Cinnolinecarboxylic acids

Ammo-4-cinnolinecarboxylic acid 1-oxide (40) with acetic anhydride gave 3-methyl-l//-[l,3]oxazino[4,5-c]cinnolin-l-one (41) (neat AC2O, reflux, h 96%). ... 

Amino-2-m-chlorophenyl-3-oxo-6-phenyl-2,3-dihydro-4,7-cinnolinedicarbonitrile (14, R = CN) gave 8-amino-2-m-chlorophenyl-7-cyano-3-oxo-6-phenyl-2,3-dihydro-4-cinnolinecarboxylic acid (14, R = CO2H) (NaOH, EtOH, reflux, 5h 94% note selective hydrolysis of the 4-cyano group). ... 

Amino-4-cinnolinecarboxylic acid 1-oxide (17) gave 3-cumoIinamine (18) (Na2S204, Me2NCHO, H2O, reflux no further details). " ... 

Cinnolinecarboxylic acid (26) and l-benzyl-4-methylperhydro-l,4-diazepin-6-amine (27) in the presence of l,l -carbonyldiimidazole gave A(-(l-benzyl-4-methylperhydro-l,4-diazepin-6-yl)-4-cinnolinecarboxamide (28) [substrate (26), l,l -carbonyldiimidazole, Me2NCHO, 20°C, 30 min then amine... 

Cinnolinecarboxylic acid 4-Cinnolinecarboxylic acid 1-oxide 4-Cinnolinecarboxylic acid 2-oxide... 

Other 1,2-diazines synthesized included 4-amino-3-cinnolinecarboxylic acids <97PHA91 >, I -aryl-6-chloro-l,4-dihydro-4-oxothieno[2,3-c]pyridazine-3-carboxylic acids <97JPR284>, 2H-benzo[2,3-g]pyridazino[4,5-<7,e]quinolin-3-ones <97M681>, 3-chloro-4-carbamoyl-5-aryl-6-methylpyridazine N-oxides <97F67>, 2-aroyl-6-(hetero substituted)-3(2//)-pyridazinones <97HCM267>, and 5-(4-hydroxycinnolin-3-yl)tetrazoles 2-methyl-5-(4-acetoxycinnolin-3-yl)-... 

Di(chloroformyl)methylene]hydrazino-3-nitroanisole (55) gave 6-methoxy-8-nitro -oxo-l,4-dihydro-3-cinnolinecarboxylic acid (56) (TiCLi, PhN02,... 

Chloro-6-fluoro-1 -methyl-4-oxo-1,4-dihydro-3-cinnolinecarboxylic acid (40, R = Me) gave 6-fluoro-l-methyl-4-oxo-7-(piperazin-l-yl)-l,4-dihydro-3-cin-nolinecarboxylic acid (41, R = Me) [HN(CH2CH2)2NH, pyridine, 85°C, 45 min 91%] analogs likewise." ... 

Bromo-l-phenyl-7-(pyridin-4-yl)-4(l//)-cinnolinone (46, R = Br) gave 4-oxo-l-phenyl-7-(pyridin-4-yl)-l,4-dihydro-3-cinnolinecarbonitrile (46, R = CN) (CuCN, MeaNCHO, reflux, 18 h crude nitrile), characterized by conversion into 4-0X0- l-phenyl-7-(pyridin-4-yl)-1,4-dihydro-3-cinnolinecarboxylic acid (46, R = C02H) (50% H2SO4, 110°C, 12 h 33% overall). ... 

Bromo-4-oxo-l,4-dihydro-3-cinnolinecarboxylic acid (34) gave a separable mixmre of 6-bromo-l-methyl-4-oxo-l,4-dihydro-3-cinnolinecarboxylic acid (35, R = Me) and 6-bromo-2-methyl-4-oxo-l,4-dihydrocinnolin-2-ium-3-car-boxylate (36, R = Me) (Me2S04, KOH, H2O, 2TC, 30 min 42% and 43%, respectively, prior to final purification of each) the latter product (36, R = Me) underwent decarboxylation easily to afford 6-bromo-2-methylcin-nolin-2-ium-4-olate (37, R = Me) (recrystaUization from Me2NCHO 33% overall).Ethylation of substrate (34) required more vigorous conditions and afforded a separable mixture of 6-bromo-l-ethyl-4-oxo-l,4-dihydro-3-cinnolinecarboxylic acid (35, R = Et) and 6-bromo-2-ethylcinnolin-2-ium-4-olate (37, R = Et) directly (EtI, EtOH, reflux, 6 h 19% and 18%, respectively, after final purification of each). o... 

Oxo-l,4-dihydro-3-cinnolinecarboxylic acid gave 6-nitro-4-oxo-l,4-dihydro-3-cinnolinecarboxylic acid (1) (96% H2SO4, 0°C substratej. slowly 96%... 

The Co(II), Ni(II), Fe(II), and Cu(II) complexes of 4-amino-3-cinnoline-carboxylic acid and 4-amino-7-chloro-6-fluoro-3-cinnolinecarboxylic acid have been prepared and characterized. ... 

This chapter deals with nuclear and extranuclear cinnolinecarboxylic acids and the corresponding carboxylic esters, acyl halides, carboxamides, carbohydrazides, carbonitriles, and carbaldehydes, and the ketonic acylketones. To avoid repetition, the interconversion of these cinnoline derivatives are discussed only at the first opportunity for example, the esterification of cinnolinecarboxylic acids is covered as a reaction of cinnolinecarboxylic acids rather than as a preparative route to carboxylic esters, simply because the section on acids precedes that on esters. To avoid any confusion, appropriate cross-references have been included. 

The formation of cinnolinecarboxylic acids by primary synthesis (see Chapter 1) and by hydrolysis of trihalogenomethylcinnolines (see Section 3.2) have been covered already the oxidative routes from alkylcinnolines, hydroxyalkylcinnolines, or cinnolinecarbaldehydes appear to be unrepresented in the 1972-2004 literature the remaining approaches are illustrated in the following classified examples. 

Ethyl (5, R = Et) or methyl 7-chloro-6-fluoro-l-p-fluorophenyl-4-oxo-l,4-di-hydro-3-cinnolinecarboxylate (5, R = Me) gave 7-chloro-6-fluoro-l-p-fluoro-phenyl-4-oxo-l,4-dihydro-3-cinnolinecarboxylic acid (KOH, MeOH, H2O, 50°C 20°C, 2h 96% or 82%, respectively). ... 

Amino-7-methoxy-3-cinnolinecarboxamide (8, R = NH2) gave 4-amino-7-methoxy-3-cinnolinecarboxylic acid (8, R = OH) (KOH, EtOH, reflux, 3 h 50% or HBr, AcOH, reflux, 3h 66%). ... 

Cinnolinecarboxylic acids undergo several useful reactions, illustrated briefly by the following classified examples gleaned from the 1972-2004 literature. 

Bromo-4-oxo-l-propyl-l,4-dihydro-3-cinnolinecarboxylic acid (16, R = C02 H) gave 6-bromo-l-propyl-4(l/l)-cinnolinone (16, R = H) (neat substrate. 

Note Routes to these esters include primary synthesis (see Chapter 1), Reissert-type additions to cinnoline (see Section 2.1.3), and esterification of cinnolinecarboxylic acids (see Section 7.1.2) also passenger introductions (e.g. alkoxycarbonylalkylations in Section 4.1.2.1). 

Note. Reduction to hydroxymethylcinnolines remains unrepresented, hydrolysis to cinnolinecarboxylic acids has been covered in Section 7.1.1, and conversion into cinnolinecarboxamides or carbohydrazides is illustrated here. 

Note Most cinnolinecarboxamides and carbohydrazides (both nuclear and extranuclear) have been made by primary synthesis (see Chapter 1), from cinnolinecarboxylic acids (directly or indirectly via cinnolinecarbonyl halides) (see Section 7.1.2), or from cinnolinecarboxylic esters (see Section 7.2). The remaining route, by hydrolysis or thiolysis of cinnolinecarbonitriles, is illustrated here. 

Note Reactions already discussed include aminolysis (Section 6.2.1), hydrolysis to cinnolinecarboxylic acids (Section 7.1.1), and controlled hydrolysis or thiolysis to carboxamides or carbothioamides, respectively (Section 7.3). Further minor reactions are illustrated here. 

Note. These reactions of acylcinnolines have been covered already reduction to alkylcinnolines (Section 2.2.1), some cyclocondensations (Section 4.1.2.2), and reduction to extranuclear hydroxycinnolines (Section 4.2). Their oxidation to cinnolinecarboxylic acids appears to be unrepresented in the more recent literature. Some other reactions are illustrated in the examples that follow. 

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