5- phthalazine cyclocondensation

Cyclocondensation of 2-aroylbenzoic acid 223 with hydrazine gave the phthalazine derivative 224, which was alkylated with ethyl chloroacetate in aqueous sodium hydroxide or pyridine to give the N-substituted derivative 225. Condensation of the latter with hydrazine afforded the hydra-zide 226, which could be cyclized to give the 2//[l,2,4]triazino[3,4-a]phthalazin-3(4tf)-one 227 (91MI3). 

Azine approach. Cyclocondensation of the hydroxylamine ester (610) yields the corresponding fused phthalazine (72BRP1285333). 

Ju Y, Varma RS (2005) Microwave-assisted cyclocondensation of hydrazine derivatives with alkyl dihalides or ditosylates in aqueous media syntheses of pyrazole, pyrazolidine and phthalazine derivatives. Tetrahedron Lett 46 6011-6014... 

Compounds 312 were also prepared by alternative routes that comprised cyclocondensation of aldonolactones (313) with 1-hydrazinophthalazines or aldonic acid hydrazides (315) with 1-chlorophthalazines. Their acetates 316 were obtained by direct acetylation of 312 or by condensation of aldonoyl chloride acetates (38) with 1-hydrazinophthalazines (90MI6) (Scheme 96). l,2,4-Triazolo[3,4-a]phthalazin-3-yl acyclo C-nucleosides derived from reducing disaccharides were similarly prepared (90MI2). 

The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2/f)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino[l,2-i>]-phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo[g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine C-nucleosides synthesized by 14-i-2 cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields... 

Phthalazine and its 1,4-disubstituted derivatives 13 are obtained by cyclocondensation of o diacylbenzenes 12 with hydrazine e.g. the parent compound is produced from benzene-1,2-dicarbaldehyde (phthaldialdehyde) and hydrazine hydrate ... 

In much the same way as synthesis of their cinnoUne counterparts (see Chapter 1), the primary synthesis of phthalazines (or hydrophthalazines) may be done by cyclization of benzene (or cyclohexane) derivatives already bearing appropriate substituents, by cyclocondensation of benzene (or cyclohexane) derivatives with acyclic synthons that provide one or more of the ring atoms needed to produce the phthalazine system, by analogous processing of other carbocyclic or pyridazine substrates, or by modification of other heterocycUc substrates in various ways, lypical pre-1972 examples in each category of synthesis may be found from cross-references to Simpson s volume (e.g., H 72) or to Singerman and Patel s volume (e.g., E 333) that appear in some section headings. A variety of pre-and post-1972 syntheses have also been reviewed elsewhere. ... 

This type of cyclocondensation is represented only by a somewhat specialized example. Thus methyl p-benzoquinone-2-carboxylate (121) with A-acetonylidene-M-methyDiydrazine (122) gave 4-acetyl-5,8-dihydroxy-2-methyl-l(2Ff)-phthalazi-none (123) [or its tautomer, 4-acetyl-8-hydroxy-2-methyl-l,5(2H,3fl) phthalazine-dione] (MeOH, 20°C, 12 h 50%). °... 

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