4- -phthalazinone, hydrolysis

Chlorophthalazine is quite reactive to many basic nucleophiles but reacts sluggishly with aqueous or alcoholic alkali. In contrast, it is very rapidly hydrolyzed by warm, concentrated hydrochloric acid as are its diazine isomers. In hydrolysis with very dilute acid or with water, it forms some phthalazinone but mostly the self-con-densation product which hydrolyses to give 2-(l -phthalazinyl)-phthalazin-l-one (70% yield). Such self-condensations in diazanaph-thalenes and in monocyclic azines are always acid-catalyzed (Sections II, C and III,B). With methanolic methoxide, 1-chlorophthalazine (65°, few mins), its 7-methoxy analog (20°), and 1,6- and 1,7-dichlorophthalazines (20°) readily undergo mono-substitution. 

Such substrates clearly should afford 1-phthalazinamines, but the only reported examples underwent concomitant or subsequent hydrolysis under the conditions of cyclocondensation to give the corresponding phthalazinones 3-formylphthalonitrile (52) gave 4-oxo-3,4-dihydro-5-phthalazinecarbonitrile (53) (H2NNH2 H2O, 12M HCl, PhH, reflux, 6h 66%). ... 

Dimethyliminio-2,2-dimethyl-2,3-dihydroimidazo[2,l-fl]phthalazin-6-olate (315) underwent hydrolysis to 4-[l-(dimethylcarbamoyl)-l-methylethyl]-amino-l(2//)-phthalazinone (316) (EtaN, H2O, 20°C, 30min 96%). ... 

Dihydro-2//-pyrimido[2,1 -a]phthalazin-2-one (329) underwent alkaline hydrolysis to give 2-(2-carboxyethyl)-l(2//)-phthalazinone (330), presumably via the corresponding phthalazinimine or carboxamide (NaOH, H2O, °C, h %) homologs likewise. " ... 

Most of these phthalazinones have been made by primary synthesis (see Chapter 8). A few have been made also by direct C-hydroxylation (see Sechons 9.1.3 and 9.2.2), by hydrolysis of halogenophthalazines (see Section 10.3.3), or by miscellaneous routes illustrated in the following classified examples. 

Cycloheptyl-4-(3-cyclopentyloxy-4-methoxyphenyl)- (116, R = OC5H9) underwent selective hydrolysis to 2-cycloheptyl-4-(3-hydroxy-4-methoxyphenyl)-4a,5,8,8a-tetrahydro-l(277)-phthalazinone (116, R = H) (TsOH- H2O, PhMe, reflux, 3h 71%). ... 

The hydrolysis of such ethers to tautomeric phthalazinones or extranuclear hydroxyphthalazines has been covered in Sections 11.1.1 and 11.2, respectively. Other reactions are illustrated by the following classihed examples. 

Chloroethoxy)-2-methyl-l(277)-phthalazinone (202) underwent rearrangement (and slower subsequent hydrolysis ) to afford a separable mixture of 2-(2-chloroethyl)-3-methyl-l,4(27/,3 /)-phthalazinedione (203) and 2-(2-hydro-xyethyl)-3-methyl-l,4(27/,3 )-phthalazinedione (204) (Me2NCHO, reflux, 6 h 38% and 8%, respectively, after separation). 

Imino-3-methyl-3,4-dihydro-l-phthalazinamine (217, X = NH) underwent hydrolysis to 4-amino-2-methyl-l(2//)-phthalazinone (217, X = 0) (hot HjO %). ... 

Note Examples have been given already for hydrolysis of the sulfones to phthalazinones (Section 11.1.1) and for their alcoholysis to alkoxyphthala-zines (Section 11.4.1). Other reactions are illustrated here. l-Phenyl-4-p-tolylsulfonylphthalazine (33) underwent cyanolysis to give 4-phenyl-l-phthalazinecarbonitrile (34) (KCN, MejNCHO, 140°C, 2h 96%). Such cyanolyses were also performed in dimethyl sulfoxide. ... 

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