Phthalazines synthesis

As previously noted, Haider and co-workers reported inverse electron demand Diels-Alder reactions of various enamines 130 with an appropriately substituted pyridazine 129 as a method for phthalazine synthesis as well (see section 6.2.4.3) <99SC1577>. 

In such a phthalazine synthesis, the synthon could supply Cl, N2, Cl +N2, N2 + N3, C1+N2 + N3, or C1+N2 + N3 + C4. Of these possibilities, the second, third, and last are unrepresented (at least in the literature under review), and of the remaining three categories only that in which the synthon supplies N2 + N3 has been used widely. 

Watanabe, N., Kabasawa, Y., Takase, Y, Matsukura, M., Miyazaki, K., Ishihara, H., Kodoma, K., Adachi, H. 1998. 4-Benzylamino-l-chloro-6-substituted phthalazines Synthesis and inhibitory activity toward phosphodiesterase 5. Journal of Medicinal Chemistry 41 3367-3372. 

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. 

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... 

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77)... 

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>. 

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