Synthesis of pyridazine derivatives. XXI. Tetrazolo-azido transformations in some fused azolopyridazines

6-Azidotetrazolo[1,5-b]pyridazine (III) has been prepared by two different routes and is easily transformed into the 6-amino derivative (IV). The attempted cyclization of 6-hydrazinotetrazolo[1,5-b] pyridazine (II) into the postulated tricycle has been shown to result in the formation of 6-azido-s-triazolo [4,3-b]pyridazine (VI), obtained also in a separate experiment from VII. The azido structure of VI has been confirmed from spectroscopic data and from its conversion into 6-amino-s-triazolo [4,3-b]pyridazine (VIII), obtained in another experiment from VII. Similarly, cyclization of II with cyanogen bromide resulted in the simultaneous formation of the s-triazolo ring and ring opening of the fused tetrazolo ring, giving IX. For 6-azido-2-phenylimidazo[1,2-b]pyridazine (XII) the expected azide structure proved to be correct.     

Pyridazines. LXXXIV. Studies on borohydride reduction of pyridazine compounds

Imidazo[1,2-b]pyridazine, s-triazolo[4,3-b]pyridazine and tetrazolo[1,5-b]pyridazine and some derivatives thereof were reduced with sodium borohydride to give the corresponding 5,6,7,8-tetrahydro derivatives. A mechanism for these reductions is proposed and reduction at the C₇-C₈ bond occurs before the reduction of the C₆? N₅ bond. Substituents at position 7 and/or 8 cause a significant decrease in the extent of reduction or lead to a 5,6-dihydro derivative by competitive attack at the 6 position.     

The synthesis of derivatives of new tetracyclic heterocyclic systems pyrazolo-bis-azolopyridazines

The synthesis of new tetracyclic systems and new stable tautomers of known systems 11H- 13 and 10H-imidazo[1, 2-b]pyrazolo[4, 3-d]-s-triazolo[3, 4-f]pyridazine 16 , 9H-pyrazolo[3, 4-d]bis-s-triazolo[4, 3-6:5′,1-f]-pyridazine 15 , 10H-pyrazolo[3, 4-d]bis-s-triazolo[4, 3-b:3′,4′-f]pyridazine 17 , and 10H-pyrazolo[4, 3-d)bis-s-triazolo[4, 3-6:5′,1′-f]pvridazine 18 is described.     

Synthesis of s-triazolo[4,3-b]pyridazine C-nucleosides

A one step synthesis of s-triazolo[4,3-b]pyridazine using 3-chloro-6-hydrazinopyridazine and an appropriate thioformimidate is described. Applying this procedure to 5-O-benzoyl-1-benzylthio-1-formimidate-D-ribofuranose, 5′ benzoyl-6-chloro-3β-D-ribofuranosyl-s-triazolo[4,3-b]pyridazine was obtained. Substitutions of chlorine by nucleophilic reagents afforded some derivatives of a new series of C-nucleo-sides. Structural determination including anomeric configuration assignment is discussed based mainly on ¹H nmr spectroscopy.     

Synthesis of new s-triazolo[4,3-b] pyridazines

A new synthesis of s-triazolo[4,3-b]pyridazine derivatives has been achieved starting from 3,6-dichloropyridazine. The method opens the way to substitutions in the 2- or 3- positions. A tri-cycloderivative, a bis-s-triazolopyridazine, has also been synthesized.     

Synthesis of imidazo[1,2-b]pyridazines: Fenbendazole,oxifenbendazole analogs and related derivatives

A series of imidazo[1,2-b]pyridazines has been prepared and evaluated for macrofilaricidal activity against Brugia pahangi or Acanthocheilonema viteae infections in jirds. The imidazo[1,2-b]pyridazine analogs of fen-bendazole and oxifenbendazole are reported. In addition, several 6-aminoimidazo[1,2-b]pyridazine derivatives have been prepared. None of these compounds possessed significant activity against human cytomega-lovirus (HCMV) or filarial infections.     

Synthesen und Reaktivität von 2,3,6,7,8-Pentachlorimidazo-[1,2—b]pyridazin und 3,6,7,8-Tetrachlor-s-triazolo-[4,3—b]pyridazin

Zusammenfassung 2,3,6,7,8-Pentachlorimidazo[1,2—b]pyridazin und 3,6,7,8-Tetrachlor-s-triazolo[4,3—b]pyridazin wurden aus unsubstituierten Verbindungen und einigen Chlor-Derivaten synthetisiert. Die Reihenfolge der Substitution von Wasserstoffatomen durch Chloratome konnte beim Imidazo[1,2—b]pyridazin als 3>2, 7>8>6 ermittelt werden, während beis-Triazolo-[4,3—b]pyridazin der Verlauf als 3>8>7>6 sichergestellt wurde. Nukleophile Substitutionen an diesen perchlorierten Systemen verlaufen am leichtesten in Stellung 8.

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Pyridazines. XLVIII: Syntheses and Reactivity of 2,3,6,7,8-Pentachloroimidazo[1,2—b]pyridazine and 3,6,7,8-Tetrachloro-s-triazolo[4,3—b]pyridazine

2,3,6,7,8-Pentachloroimidazo[1,2—b]pyridazine and 3,6,7,8-Tetrachloro-s-triazolo[4,3—b]pyridazine were synthesized from the parent compounds and some of their chloro derivatives. It could be established that in the case of the first condensed system the stepwise introduction of chlorine atoms followed the order of 3>2, 7>8>6 and in the case of the second system this appears to be 3>8>7>6. Nucleophilic substitutions on these perchloro compounds proceed most easily at position 8.

     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthesis of pyridazine derivatives XXII. s-triazolo[4, 3-b]pyridazine 5-oxides

The synthesis of s-triazolo[4,3-b] pyridazine 5-oxides is reported. To our knowledge, they are the first example of N-oxides of heteroaromatic azoloazines with a bridgehead nitrogen. They are easily rearranged, in particular when irradiated with ultraviolet light, into 6-hydroxy-s-triazolo[4,3-b]pyridazines.     

Methyl imidazo[1,2-b]pyridazine-2-carbamates and related compounds as potential antifilarial agents

A series of imidazo[1,2-b]pyridazines have been synthesized for antifilarial evaluation. The compounds prepared include methyl 6-benzoylimidazo[1,2-b]pyridazine-2-carbamate ( 12 ), 6-benzoyl-2-t-butylimidazo[1,2-b]pyridazine ( 13 ), methyl 6-(4-fluorobenzoyl)imidazo[1,2-b]pyridazine-2-carbamate ( 14 ), and methyl 6-(2-thienylcarbonylcarbonyl)imidazo[1,2-b]pyridazine-2-carbamate ( 15 ) which are aza analogs of the anthelmintic agents mebendazole, flubendazole and nocadazole. In addition, the preparation of a series of 2-t-butylimidazo[1,2-b]-pyridazine-6-carboxylic acid derivatives is described. Electrophilic bromination and iodination substitutions of 2-t-butyl-6-methylimidazo[1,2-b]pyridazine afforded 3-halo derivatives. Methyl 6-(4-fluorobenzoyl)pyridazine-3-carbamate was also prepared for antifilarial evaluation. None of these compounds possessed significant antifilarial activity against Brugia pahangi or Acanthocheilonema viteae infections in jirds.     

The synthesis of substituted pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazines

The synthesis of 1,2,4-triazolo[4,3-b]pyridazines and the unknown ring system, pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine, has been achieved. The preparation of the new tricyclic 1,2,4-triazole was accomplished first by ring closure of the triazole ring followed by formation of the pyrazine ring. Substitution of the pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine ring system was carried out in order to provide information of its reactivity and to provide a variety of interesting compounds for biological testing.     

Heterocyclization of 3-(R-amino)-3-methylthio-1-phenylpropenones and 5-benzoyl-6-methylthio-1,2-dihydropyridin-2-ones with 1,2- and 1,3-dinucleophilic reagents

The interaction of 3-(R-amino)-3-methylthio-1-phenylpropenones and 1-alkyl-5-benzoyl-3-ethoxy-carbonyl-6-methylthio-1,2-dihydropyridin-2-ones with N,N- and N,C-1,2- and 1,3-dinucleophiles proceeded regioselectively by [3 + 2] and [3 + 3] cyclocondensation with the formation of derivatives of pyrazole, benzimidazo[1,2-a]-pyridine, benzimidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrimidine, [1,2,4]triazolo[4,3-b]pyridazine, and 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine. The regioselectivity of the reactions carried out was analyzed.     

Preparation of 5-substituted- and 3,5-disubstituted-s-triazolo[4,3-a]pyridines

Cyclization of N-acyl-N′-(6-chloropyrid-2-yl)hydrazines ( 2a-2e ) with phosphorus oxychloride has produced several 5-chloro-s-triazolo[4,3-a]pyridines ( 3a-3e ). Nucleophilic displacement of the chlorosubstituent of 5-chloro-s-triazolo[4,3-a]pyridine ( 3a ) availed the 5-ethoxy ( 4a ) and 5-thioethoxy ( 4b ) derivatives and di(s-triazolo[4,3-a]pyrid-5-yl)sulfide ( 8 ) while reaction of 5-ethylsulfonyl-s-triazolo[4,3-a]pyridine ( 4d ) with potassium hydroxide yielded the 5-hydroxy/5-one system ( 4c or 6 ). Further reaction of 3a with bromine to give 3-bromo-5-chloro-s-triazolo-[4,3-a]pyridine ( 3g ) has provided the corresponding 3-cyano- and 3-carboxamido-5-chloro-s-triazolo[4,3-a]pyridine derivatives ( 3h and 3i ). Treatment of 6-chloro-2-hydrazinopyridine ( 1 ) with cyanogen bromide has provided 3-amino-5-chloro-s-triazolo[4,3-a]pyridine ( 3f ) which, with bromoacetaldehyde dimethyl acetal, transformed into 7-chloroimidazo[1,2-b]-s-triazolo[4,3-a]-pyridine ( 7 ). Finally, attempts at cyclizing N-oxalyl-N′-(6-chloropyrid-2-yl)hydrazine derivatives ( 2g-2i ) with intentions of preparing various 3-acyl-5-chloro-s-triazolo[4,3-a]pyridines for entry into other 3,5-disubstituted systems were unsuccessful.     

Photoelectron spectroscopy of heterocycles. Azaindenes and azaindolizines

The HeI photoelectron (PE) spectra of indole ( 1 ), benzimidazole ( 2 ), indazole ( 3 ), 3-chloro-indazole ( 4 ), imidazo[1,2-b]pyridazine ( 5 ), 6-chloroimidazo[1,2-b]pyridazine ( 6 ), 2-phenyl-imidazo[1,2-b]pyridazine ( 7 ), 2-phenyl-6-chloroimidazo[1,2-b]pyridazine ( 8 ), tetrazolo[1,2-a]-pyridine ( 9 ) and 8-cyanotetrazolo[1,5-a]pyridine ( 10 ) have been recorded. The spectra of 2–10 are of special interest for studying lone pair interactions. The assignment of the PE spectra submitted here, conjointly with the electronic structure of the studied compounds is discussed on the basis of molecular orbital calculations.     

Synthesis of new 1,2,3-triazolo[1,2-a]benzotriazole derivatives or substituted 2,3-benzo-1,3a,6,6a-tetraazapentalenes. II

This paper continues the synthesis of new 1,2,3-triazolo[1,2-a]benzotriazoles or 2,3-benzo-1,3a,6,6a-tetrazapentalenes to submit to biological assays. The derivatives were obtained by deoxycyclization reactions of appropriate nitrophenyl-1,2,3-triazole derivatives and by thermal decomposition of appropriate azidophenyl-1,2,3-triazoles (Schemes 1 and 2). Some attempts to extend these synthetic routes to the preparation of 1,2,4-triazolo[1,2-a]benzotriazoles (Scheme 3) and 1,2,3-triazolo[1,2-b]-4H-1,2,3-benzo-triazines (Scheme 4) completely failed.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo [4,3-b] pyridazine,III

s-Triazolo[4,3-b]pyridazine (I) reacted photochemieally with bieyélo[2.2.1] hepla-2,5-diene, 1,5-cyclooctadiene, 1,3-cyclooctadiene, methylene cyclohexane, diethyl cis-1,2,3,6-tetrahydro-phthalate and ethyl 2-cyclopentene-1-acetate to givt: the following products: the endo and exo isomers of 4a, 5, 8a, 9-tetrahydro-9-rnethylene-5,8-rnethano-8H-s-triuzolo[1, 5-a]indole (II) and the endo and exo-9-cyanometliyl products (III and IV) from bicyclo[2.2.1] hepta-2,5-diene; 4a,5,-9, 10, 10a, 11-huxahydro-11-methylene-6H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole (V) and the 11-cyanomethyl product VI from 1,5-cyclooctadiene: 4a,7,8,9,10,10a-hexahydro-11 -inethylene-11H-cycloocta[4,5]pyrrolo[1,2-b]-s-triazole(VII),4a, 5, 7, 8, 10a, 11-hexahydro-11-methylene-6H-cycloocta[4,5]pyrroIo[1,2-b]-s-triazole (VIII) and their respective 9-cyanomethyl products (X and 1X) from 1,3-cyclooctadiene; 6′, 7′ -dihydro-7′ -methylenespiro[cyclohexane-1, 5′-[5H] pyr-rolo[1,2-b]-s-triazole] (XI), 6′, 7′-dihydro-7′-meth) lene. spiro cyclohexane-1, 6′-[5H]pyrrolo[1,2-b]-s-triazole] (XII) and their respective 7 -eyanomethyl products (XIII and XIV) from melhylene cyclohexane; 6,7-dicarbethoxy-9-cyanomelhyl-4a, 5, 7, 8, 8a, 9-hexahydro-6H-s-triazolo[1,5-a]indole (XV) from diethyl cis-1, 2, 3, 6-tetrahydrophlhalate: and 5-earl)elhoxymethyl-8-eyanomethyl-4a, 5, 6, 7, 7a, 8-hexahydrocyclopenta[4,5]pyrrolo( 1, 2-b]-s-triazole (XVI) from ethyl 2, 2-cyclo-pentene-1-acetate. Many other alkenes, particularly the phenyl ethylenes, did not react with compound 1. In general, more than one product was isolated for each reaction except in the case of the two ester alkenes where a single eyanomethyl product was observed.     

1,2,4-Triazoles. XX. Pyrolytic decomposition of ketone hydrazones derived from pyrid-2-ylhydrazine and related bases. Some further examples of the s-triazolo[4, 3-α]pyrazine and s-triazolo[4, 3-a]quinoxaline series

Pyrolytic decomposition of ketone 2-heterylhydrazones has been shown to be unsatisfactory for the preparation of fused s-triazole derivatives. The introduction of more diversified substituents into the s-triazolo[4, 3-a]pyrazine and s-triazolo[4,3-a]quinoxaline systems has been accomplished and some reactions and spectral characteristics of these ring systems are reported. Isomerization of the s-triazolo[4, 3-a]pyrazine system to the s-triazolo[1,5-a]pyrazine system is described.     

A general synthesis of s-triazolo[1,5-x] diazines

Treatment of 2-aminopyrimidime, a 4-aminopyrimidine, aminopyrazine, and 3-aminopyridazines with O-mesilylenesulfonylhydroxylamine gave the corresponding N-aminodiazinium salts in high yields. These salts could be transformed into s-triazolo[1, 5-a] pyrimidines, s-triazolo[1, 5-a]-pyrazines, s-triazolo[1, 5-c]pyrimidines, and s-triazolo[1, 5-b]pyridazines hy treatment with acylating agents.     

Reactions of α-ketohydrazidoyl halides with some heterocyclic amines. Facile synthesis of arylazo derivatives of fused heterocycles with a bridgehead nitrogen atom

Arylazo derivatives of imidazo[2,1-b]thiazoles, imidazo[1,2-b]pyrazoles, imidazo[1,2-b]-s-triazoles, imidazo[1,2-a]pyrimidines, and imidazo[1,2-a]pyridines were obtained in good yields from α-keto hydrazidoyl halides and 2-aminothiazole, 5-aminopyrazole, 5-aminotriazole, 2-aminopyrimidine, and 2-aminopyridine, respectively (cf. Tables I and II). The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectra, and alternate synthesis wherever possible.     

Carbon-13 NMR investigation of the structure of hydroxy-azoloazines with a bridgehead nitrogen

Carbon-13 nmr data has been obtained on four hydroxy-azoloazines containing a bridgehead nitrogen atom, on the corresponding methoxide derivatives, and on selected anionic and cationic derivatives. These results have been interpreted in terms of the site of protonation of the parent hydroxy-compounds. A comparison of the anionic derivatives with those of the parent compounds demonstrate that the neutral parent hydroxy-species exist predominately in the “hydroxy form” rather than as the ionized species. The chemical shift data also provides information on the conformation of the hydroxy- and methoxy-groups in 8-hydroxy-6-methyl-s-triazolo[4,3-6]-pyridazine and 8-rnethoxy-6-methyl-s-triazolo[4,3-6]pyridazine.