4- Hydroxycinnolines cinnolines

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... 

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). ... 

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... 

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. 

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) ... 

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... 

Lithium tetrahydridoaluminatelmercuric oxide Cinnolines from 4-hydroxycinnolines... 

---