The synthesis of imidazo[4,5-c] - and v-triazolo[4,5-c] pyridazines

The parent imidazo[4,5-c]pyridazine (IV) has been prepared for the first time by three different routes. 1-Methylimidazo[4,5-c]pyridazine (XX) and 3-methylimidazo[4,5-c]pyridazine (XXVII) have been prepared by unequivocal syntheses. The constitution of the methylation product of imidazo[4,5-c]pyridazine-2-thiol (VIII) has been shown to be 2-methylthioimidazo[4,5-c]-pyridazine (IX) by the unequivocal syntheses of 1-methylimidazo[4,5-c]pyridazine-2-thiol (XXIII) and 3-methylimidazo[4,5-c]pyridazine-2-thiol (XXXIII). Likewise, the structure of the methylation product (XIII) was shown to be S-methylation by the unequivocal syntheses of 1-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXIV) and 3-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXXI), respectively. Several 7-substituted amino-v-triazolo-[4,5-c]pyridazines (XXXVIII) have been prepared from 7-chloro-v-triazolo[4,5-c]pyridazine (XXXVII).     

The synthesis of lmidazo[4,5-d] pyridazines. VI. v-Triazolo[4,5-d] pyridazines,pyrazino[ 2,3-d ] pyridazines and 7H-Imidazo [4,5-d] tetrazolo[ 1,5-b] pyridazine

Several pyridazines have been prepared as intermediates in the synthesis of monosubstituted imidazo[4,5-d]pyridazines, monosubstituted v-triazoIo[4,5-d]pyridazines and monosubstituted pyrazino [2,3d] pyridazines. The new ring system, 7H-imidazo[4,5-d]tetrazolo[l,5-b] pyridazine (XIV) has been prepared unsubstituted. Furthermore, unsubstituted imidazo[4,5-d]pyridazine (XI) has been prepared. Calculations for XI and XIV were made by approximate SCF LCAO-MO with CNSO II theory.     

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.     

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).     

Synthesis of 10-deazariboflavin and related 2,4-Dioxopyrimido[4,5-b]quinolines

Condensation of substituted anthranilaldehydes with barbituric acid results in the formation of 2,4-dioxopyrimido[4,5-b]quinolines. Using this general synthetic approach, 7,8-dimethyl-2,4-dioxo-10-ribityl-2,3,4,10-tetrahydropyrimido[4,5-b]quinoline (10-deazariboflavin) was prepared by the condensation of barbituric acid with 4,5-dimethyl-N-ribitylanthranilaldehyde. The latter was obtained in situ by the treatment of 1-[4,5-dimethyl-N-(ribityl)anthraniloyl]-2-(p-toluenesulfonyl)hydrazine, prepared from 4,5-dimethylanthranilic acid with anhydrous sodium carbonate.     

1,2,3-Triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines

Some new 1,2,3-triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyridazines via the formation of the 1,2,4-triazole ring, by condensation of an appropriate monocarbon fragment with the 4-hydrazino substituent and the nitrogen atom in the 5 position of the heterocycle. Condensation of 4-phenylhydrazino substituted derivatives with formic acid gave zwitterionic compounds.     

Synthesis and Properties of Derivatives of the new Heterocyclic System Benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine

Derivatives of a new heterocyclic system - benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine have been obtained by successive reactions in three stages - alkylation of 3-cyanopyridine-2(1H)-thiones with 2-chloromethylbenzylimidazole to give 2-benzimidazolylmethylthio-3-cyanopyridines, closing the thiophene ring in the latter to form 3-amino-2-(benzimidazolyl-2)thieno[2,3-b]pyridines, and cyclization of the pyrimidine ring by acylation with carboxylic acid anhydrides or chlorides.     

1,4-disubstituted pyridazino[4,5-d] pyridazines

1,4-Bis(methyIthio)pyridazino[4,5-d]pyridazine (IV) was synthesized from 4,5-pyridazinedi-carboxylic acid in three steps. By employing IV as an intermediate, various 1,4-disubstituted pyridazino[4,5-d]pyridazine derivatives of classes 1,4-N,S; 1,4-N,O; 1,4-O,S; and 1,4-O,O were prepared by one-step or two-step nucleophilic substitution reactions. Steric, polar and resonance effects were observed in some of these reactions and are discussed.     

The preparation of the benzo[4,5]cyclohepta[1,2-b]pyrazine and benzo[4,5]cyclohepta[1,2-b]quinoxaline systems

Benzo[4,5]cyclohepta[1,2-b]quinoxaIine 2 , benzo[4,5]cyclohepta[1,2-b]pyrazine 3a and benzo[4,5]cyclohepta[1,2-b]quinoxaline 4 were prepared from 4,5-benzotropolone and 1,2-phenylenediamine, ethylenediamine and 1,2-diaminocyclohexane, respectively. Compound 3a was methylated to 3b .     

Etude des conditions d'accès au triazino-1,2,4-[4,5-b] indazole

1,2,4-Triazino[4,5-b]indazol-1(2H)one and its derivatives were prepared by transposition of 3-[2-(-1,3,4-oxadiazolyl)]indazole or by ring closure of indazole ethoxymethylidenehydrazides. The synthesis of 1,2,3,4-tetrahydro-l,2,4-triazino[4,5-b]indazole-1,4-dione was achieved by cyclising the N-carbethoxyhydrazide of indazole-3-carboxylic acid and the synthesis of 1,2,4-triazino-[4,5-b]indazol-4(3H)one was made by cyclising the N-carbethoxy-hydrazone of indazole-3-carboxaldehyde. The Oxydation of 1,2,4-triazino[4,5-b]indazole-l(2H)thione gave 1,2,4-triazino-[4,5-b]indazoles. Nmr spectral data are reported.     

The synthesis of pyrimido[4,5-c] pyridazines and pyrido[2,3-d]pyrimidines related to toxoflavin and fervenulin

4-Deazatoxoflavin (1,6-dimethyl-1,5,6,7-tetrahydropyrimido[4,5-c]-5,7-pyridazinedione) ( 7 ) and several other 4-deazatoxoflavin and 4-deazafervenulin analogs have been prepared with the required intermediates. 3,5,7-Trimethyl-1,2,3,4-tetrahydropyrido[2,3-d]-2,4-pyrimidinedione ( 19 ) and 8-phenyl-3,5,7-trimethyl-2,3,4,8-tetrahydropyrido[2,3-d]-2,4-pyrimidinedione ( 20 ) were also prepared.     

Benzothiazolo[3,2-c]-1,3-dioxolo[4,5-g]quinazolines

Zusammenfassung Es wurde eine Reihe von 5,12a-Dihydro-6-alkyl/aryl-6H-benzothiazolo [3,2-c]-1,3-dioxolo[4,5-g]chinazoline, sowohl mitcis-als auchtrans-ständigen Wasserstoffatomen an Kohlenstoff 6 und 12a, synthetisiert. Ebenso wurden auch Verbindungen dieses Systems mit Thiazol an Position 6 hergestellt. Die Strukturen wurden mittels IR- und NMR-spektroskopischen Daten abgesichert.

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Benzothiazolo[3,2-c]-1,3-dioxolo[4,5-g]quinazolines

Some 5,12a-dihydro-6-alkyl/aryl-6H-benzothiazolo[3,2-c]-1,3-dioxolo [4,5-g]quinazolines withcis as well astrans stereochemistry of the hydrogens at carbon 6 and 12a have been synthesised. The synthesis of another series of compounds of the above system with thiazole ring at position 6 has also been accomplished. The structures have been established on the basis of IR and PMR data.

     

A novel preparation of thiazolo[5,4-c]pyridines and the synthesis of some imidazo[4,5-c]pyridines and oxazolo[4,5-c]pyridines

Diethoxymethyl acetate was used to cyclize o-disubstituted aminopyridines to oxazolo[4,5-c]pyridines and imidazo[4,5-c]pyridines. All the possible imidazole-methylated imidazo[4,5-c]pyridines were prepared. A novel synthesis of 2-substituted thiazolo[5,4-c]pyridines and 4-amino-3-pyridinethiol was discovered.     

Furopyridines. X. Synthesis of tricyclic heterocycles,furo[2,3-b:4,5-c']-, furo[3,2-b:4,5-c']-, furo[2,3-c:4,5-c']- and furo[3,2-c:4,5-c']dipyridine

This paper describes the synthesis of four tricyclic heterocycles, furo[2,3–6:4,5-c']- ( 5a ), furo[3,2-b:4,5-c']- ( 5b ), furo[2,3-c:4,5-c']- ( 5c ) and furo[3,2-c:4,5-c']dipyridine ( 5d ). Starting with 2-formylfuropyridines ( 1a-d ), β-(2-furopyridyl)acrylic acids 2a-d were obtained by condensing with malonic acid. The acrylic acids were converted to the acid azides by reaction with ethyl chloroformate and the subsequent reaction with sodium azide. Heating of the acid azides at 230–240° with diphenylmethane and tributylamine gave tricyclic pyridinones 3a-d , which were converted to the respective chloro derivatives 4a-d by reaction with phosphorus oxychloride. Reduction of the chloro compounds over palladium-charcoal yielded compounds 5a-d respectively. All the compounds 2 to 5 were characterized by elemental analysis and spectral data. The H and ¹³C nmr and electronic spectral features of the furodipyridines were discussed comparing with those of the parent furopyridines.     

Synthesis of imidazo[4,5-d]pyridazine nucleosides related to inosine

Several imidazo[4,5-d]pyridazine nucleosides which are structurally similar to inosine were synthesized. Anhydrous stannic chloride-catalyzed condensation of persilylated imidazo[4,5-d]-pyridazin-4(5H)one (1) and imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 16 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) provided (after sodium methoxide deblocking) 6-β-D-ribo furanosylimidazo[4,5-d]pyridazin-4(5H)one (5) and 3,6-di-(β-D-ribofuranosyI)imidazo[4,5-d]pyridazin-4-one ( 7 ); and 1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 19 ) and 1,5 or 6-di-(β-D-ribofuranosyl)imidazo[4,5-d ]pyridazine-4,7(5H or 6H)dione ( 21 ), respeeitvely. 4,7-Diehloro-1-β-D-ribofuranosylimidazo[4,5-d]pyridazine ( 12 ) and dimethyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate ( 26 ), both prepared from stannic chloride-catalyzed ribosylations of the corresponding heterocycles, were converted in several steps to 3-β-D-ribo-furanosy limidazo[4,5-d]pyridazin-4(5H)one ( 14 ) and nucleosidc 19 , respectively. Acid-catalyzed isopropylidenation of mesomeric betaine 7 or nuclcoside 14 provided 3-(2,3-isopropylidene-β-D-ribofuranosyl)imidazo[4,5-d]pyrizin-4(5H)one ( 31 ). 1-β-D-Ribofuranosylimidazo[4,5-d]-pyridazine ( 29 ) was obtained in several steps from nueleoside 12 . The structure of the nucleosides was established by the use of carbon-13 and proton nmr.     

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.     

Reduction of Imidazo[4,5-c]pyridine and [1,2,3]Triazolo[4,5-c]pyridine Derivatives to Spinaceamines and 2-Azaspinaceamines

Reduction of 1-substituted [1,2,3]triazolo[4,5-c]pyridines with nickel-aluminum alloy in aqueous alkali gave 2-azaspinaceamines. Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine derivatives with formic acid in the presence of triethylamine resulted in formation of 5-formylspinaceamines and 2-azaspinaceamines. The 5-formyl group in the latter can be removed by acid hydrolysis. Unsubstituted 2-azaspinaceamine, an aza analog of natural spinaceamine, was synthesized for the first time.     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones

Abstract  

The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

v-Triazolines. Part XIX. Thiocino[4,5-d]-1,2,3-triazole and thiocino[4,5-d]isoxazole derivatives

5-Amino-2,3,6,7-tetrahydrothiocines were reacted with arylazides yielding 1-aryl-9a-amino-1,3a,4,5,7,8,9,9a-octahydrothiocino[4,5-d]-1,2,3-triazoles which could be deaminated to 1-aryl-1,4,5,7,8,9-hexahydrothiocino-[4,5-d]-1,2,3-triazoles. Similarly, the above enamines yielded, with nitrile oxides, 3-aryl-9a-amino-3a,4,5,8,9,9a-hexahydrothiocino[4,5-d]isoxazoles which were transformed with acids into 3-aril-4,5,8,9-tetrahydrothiocino-[4,5-d]isoxazoles.