Cinnolines

The reaction of cinnoline 2-oxide with phenylmagnesium bromide gives phenanthrene, trans- and cfs-stilbene, 2,3-diphenyl-l,2-dihydrocinnoline and 2-styrylazobenzene in yields of 1-15%. Analogous results are also obtained from 4-methylcinnoline 2-oxide. 

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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 compounds to be discussed are the quinolines, isoquinolines, cinnolines, quinazolines, quinoxalines, and phthalazines. Once again, this is a family of compounds for which much qualitative, but little quantitative information is available. 

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)... 

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... 

Partial rate factors for the nitration of 4-hydroxyquinoline and its derivatives are given in table 10.6. Comparison with the values for quinolinium (table 10.4) show that the introduction of a 4-hydroxy or a 4-methoxy group into the latter activates the 6-position by factors of 3-3 X 10 and 1-6 X 10 , respectively, and the 8-position by factors of 29-5 and 23, respectively. What has been said above makes the significance of partial rate factors which may be calculated for 4-hydroxy-cinnoline uncertain. 

Comparison of the behaviour of cinnoline 2-oxide (vi, i = O) with that of 2-methoxycinnolinium (vi, R = OMe) suggests that at high acidities the former is nitrated as its conjugate acid (vi, R = OH), but that as the acidity is lowered the free base becomes active. At high acidities 5- and 8-nitration are dominant, but as the acidity is lowered 6-nitration becomes increasingly important. The 5- and 8-nitro compounds are probably formed mainly or wholly by nitration of the conjugate acid, and the 6-nitro compound wholly or mainly from the free base. ... 

This representation is intended to encompass 4-oxo-3-quinolinecarboxyhc acids as well as the corresponding 1,8-naphthyridines, cinnolines, and pyrido[2,3-<55pyrimidines. These classes are illustrated by ciprofloxacin [85721-33-1] (2) (1), naUdixic acid [389-08-2] (3) (2), cinoxacin [28657-80-9] (4) (3), and piromidic acid [19562-30-2] (5) (4), respectively. 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Pyridazine-3(2//)-thiones exist in the thione form (14), as is evident from an X-ray structure analysis of pyridazine-3(2//)-thione. 6-Mercaptopyridazine-3(2//)-thione is predominantly in the monothiolmonothione form (15) in aqueous solution and in the solid state, 6-hydroxypyridazine-3(2//)-thiones are in the hydroxythione form (16) and 6-aminopyridazine-3(2//)-thiones exist in the aminothione form (17) for further details see (73HC(28)755). Cinnoline-4(l//)-thiones and phthalazine-l(2//)-thione have been shown on the basis of UV data and ionization constants to exist in the thione forms. 

The NMR spectra of cinnoline and its derivatives are complex. The unequivocal assignments are based on the complete iterative analysis of the spectra of a large number... 

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. 

IV-Oxidation of cinnoline (2) with hydrogen peroxide in acetic acid results in the formation of four products cinnoline 1-oxide (92 26%), cinnoline 2-oxide (93 50%), cinnoline... 

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%). 

Nitration of cinnolin-4(lFf)-one yields a mixture of the 3-nitro (0.9%), 5-nitro (0.38%), 6-nitro (58.4%), 7-nitro (0.36%) and 8-nitro (39.9%) derivatives. The 3-nitro isomer is postulated to result from nitration of the free base, while the other mononitro isomers are formed from the protonated molecule. 

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. 

When cinnoline 1-oxide is treated with nitric and sulfuric acids or potassium nitrate in sulfuric acid, 4-nitrocinnoline 1-oxide is obtained in yields ranging from 3-64% depending on the reaction conditions. With a mixture of fuming nitric and sulfuric acids, the corresponding 4-nitro-, 4,5-dinitro- and a small amount of the 5-nitro-cinnoline derivatives are obtained. 

Both 4-nitrocinnoline 1-oxide and the 5-nitro isomer give 4,5-dinitrocinnoline 1-oxide when treated with fuming nitric and sulfuric acids. Cinnoline 1-oxide also reacts with benzoyl chloride/silver nitrate to give 3-nitrocinnoline 1-oxide in 71% yield. 

Nitration of cinnoline 2-oxide takes a different course. With nitric and sulfuric acids or with potassium nitrate and sulfuric acid a mixture of 8-nitrocinnoline 2-oxide, 6-nitrocinno-line 2-oxide and 5-nitrocinnoline 2-oxide is obtained, while with benzoyl nitrate in chloroform only a low yield (1.5%) of the 5-nitro derivative is obtained. 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

This type of cyclization is important only for the formation of cinnolines. In all cases, the starting compounds have an ortho amino group, which upon diazotization undergoes ring closure with the other functionality, most frequently with a multiple bond. 

One of the widely used cinnoline syntheses is the transformation of diazotized o-aminoarylethylenes into this bicyclic system (Widman-Stoermer synthesis) (Scheme 69). 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

In a similar manner to the formation of pyridazines from AT-aminopyrroles, cinnolines or phthalazines are obtainable from the corresponding 1-aminooxindoles or 2-amino-phthalimides. If the relatively inaccessible 1-aminooxindoles are treated with lead tetraacetate, mercuric acetate, r-butyl hypochlorite (69JCS(C)772) or other agents, cinnolones are formed as shown in Scheme 105. The reaction was postulated to proceed via an intermediate... 

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