4- Hydroxycinnolines

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at With nitric acid, 4-hydroxycinnoline... 

Similarly, 3- and 4-hydroxycinnolines and their derivatives exist predominantly in the 0X0 forms (7) and (8), as supported by both pjSTa values and UV spectral data. The oxo forms for 3-hydroxycinnolines have been further supported by IR data <76MI21200>. Phthalazin-4-ones exist in the oxo form and phthalic hydrazide in the monohydroxymonooxo... 

Cinnolin-4(lF/)-one and its 6-chloro, 6-bromo, 6-nitro and 8-nitro derivatives react with sulfuryl chloride or bromine in acetic acid to give the corresponding 3-halo derivatives in about 20% yields. lodination of 8-hydroxycinnolin-4(lF/)-one with a mixture of potassium iodide and potassium iodate gives the 5,7-diiodo derivative the 6,8-diiodo derivative is formed from 5-hydroxycinnolin-4(lF/)-one. 

The thermal cyclization of 2-alkynylbenzenediazonium salts represented by 2 to provide the 4-hydroxycinnoline derivatives 3 respectively is regarded as the von Richter cinnoline synthesis. " ... 

The first synthesis of cinnoline was reported by von Richter in 1883. The diazonium chloride 5 which was obtained from o-aminophenylpropiolic acid (4), was heated in water at 70°C to provide the 4-hydroxycinnoline-3-carboxylic acid (6). When this acid 6 was heated above its melting point, carbon dioxide was liberated and 4-hydroxycinnoline (7) was obtained. Distillation of 4-hydroxycinnoline (7) with zinc dust furnished a small amount of oil, which was assumed to be cinnoline (8). The preparation of 4-hydroxycinnoline (7) was repeated by Busch and Klett, although in lower yield when compared to the original report. Busch and Rast later converted the 4-hydroxycinnoline (7) successfully to cinnoline (8) via the 4-chlorocinnoline (9). ... 

B (11— 12— 14). Examination of a more recent study suggests the von Richter reaction probably involves simultaneous attack of the triple bond on the diazo group accompanied by attack by a halide ion but not by a water molecule. The halocinnoline 13 is then hydrolyzed under the von Richter reaction conditions to furnish the 4-hydroxycinnoline derivative 14 (11 - 12- 13 14, pathway A). 

The action of dimethyl sulfate on 3-hydroxycinnoline can give two different products. In the presence of excess alkali a low yield of an orange product was obtained, for which the zwitterionic stmcture 57 was tentatively advanced, but with insufficient alkali the product is 2-methyl-3-cinnolone (58). The formation of 57 parallels the formation of the betaine (41) from 4-hydroxypyridazine. ... 

Methylation of 4-hydroxycinnoline with dimethyl sulfate gives a colorless crystalline product, mp 165-166.5°C, which was originally assumed to be... 

Hydroxycinnoline (252) slowly dissolves in ethereal diazomethane producing a brilliant emerald green colour which changes to deep blue. Comparison with the analogous reaction of 8-hydroxyquinoline (Section III,B,5) has led to the suggestion that this blue product, mp 120°C, is l-methylcinnolinium-8-olate (251 R = Me). 

An orange compound (mp 280-283 C) obtained by methylation of 3-hydroxycinnoline with dimethyl sulfate and alkali has been formulated as the betaine 285 (R = Me). 2 ... 

A number of cinnolines have been obtained by alkali treatment of isatins. Thus, 214 gave 215,88-70 while isatin on treatment with base followed by hydrogen and palladium, diazotization, and reduction gave 3-hydroxycinnoline.62 4... 

Halocinnolines can be prepared by treatment of polystyrene-bound (2-alkynyl-phenyl)triazenes with hydrogen chloride or hydrogen bromide (Entry 6, Table 15.27). This reaction involves the initial release of 2-alkynylphenyldiazonium salts into solution, which then cyclize to the halocinnolines. The corresponding 4-hydroxycinnolines are obtained as by-products in variable amounts. Hydrogen fluoride or hydrogen iodide do not lead to the formation of cinnolines [324]. 

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at C(3).31 With nitric acid, 4-hydroxycinnoline still gives mainly 4-hydroxy-6-nitrocinnoline, but some of the 3-nitro compound can also be isolated.81 51 The change of orientation with reagent could be due to a change to free-base nitration in the more weakly acidic medium, or to the occurrence in nitric acid of nitration via nitrosation.31... 

The alkylation of 3- or 4-hydroxycinnolines has been shown to occur at the 2-position. Reduction of these cinnolinium salts with lithium aluminum hydride gave 2-alkyl-l,2,3,4-tetrahydrocinnolines which darkened rapidly on exposure to air but could be converted to stable derivatives.1370,6... 

The difference between the two ways of controlling the electrolytic reaction is illustrated in Fig. 4, which shows polarograms of the cathc -lyte recorded during the controlled potential reduction (at —0.65 volt vs. SCE) in hydrochloric acid of 4-hydroxycinnoline (7) to l,2,3,4-tetrahydro-4-cinnolone (8).44... 

Fig. 4. Polarograms obtained during a controlled potential ( — 0.65 volt vs. SCE) reduction of 4-hydroxycinnoline. (a) Initial solution, (b) partly reduced solution, and (c) nearly completely reduced solution (see text).

Reduction of pyridazin-4-ones seems not to have been reported, f. Derivatives of Cinnoline. 3-Hydroxycinnoline (222)44 is reduced in a two-electron wave from pH 0 to 11. In strongly acid solution the main product is 1-aminooxindole (223), which is also obtained on reduction with zinc and sulfuric acid.232 Reduction in an emulsion of an aqueous phosphate buffer (pH 6.5) and n-butanol produced a nearly quantitative yield of 3-keto-l,2,3,4-tetrahydrocinnoline (224) this compound was easily reoxidized to 3-hydroxycinnoline. 

The 2-alkylcinnolinium-4-olates (233) are stable, colorless compounds. In the H NMR the N-methyl resonance is observed at lower field than for nonpolar isomers (i.e., 234 R = Me and 246) this trend is useful for diagnosing the position of alkylation of 4-hydroxycinnolines. ° ... 

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