Phthalazine 1-aryl

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

In a similar manner, phthalazine or its alkyl- or aryl-substituted derivatives are obtainable from 1,2-diacylarenes (Scheme 76). Phthalaldehydic acid and its analogs are transformed by hydrazines into the corresponding phthalazin-l(2//)-ones. Phthalazin-l(2iT)-one itself is prepared from naphthalene by oxidation, subsequent treatment with hydrazine and decarboxylation as shown in Scheme 77 (55YZ1423,64FRP1335759). 4-Substituted phthalazin-l(2iT)-ones are prepared in a similar way from 2-acylbenzoic acids. 3-Hydroxyphthalides,... 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

Palladium-catalyzed hydroarylation of sterically hindered PTAD adduct 157 with aryl halides in the presence of triphenylarsine, sodium acetate, and DMSO provides a 1 1 mixture of 170 and 171. The same reaction done with sodium fluoride and formic acid provides mixtures containing 171 as the major product. Apparently, the use of sodium fluoride as a base allows the selective formation of the opening products 171 in good yields (Equation 19). Similarly, the 2,3-phthalazine-l,4-dione adduct 172 provides the corresponding products 173 and 174 (Equation 20) <2002AGE3375>. 

Reduction of 3-aryl-4-oxo-4//-pyrido[2,l-fl]phthalazine-l-carboxamides with sodium cyanoborohydride in acidified methanol or lithium borohy-dride in tetrahydrofuran afforded 6,7-dihydro derivatives 47 (R = H) (88EUP294599). 

The reactions of anhydro 2-aryl-3-hydroxythiazolo[2,3-a]phthalizinium hydroxides (171) with methyl propiolate (87EUP226196 88EUP294599), dimethyl acetylenedicarboxylate (85JOC1677), or fumaronitrile (85JOC1677) gave 4//-pyrido[2,l-a]phthalazin-4-ones (173) via cycloadducts 171. When methyl vinyl ketone was reacted with 171 (R = H), in addition to 9% of 4//-pyrido[2,l-a]phthalazin-4-one (173, R = H, R = COMe), a cycloadduct was also isolated (85JOC1677). 

Aryl halides bearing strong electron-withdrawing groups and thus allowing nucleophilic aromatic substitution can be used for the arylation of azinone anions. 4-(4-Hydroxy-3-methylphenyl)phthalazin-l(2//)-one has been arylated simultaneously at N-2 and at the phenolic OH with 4-chlorobenzonitrile and potassium carbonate in dimethyl-acetamide (DMA) <2005CHJ200>. 

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>. 

The annelation of benzo rings on pyridazines was covered in CHEC-II(1996) <1996CHEC-II(6)1>. Maes and Matyus reported new examples in their synthesis of the dibenzo[// ]phthalazin-l(27r)-one and dibenzo[//]cinnolin-3(27/)-one skeleton. Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one yielded 2-benzyldibenzo[/,4]phthalazin-l(2//)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl) -phenylpyridazin-3(2//)-one via a Pschorr-type reaction was also investigated. Similarly, the con-stmction of 2-methyldibenzo[/, ]cinnolin-3(2//)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(27T)-one and 2-methyl-5-(2-aminophenyl)-6-phenyl-pyridazin-3(2//)-one was performed <2003T5919>. 

In a similar manner, aryl acid hydrazides 150 were condensed with benzaldehydes 151 <99SC3503>. Intermediates 152 underwent cyclodehydration in the presence of polyphosphate ester (PPE) to provide phthalazines 153 in good yields. 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

The phenylation of pyridazine and quinoxaline has been carried out using dibenzoyl peroxide, iV-nitrosoacetanilide, and benzenedia-zonium hydroxide as the sources of phenyl radical, the first two methods giving very much better yields than the third.63 The most reactive positions in these ring systems are the 4-position in pyridazine and the 2-position in quinoxaline. Phthalazine has been phenylated with iV-nitrosoacetanilide, giving a low yield of 5-phenylphthalazine, but the main product from cinnoline in this reaction was 4,4 -bicin-nolyl, although a small quantity of 4-phenylcinnoline was obtained.63 Pyrimidine has been arylated only with the 4-nitrophenyl radical, substitution occurring at the 2- and 4-positions.12... 

Halogenated benzo fused derivatives have also been successfully used as substrates exemplified by the synthesis of l-aryl-4-(4-methylpiperazinyl)phthalazines (89), possessing... 

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