2- Ethyl-4- -phthalazinone

Smith and Otremba138 have found that the sodium borohydride reduction of 2-methyl- and 2-ethyl-phthalazinium iodide (113) in aqueous medium results in good yields of the corresponding 1,2-dihydrophthalazines (114). The dihydrophthalazines were found to be stable to excess sodium borohydride in refluxing methanol but underwent a facile air oxidation to phthalazinones (115). The borohydride reduction of 2-benzyl-phthalazinium chloride proceeded with apparent partial debenzylation, for a 31% yield of the parent 1,2-dihydrophthalazine (114, R = H) was isolated as the 2,2-dimethyl quaternary salt. 

Competition between the two carboxy residues in the cyclization of alkyl 1,3-dihydro-l-hydroxy-a,a-disubstituted-3-oxo-l-benzoisofuranacetates with hydrazines can lead to phthalazinones and/or pyrazolones (Equation (39)). With ethyl esters a mixture of both products may be obtained, and while increased bulk at the a-position leads to the pyrazolone as the sole product, phthalazinones are the exclusive products from /-butyl esters <9lJOC2587). 

Although seldom used, such substrates also give l(2//)-phthalazinones. Thus diethyl 4-formyl-2,6-dimethylisophthalate (50) with hydrazine hydrate gave ethyl 5,7-dimethyl-4-oxo-3,4-dihydro-6-phthalazmecarboxylate (51) (EtOH, reflux, 3h ... 

Ethyl-2-thenoyl)-3,4,5,6-tetrahydrobenzoic acid (69) gave 4-(5-ethylthien-2-yl)-5,6,7,8-tetrahydro-l(2fl)-phthalazinone (70) (H2NNH2 H2O, EtOH,... 

Like the corresponding carboxylic acids, these substrates give 4-aIkyl(or aryl)-l(2//)-phthalazinone. However, the esters are seldom used simply because the acids are usually made more easily. An example of the use of keto esters is the condensation of ethyl 2-(2-methoxy-l-naphthoyl)benzoate (95) with hydrazine to afford 4-(2-methoxynaphthalen-l-yl)-l(27/)-phthalazinone (96) (neat H2NNH2-H2O, reflux, 4h 94%). ... 

The conversion of these substrates into phthalazines clearly has synthetic potential. For example, 4-phenylpyridazino[4,5- i]pyridazin-l(2F/)-oiie (290) and A -(l-ethylprop-l-enyl)pyrrolidine (289) in refluxing dioxane for 1 h gave a mixture of the Diels-Alder adducts (291) and (292) that lost nitrogen and pyrrolidine on refluxing in dilute propanolic acetic acid during 24h to afford a 1 2 mixture (61%) of 7-ethyl-6-methyl-4-phenyl-l(2//)-phthalazinone (293) and 6-ethyl-7-methyl-4-phenyl-l(27/)-phthalazinone (294), from which only the latter could be obtained in... 

Methyl-l(27/)-phthalazinone with p-(2-bromoethoxy)benzaldehyde gave 2-[2-(p-formylphenoxy)ethyl] -methyl-l(27/)-phthalazinone (50) (substrate, K2CO3, MeaNCHO, 25°C, 30 min BrCH2CH20C6H4CH0-pi, 65%, 24 h ... 

Phenyl-l(27/)-phthalazinone with l-(2-bromoethyl)imidazole hydrochloride gave 2-[2-(imidazol-l-yl)ethyl]-4-phenyl-l(2H)-phthalazinone (51) (reactants, K2CO3, MeaNCHO, 80°C, 6 h 82%) analogs likewise. ... 

Ethyl 4-oxo-3-phenyl-3,4-dihydro-6-phthalazmecarboxylate (102, R = C02Et) gave 7-hydroxymethyl-2-phenyl-l(2/l)-phthalazinone (102, R = CH2OH) (NaBH4, EtOH, 20°C reflux, 2h 76%) analogs Ukewise." ... 

Ethyl 4-oxo-3,4-dihydro-l-phthalazinecarboxylate (106) with methylmagnesium bromide gave 4-(l-hydroxy-l-methylethyl)-l(2fl)-phthalazinone (107) (substrate, THE, <5°C MeMgBr in Et20J. dropwise reflux, 2 h >80%)." " ... 

The chemistry of these phthalazines has been better explored than might be expected, probably because of the biological activities possessed by some. For example, the marked bronchodilatory effects of 2-ethyl-4-(pyridin-3-yl)-l(2//)-phthalazinone (209) and 4-(p-chlorobenzyl)-2-(l-methylhexahydro-17/-azepin-4-yl)-l(2//)-phthalazinone hydrochloride (Azelastin) (210) ° led to the synthesis and investigation of a variety of phthalazinone, fused phthalazine, and nonphthalazine analogs as antiasthmatics. " " °° ... 

Diphenyl-l(277)-phthalazinone (235, R = Ph) with triethyloxonium tetra-fluoroborate gave 2-ethyl-4-oxo-l,3-diphenyl-3,4-dihydrophthaIazin-2-ium tetrafluoroborate (236) (reactants, CH2CI2, 20°C, 1 week 86%), but similar treatment of the analogous substrate, 2-methyl-4-phenyl-l(27/)-phthalazinone (235, R = Me), gave only l-ethoxy-2-methyl-4-phenylphthalazin-2-ium tetrafluoroborate (237) (20%) analogs behaved similarly." ... 

Aminoethyl)-l(2//)-phthalazinone with 6-chloropurine gave 2-[2-(purin-6-ylamino)ethyl]-l(2//)-phthalazinone (31) (EtsN, EtOH, reflux, 20 h 60%). ... 

Carboxymethyl-l(2fl)-phthalazinone (26a, R = OH) with ethyl chloroformate gave the unisolated intermediate (26a, R = 0C02Et) and thence with... 

Dimethylaminoacryloyl)methoxy] -1 (2//)-phthalazinone (138) condensed with ethyl acetoacetate and ammonia (supplied as ACONH4) to give 4-[(5-ethoxycarbonyl-6-methylpyridin-2-yl)methoxy]-1 (2//)-phthalazinone (139) (reactants, AcOH, reflux, <2h 60%). ° " ... 

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