6-Methoxy-4- phthalazine

Aryl-2-(dialkylaminomethyl)-6-methoxyphthalazin-l(2//)-ones have been prepared from the 4-aryl-6-methoxy-phthalazin-l(2//)-ones by a Mannich reaction (formaldehyde, dialkylamine, methanol, and reflux) <2005SC179>. 

Chloro-5-cyclopentyloxy-6-methoxyphthalazine with 3,5-dichloro-4-pyridina-mine gave 5-cyclopentyloxy-l-(3,5-dichloropyridin-4-ylamino)-6-methoxy-phthalazine (53) (reactants, NaH, Me2NCHO, 20°C, 90 min >22%). ... 

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... 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

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. 

A similar reaction sequence is expected from some other phthalazine derivatives, such as methoxy (88) and aminophthalazines,05 e.g., Scheme 10. 

Phthalazine 4-(Ethoxycarbonyl-methyl)-l -hydroxy-6-methoxy-E9a, 760 [5-OR — 1-oxo —3-(COOR — methylen) — 1,3-H2 —2-benzofuran/N2HJ Propansaure 3-(3-Indolyl)-2-nitro- ... 

Oxidative cleavage of hydrazino substituents in pyridazines and phthalazines proceeds with thallium trinitrate in methanol, under mild conditions (Equation (24)) to give the corresponding methoxy derivatives in moderate yields <95JOCl466>. 

Phthalazine (54) with 3-chloro-2-sulfopropionic acid (55, R = H) gave l-carboxy-2-(2-phthalazinio)ethanesulfonate (56, R = H) (synthon, MeOH, substrate slowly, then reflux, 30 min 40%) or with 3-chloro-2-methoxy-carbonylethanesulfonic acid (55, R = Me) (made in situ) gave 1-methoxy-carbonyl-2-(2-phthalazinio)ethanesulfonate (56, R = Me) (MeOH, reflux, -3 h 37%). ... 

Methoxy-gave l-(a-cyanobenzyl)phthalazine (NaH, PhCH2CN, THF, reflux, 30 min substrate], reflux, N2, tic monitored 46%). ... 

Chloro- (33) gave l-[(3,5-dichloropyridin-4-yl)methyl]-6-methoxy-5-(5-phe-nylpent-l-ynyl)phthalazine (34) [3,5-Cl2-4-Me-pyridine, NaH, Me2NCHO, 20°C, 3h 51%]. ... 

Note This nonoxidative route to heterocyclic sulfones is often overlooked. l-Chloro-7-methoxyphthalazine (118) and sodium p-toluenesulfinate gave 6-methoxy-4-(p-tolylsulfonyl)phthalazine (119) (Me2NCHO, 100°C, 2h 63%). ... 

Cyclopentyloxy-l-(3,5-dichlQTopyridin-4-ylmethyl)-6-methoxy-3,4-dihydro-phthalazine (50, R = H) with methanesulfonyl chloride gave 5-cyclopenty-loxy-l-(3,5-dichlQTopyridm-4-yhnethyl)-3-methanesulfonyl-6-methoxy-3,4-dihydrophthalazine (50, R = S02Me) (EtaN, CH2CI2, 20°C, 1 h >60%). ... 

Chloromethyl-7-methoxy-1 (2H)-phthalazinone l-Chloro-4-(A -methyl-A -methylenehydrazino)phthalazine 1 -Chloro-3-methyl-4-methylimino-3, 4-dihydrophthalazine... 

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