1- Methylphthalazine

The reductions of cinnolines and phthalazines were discussed in Part I, Section IV,B (Ring Contractions) or V,D. 1-Methylisoindole (190) has since been isolated as a hydrochloride from reduction in hydrochloric acid of 1-methylphthalazine with strict control of the potential to avoid further reduction to methylisoindoline (191). Purification requires acidic conditions the free base turned quickly to a tar299,300 [Eq. (113)]. 

The reduction course of substituted phthalazines depends on the substituents. Thus, 1-methylphthalazine (158) in alkaline solution... 

Alkylation of the phthalazine Reissert compound (6) with methyl iodide proceeded normally to give 1-methylphthalazine."... 

These compounds are reduced in acid solution somewhat differently from cinnolines. Phthalazine is reduced polarographically in acid solution in a six-electron wave [309], presumably to o-xylene-Q, 0 -diamine, but 6 N hydrochloric acid [150] is required as medium if the diamine is the desired product. 1 -Methylphthalazine is reduced as follows ... 

Reissert type reactions of pyridazine 1-A -oxides to give 6-cyanopyridazines in poor yield, and the alkylation of a phthalazine Reissert compound to give 1 -methylphthalazine after hydrolysis, were discussed in CHEC-I <84CHEC-1(3B)1). Examples of the use of Reissert type chemistry and an unusual reaction with cyanide ion are described below. 

The influence of acid on these additions is considerable. In ethanol, for example, ethyl nicotinate is converted into the corresponding 6a-hydroxyethylpyridine, whereas in acidified solution the 6-ethylpyridine derivative is obtained.147 The function of the acid may, of course, simply be to promote dehydration of the intermediate 6a-hydroxyethyldihydropyridine. Phthalazine and quinoxaline are converted by irradiation in acidified methanol into 1-methylphthalazine and 2-methylquinoxaline, respectively.148 In this case, however, there is evidence to suggest that the alkylations proceed by way of electron transfer from the solvent to an excited state of the protonated diazines in neutral solution, a hydrogen... 

Phthalazine (16) underwent addition of methanol under irradiation and subsequent dehydration to give 1-methylphthalazine (19) (HCl gas in methanol. 

Methylphthalazine (146) with p-methoxyphenacyl bromide apparently gave only 2-(p-methoxyphenacyl)-4-methylphthalazin-2-ium bromide (147) and thence, by treatment with potassium carbonate, p-methoxybenzoyl(4-methylphthalazin-2-io)methanide (148) (for details, see original). " ... 

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. 

Although early investigators considered that 4-hydroxy-l-methyl-phthalazine existed as such in neutral solution, they refer to basicity data which, in the light of present knowledge, would lead to assignment of the l-methylphthalazin-4-one structure (84, R = Me) to the predominant tautomer. The correctness of the oxo structure for phthal-azin-l-one (84, R — H) has been demonstrated using infrared spectroscopy. ... 

Although there has been interest recently in phthalazine quaternary salts, no work has been reported on the position of quatemization since the classic studies of Gabriel and co-workers. For the sake of completeness, it may be noted that 4-methylphthalazine (59) and methyl iodide gave the salt 60 alkaline degradation of 60 gave a... 

Methylphthalazine in acetonitrile gave 416 and 417, initial attack having taken place on the less hindered nitrogen atom.418... 

Other cationic rings. Diazinium salts resemble pyridinium salts in their behavior. They form pseudobases with hydroxide ions which can disproportionate (e.g., 2-methylphthalazinium ion 217 2-methylphthalazin-l-one + 2-methyl-1,2-dihydrophthalazine) or undergo ring fission (e.g., 3-methylquinazolinium ion 218). 2-Alkyl-1,2,3-triazinium salts add nucleophiles at C(5) <2003S413>. 

Methoxy-2-methylphthalazin-2-ium p-toluenesulfonate (205) gave 2,3-dimethyl-4-oxo-3,4-dihydrophthalazin-2-ium p-toluenesulfonate (206) (neat... 

Methylphthalazin-2-ium-4-olate (225, R = Me) with diphenylacetylene gave 10-methyl-3,4-diphenyl-l,5-dihydro-2,5-imino-2//-2-benzazepin-1 -one (226,... 

Methylphthalazin-2-ium-4-olate (231) underwent photolysis in methanol to give 2-(o-methoxycarbonylphenyl)-l-methyldiaziridine (232, R = OMe)... 

Note Several reactions of these thioethers have been reported, as exemplified here. l-Ethylthio-4-methylphthalazine (21, R=Et) underwent oxidation to 1-ethyl-sulfonyl-4-methylphthalazine (22, R Et) (substrate, CHCI3, H2SO4, H2O, ice slowly, 0°C 50%) somewhat similarly, l-methyl-4-... 

Phthalazinamine (60) gave a separable mixture of 1-amino- (61) and 4-amino-2-methylphthalazin-2-ium iodide (62) (Mel, MeOH, 50°C, sealed, 24 h 90% before separation). ... 

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