2- phthalazine cyclization

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... 

Cyclocondensation of 2-aroylbenzoic acid 223 with hydrazine gave the phthalazine derivative 224, which was alkylated with ethyl chloroacetate in aqueous sodium hydroxide or pyridine to give the N-substituted derivative 225. Condensation of the latter with hydrazine afforded the hydra-zide 226, which could be cyclized to give the 2//[l,2,4]triazino[3,4-a]phthalazin-3(4tf)-one 227 (91MI3). 

Dichlorophthalazine on condensation with thiosemicarbazide in DMF afforded l,4-bis(thiosemicarbazi-do)phthalazine 444, that undergoes cyclization with carbon disulfide in the presence of potassium hydroxide to give l,4-bis(3, 5 -dithioxy-[l,2,4]triazol-l-yl)phthalazine 445. Compound 445 reacts with monochloric acid in the presence of NaOH to give l,4-bis-(l -thioxy-6 -oxo-[l,2,4]triazolo[3,4-A]-l,3-thiazol-2 -yl]phthalazine 446 (Scheme 51) <2001IJC(B)500>. 

Several applications of established ring-closure methodologies have been applied for the syntheses of the benzo-logues of the triazolopyridazine ring system - all these refer to cyclization to [l,2,3]triazolo[3,4- ]phthalazine derivatives. In Table 13, such products are shown together with yields and literature references. The product in entry 8 is somewhat outstanding in this list these compounds have been synthesized by solid-phase methodology, and the yields refer to the amounts of the crude products mostly of 90% purity. 

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

Bischler-Napieralski cyclization of pyridazin-6-one 134 with POCI3, and subsequent hydrogenation of the cyclized product 135 over Pt02, gave rise to 2,3,4,6,7,llZ -hexahydro-l//-pyridazino[6,l-fl]isoquinoline (51) (75CPB3056). Treatment of Reissert compound 136 with NaH gave 116-cyano-l, 2,3,116-tetrahydro-4//-pyrido[2,l-fl]phthalazin-4-one (137) (80JHC433). 

Hydrazone formation of pyridazine-3-hydrazines with aldoses, dialdofuranoses, and dialdopyranoses was studied by Stanovnik and co-workers. The respective hydrazones could be cyclized with Bt2 in MeOH or Pb(OAc)4 to j-triazolo[4,3-3]pyridazin-3-yl substituted polyols <1997JHC1115, 1998JHC513>. Similarly, 4-[(dimethylamino)-methylene]-l,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one was reacted with pyridazine-3-hydrazines and the resulting mixtures were subsequently treated with Pb(OAc)4. Besides j-triazolo[4,3-3]pyridazine formation also diazenes were obtained. This can be rationalized by the enehydrazine-hydrazone mixtures observed in the first reaction. For phthalazin-l-hydrazines only diazenes were obtained after oxidation <2005TA2927>. Also cyclizations of... 

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>. 

Azine approach. The pyridazines and their cinnoline and phthalazine benzologues can be fused with thiazoles in the same way as pyridine derivatives. The cyclization of the... 

Except for a demonstration that the phthalazine Reissert compound (3 R = Ph) behaves normally in giving benzaldehyde on acid-catalyzed hydrolysis, no new reports have appeared of Reissert compounds being used in aldehyde synthesis. Acid-catalyzed hydrolysis has been used, however, in some cases to prepare heterocyclic carboxylic acids. Thus in addition to the preparation of isoquinaldic acid, phthalazine-1-carboxyIic acid and 15 have been prepared from 3(R = Ph) and 11, respectively. Acid-catalyzed hydrolysis of 16 occurs with cyclization to give 17. A series of Reissert compounds derived from substituted 3-aminoquinolines have been converted to the corresponding quinaldic acids by acid-catalyzed hydrolysis. ... 

A series of these acyclo C-nucleosides (312) were prepared from aldose phthalazin-l-ylhydrazones (311), which underwent facile thermal dehydro-genative cyclization to 312. The cyclization was expedited by catalytic dehydrogenation with palladium on charcoal (81MI5 83MI8 89BCJ2701 91MI9) (Scheme 95). 

Indenetriones(31.1) react in an unexpected fashion when stirred at 50 with tosyl chloride in anhydrous pyridine. A possible mechanism through tosylation of the hydroxy group and then formation of a bond between pyridine-N and C-1 of indanone is suggested. Pyridines may be replaced by isoquinoline or phthalazine in this cyclization [3071, 3785]. A 2-phenacylidenepyridine may be cyclized to an indolizine by heating with an anhydride [2458]. 

Phthalazine-l(2 T)-thione reacts in a similar manner with alkenes by [2 + 2] addition, but the intermediate diradical either cyclizes on to the /jen-position to give, after oxidation, the fused tricyclic system (105), or undergoes hydrogen transfer to give open chain sulfides (Scheme 68). The formation of the fused products is favoured by stabilization of the terminal alkyl radical by geminal methyl substitution <90CPB1205>. 

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 an unusual reaction, a furan derivative has been cyclized with hydrazine to give, after aerial oxidation in alkali, 6,9-dihydroxybenzo[ ]phthalazine-5,10-dione in excellent yield (Equation (40)). Normally furans need to be converted into unsaturated 1,4-dicarbonyl derivatives (bromine/ methanol, followed by hydrolysis) prior to reaction with hydrazine to give pyridazines, but in this case the carbonyl groups activate the furan to attack by hydrazine <93JHC1597>. 

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