4-Methyl-2- phthalazinone

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

Phthalazin-1 (2H)-one, 4-hydroxy-2-methyl-methylation, 3, 17 Phthalazin-l(2H)-one, 4-methoxy-methylation, 3, 17 Phthalazinones in thermography, 1, 392 Phthalazin-l(2H)-ones alkylation, 3, 17 reaction... 

CN 4-[(4-chlorophenyl)methyl]-2-(hexahydro-l-methyl-l/f-azepin-4-yl)-l(2//) phthalazinone hydrochloride... 

Nl - 1(2H)-PHTHALAZINONE, 4-C C4-CHL0R0PHENYL)METHYl)-2-(HEXAHYDR0-l-METHYL-lH-AZEPIN-4-YL)-, HYOROCHLORIOE... 

Smith and Otremba138 have found that the sodium borohydride reduction of 2-methyl- and 2-ethyl-phthalazinium iodide (113) in aqueous medium results in good yields of the corresponding 1,2-dihydrophthalazines (114). The dihydrophthalazines were found to be stable to excess sodium borohydride in refluxing methanol but underwent a facile air oxidation to phthalazinones (115). The borohydride reduction of 2-benzyl-phthalazinium chloride proceeded with apparent partial debenzylation, for a 31% yield of the parent 1,2-dihydrophthalazine (114, R = H) was isolated as the 2,2-dimethyl quaternary salt. 

The disproportionation of heteroaromatic cations in aqueous base has been known for many years.277 279 For example, fresh organic extracts of basic aqueous solutions of the 2-methylphthalazinium cation (119) contain26,277,280 a mixture of 2-methyl-l,2-dihydrophthalazine (120) and 2-methyl-l-phthalazinone (121). Similar reactions have been reported for... 

The electrode reactions were investigated by reducing the compound at pH 0 and 9 the reduction in acid solution produced 2-methyl-phthalimidine (2) by a six-electron reaction, whereas that at pH 9 yielded 3,4-dihydro-2,3-dimethyl-4-hydroxy-l-phthalazinone (3) in a two-electron reduction. This compound (3) was then investigated polarographically (Fig. 3) it is reduced in acid solution in 2 two-electron waves, at pH 4 in 2 one-electron waves, and not reducible in... 

Dihydroxyphthalazines40 such as 2,3-dihydro-2,3-dimethyl-l,4-phthalazinedione are reduced at low pH to a phthalimidine in a six-electron reduction in alkaline solution 4-hydroxy-3,4-dihydro-2,3-dimethyl-l-phthalazinone is formed in a two-electron reaction. In this medium it is not further reducible, but in acid solution it loses water to the reducible phthalazinonium compound. The product from this reaction is 3,4-dihydro-2,3-dimethyl-l-phthalazinone, which at low pH can be reduced to V-methylphthalimidine and its precursor V-methyl-2-(methylaminomethyl)benzamide. The reduction scheme was given in Section II, D (Scheme 1). 

Nitration of 4-hydroxymethyl-l(2//)-phthalazinone and its derivative EG-626 with acetyl nitrate has been shown to give, after formation of the methyl nitrate esters, the N-2-nitro derivatives (Scheme 54). An earlier suggestion that the second nitration of EG-626 occurred on the phthal-azinone oxygen was disproved by a combination of spectroscopic methods and an x-ray structure determination <92CPB3327>. 

The cyclocondensation of these substrates with hydrazines is represented by only one example. Methyl o-cyanobenzoate (116) with methylhydrazine gave 4-amino-2-methyl-l(2H)-phthalazinone (117) (MeONa, MeOH, 20°C, 12 h 24%). " ... 

Acetyl-2-chlorocycloheptatrien-l-one (136) or the isomeric substrate, 2-acetyl-7-chlorocycloheptatrien-l-one (138), underwent condensation and rearrangement with hydrazine to give 4-methyl-l(27/)-phthalazinone (137) (H2NNH2 H2O, MeOH, reflux, 2h 29 or %, respectively) substrate (138) with methylhydrazine gave 2,4-dimethyl-l(2fl)-phthalazinone (139) (MeOH,... 

Methyl-5-phenylsulfonyl-3(2iJ)-pyridazinone (152, R = SOaPh) underwent Diels-Alder addition by 2,3-dimethyl-l,3-butadiene (151) to give 2,6,7-trimethyl-4a-phenylsulfonyl-4a,5,8,8a-tetrahydro-1 (2fl)-phthalazinone (153, R = S02Ph) (reactants, PhH, reflux, 10 days 90%) methyl l-methyl-6-oxo-l,6-dihydro-4-pyridazinecarboxylate (152, R = C02Me) likewise gave methyl 2,6,7-trimethyl-1 -oxo-1,2,4a,5,8,8a-hexahydro-4a-phthalazinecarbox-ylate (153, R = C02Me) (70%) such additions by an unsymmetric diene... 

Hydroxy-6,7-dimethoxy-l,3-dihydro-l-isobenzofuranone (215) gave 7,8-di-methoxy-2-methyl-l(2//)-phthalazinone (216) (MeNHNH2, EtOH, reflux. 

Amino-6-chloro-3-hydroxy-l-isoindolinone (259) with hydrazine gave 6-amino-7-chloro-l(2//)-phthalazinone (260, R = H) (H2O, 95°C, N2, 2h 77%) or with methylhydrazine gave 6-amino-7-chloro-2-methyl-l(277)-phthalazinone (260, R = Me) (H2O, 90°C, 3 h 60%) analogs likewise. " ... 

The conversion of these substrates into phthalazines clearly has synthetic potential. For example, 4-phenylpyridazino[4,5- i]pyridazin-l(2F/)-oiie (290) and A -(l-ethylprop-l-enyl)pyrrolidine (289) in refluxing dioxane for 1 h gave a mixture of the Diels-Alder adducts (291) and (292) that lost nitrogen and pyrrolidine on refluxing in dilute propanolic acetic acid during 24h to afford a 1 2 mixture (61%) of 7-ethyl-6-methyl-4-phenyl-l(2//)-phthalazinone (293) and 6-ethyl-7-methyl-4-phenyl-l(27/)-phthalazinone (294), from which only the latter could be obtained in... 

Dihydroimidazo[l,2-fo]isoquinoline-5,10-dione (313) with hydrazine hydrate gave 4-(imidazol-2-yl)-l(2F/)-phthalazinone (314, R = H) (neat reactants, reflux, 3 h 87%) or with methylhydrazine gave 4-(imidazol-2-yl)-2-methyl-... 

Methyl-1,4(277,37/)-phthalazinedione (9) gave 4-chloro-2-methyl-1(277)-phthalazinone (10) (POCI3, reflux, 2h % note the immunity of the nontautomeric 0x0 substituent to halogenolysis). ... 

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