Phthalazinecarboxylic acids

This chapter covers nuclear and extranuclear phthalazinecarboxylic acids, their derivatifes, phthalazinecarbaldehydes, and the ketonic C-acylthalazines. To avoid repetition, the interconversions of these entities are discussed only at the first opportunity for example, the conversion of esters into amides appears as a reaction of esters rather than as a preparative route to amides, simply because treatment of esters precedes that of amides. 

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Nl - 6-PHTHALAZINECARBOXYLIC ACID, 3 4-OIHYDRO-l-(HYOROXYMETHYL )-5,7-DIMETHYL-4-0X0- ETHYL ESTER... 

Ethyl 1 -hydroxy-1,4,6-trimethyl-3-oxo-1,3-dihydro-5-isobenzofurancarboxylate (226) gave a separable mixture of 6-ethoxycarbonyl-5,7-dimethyl-4-oxo-3,4-dihydro-l-phthalazinecarboxylic acid (227, R = C02H) and its decarboxy-lated derivative, ethyl 5,7-dimethyl-4-oxo-3,4-dihydro-6-phthalazinecarbox-ylate (227, R = H) (substrate, KOH, H2O, KMn04i slowly, 10°C, 90 min ... 

The formation of nuclear or extranuclear phthalazinecarboxylic acids by primary synthesis (Chapter 8) or by Reissert-like reactions (Section 9.1.3) has been covered. Classical oxidative approaches from alkyl- or hydroxyalkylphthalazines do not appear to have been used in the 1972-2004 period. Other routes are illustrated by the following classified examples. 

Methyl 4-oxo-3-(3-phenylpropyl)-3,4-dihydro-5-phthalazinecarboxylate (1, R = Me) gave 4-oxo-3-(3-phenylpropyl)-3,4-dihydro-5-phthalazinecarboxylic acid (1, R = H) (2M NaOH, reflux, 1 h -60%). ... 

Ethyl 5-amino-6-cyano-4-oxo-3,7-diphenyl-3,4-dihydro-1 -phthalazinecarboxylate (2, R = Et) gave 5-amino-6-cyano-4-oxo-3,7-diphenyl-3,4-dihydro-l-phthalazinecarboxylic acid (2, R = H) (NaOH, EtOH, reflux, 30 min 75%)." ... 

Oxo-3-phenyl-3,4-dibydro-6-phthalazinecarbonitrile (8) gave 4-oxo-3-phenyl-3,4-dihydro-6-phthalazinecarboxylic acid (9) (NaOH, H2O, EtOH, reflux, 3 h 91%). "... 

Ethyl l-cyano-4-methoxy-5,7-dimethyl-6-phthalazinecarboxylate (10) underwent selective hydrolysis to 6-ethoxycarbonyl-4-methoxy-5,7-dimethyl-l-phthalazinecarboxylic acid (11) [Ba(OH)2, EtOH, H2O, reflux, 6h 78%]. ... 

The various reactions of phthalazinecarboxylic acids are illustrated by the following classified examples. 

Oxo-3,4-dihydro-5-phthalazinecarboxylic acid (19, R = OH) gave 4-oxo-3,4-dihydro-5-phthalazinecarbonyl chloride (19, R = C1) (neat SOCI2, reflux, 2.5 h 88% or SOCI2, PhCl, reflux, 4h >75%)... 

Note Esterification may be done indirectly via phthalazinecarbonyl halides or directly (as illustrated here) by treatment with alcoholic sulfuric acid, a diazoalkane, or some other alkylating agent. l-(5-Ethylthien-2-yl)-4-oxo-3,4-dihydro-6-phthalazinecarboxylic acid (21, R = H) gave ethyl l-(5-ethylthien-2-yl)-4-oxo-3,4-dihydro-6-phthalazinecarboxy-late (21, R = Et) (EtOH, H2SO4, reflux, 12 h 88%). °... 

Oxo-3,4-dihydro-5-phthalazinecarboxylic acid (29) with hydrazine hydrate gave 17/-pyridazino[3,4,5-6ic]phthalazin-3(2//)-one (30) (reactants, H2O, reflux, 84 h 65%). ... 

Note Phthalazinecarbonyl halides may be made by Reissert reactions (see Section 9.1.3) but usually from phthalazinecarboxylic acids with thionyl chloride or the like (see Section 14.1.2). 

Several routes to such esters have been covered already by primary synthesis (Chapter 8), by Reissert or Reissert-like reactions (Section 9.1.3), by esterification of phthalazinecarboxylic acids (Section 14.1.2), by alcoholysis of phthalazinecar-bonyl halides (Section 14.2), or by a variety of passenger introductions (several chapters). Other minor preparative methods are illustrated in the following examples. 

Several reactions of these esters have been covered already reduction to alkylphthalazines (Section 9.2.1), reduction to extranuclear hydroxyphthalazines (Section 11.2.1), conversion into extranuclear hydroxyphthalazines with Grignard reagents (Section 11.2.1), conversion into aminophthalazines by the Curtius reaction reaction (Section 13.2.1), hydrolysis to phthalazinecarboxylic acids (Section 14.1.1), and transesterification (Section 14.3.1). Other reactions are illustrated in the following classified examples. 

Note These processes may be used to afford amides or thioamides but not the corresponding hydrazides. The hydrolysis of phthalazinecarbonitriles can give phthalazinecarboxylic acids unless conditions are controlled carefully or the Radziszewski procedure (H2O2, HO ) is adopted. 

The hydrolysis of phthalazinecarboxamides to phthalazinecarboxylic acids has been exemplified in Section 14.1.1. Some other reactions are illustrated in the following classified examples. 

Amino-6-cyano-4-oxo-3,7-diphenyl-3, 4-dihydio-l-phthalazinecarboxylic acid 240 or 252, IR, NMR 489, 535... 

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