Phthalazine preparation

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,... 

Phthalic anhydride and diethyl phthalate are easily converted with hydrazine into 4-hydroxyphthalazin-l(2/f)-one. Its substituted derivatives have been prepared using substituted hydrazines, substituted phthalic anhydrides, or diesters or disodium salts of substituted phthalic acids (Scheme 81). However, condensation of phenylhydrazine with phthalic anhydride gives only a small amount of the corresponding phthalazine, the main product being 2-anilinophthalimide. This can be rearranged in the presence of base into the phthalazine derivative. For the preparation of 2,3-disubstituted derivatives, 1,2-disub-stituted hydrazines are reacted with the appropriate phthalic anhydrides or phthaloyl chlorides. Derivatives of 4-amino- or 4-hydrazino-phthalazin-l(2iT)-one have been prepared either from the corresponding monothiophthalimide and 3-aminoisoindolin-3-one (1S4) or from ethyl 2-cyanobenzoate (155) and hydrazine hydrate (Scheme 82). Similarly,... 

Hydroxyphthalazin-l(2//)-one is obtained in a smooth reaction between phthalic anhydride and hydrazine hydrate and this is again the starting compound for many 1-substituted and/or 1,4-disubstituted phthalazines. The transformations of 1,4-dichloro-phthalazine, which is prepared in the usual manner, follow a similar pattern as shown for pyridazines in Scheme 110. On the other hand, phthalonitrile is the preferential starting compound for amino- and hydrazino-phthalazines. The most satisfactory synthesis of phthalazine is the reaction between a,a,a, a -tetrachloro-o-xylene and hydrazine sulfate in sulfuric acid (67FRP1438827), alt iough catalytic dehalogenation of 1-chloro- or 1,4-dichloro-phthalazine or oxidation of 1-hydrazinophthalazine also provides the parent compound in moderate yield. 

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... 

Dihydroxypyridazines are readily prepared from the diene 103 and DEAZD or PTAD,159 and the amino acid 104, a constituent of the Monamycin antibiotics, was synthesized from the Diels-Alder adduct of phthalazine-l,4-dione and penta-2,4-dienoic acid.160 These unusual amino acids can also be synthesized from the PTAD and parent HTAD adducts of penta-2,4-dienoic acid,161 and a variety of similar adducts, triazolo-pyridazines 105, has been synthesized from a wide range of 4-substituted 1,2,4-triazole-3,5-diones.162... 

Sydnonimimes are prepared in a similar way to sydnones (Section 5.03.9.2) but rely on the availability of the appropriate aminonitrile (Scheme 8) <2002CRV1091>. Substituted dihydro- and tetrahydrophthalazine 122 and 124, formed from phthalazine by modification of the Reissert reaction, were converted to the novel sydnonimines 123 and 125 (Equation 22) <1995JHC643>. 

As with pyridazines, phthalazines, the other benzopyridazines, were also prepared most frequently through the condensation of hydrazines with carbonyl-containing compounds, typically phthalate derivatives. Recently, Napoletano and co-workers demonstrated the condensation of hydroxylactone 189 and hydrazine to afford phthalazones 190. After POCI3 chlorination, advanced intermediates for a novel series of PDE4 inhibitor I, phthalazines 191 were prepared <00BMC2235>. 

Hydralazine has been prepared by various procedures from 1-chlorophthalazine (2,21,22,24,28), phthalazine-1-thione (20,23,25), 1, 4-dichlorophthalazine (29,30,31), 1-(methylsulfonyl)-phthalazine (27), or 1-cyano-2-benzal acetate (26). Phthalazone, used to prepare 1-chloro-phthalazine, has been prepared from naphthalene (3,28) or from phthalic anhydride (3)- A comprehensive survey on hydrazinophthalazines and related compounds has been published by Druey and Tripod (3)- Some of these procedures are outlined in Figures 9 and 10. 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

Dienophilic cyclic a-carbonylazo compounds (triazoline diones, indazolone, phthalazine dione) prepared in a flow cell, by anodic oxidation of the corresponding hydrazino compounds in acidic methanol or acetonitrile, react with dienes (Scheme 50) [72, 73]. 

Figure 1.12). It is beyond the scope of the present review article to discuss all of the findings of these studies in detail. However, in general, it can be stated that also these CSPs may reveal valuable complementary selectivity profiles for particular classes of chiral solutes. This may apply to an even greater extent to CSPs based on Sharpless phthalazine-derived cinchona alkaloids (see Figure 1.9) (type IV CSPs bottom) [38,59] and mutants thereof (N.M. Maier and W. Lindner, in preparation). They partly showed exceptionally high enantioselectivities for some specific applications (vide infra). 

Janda, Bolm and Zhang generated soluble polymer-bound catalysts for the asymmetric dihydroxylation by attaching cinchona alkaloid derivatives to polyethylene glycol monomethyl ether (MeO-PEG) [84—87]. Since these polymeric catalysts like (24) are soluble in many common solvents they are often as effective as their small homogenous counterparts. Janda et al. prepared catalyst (24) in which two dihydroquinidine (DHQD) units were linked together by phthalazine and finally were attached to MeO-PEG via one of the bicyclic ring system moieties (Scheme... 

Electrophilic attack of a metal complex on one of the nitrogen atoms of 1,2-diazines has been reported to occur in the mechanism of new metal mediated methods to prepare C-N bonds. Pyrrolo-fused pyridazines and phthalazines for instance were synthesized via attack of the 1,2-diazine on a palladacyclobutane intermediate 34 formed via oxidative addition of an alkylidenecyclopropane to Pd(PPh3)2 (Equation 7) <2004JOC3202>. 

In a synthesis of nucleoside analogs, the sodium salts of phthalazine-l,4-dione, phthalazin-l(2//)-one, and two pyridazin-3(2//)-ones, prepared with sodium hydride in DMF, were alkylated with ( )-2,3-0-isopropylidene-l-0-(4-toluenesulfonyl)glycerol by a nucleophilic substitution of the tosyloxy group <1999AP327>. 

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>. 

In CHEC(1984) and CHEG-II(1996) the most important ways to prepare the commercially available parent compounds pyridazine, phthalazine, and cinnoline were described <1984CHEC(2)1, 1996CHEC-II(6)1>. Also functionalized derivatives that are useful in synthetic programs were nicely covered. The most important type of substrates for this purpose are the easily accessible, halogenated (commonly chlorinated) derivatives exemplified by 3,6-dichloropyrid-azine, 3,4,5- and 3,4,6-trichloropyridazine, 2-substituted 4,5-dichloropyridazin-3(2//)-ones, 1,4-dichlorophthalazine, and... 

As with ciimolines, phthalazines were also prepared most frequently through condensations of hydrazine derivatives and carbonyl-containing compounds. For example, Monneret and co-workers reported the condensation of dialdehyde 148 with hydrazine to produce phthalazine derivative 149, an advanced intermediate in the preparation of anticancer analogs of etoposide <99T12805>. 

Dihydralazine (67-3) is the less important of the two phthalazine antihypetensive agents its preparation is however recorded first because of its simplicity. Thus, reaction of phthaUiydrazide (67-1) with phosphorus oxychloride leads to the by now very famihar conversion of the amide functions to enol chlorides (67-2). The displacement of halogen by hydrazine leads directly to the antihypertensive agent dihydralazine (67-3) [76]. 

The preparation of a monosubstituted phthalazine hinges on the differing oxidation states of the starting carbonyl groups. Thus reaction of acid-aldehyde (67-4) with hydrazine gives an intermediate (67-5) that contains a hydrazone as well as a... 

Poly(arylene ether phthalazine)s were prepared by two different routes [47], As shown in Eq. (13), one route involved the preparation of precursor poly(arylene ether diketone)s and subsequent reaction with hydrazine while the other route concerned the reaction of difluorophthalazine monomers with various bisphen-ols. The poly(arylene ether phthalazine)s prepared by the two routes exhibited very similar Tgs. The synthetic route to the difluorophthalazine monomers is also shown in Eq. (13). A comparison of the properties of a representative series of poly (ary lene ether diketone)s and the corresponding poly(arylene ether... 

Furo[3,4-g]phthalazines and isobenzo[5,4-d]tropones have been prepared from 68 by similar condensation reactions [77TL1495, 79JCR(M)3518, 79JCR(S)302]. 

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