Pyridazines 1,6-dihydro- from

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Another interesting scavenger is polymer-supported anthracene, developed by Porco for the scavenging of dienophiles [109]. An example of its application to the synthesis of a complex 5,8-dihydro-(l,2,4)triazolo[l,2-a]pyridazine-l,3-diones via hetero-Diels-Alder reaction followed by removal of the excess of triazole-3,5-dione under microwave irradiation is depicted in Scheme 24. For this particular example, moving from thermal heating (toluene, 100 °C) to a microwave-assisted protocol (DCE, 150 °C) reduced scavenging time from 3 h to just 15 min. 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

Substituted 3,5-dihydro-4//-pyridazino[4,5-, ]indol-4-ones 50 <2001H(55)1105, 2002T10137> and 2,5-dihydro-l/7-pyridazino[4,5-7]indol-l-ones 52 <2006T121> have been synthesized from 5-(2-aminophenyl)pyridazin-3(2/0-ones 49 and 4-(2-aminophenyl)pyridazin-3(27/)-ones 51, respectively. For this purpose diazotization of the amino groups was followed by a nucleophilic substitution with sodium azide affording aryl azides. Upon heating of these compounds, the ring-closed products were obtained most probably via the formation of an electrophilic nitrene (Scheme 10). 

The 1,3-dipolar cycloaddition of diarylnitrile imines 98, generated in situ from arylhydrazones with chloramine T or from a-chlorobenzylidenephenylhydrazine with triethylamine, to some 5-substituted 2-methylpyridazin-3(2//)-ones 88, 99-101 has been shown to afford l,3-diaryl-l,5-dihydro-4//-pyrazolo[3,4- ]pyridazin-4-ones 102 regioselectively (Scheme 21) <2000JMT(528)13>. 

A novel ring-closure starting from 2-aryl-l-(12/-l,2,4-triazol-l-yl)alk-3-yn-2-ols has been reported <2006T8966>. Treatment of these alkynols with Bt2 at room temperature yielded 5-alkyl-7-aryl-6-bromo-7-hydroxy-7,8-dihydro-[l,2,4]triazolo[l,2- ]pyridazin-4-ium bromides which upon hydrolysis give 3-alkyl-5-arylpyridazines. 

Reaction of l-aryl-3-carbethoxy-6-phenyl-l,4,5,6-tetrahydropyridazin-4-ones 718 with activated olefins such as benzalacetophenone, benzalacetone, 3-benzylideneacetylacetone, diethyl 2-benzylidenemalonate, and a-cyano-/3-phenylacrylic acid in the presence of an organic base like pyrrolidine, morpholine, piperidine, or triethylamine gave the corresponding 2,8-dihydro-l//-pyrano[2,3-t7 pyridazines 719-723, respectively. The 1-oxo- and 1-imino derivatives of the pyrano[2,3-r/ pyridazine ring system were also prepared from the respective 6-oxo or 6-imino derivative of the starting pyridazine 718 under the same conditions (Equation 60) <1989IJB733>. 

In connection with the synthesis of new crown ethers of the pyridazine series, fused 1,4,5-oxadiazepine 52 was prepared from l,2-dihydro-3,6-dioxopyridazine 271 and 3-oxa-l,5-dichloropentane 272 under basic conditions (Scheme 62) <1997CHE1466>. 

Other syntheses involve the preparation from the monoacetate of the enolic form of nitrosuccindialdehyde/ or the dibenzoyldioxime of maleic aldehyde/ or by dehydrogenation of l-tosyl-l,4-dihydro-pyridazine. From 2,5-diacetoxy- or 2,5-dimethoxy-2,5-dihydro-furan pyridazine can be obtained in high yield. Maleic aldehyde has been obtained also when decomposing the adduct obtained in the Diels-Alder reaction between furan and diethyl azodicarboxylate and straightforward condensation with hydrazine afforded pyridazine in 55% yield.Another direct reaction involving maleic aldehyde... 

The formation of pyridazines from 1,4-ketoacids (10) or their esters and unsubstituted or substituted hydrazines is one of the most widely used methods of synthesis. It is possible to conduct the reaction in a single step or via the intermediate hydrazones or semicarbazones. The resulting 4,5-dihydro-3(2.fif)-pyridazinones (11) are then converted into the corresponding 3(2fl )-pyridazinones (12) upon dehydrogenation. Bromine in glacial acetic acid is the commonest and most useful... 

Like other azines with a hydroxyl group a or y to a ring nitrogen atom, 3- and 4-hydroxypyridazines exist predominantly in the oxo form in the solid state and in aqueous solution. This has been established for 3(2/f)-pyridazinone and related compounds from correlations of ultraviolet spectra of unsubstituted compounds and their 0- and iV-methyl derivatives in neutral, acid, and alkaline solution, on the basis of infrared spectra (for a summary of this aspect of tauto-merism see Volume 1, Chapter VII, Section II, K) and from the determined crystal structure of 6-oxo-l,6-dihydro-3-pyridazine-carboxamide. Here, the bond lengths and positions of hydrogen atoms clearly indicate its structure as the oxo form. Similar conclusions were reached also for 4(lJ )-pyridazinones (75) and the predominant cationic structure is represented by... 

Pyridazine side chain carboxylic acids are most conveniently prepared from open-chain compounds, as for example (6-oxo-l,6-dihydro-4-pyridazinyl)acetic or j8-(6-oxo-l,6-dihydro-3-pyrida-zinyl)propionic acids and derivatives. 

Decarboxylation of pyridazinecarboxylic acids usually presents no difficulty and it has been carried out by heating the acid alone or in sulfuric acid, generally over 200°. Decarboxylation of 4,5-pyrida-ziriedicarboxylic acid has been discussed earlier (Section II). Removal of both carboxyl groups has been performed with 3,6-diphenyl-4,5-pyridazinedicarboxylic acid and 4-oxo-l,4-dihydro-3,6-pyridazine-dicarboxylic acid, but more frequently stepwise decarboxylation is reported. The 4-carboxyl group is usually split off first from a 4,5-pyridazinedicarboxylic acid or 6-oxo-l,6-dihydro-3,4-pyrida-zinedicarboxylic acid, but not in the case of a 3,4-pyridazine-dicarboxylio acid where the 3-carboxyl is removed. ... 

Dihydropyridazines have not been prepared by direct cycliza-tions reductions of pyridazines and oxidations of reduced pyridazines are known. 3,6-Diphenylp3n idazine is reduced with sodium and ethanol to the 1,2-dihydro derivative and the 1,2-dicarbethoxy analog is formed in a selenium dioxide oxidation of the corresponding 1,2,3,6-tetrahydro compound. 1-Carbethoxy- or 1,2-dicarbethoxy-1,2-dihydropyridazine was obtained similarly from an alkali treatment of 1,2-dicarbethoxyhexahydropyridazine. l,2-Dihydro-3,6-diphenylpyridazine is unstable and oxidizes to the parent pyridazine in the presence of air or on attempted acetylation. ... 

Dihydropyridazines are obtained from 1,4-dicarbonyl compounds and hydrazine (Section III,B) or from the reaction of sym-tetrazines and simple ethylenic compounds (Section III,H). There are also a few special reactions, such as that between a tetrahydrofuran and phenylhydrazine, or from a 1,4,5,6-tetrahydropyridazine derivative. The 1,4-dihydro structure has been found to be correct, rather than the 1,6-dihydro structure, postulated earlier for some of these reduced pyridazines (Section III,H). 1,4-Dihydropyridazines can be reduced or oxidized easily and acid treatment of l-tosyl-1,4-dihydropyridazine causes rearrangement to 1-tosylaminopyrrole. ... 

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