Phthalazines, alkyl-, reactions

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. 

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. 

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... 

In a representative example alkylation of 4-phenyl-2H-phthalazin-l-one (Scheme 2.67) was achieved using PS-BEMP at ambient temperature in acetonitrile. Purification of the reaction mixture was realized by removal of the excess alkylating agent using an aminomethylpolystyrene scavenger. 

Disappointingly, a Heck reaction on 5-bromo-2-methoxymethyl-6-phenylpyridazin-3(2//)-one (172) afforded only a low yield of 5-alkenyl-2-methoxymethyl-6-phenylpyridazin-3(2//)-ones (232). The major compounds were dehalogenated substrate (230) and 6-substituted 2-methoxymethyl-4-phenylphthalazin-1 (2/7)-oncs (231). The formation of the latter compound depends on the alkene since when styrene was used no phthalazin-l(2//)-one formation occurred. In this case, 65% of 2-methoxymethyl-6-phenylpyridazin-3(2//)-one and 5% 2-methoxymethyl-6-phenyl-5-(2-phenylvinyl)pyridazin-3(2//)-onc could be isolated. The formation of alkyl (2-methoxymethyl)-1 -oxo-4-phenyl-1,2-dihydrophthalazine-6-carboxylates and (2-methoxymethyl)-1 -oxo-4-phenyl-1,2-dihydrophthalazine-6-carbonitrile, using alkyl acrylates and acrylonitrile as alkenes, respectively, can be rationalized by a tandem Pd-catalyzed process. 

The paper reporting the reaction of isoquinoline and potassium cyanide with dialkyl chlorophosphates and dialkyl chlorothiophosphates to give products of the type 114 has now appeared. These compounds can be alkylated in the same manner as a normal Reissert compound, and hydrolysis of the alkylation product gives 1-methylisoquinoline. A phthalazine analog (115) has also been prepared. ... 

Reissert type reactions of pyridazine 1-A -oxides to give 6-cyanopyridazines in poor yield, and the alkylation of a phthalazine Reissert compound to give 1 -methylphthalazine after hydrolysis, were discussed in CHEC-I <84CHEC-1(3B)1). Examples of the use of Reissert type chemistry and an unusual reaction with cyanide ion are described below. 

In principle, the interaction of a phosphorus(III) ester with an co-haloalkylamine should lead to an (co-aminoalkyl)phosphonic diester or a phosphinic acid analogue (Scheme 11). Such examples in the classical Michaelis-Arbuzov mould have been widely reported, but success in their outcome depends on the relative nucleophilicities of nitrogen and phos-phorus(III) centres towards the displacement of halogen. The interaction of triethyl phosphite and a halogen-substituted tertiary amine, such as 2-chloroethyldiethylamine, does not lead to a phosphonic diester, and in this particular case the product is a piperazinium diquaternary salt. However, successful Michaelis-Arbuzov reactions have been carried out between the bis(bromomethyl)phthalazines 130 (to both the mono- and di-phosphonic acid stages) and the series of [co-(2-cyano-4-pyridine)alkyl]phosphonic diesters 132 (n = 1-4) have been prepared from the 4-pyridinealkyl bromides 131 as precursors to the phosphonoalkylpiperidinecarboxylic acids 133 . ... 

The data on the Sn reactions of phosphorus-centered nucleophiles with electro-phihc nitroarenes and azines are scarcely available in the literature [11, 159] Although a number of o -adducts derived from the addition of P-nucleophiles to isoquinoline [140], phthalazine [160], 4,7-phenanthroline [161, 162], A -alkyl-pyrazinium, and quinoxalinium salts [163] have been isolated and identified by NMR and X-ray crystallography, no attempts to convert these o -adducts into the corresponding Sn products have been done. For instance, Af-ethylpyrazinium tetrafluoroborate reacts with dialkyl and diaryl phosphonates under very mild conditicHis (room temperature, acetonitrile) to give stable dialkyl 3-phenyl-5,6-dicyano-l-ethyl-l,2-dihydropyrazin-2-yl phosphonates in good yields (Scheme 50) [163],... 

Unequivocal evidence for the formation of o -adducts has been obtained by X-ray diffraction analysis of those adducts which are stable enough to obtain their single crystals [11]. Indeed, the X-ray crystallography data are available for the anionic trinitrobenzene-methoxide and the Janovsky trinitrobenzene-acetone complexes [11, 201, 202] and for the o -adducts of isoquinoline [203], phthalazine [160], and 4,7-phenanthroline [161, 162] with dialkyl phosphonates. Also the X-ray data have been obtained for the neutral o -adducts resulting from the reactions of iV-methylacridinium ion with N-nucleophiles [204, 205] and for the o -adducts of iV-alkyl-substituted 2,3-dicyanopyrazinium and quinoxalinium salts with 0-, C-and P-nucleophiles [163, 194]. 

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