Pyrido pyridazine-5,8-diones

The NMR spectra of pyrido[2,3-d]pyridazine Af-oxides reduced derivatives and quaternary salts have also been studied and alkaline deuterium exchange reactions investigated <77BSF919). 

The UV spectra of pyrido[2,3-d]pyridazine-l,4-diones have been recorded (68MI21501), whilst several of the latter were also used in chemiluminescence studies. Quinolinic and cinchomeronic hydrazides showed no chemiluminescence (60NKK173, 37JPR(148)135), but it was observed in the 8-hydroxy derivative (305) (72YZ703). 

There seems to have been no systematic study of tautomerism in the pyridopyridazines, but isolated observations in the pyrido[3,4-d]pyridazinedione (75BSF702, 69CPB2266) and pyrido[2,3-d]pyridazinedione (74JHC351) series have involved methylation studies. The pyrido[2,3-d]pyridazine-5,8-diones are believed to be enolized at the 8-position, from metal complexation results (67MI21500). 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

An aza analog of phthalazine 240 (pyrido[3,4-r/]pyridazine skeleton) was obtained via intramolecular addition-elimination reaction in azaphthalohydrazide 239 with the loss of hydrazine (Equation 56) <1997T8225>. In a similar approach also the 5,6-dihydro[l,2,3]triazolo[4,5-r/]pyridazin-4,7-dione skeleton was constructed <2002JHC889>. 

Similarly, reaction of hydrazine hydrate with pyridinedicarboxylates 281 in boiling alcohol, followed by cyclization of the resulting dihydrazides 282, gave the pyrido[3,4-r/ pyridazine-l,4-diones 283, where deacetylation has occurred during the formation of 282 (Equation 21) <1997T8225>. 

The fluorescence excitation and emission maximum of pyrido[2,3-d]pyridazine-1,4(277,3//)-dione are found at 285 and 380 nm, respectively <83MI 716-01 >. 

Oxidation of pyrido[2,3-<7]pyridazine-5,8-dione with peracetic acid gave the N( )-oxide <84AJC87>, which could also be obtained by reaction of pyridine-2,3-dicarboxylate 1-oxide with hydrazine hydrate. Similarly, the pyrido[3,4-r/]pyridazine-1,4-dione was oxidized to the 6-oxide. 

Pyrido[2,3-i/]pyridazine-5,8(6/7,7/7)-dione 1 can be synthesized by refluxing pyridine-2,3-dicarboxylic acid (5) with hydrazine in water/ethanol39 or water and then heating the mixture to 190-250 C 40... 

In a related reaction sequence, either arylhydrazones of diethyl 3-amino-2-cyano-4-oxopent-enedioate or their cyclization products, the corresponding ethyl 4-amino-l-aryl-5-cyano-6-oxo-l,6-dihydropyridazine-3-carboxylates react with malononitrile or ethyl cyanoacetate to give pyrido[2,3-d]pyridazine-2,5(1 f/,6//)-diones 2 or 3.71... 

In analogy to phthalazine syntheses, 5,7-dihydrofuro 3,4-A pyridinc (pyndine-2,3-dicarboxylic acid anhydride) and hydrazine readily condense in refluxing aqueous solution,42 refluxing acetic acid, or alternatively with lower yield in refluxing ethanol, to give pyrido[2,3-r/]-pyridazine-5,8(6/7,7//)-dione (la).78 A similar reaction is observed starting from pyridine-2,3-dicarboxylic acid anhydride and hydrazine hydrate in refluxing acetic acid.45... 

Pyrido 2,3-rf]pyridazine-5,8(6//,7//)-dione 1-Oxide (1) Typical Procedure 45... 

Position 6 of pyrido[2,3-r7]pyridazine-5,8(677,7i/)-dione can be alkylated by a Mannich reaction with formaldehyde/morpholine to give 13.91... 

Pyrido[2,3-<7]pyridazine-5,8(6//,77/)-dione is arylated in position 6 by l-chloro-2,4-dinitrobenzene to give 14.79... 

The oxidation of pyrido[2,3-r/]pyridazine-5,8(6//,7//)-dione with lead(IV) acetate gives an unstable diazaquinone 3, which in the presence of cyclopenta-1,3-diene or penta-1,3-diene gives Diels-Alder adducts.101... 

The bis-adducts of 4-phenyl-4/f-l,2,4-triazole-3,5-dione with 2-vinylpyridines are reported to yield, on treatment with hydrazine, pyrido[3,2-c]pyridazines unsubstituted in the pyridazine moiety together with the corresponding 4-hydrazino compounds.106... 

Refluxing 7V -benzylidene-5-cyano-4-methyl-6-oxo-l -(4-tolyl)-l, 6-dihydropyridazine-3-carbo-hydrazide with two equivalents of benzaldehyde in ethanol/piperidine gives 7-(benzylidene-amino)-4-cyano-6-phenyl-2-(4-lolyl)pyrido[3,4-r]pyridazine-3,8(2//,77T)-dione (6).116... 

Hydrazinolysis of dimethyl pyridine-3,4-dicarboxylate gives the hydrazinium salt of a pyridine-3,4-dicarboxylic acid monohydrazide, thought to be the 4-carboxylic acid 1. The hydrazinium salt or free acid, respectively, on heating at 365-370°C cyclizes to give pyrido[3,4-t/]-pyridazine-1,4-(2//,3//)-dione (2).117... 

When heated to 100-110"C, the bis(phenylhydrazide) of pyridine-3,4-dicarboxylic acid cy-clized with loss of one molecule of phenylhydrazine to give 2- or 3-phenylpyrido[3,4-(/]-pyridazinc-1,4(2/7,37/)-dione.118 With 2-methyl-6-(4-tolyl)pyridine-3,4-dicarbohydrazide, cy-clization to the corresponding pyrido[3,4-c/]pyridazine-l,4(2/7,3//)-dione 3 occurred by refluxing with hydrazine in ethanol the product was isolated as the hydrazinium salt.119... 

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