3- Methyl-4- cinnoline

V-aminoindoles from, 4, 361 Cinnoline, 3,4-diphenyl-synthesis, 3, 42 Cinnoline, 3-hydroxy-synthesis, 2, 92 tautomerism, 3, 4 Cinnoline, 4-hydroxy-tautomerism, 3, 4 Cinnoline, 4-methyl-nitration, 3, 21... 

This method is exemplified by its application to quinoline, isoquinoline, cinnoline, and isoquinoline 2-oxide, which are nitrated as their conjugate acids. The rate profiles for these compounds and their N- or O-methyl perchlorates show closely parallel dependences upon acidity (fig. 2.4). Quaternisation had in each case only a small effect upon the rate, making the criterion a very reliable one. It has the additional advantage of being applicable at any temperature for which kinetic measurements can be made (table 8.1, sections B and D). 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

Cinnolin-3(2//)-one (7) is methylated with diazomethane or methyl sulfate to give 2-methylcinnolin-3(2H)-one. In a similar manner, benzylation with benzyl chloride, cyanoethylation with acrylonitrile in the presence of benzyltrimethylammonium hydroxide and glucosidation with tetra-O-acetyl-a-o-glucopyranosyl bromide in the presence of a base affords the corresponding 2-substituted cinnolin-3(2//)-ones. However, glucosidation of the silver salt of cinnolin-3(2//)-one produces the corresponding O-substituted compound. 

Alkylations of cinnolin-4(lf/)-one (8) with methyl iodide, ethyl iodide, dimethyl and diethyl sulfates, isopropyl bromide, benzyl chloride, etc. take place predominantly at position 2 to give 2-alkyl-4-hydroxycinnolinium anhydro salts (83), together with small amounts of l-methylcinnolin-4-one (84). 

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. 

MO calculations of the cinnoline ring system show that the relative order of reactivities for electrophilic substitution is 5=8>6 = 7>3 4. This is confirmed experimentally, as nitration of cinnoline with a mixture of nitric and sulfuric acids affords 5-nitrocinnoline (33%) and 8-nitrocinnoline (28%). Similarly, 4-methylcinnoline gives a mixture of 4-methyl-8-nitrocinnoline (28%) and 4-methyl-5-nitrocinnoline (13%). 

The photodecomposition of benzotriazine A/ -oxides produced 3-substituted 2,1-benzisoxazoles (Scheme 183) (73JA2390). The photolysis of cinnoline 1-oxides produced 3-methyl-2,1-benzisoxazoles (Scheme 183) (74TL2643, 74T2645). 

The reactivity of the methyl group in 4-methylcinnoline ethiodide indicates that the structure of this compound is 5, and this evidence has also been interpreted to mean that N-1 is the basic group in cinnolines. However, evidence of this type is only indicative since the formation of quaternary salts is subject to kinetic control, whereas protonation yields predominantly the thermodynamically more stable cation. The quinazoline cation has been shown to exist in the hydrated, resonance-stabilized form 6 7 by ultraviolet spectro-... 

Atkinson and Taylor summarized the evidence in support of the earlier assumption, arising from the evidence discussed above, that quatemization occurs on N-1 and also showed that 4-amino-, 4-amino-6-nitro-, and 4-amino-7-chloro-cinnoline gave two salts with methyl iodide, while 4-amino-8-nitrocinnoline gave only one salt and the... 

Recent work has justified the suspicions that the methylated cinnolones had been allocated the incorrect structures. D. E. Ames and H. Z. Kucharska [J. Chem. Soc. 4924 (1963)] have shown that the compound previously believed to be l-methyl-4-cinnolone is the dipolar anhydro-base of 4-hydroxy-2-methyl-cinnolinium hydroxide. It is likely, therefore, that those cinnoline salts whose structures had been based upon the presumed l-methyl-4-cinnolones are, in fact, 2-salts of structure 56. (Cf. p. 28.)... 

X-ray investigations on 3,3-bis(tcrt-butoxycarbonyl)-4,5-difluoro-l-methyl-7-oxo-2,3-dihydro-l//,7//-pyrido[3,2,l-(/]cinnoline-8-carboxylate 57 revealed, that 1-methyl group is perpendicular to the plane of the 4-quinolone moiety (96BCJ1371). 

The reaction conditions of this modified indazole synthesis can also be applied to the preparation of 1,2-diazanaphthalenes, the so-called cinnolines, although in such syntheses no deprotonation prior to cyclization is likely to occur. Ruchardt and Hassmann (1980) obtained 4-phenylcinnoline (6.85) in 53% yield from 2-(a-methyl-ene-benzyl)aniline (Scheme 6-53). 

Cinnolin sowie dessen 3-Phenyl- und 4-Methyl-Derivate konnen in verdunnter alkoho-lischer Salzsaure bei —0,4 bis —0,5 V in guter Ausbeute zu 3,4-Dihydro-cinnolin (F 81-82,5°) bzw.3-Phenyl- (93%d.Th. F 150-152°) oder4-Methyl-3,4-dihydro-cinnolin (F 63—65°) kathodisch reduziert werden. Bei —1,0 Verhalt man allerdings aus 4-Methyl-cinnolin unter Ringverengung 93% d.Th. Skatol1 ... 

The values of perhydropyrido[l,2-f)]pyridazine and its 2-oxo derivative were found to be 2.80 0.04 and 7.32 0.03, respectively (72KGS220), whereas that of anhydro 4-hydroxy-2-methyl-5,6,7,8-tetrahydropyrido(l,2-6]pyridazinium hydroxide (16) was determined by spectrophotometry to be 2.77 (71CPB159). UV spectroscopic measurements in sulfuric acid gave a pKa value of -0.25 for pyrido[l,2-6]cinnoline derivative (17, R = H) (74JHC125). 

Ring-opened products were obtained from pyrido[l,2-6]cinnolin-6-ium hydroxide inner salt (17, R = H) by oxidation with 3-chloroperoxybenzoic acid, or by reduction with Zn in acetic acid, and from the 5-methyl derivative 43 by reduction with Zn in acetic acid (74JHC125). 

Methyl 5-fluoro-4-(trifluoromethylsulfonyloxy)-2,3-dihydro-l-methyl-7-0X0-1//,7//-pyrido[3,2,l-iy]cinnoline-8-carboxylate(68,R = Me,R = R = H, R = F, R = Me, R = CF3SO2O) was reacted with 3-tributylstannyl-2-cyclohexen-l-one in the presence of lithium chloride and bis(triphenyl-phosphine)palladium(II) chloride in tetrahydrofuran for 3 days to give a 4-(3-oxo-l-cyclohexen-l-yl)derivative (92EUP470578). 

Alkylation of ll-mercaptopyrido[l,2-h]cinnolin-6-ium hydroxide inner salts (e.g., 41) with ethyl bromoacetate gave ll-(ethoxycarbonylmethyl(thio derivatives 64 (R = H), which could be hydrolyzed to the ll-(carboxy-methyl)thio derivative or back to the starting compound 41 (74JHC125). Hydrolysis of the ll-bis(methoxycarbonyl)methylene 66 (R = H), and 2-cyano derivatives of 17 (R = H) in boiling HCl afforded 11-methyl and 2-carboxylic acid derivatives, respectively (74JHC125). The 2-nitro derivative of 17 (R = H) was reduced to the 2-amino derivative over Pd/C with NaBH4 in aqueous methanol, and the 2-amino group was acylated with acetic anhydride at 100°C. 

Heating ethyl 5-fluoro-4-[cyano(ethoxycarbonyl)methyl]-2,3-dihydro-l-methyl-7-oxo-l//,7//-pyrido[3,2,l-i7]cinnoline-8-carboxylate (83, R = COOEt) in a mixture of cone. HCl and acetic acid gave the 8-carboxy-4-acetic acid derivative (92EUP470578). The acetic acid group was decarboxylated by heating in boiling ethanol in the presence of NEts to give the 4-methyl derivative. When the 4-[cyano(tert-butoxycarbonyl)methyl]-8-carboxylate 83 (R = COOrBu) was treated with trifluoroacetic acid in methylene chloride at room temperature, the 4-cyanomethyl-8-carboxylate 83 (R = H) was obtained. 

Cyclization of l-[M2,2-bis(fer/)-butyloxycarbonyl)ethyl -A -methyl-amino]-5,6,7,8-tetrafluoro-4-oxoquinoline-3-carboxylates (142, R = F) in the presence of CS2CO3 gave 7-oxopyrido[3,2,l-//]cinnoline-3,3,8-tricarbox-ylates (143) (92EUP470578,92MIP1 95JOC3928 96JCS(CC)61). The cyclization was accompanied by some N—N bond cleavage (5-20%). 

The crystal structure of ethyl 4-(4-rert-butoxycarbonyl-l-piperazinyl)-5-fluoro-2,3-dihydro-l-methyl-2,7-dioxo-l//,7//-pyrido[3,2,l-iy]cinnoline-8-carboxylate (186, R = Et, R = tert-Qu, R = 4-tm-butoxycarbonyl-l-piperazinyl) was determined by means of X-ray diffraction investigation [95T11125]. 

This section did not appear in CHEC-I(1984) and CHEC-II(1996) <1984CHEC(2)1, 1996CHEC-II(6)1>. Examples are the intramolecular Heck-type reaction of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one and 5-(2-bromophenyl)-2-methyl-6-phenylpyridazin-3(2//)-one which yields 2-benzyldibenzo[/, ]phthalazin-l(2//)-one and 2-methyldibenzo[/,. ]cinnolin-3(270-one, respectively <2003T5919>. The same compounds were also obtained from the corresponding 2-aminophenyl (instead of 2-bromophenyl) derivatives via diazotization and subsequent Pschorr reaction. 

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