oxide yields the angular isomer. The structures of these compounds have been established by comparing their nmr spectra to those of pyrazolo [5,1-c]- and s-triazolo[5,1-c]benzo-as-triazines obtained form the appropriate azo derivatives by intramolecular cyclization.     

The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

A novel crystalline tetrazolo-azido isomer pair: Pyrido[ 2,3-e] tetrazolo[5,1-c]-as-triazine and 3-azidopyrido[2,3-e]-as-triazine; the synthesis of tetrazolo[5,1-c] benzo-as-triazine and pyrido[2,3-e]-s-triazolo[3,4-c] -as-triazine

The deoxygenated derivative of 3-azidobenzo-as-triazine 1-oxide (II) exists in solution predominantly as 3-azidobenzo-as-triazine form (IVa) but in the crystalline state as tetrazolo[5,]-c]-benzo-as-triazine (IVb), a new fused heteroaromatie ring system. With the pyrido[2,3-e]-as-triazine derivatives, however, both 3-azidopyrido[2,3-e]-as-triazine (X) and pyrido[2,3-e] tetra-zolo[5,1-e]-as-triazine (XI) can be isolated in crystalline form, and these are interconvertible. Another new ring system, the pyrido[2,3-e] triazolo [3,4-c]-as-triazine (XVII) and its derivatives has also been synthesized.     

Azinotriazines. I. Synthesis and spectral data of pyrido[3,2-e] -as-triazines

A series of pyrido[3,2-e]-as-triazines (VI) was prepared via acid-catalyzed cyclization of suitable 2-substituted 3-aminopyridines obtained by reduction of the corresponding 3-nitro-pyridines. Cyclization of 3-amino-2-hydrazinopyridines (III) with triethyl orthoformate and hydrochloric acid, or cyclodehydration of 2-(2-acetylhydrazino)-3-aminopyridines (IV) with alcoholic hydrogen chloride gave 1,2-dihydropyrido[3,2-e]-as-triazine hydrochloride (V). Mild dehydrogenation with alkaline potassium ferricyanide yielded heteroaromatic pyrido[3,2-e]-as-triazines (VI), for which ultraviolet and nmr spectral data are reported.     

The chemistry of 1,2,5-thiadiazoles V. Synthesis of 3,4-diamino-1,2,5-thiadiazole and [1,2,5] thiadiazolo[3,4-b]pyrazines

The o-diamine, 3,4-diamino-1,2,5-thiadiazole ( 2 ), was synthesized from 3,4-dichloro-1,2,5-thiadiazole ( 3 ) hy three methods. Aqueous glyoxal cyclized 2 into [1,2,5]thiadiazolo[3,4–6]-pyrazine ( 14 ). 3,4-Dichloro-1,2,5-thiadiazole 1,1-dioxide ( 18 ) reaeted with 2 to give 1,3-dihydro-bis[1,2,5]thiadiazolo[3,4-b:3′,4′-e]pyrazine 2,2-dioxide ( 19 ). The reaction of 2 with selenium oxyehloride led to [1,2,5]selenadiazolo[3,4-c] [1,2,5]thiadiazole ( 12 ). Ring closure of 2,3-diaminoquinoxaline ( 4 ) with thionyl chloride or selenium oxychloride gave [1,2,5]thiadiazolo-[3,4-b]quinoxaline ( 21 ) and [1,2,5]selenadiazolo[3,4-b]quinoxaline ( 22 ), respectively. Sulfurous acid reduced 21 to the 4,9-dihydro derivative 23 , which was reoxidized to 21 with chloranil. Aqueous hase hydrolyzed 21 to 4 via the hydrated intermediate 24 . Aqueous glyoxal cyclized 4 to the covalent hydrate of pyrazino[2,3-b]quinoxaline ( 26 ), 27 , which was dehydrated to 26 . Compound 26 underwent rapid addition of two alcohols in a process analogous to covalent hydration.     

N-bromosuccinimide in heterocyclic synthesis. Synthesis of pyrazolo[3,4-d]pyrimidines,Pyrimido[5,4-e]-as-triazines,and pyrimido[4,5-c]pyridazines from 6-arylidenehydrazino-1,3-dimethyluracil derivatives

Reactions of 6-arylidenehydrazino-1,3-dimethyluracil derivatives with N-bromosuccinimide leading to pyrazolo[3,4-d]pyrimidines, pyrimido[5,4-e]-as-triazines, and pyrimido[4,5-c]pyridazines are described.     

Azinotriazines. II Cyclizations leading to pyrido[3,4-e] - and [4,3-e]-as-triazines. Ring interconversion of a pyrido-as-triazine 1-oxide to a pyridotriazole

Treatment of 4-chloro-3-nitropyridine (I) with hydrazine hydrate followed by catalytic reduction gave 3-amino-4-hydrazinopyridine (III). Acid-catalyzed cyclizations of III and subsequent dehydrogenation gave pyrido[3,4-e]-as-triazines (V). Treatment of I with guanidine followed by base-catalyzed cyclization gave 3-aminopyrido[4,3-e]-as-triazine 1-oxide (VII). The 1-oxide function was removed by reduction and subsequent dehydrogenation gave the 3-amino derivative (IX). On treatment with hot alkali VII rearranged to a triazolo[4,5-c]pyridine (X). The ultraviolet and nmr spectra of derivatives of the title ring systems are reported.     

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.     

Saturated heterocycles, 248. Synthesis of 2,4-dioxo and 4-oxo-2-thioxo derivatives of octahydrocyclopenta[d]pyrimidines

Unsubstituted and 1-benzyl-substituted cis-cyclopenta[d]pyrirnidine-2,4-diones and cis-2-thioxo-cyclopenta[d]pyrimidin-4-ones 9a,b and 10a,b were prepared from the corresponding cis-2-amino-1-cyclopentanecarboxylates 3 and 5 with potassium cyanate and thiocyanate. It was found that the cis derivatives 7a-h readily underwent ring closure, resulting in 3-substituted cis-2,4-cyclopenta[d]pyrimidinediones and cis-2-thioxocyclopenta[d]pyrimidin-4-ones 11a-d and 12a-d , whereas the trans counterparts 8a-d failed to cyclize, but gave hydrolysed amino acid derivatives 13a,b and 14 . This difference in the reactivities of the cis and trans isomers is a further example of the difficulty of preparing cyclopentane trans-fused six-membered 1,3-heterocycles by ring closure.     

Synthesis of thieno[2,3-e]-1,2,4-triazines

3-Methylmercapto-5-oxo-6-vinyl- and 2-methyl-3-mercapto-5-oxo-6-vinyl-2,5-dihydro-1,2,4-triazines were readily converted into the corresponding thieno[2,3-e]-1,2,4-triazine in one step by the action of phosphorus pentasulfide in pyridine. 4-Methyl-3-mercapto-5-oxo-4,5-dihydro-1,2,4-triazine is only converted into the 5-thioxo analog and no thiophene ring product was obtained under the same conditions. Thieno[2,3-e]-1,2,4-triazines were also more efficiently obtained by the action of phosphorus petnasulfide in pyridine on the appropriate 6-acylmethyl-3-mercapto-5-oxo-2,5-dihydro-1,2,4-triazine.     

Synthesis and transformations of stereoisomeric ethyl 2‐isothiocyanato‐1‐cyclopentanecarboxylatesm

Ethyl vis‐ and trans‐2‐isothiocyanato‐1‐cyclopentanecarboxylates 2 and 7 were prepared by the reaction of the corresponding alicyclic ethyl 2‐amino‐1‐carboxylates and thiophosgene. The cis‐isothiocyanato compound 2 underwent ring closure with amines in one or two steps, resulting in 3‐substituted‐cis‐2‐thioxocyclopenta[d]pyrimidin‐4‐ones 3a‐g. The trans isomer 7 failed to cyclize, but gave carboxamide 8a,b or thiourea ester derivatives 9a,b.     

1,2,4-Triazines. VI. Imidazo[1,2-b]-as-triazines

Imidazo[1,2-b]-as-triazines were obtained in high yields by heating substituted glyoxaldoximes with 1,2-diaminoimidazoles in the presence of hydrochloric acid. Phenylglyoxal hydrate in a similar reaction afforded a mixture of 2- and 3-diphenyl-6-arylimidazo[1,2-b]-as-triazines. α-Ketoacids and 1,2-diaminoimidazoles in the presence of hydrochloric acid afforded 2,6-disubstituted-4H-imidazo[1,2-b]-as-triazin-3-ones.     

Reaction of sulfene and dichloroketene with N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones. Synthesis of 1,2-oxathiino[6,5-E] indole and of pyrano[2,3-e] indole derivatives

The 1,4-cycloaddition of sulfene to N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones afforded N,N-disubstituted 3,4,5,6-tetrahydro-8-methyl-7-phenyl-7H-1,2-oxathiino[6,5-e]indol-4-amine 2,2-dioxides only in the case of aliphatic N-substitution. The 1,4-cycloaddition of dichloroketene occurred normally only in the case of 1,5,6,7-tetrahydro-2-methyl-1-phenyl-5-piperidinomethyleneindol-4-one to give 3,3-dichloro-3,4,5,6-tetrahydro-8-methyl-7-phenyl-4-piperidino-7H-pyrano[2,3-e]indol-4-one. Attempted recrystallisation, dehydro-chlorination or treatment with palladium on carbon of this adduct, as well as reaction of similar enaminoketones with dichloroketene, gave instead the same product, namely 3-chloro-8-methyl-7-phenyl-7H-pyrano[2,3-e]indol-4-one, as a result of dehydrochlorination, dehydrogenation and subsequent hydrogenolysis of the C-NR₂ bond in the primary adduct.     

Reactions with 5-aminopyrazoles. I. Synthesis of halogen-containing fused pyrazoles

5-Amino-3-phenylpyrazole (I) and 5-amino-4-bromo-3-phenylpyrazole (II) reacted with ethyl acetoacetate and acetylacetone to give various pyrazolo[1,5-a]pyrimidines IV-VI and with benzoins to give different fused pyrazoles, namely, imidazo[1,2-b]pyrazoles IX, pyrrolo[2,3-c]pyrazoles X and pyrazolo[4,3-b][1,4]oxazines XII. Diazotized II was coupled with active methylene-containing nitriles to afford pyrazolo[5,1-c]-as-triazines XIV.     

6H-indeno[1,2-b]pyrido[3,2-e]pyrazines. A new heterocyclic ring system

Condensation of 1,2-indanedione and 1,2,3-indanetrione hydrate (ninhydrin) with 2,3-diamino-pyridines gave a number of compounds belonging to the hitherto unknown 6H-indeno[1,2-b]-pyrido[3,2-e]pyrazine ring system. The unsymmetrical nature of the reactants can theoretically result in isomeric ring closure products. Assignment of the 6H- ring system was based upon the identity of 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one obtained from 2,3-diaminopyridine and ninhydrin with material prepared by unequivocal synthesis. The direction of cyclization of ninhydrin and 1,2-indanedione with the diamines was shown to be the same by reduction of the indenopyridopyrazinones to the corresponding indenopyridopyrazines. Some physical, chemical, and tumor growth-inhibitory properties of the products are reported.     

Quinazolincs and 1,4-benzodiazepines. LXXXVI. The synthesis of imidazothienodiazepines and imidazopyrazolodiazepines

The thieno[3,2-e][1,4]diazepin-2-one ( 1a ), the thieno[2,3-e] [ 1,4] diazepin-2-one ( 1b ), the pyrazolo[3,4-e][1,4]diazepin-2-one ( 1c ) and a chloro analog of 1b , compound 1d , were each converted to derivatives of the novel tricyclic ring systems 4H-imidazo[1,5-a]thieno[2,3-f] [1,4]-diazepine, 4Himidazo[1,5a]thieno[2,3f][1,4]diazepine and 4H-imidazo[ 1,5-a]pyrazolo[4,3-f]-[1,4]diazepine. Depending on the substituents desired on the imidazo ring, two different synthetic pathways were employed.     

Valenzisomerisierung von cis-Dienonen,II. 5-Phenylpenta-2, 4-dienaldehyde [1]

The 5-Phenylpenta-2,4-dienaldehydes 4 , and 7 , show an uncatalized cis-trans-isomerization of the 4,5-double bond above 70 °C. The negative value of the activation entropy for these reactions points to the formation of the bicyclic valence isomeric 2H-Pyrans 5 and 8 respectively in the rate determining step. Intermediate 5 can be trapped as its tetracyanoethylene cycloadduct 11 . The cis-trans isomeric 1,6-diphenyl-hexa-1,3,5-trienes 12a and 12b undergo above 150° a disrotatory ring closure to the bicyclic dienes 13 and 14 respectively.