2- Phenyl-3 -pyridazinone, reaction with

On the other hand, reaction of 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone 287 with A -methyl-/3-alaninenitrile afforded the 4-(2-cyanoethyl) derivative 288, which was cyclized by heating with sodium ethoxide in ethanol to the pyrido[2,3-rflpyridazine 289 (Equation 22) <1994S669>. 

Regioselective displacement of chlorine from 4,5-dichloro-3(2//)-pyridazinones has been shown to be exceptionally dependent on the solvent and has been the subject of several studies. With 2-methyl and 2-phenyl-4,5-dichloro-3(2//)-pyridazinones as substrates, reaction with alkoxides occurs selectively at C-4 in less polar solvents (carbon tetrachloride, dioxane, THF, t-BuOH, pyridine), is nonselective in solvents of intermediate polarity (acetone, 2-propanol), and is selective for C-5 in polar solvents (EtOH, MeOH, DMF, DMSO) with the exception of acetonitrile, in which mixtures are obtained. Similar selectivity was seen with phenol and ethanethiol, but with thiophenol and ethyl... 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Pd-catalyzed coupling reactions at the 5-position of 6-phenyl-3(2W)-pyridazinones using a retro-ene transformation have been reported <02SL2062>, and the Pd-catalyzed arylation of 4-bromo-6-chloro-3-phenylpyridazine has been shown to be efficient and regioselective <02SL223>. The N-methylation of substituted 3(2//)-pyridazinones with Ai,iV-dimethylformamide dimethylacetal has been explored <02SC1675>, as have the preparation of 3-nitro-, -nitroso- and -chloro-derivatives of... 

Hydroxymethylation and Mannich reaction have been performed with pyridazinones and maleic hydrazide, because they are acidic enough for these types of additions. Although it has been claimed that pyridazinones form only A-hydroxymethyl derivatives in the Mannich reaction it was reported that the corresponding Mannich bases are formed easily. The substituted aminomethyl residue is attached always on the ring nitrogen. Mannich bases were likewise obtained from maleic hydrazide and its analogs, but not from its 2-phenyl... 

Direct amination of 3(2//)-pyridazinones occurs when they are heated with hydrazine hydrate and this is a convenient route to many 4-amino-6-substituted-3(2//)-pyridazinones (Scheme 11). The reaction generally gives high yields and amination is regiospecific when the 6-position is occupied by an aromatic or heteroaromatic ring, but the parent 3(2/ -pyridazinone gives a mixture of the 4- and 5-amino-3(2//)-pyridazinones. The reaction tolerates jV-methyl substitution of the pyridazinone, but is sensitive to steric factors the presence of a 5-substituent causes a marked reduction in reaction rate, and amination does not occur with 4-phenyl-3(2//)-pyridazinone. With maleic hydrazide 4-hydrazination occurs, possibly by displacement of an intermediate amino compound or by oxidation of an intermediate 4,5-dihydro-4-hydrazino adduct both 4-hydrazino- and... 

Both 6-(4-(l-imidazolyl)phenyl)-3(2//)-pyridazinone (64) and its 4-chloro analogue (65) reacted with potassium cyanide in DMSO to give the 4,5-dicyano derivative (66) (Scheme 21). The 5-cyano-3(2//)-pyridazinone (67) was isolated from reaction of the des-chloropyridazine, but the 4-cyano analogue was not observed from either substrate. This unusual reaction proceeds faster in an oxygen atmosphere and more slowly under an inert atmosphere the nitriles were not produced in other solvents or when copper cyanide was used <86JHC1515>. 

In an unusual reaction, treatment of 2-benzyl-6-phenyl-4,5-dihydro-3(2//)-pyridazinone with a mixture of phosphorus oxychloride and pentachloride resulted in debenzylation, aromatization, and chlorination (Equation (16)). The presence of the benzyl group in the substrate is important, as the dichloropyridazine product is only formed in very low yield from the corresponding reaction of 6-phenyl-4,5-dihydro-3(2 0 Pyt dazinone <83JHC1473>. 

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>. 

The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2/f)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino[l,2-i>]-phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo[g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine C-nucleosides synthesized by 14-i-2 cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields... 

Azolopyridazines bearing no nitro substituent are, nevertheless, sufficiently active electrophiles to enter the VNS reaction. However, similar to the series of quinoxalines [127] and pyridazinones [67], in the reactions of azolopyridazines with the carbanion of bromomethyl phenyl sulfone, two ways for conversion of the intermediate adducts are observed, depending on the structure of these heterocyclic compounds - p-elimination, leading to the VNS product, or intramolecular substitution, resulting in formation of the cyclopropane ring (Scheme 34) [128]. 

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