Phthalazine-l,4-diones

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>. 

It is the combination of exceptional reactivity and reasonable stability, either as a solid or in solution, that makes PTAD such an ideal dienophile. However, PTAD is decomposed to N2, CO and phenyl isocyanate by the action of UV light.61 The cyclic ADC compounds (6-23) all undergo the Diels-Alder reaction, although with the exception of phthalazine-l,4-dione (13, R = H), they have been used only occasionally. l,3,4-Thiadiazole-2,5-dione (11) is of comparable reactivity to PTAD,38 but like the other cyclic compounds (6-23) has the slight disadvantage in that it has to be generated in situ. 

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... 

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>. 

Phthalazine-l,4-diones have been prepared by nucleophilic cleavage of polystyrene-bound phthalimides (Entry 7, Table 15.27). The reaction rate proved to be highly dependent on the solvent used, being low in EtOH but high in DCM. Using DMF as solvent, no phthalazinediones could be isolated [325]. Hexahydropyridazines have been prepared on cross-linked polystyrene in low yields by treatment of support-bound 1-acyloxy-l, 3-dienes with diimide [326]. 

On the other hand, the diazetidines 5 and 7 only are produced by the reaction of indene with phthalazine-l,4-dione (4)4 and 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione (6)1. The adduct 7 was successively converted to fra .v-(l,2-dihydro-3-hydroxy-2-indenyl)triazolidinone by acidic hydrolysis T Furthermore, the diazctine was prepared by a sequence involving hydrolysis of the triazolidine ring with concomitant decarboxylation, and oxidation of the intermediate diaze-tidine5. 

Similarly, a mixture of stereoisomers (47% yield fija 80 20) is obtained in the cycloaddition of phthalazine-l,4-dione (generated in situ) to vitamin D3n, the configuration of the diastereomers was assigned by analogy with the previously reported triazole adducts. 

Surprisingly, neoalloocimene (18) is more reactive than alloocimene (16) toward phthalazine-1,4-dionc and benzo[g]phthalazine-l,4-dione, generated in situ by oxidation of the corresponding cyclic hydrazides with lead tetraacetate or tm-butyl hypochlorite, the civ-adducts 21 and 22 are predominantly obtained from either of the isomeric trienes37. The II-NMR spectra of the predominant isomers shows the C-l and C-4 substituents occupying pseudoaxial positions. 

Some authors used a completely different approaeh HA or the degradation products of HA were not directly detected, but the competition between HA and another (exogenously added) compound for the HO radicals was used as a measure of reactivity. In this context, the luminol-amplified chemiluminescence was often used [251] Luminol (5-amino-2,3-dihydro-phthalazine-l,4-dione) reacts with HO radicals under the emission of light. When luminol is present in excess over the generated radicals, the intensity of light... 

Diels-Alder reactions of phthalazine-1,4-dione and benzo[gr]phthalazine-l,4-dione, generated in situ by LTA or t-butyl hypochlorite oxidation of the cyclic hydrazides, with isoprenoid dienes gave the expected cycloadducts (Scheme 33), sometimes in high yields <87H(25)193>. A-Bromosuccinimide has been claimed to be a superior oxidant for the in situ preparation of phthalazine-1,4-dione for... 

Diels-Alder cycloaddition with, for example, butadiene <85JOC5604>. 7V-Bromosuccinimide can be used to oxidise the initial adduct formed between phthalazine-l,4-dione and 1,4-diphenyl butadiene via benzylic bromination and thermal elimination of hydrogen bromide the intermediate bromide is, however, very labile towards nucleophiles, and base causes cleavage of the phthaloyl residue, leaving 3,6-diphenylpyridazine <86JOC3123>. 

The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2/f)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino[l,2-i>]-phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo[g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine C-nucleosides synthesized by 14-i-2 cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields... 

Thirupaiah and Vedula devised a one-pot synthesis of substituted 2,3-dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2f/-pyran-3-yl)-7f/- [ 1,2,4] tr iazolo [3,4-i ] [ 1,3 >4] -thiadiazin-3-yl)phthalazine-l, 4-diones 13 (Scheme 9) (14SC513). Treatment of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2f/-pyran-2-one (14) with 4-amino-5-hydrazino-4f/-[l,2,4]triazole-... 

Phthalimide is quite acidic = 9) it can be converted to potassium phthalimide by potassium hydroxide (step 1). The phthalimide anion is a strong nucleophile and (in step 2) it reacts with an alkyl halide by an Sn2 mechanism to give an A -alkylphthalimide. At this point, the A-alkylphthalimide can be hydrolyzed with aqueous acid or base, but the hydrolysis is often difficult. It is often more convenient to treat the A-alkylphthaUmide with hydrazine (NH2NH2) in refluxing ethanol (step 3) to give a primary amine and phthalazine-l,4-dione. 

Benzo[b]phthalazine-l,4-dione (43) was synthesized from sodium naph-thalene-2,3-dicarboxylic acid hy dr azide and chlorine in diglyme at — 50 . It reacted with H202/alkali to give light with a quantum efficiency of about 5% of that of luminol and the same emission spectrum obtained from the starting hydrazide [55]. 

The anthracene derivative (44), naphtho-[2,3-g]-phthalazine-l,4-dione (NPD) is fairly stable, and it chemiluminesces on oxidation with basic hydrogen peroxide with an emission maximum of 430 nm, similar to the luminol emission maximum [43, 56, 57]. 

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