4- bromo-3- cinnolin

Ethyl l,4-dihydro-3-cinnolinecarboxylate (2) gave ethyl 4-bromo-3-cinnoline-carboxylate (3) (substrate, AcOH, then Br2i dropwise, 20°C reflux, 30 min 60% note additional dehydrogenation). " ... 

Vasilevsky et al. reported that diazotization of phenylethynylaminopyrazole 19 in hydrochloric or hydrobromic acid furnished the 4-chloro- or 4-bromo cinnoline derivative... 

Coupling of terminal acetylenes with 3-chloropyridazines has been performed, using the Pd -Cu -EtjNH system, giving 3-(alkynyl)pyridazines in yields of up to 78% phenylacetylene gives (90) with 3-chloropyridazine 1-oxide but only gives tars with the isomeric 2-oxide/ 3-(Alkynyl)cinnolines have been similarly prepared from 3-iodo- and 3-bromo-cinnolines, and attempts to couple alkenes have been reported it is not unusual, in this type of reaction, to obtain small amounts of homo-coupling products i.e. biaryls), but an excellent yield of 3,3 -bicinnolinyl (81%) was obtained from 3-bromo-cinnoline and styrene. 

Bromo-4-phenoxycinnoline (78, R = OPh) likewise gave 4-anilino-3-bromo-cinnoline (78, R = NHPh) (neat PhNH2, 175°C, 20 min 83% note the... 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

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. 

Borsche cinnoline synthesis 141 Bromo-de-diazoniation 194, 230ff., 270, 301... 

Nitration of pyrido[l,2-f>]cinnolin-6-ium hydroxide inner salt 17 (R = H) and its 2-acetamide derivative afforded its 2-nitro and 2-acetamido-3-nitro derivatives, respectively. The reaction of 17 (R = H) with iodine monochloride afforded the 2-iodo derivative. The 2-cyano derivative was obtained from the 2-bromo derivative of 17 (R = H) with Cu(I)CN. Treatment of 17 (R = H) with P4S10 afforded the 11-mercapto derivative 41 (74JHC125). 

Cinnoline 3-Bromo-4-hydroxy-6-nitro- E9a, 714 (H - Br) Phthalazine 4-Bromo-l-hydroxy-7-nitro- E9a, 757 f. (3-Br - 6-N02 -1 -oxo — 1,3-H2 — 2-benzofuran/ N2H4)... 

With azines the situation is varied. In the radical cations of pyridine and diazines the semi-occupied orbital is largely confined to the nn orbital(s) (see Scheme 2, structure 2), while the radical cation is of the n type with monoazanaphthalenes, -phenanthrenes and -anthracenes. The situation might change with substitution. As an example, alkylpyridine radical cations are of the n type, like the parent compound, whereas for the 2,5-dimethyl, 2-chloro, and 2-bromo derivatives the structure is of the n type [13]. Likewise, with benzo[c]cinnoline the parent compound and its alkyl derivatives give an n radical cation, but with some dimethoxy derivatives a n structure is found [14] and a switch from n to 7t structure occurs also in passing from 1,2,4,5-tetrazine to its 3,6-diamino derivatives [15]. 

C C8H6BrN a-bromo-p-tolunitnle 17201-43-3 27.00 1.5510 2 12864 C8H6N2 cinnoline 253-66-7 34.00 1.1717 2... 

Benzo[c]cinnoline forms molecular complexes with halogens in organic solvents thus attempts to brominate it with molecular bromine have been unsuccessful. Using a source of positive bromine, bromine/silver sulfate in sulfuric acid, Corbett and Holt found that reaction occurred at room temperature to give 27% of a monobromo and 4% of a dibromo derivative. These compounds were at first identified as 1-bromo- and l,4-dibromo-(or l,7-dibromo-)benzo[c]cinnolines, but the former was subsequently shown to be the 4 isomer. A reinvestigation of the reaction has shown that both 1- and 4-bromobenzo[c]cinnolines are primary products, formed in the ratio of ca. 2.3 1 at room temperature. The lower isomer ratio as compared with nitration in sulfuric acid probably reflects the greater steric demand of the attacking species. The dibromo compound formed is the 1,4-isomer. The formation of the octachloro derivative by chlorination of benzo[c]cinnoline in the presence of aluminum chloride has been mentioned,but no details are available. 

Of the halogenobenzo[c]dnnolines the 1-bromo, 4-bromo, and 1,4-dibromo are obtainable by direct bromination (Section IV,B). Some, including the 2- and 3-monobromo compounds, have been prepared by the cyclization of halogenobiphenyls, - - and others, including all the monochloro and monoiodo isomers, by the photocyclization of halogenoazo-benzenes. Several have also been prepared by Sandmeyer reactions of aminobenzo [c] cinnolines. 

Halogeno substituents at the 3- or 4-position of cinnoline are appreciably activated by N2 and Nl, respectively those at positions 5-8 or an extranuclear position have activities only marginally better than those in corresponding carbo-cyclic compounds. There seems to be little difference in reactivity of a fluoro, chloro, bromo, or iodo substituent at the same position. 

Bromo-4-chloro-6,7-dimethoxycinnoline (78) gave 7,8-dimethoxythiazolo[4,5-c]cinnolin-2-amine (79) [S=C(NH2)2, EtOH, reflux, 5h 36%] analogs... 

This route has been extensively used for more than 50 years to prepare cinnolines from 2-aminoacetophenone derivatives. For example, diazotizing 293 afforded 294 (1945JSC512, 1949JCS2393, 1981AJC2619). The recent literature reported several applications that employ substituted acetophenones (2006BMC6832). For example, bromo derivative 295 was prepared by initial bromination of 293 and subsequent diazotization (Scheme 53). 

An early example of this arene coupling was reported by Ames and BuU,t who noted the formation of benzofuro[3,2-c]cinnoline in the reaction of 3-bromo -phenoxycinnohne with ethyl acrylate in the presence of a catalytic amount of paUadium(n) acetate (Scheme 2, Eq. 1). Subsequent studies showed that ethyl acrylate is not necessary, and the arylation reaction was achieved by using 0.1 equiv of palladium acetate, 0.2 equiv of triphenylphosphine, and 3 equiv of sodium acetate in DMA at 170 °C (Scheme 2, Eq. 

Walther Borsche and Alfred Herbert first reported the spontaneous cyclization of an ort/io-diazonium acetophenone in 1941, as part of a larger study on the synthetic transformations of 2-bromo-5-nitroacetophenone carried out at the University of Frankfurt am Main. The authors did not draw especial attention to this observation, and it was not until four years later that Schofield and Simpson suggested that this reaction might offer a general route to 4-cinnolones. After 70 years, this general reaction yielding 4-cinnolones remains one of the most useful methods for the synthesis of cinnolines. 

Vinogradova OV, Sorokoumov VN, Balova lA (2009) A short route to 3-alkynyl-4-bromo (chloro)cinnolines by Richter-type cyclization of OTtho-(dodeca-l,3-diynyl)aryltriaz-l-enes. Tetrahedron Lett 50 6358-6360... 

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