Quinoline 5-nitroquinoline

These systems nitrate aromatie eompounds by a proeess of electro-philie substitution, the eharacter of whieh is now understood in some detail ( 6.1). It should be noted, however, that some of them ean eause nitration and various other reactions by less well understood processes. Among sueh nitrations that of nitration via nitrosation is especially important when the aromatic substrate is a reactive one ( 4.3). In reaetion with lithium nitrate in aeetie anhydride, or with fuming nitrie aeid, quinoline gives a small yield of 3-nitroquinoline this untypieal orientation (ef. 10.4.2 ) may be a eonsequenee of nitration following nucleophilic addition. ... 

The preparative nitration of quinoline in mixed acid has been described several times, and has usually been carried out under unnecessarily severe conditions good yields of 5- and 8-nitroquinoline in roughly... 

Ochiai and Okamoto showed that nitration of quinoline i-oxide in sulphuric acid at o °C gave 5- and 8-nitroquinoline i-oxides with a trace of the 4-isomer, but that at 60-100 °C 4-nitration became overwhelmingly dominant. The orientation depends not only upon temperature but also upon acidity, and kinetic studies (table 8.4 table 10.3) show that two processes are occurring the nitration of the free base (vil, R = O at C(4), favoured by low acidities and high temperatures, and the nitration of the cation (vil, R = OH), favoured by high acidities and low temperatures. ... 

Among the aromatics, it was found that 4-nitroquinoline N-oxide [56-57-5] is a powerful carcinogen producing malignant tumors when painted on the skin of mice (80). It was further estabUshed that the 2-methyl, 2-ethyl, and 6-chloro derivatives of 4-nitro quinoline oxide are also carcinogens (81). 

The order NO2 > Cl, which is known for the reactions of nitro-activated aromatic compounds, is also found for pyridine and quinoline derivatives. In the reaction of 2-chloro-4-nitroquinoline with methoxide ion, only the 4-methoxide derivative is formed, as shown by gas-chromatography, whereas 2,4-dichloroquinoline yields a mixture of the isomeric chloro-methoxy derivatives in comparable amounts. ... 

Various reactions of nitroquinolines with hydroxylamine in potassium hydroxide alkalinity afforded oxadiazoloquinolines besides the known aminonitroquinolines. l,2,5-Oxadiazolo[3,4-/]quinolines were obtained from the 5- or 6-nitroquinolines. The 7- and 8-nitroquinolines gave the appropriate l,2,5-oxadiazolo[3,4-/i]quino-lines. 

In a similar way, 3-amino-1,2,4-triazino[6,5-c]quinoline 4-oxides 127 were synthesized by the reaction of 4-chloro-3-nitroquinoline 128 with guanidine, followed by the cyclization of intermediate arylguanidines under basic conditions (81JHC1537). 

Nitroquinoline (138) undergoes direct cyclocondensation with aromatic hydra-zones 139 in the presence of sodium hydride in DMF to give low yields of the corresponding [l,2,4]triazino[6,5-fc]quinolines 140 and pyrazolo[3,4-/] quinolines... 

Den Hertog and Overhoff - observed that when pyridine in sulfuric acid is added to molten potassium sodium nitrate the 3-nitro derivative is formed at 300°C, whereas at 450°C 2-nitropyridme is the main product. The latter is probably a free-radical process. Schorigin and Toptschiew obtained 7-nitroquinoline by the action of nitrogen peroxide on quinoline at 100°C, possibly through the homolytic addition of NOa. Laville and Waters reported that during the decomposition of pernitrous acid in aqueous acetic acid, quinoline is nitrated in the 6- and 7-positions. They considered that the reaction proceeds as shown in Scheme 3. 

In the Meisenheimer reaction of quinoline 1-oxides chlorine atoms usually enter the 2-and 4-positions, but not exclusively. 2,4-Dibromoquinoline 1-oxide was 6-chlorinated (57MI1), and the 5- and 6-nitroquinoline 1-oxides were 3-chlorinated to some extent (44JOC302). This reaction with phosphoryl chloride-phosphorus pentachloride has also been used in the preparation of chlorinated phenanthrolines (88YZ1148). 

Acids and Lewis acids react with quinoline at the basic nitrogen atom to form quinolinium salts, and there is a question over the nature of the substrate for electrophilic attack, i.e. is it quinoline or the quinolinium cation The answer is not a simple one and appears to depend upon the reagents and reaction conditions. Thus, whereas acetyl nitrate at 20 °C gives mainly 3-nitroquinoline (Scheme 3.2), fuming nitric acid in concentrated sulfuric acid containing sulfur trioxide at 15-20 °C yields a mixture of 5-nitroquinoline (35%) and 8-nitroquinoline (43%) (Scheme 3.3). In the case of acetyl nitrate, the reaction may proceed by the 1,4-addition of the reagent to quinoline, followed by electrophilic attack upon the 1,4-dihydro derivative. 

In the early days, greatest interest was focused on the acid-catalyzed hydrolysis (by hydrochloric acid in the presence of 2,4-dinitrophenylhydrazine) of Reissert compounds to aldehydes and the corresponding heterocyclic carboxylic acid derivatives. This reaction is fairly general for compounds of quinoline (178) and isoquinoline (179) (Table 18), but it is not applicable to pyridines as they rarely form Reissert compounds. The 3-hydroxyquino-line Reissert compound does not yield benzaldehyde, probably because acylation of the 3-hydroxy group prevents formation of the required cyclic intermediate (180). Some nitroquinolines and isoquinolines give low yields of benzaldehyde. Rather curiously, disub-stituted quinoline Reissert compounds yield less of the aldehyde than of the corresponding... 

Under more vigorous nitration conditions the products from quinoline are 5,7- and 6,8-dinitroquinoline. Nitration of 6-nitroquinoline with potassium nitrate and sulfuric acid in a sealed tube at 140°C gives 5,6- and 6,8-dinitroquinoline under the same conditions 7-nitroquinoline gives 5,7- and 7,8-dinitroquinoline. 

The use of transition metal nitrato compounds can be of value. For example, tetranitratozirconium(IV), Zr(N03)4, on shaking with quinoline at room temperature, gives a 90% yield of almost pure 7-nitroquinoline (74JCS(Pl)175l). 

Electrophilic chlorination of quinoline under neutral conditions occurs in the orientation order 3 > 6 > 8. Hammett ct+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. The reactivity order can be affected by substitution of an electron-withdrawing group in the benzene ring, which directs the chlorination to the pyridine ring. Thus, NCS in acetic acid or sulfuryl chloride in o-dichlorobenzene converts 8-nitroquinoline into 3-chloro-8-nitroquinoline in high yield (91M935). 

Pyruvic acid and isatins gave quinoline-2,4-dicarboxylic acids.16 36 Use of malonic acid with isatins gave 2-quinolone-4-carboxylic acids.169 620 Nitromethane and isatin with 50% potassium hydroxide gave 3-nitroquinoline-4-carboxylic acid.623... 

The examples selected to illustrate some of the important cyclisation reactions leading to substituted quinolines and isoquinolines are quinoline [(100), X = H], 8-nitroquinoline [(100), X = N02], 8-hydroxyquinoline [(100), X = OH], 2-methylquinoline (101), 2,4,6-trimethylquinoline (102), 2-phenylquinoline-4-carboxylic acid (103) and 6-methylisoquinoline (104). 

Nitroquinoline 209 enters into a direct cyclocondensation with aromatic hydra-zones in NaOH/DMF giving pyrazolo[3,4-/]quinolines 210 and (or) triazino[6,5-/ quinolines 211 in low to moderate yield (Scheme 62) (OOOL413). Their ratio mainly depends on the structure of the starting hydrazone. For example, electron-donating substituents in its aryl moiety assist triazine ring closure. Evidently, pyrazoles 210 are products of two consecutive SNH and SN ipso reactions, whereas conversion of 209 into 211 looks rather complicated and better corresponds with cascade hetero-cyclizations considered in Section III.D.l. 

In similar manner, 8-nitroquinoline interacts with phenylcinnamylsulfone yielding a mixture of o-phenantroline 270 and isoxazolo[4,3-/z]quinoline 271 (Scheme 78) [98T2607], The difference is that transiently formed anions 272a,b manifests here... 

Quinoline-l-oxide undergoes nitration at the 2-, 5-, and 8-positions. While it is known that isomer ratios are temperature dependent, it has been recently shown that the orientation of nitration is also dependent on the acidity of the reaction medium <1997CPB279>. 2-Nitroquinoline 1-oxide, arising from nitration of unprotonated substrate, predominates under weakly acidic conditions. Nitration in stronger acidic media occurs on the hydroxyquinolinium ion and yields 5- and 8-nitroquinoline 1-oxide as the major products with increasing amounts of the 5-isomer formed in very highly acidic media. 

Oxidative methylamination of 2-, 3-, 4-, 5-, 6-, 7-, and 8-nitroquinolines at —7 °C leads, as could be expected, to similar results as obtained in the oxidative amination (93LAC823). In general, the methylamination differs from the oxidative amination in several aspects (a) the reaction occurs faster than the amination, due to the higher temperature at which the reaction is carried out, (b) gives higher yields, (c) the site specificity is less than observed in the amination, as it appears by the sometimes occurring formation of mixtures of (methylamino)nitroquinolines, and even in the case of 5-nitro-quinoline formation of bis(methylamino)-5-nitroquinolines (Table III). 

A series of l,2,4-triazino[5,6-c]quinolines have been prepared via a common route. Thus, 4-[fi-(ethoxymethylene)hydrazino]-3-nitroquinoline (244), prepared from 4-hydrazino-3-nitroquinoline (243) by reaction with triethyl orthoformate, was hydrogenated in ethanol over a palladium catalyst to give the dihydro compound (184) (96%). Dehydrogenation yielded the desired compound (185) (90%) (Scheme 19) <73GEP(0)2322394>. 

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