4-hydroxycinnoline

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... 

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). 

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

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).

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. ° ... 

Hydroxycinnoline (LXXVI) [101] in acid solution is reducible in two, two-electron steps. The product from the first two-electron reduction is 4-keto-l,2,3,4-tetrahydrocinno-line (LXXVII). This compound is a derivative of phenylhydrazine and can thus be oxidized anodically in alkaline solution to an azo compound (LXXVIIT), which then tautomerizes to LXXVI. The carbonyl group of LXXVII is activated by the phenyl ring and—in contrast to 3-keto-l,2,3,4-tetrahydrocinnoline—is thus further reducible the reduction yields 4-hydroxy-1,2,3,4-tetrahydrocinnoline (LXXIX). On standing, this compound loses water with the formation of 1,4-dihydrocinnoline. If, however, the compound is oxidized in alkaline solution, the product (LXXX) loses water and forms cinnoline. 

Cinnolines are prepared by an intramolecular cyclization of o-alkenyl or o-alkynyl aryldiazonium salts. For instance, (o-aminophenyl)alkynes 6 or alkyl(o-aminophenyl)ketones 8 (via the enol form) yield 4-hydroxycinnolines 7 (the v. Richter and Borsche syntheses, respectively), o-Aminostyrenes 10 afford 3,4-disubstituted cinnolines 11 (Widman-Stoermer synthesis) ... 

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)-... 

This reaction is generally used to prepare 4-hydroxycinnolines. 

The Borsche (or Borsche-Herbert) cinnoline synthesis constitutes the cyclization of an ort/zo-diazonium aryl ketone to form a 4-cinnolone, or 4-hydroxycinnoline. It is mechanistically related to the Widman-Stoermer and Richter cinnoline syntheses, which involve the cyclization of ortho-diazonium aryl olefins and ortho-diazomnm aryl alkynes, respectively. 

Lithium tetrahydridoaluminate/mercuric oxide Cinnolines from 4-hydroxycinnolines s. 16, 137 Li[AlHJ/HgO... 

Wagner-Meerwein rearrangement s. 16, 938 Titanium tetrachloride 4-Hydroxycinnolines s. 17, 962 Staimic chloride Syntheses via S-heterocyclics... 

TiCl4 added with stirring to a suspension of mesoxalyl chloride o-chlorophenyl-hydrazone in dry nitrobenzene, cooled below 100° during the initial exothermic reaction, then heated 6 hrs. at 95° until HCl-evolution ceases, aq. NaOH added, and nitrobenzene removed by steam-distillation 8-chloro-4-hydroxycinnoline-3-carboxylic acid. Y 90%. F. e. and limitations s. H. J. Barber et al., Soc. 1961, 2828. 

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