Synthesis of Phthalazines

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. 

This type of cyclization was reviewed in CHEC-I <84CHEC-I(3B)1>, particularly with reference to the formation of pyridazines by formation of a bond between the terminal nitrogen of hydrazones and an appropriately positioned cyano group or Michael aeceptor. Developments of this approach have been published, including application to the synthesis of phthalazines and cinnolines. 

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. ... 

Both carbomonocyclic (other than benzene derivatives, already discussed) and carbobicyclic substrates have been used sparingly (with or without ancillary synthons) for the primary synthesis of phthalazines. The examples that follow are grouped under the parent name of the system used as substrate. 

The only heteromonocyclic system (other than pyridazine) that has been used as a substrate for the primary synthesis of phthalazines is 1,2,4,5-tetrazine. It undergoes Diels-Alder condensation with a variety of appropriate cyclic synthons (with loss of nitrogen) to afford phthalazines or reduced phthalazines. The following examples illustrate such syntheses. 

A variety of heterobicyclic derivatives have been used as substrates for the primary synthesis of phthalazines in this respect, isobenzofurans (including phthalic anhydride and the like) and isoindoles (including phthalimides, etc.) have been particularly heavily employed. The use of such bicyclic substrates is discussed in the following subsections, arranged alphabetically according to the parent system involved. 

This is the most generally used approach for the synthesis of pyridazines, and has been adopted for the synthesis of phthalazines and cinnolines. In addition, several other condensed pju idazines were synthesized in this way. 

Reissert type reaction, 3, 25 Phthalazine, tetrahydro-synthesis, 3, 44 Phthalazinediones in synthesis of (3S,5S)-5-... 

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... 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

Hu and co-workers reported a facile synthesis of pyrrolo[2,l-n]phthalazine 205 by a 13-dipolar cycloaddition of phthalazium N-ylides generated from 203 with electron deficient alkenes to give 204, followed by treating 204 with tetrakispyridine cobalt(II) dichromate [Py4Co(HCr04)2, TPCD] to complete the aromatization <00JHC1165>. 

A general approach to rhenium hydrazido complexes is the reaction of oxo or chloro compounds with organohydrazines as has been demonstrated in an early report with the synthesis of [Re NNC(Ph)0 Cl2(PPh3)2] (310), " the molecular structure of which was solved in 1988. A detailed study on [Re(NNR)Cl2(PPh3)2] complexes with R = COPh or phthalazine shows that the course of subsequent reactions is governed both by the nature of the donor group R responsible for chelate closure and by the type of donor ligand introduced. No simple substitution chemistry has been observed for R = phthalazine. The benzoyl compound... 

Nagarapu L, Bantu R, Mereyala HB (2009) TMSCl-mediated one-pot, three-component synthesis of 2H-indazolo 2, 1-b phthalazine-triones. J Heterocycl (Them 46 728-731... 

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>. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

Pyridazino[4,5-, pyridazin-l(277)-one 82 shows a similar behavior as pyridazin, 5-dicarbonitrile 77 since it is a pyridazine derivative with electron-withdrawing groups at C-4 and C-5 too. Haider used this fused pyridazine for the synthesis of cycloalkene annelated phthalazin-l(2//)-ones 83 in good yields (54-87%) (Scheme 17) <1995H(41)2519>. 

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>. 

Koizumi et al.266 have reported the synthesis of Reissert compounds under PT conditions. Ulf and Budrham267 report the same reaction with phthalazines (171). 

A method has been reported for the solid-phase synthesis of tetrazolo[5,1 -tf]phthalazine derivatives 501 based on the cyclization of resin-bound chlorophthalazines 500 with NaN3 in l-methyl-2-pyrrolidinone (NMP) at 120°C (Scheme 63) <2005TL3107>. 

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. 

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