4- phthalazinone alkylation

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... 

Several therapeutic agents are based on phthalazinone nuclei, in which the hydrazide carbonyl group persists in unmodified form. Reaction of keto-acid (69-1) with hydrazine leads to the phthalazinone (69-2). Alkylation of the hydrazide nitrogen with 2-(chloroethyl)-A-methylpyrrolidine (69-3) surprisingly leads to the incorporation of a seven-membered azepine ring rather than the expected ethylpyrroldine. This can be explained by keeping in mind that it is likely that the... 

The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase. 

Competition between the two carboxy residues in the cyclization of alkyl 1,3-dihydro-l-hydroxy-a,a-disubstituted-3-oxo-l-benzoisofuranacetates with hydrazines can lead to phthalazinones and/or pyrazolones (Equation (39)). With ethyl esters a mixture of both products may be obtained, and while increased bulk at the a-position leads to the pyrazolone as the sole product, phthalazinones are the exclusive products from /-butyl esters <9lJOC2587). 

These substrates afford 4-alkyl(or aryl)-l(2//)-phthalazinones. The examples that follow are so numerous that they have been divided into groups according to the type of hydrazine used as synthon. 

Most such compounds have been made by primary synthesis (see Chapter 8), by ozonolysis of alkenylphthalazines (see Section 9.2.2), or by alkylation or acylation of tautomeric phthalazinones (see Section 11.1.2.1). Minor preparative routes are... 

Ammo-5,6,7,8-tetrabromo-4-tolyl-l(2/i/)-phthalazinone (72) underwent sub-stituted-alkylation by 2-chloroacetanilide to give 5,6,7,8-tetrabromo-2-[(iV-phenylcarbamoylmethyl)aniino]-4-tolyl-1 (2f/)-phthalazinone (72a) (reactants, EtOH, reflux, 4h 73% o, m, or -tolyl unspecified). ... 

Yamaguchi, M., Kamei, K., Koga, T., Akima, M., Kuroki, T. and Ohi, N. 1993. Novel antiasthmatic agents with dual activities of thromboxane A2 synthetase inhibition and bronchodi-lation. 1. 2-[2-(l-Imidazolyl)alkyl]-l(2//)-phthalazinones. J. Med. Chem. 36 4052-4060. 

---