Nitroquinolines

The synthesis can be carried out with most aromatic amines and is usually termed the Skraup reaction. The nitrobenzene is frequently replaced by arsenic acid, as in the prep)aration of 8-nitroquinoline from o-nitroanUine ... 

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... 

At 25 °C unless otherwise stated. t The total yield of nitroquinolines was about 94%. An unidentified yellow com- ... 

A more detailed study of the nitration of quinolinium (l) in 80-05 % sulphuric acid at 25 °C, using isotopic dilution analysis, has shown that 3-) 5-) 6-, 7- and 8-nitroquinoline are formed (table 10.3). Combining these results with the kinetic ones, and assuming that no 2- and 4-nitration occurs, gives the partial rate factors listed in table 10.4. Isoquinolinium is 14 times more reactive than quinolinium. The strong deactivation of the 3-position is in accord with an estimated partial rate factor of io for hydrogen isotope exchange at the 3-position in the pyridinium ion. It has been estimated that the reactivity of this ion is at least 10 less than that of the quinolinium ion. Based on this estimate, the partial rate factor for 3-nitration of the pyridinium ion would be less than 5 x io . 

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). 

Synthesis of o-aminoaryinilnles (useful in pynmidine synthests) from nitroquinolines, niiro naphthalenes, and m-subsMuted (CFa, COCH3 and COCeHs) nitrobenzenes... 

Nitroquinoline 1-oxide [56-57-5] M 190.2, m 157 . Recrystd from aqueous acetone [Seki et al. J Phys Chem 91 126 1987]. 

A few comments on the polar effects of the substituents reported in Tables IX—XI are now relevant. With the exception of 4-chloro-5-nitroquinoline (see Section IV, C, l,c), they involve only positions not subject to primary steric effects. The relations to the reaction center are of the conjugative cata, amphi) as well as of the non-conjugative class meta, epi, pros) as shown in Chart 3 by structures 45 and 46. 

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. ... 

In 2-chloro-8-nitroquinoline (196), where resonance activation by the nitro group in the adjoining ring is possible, the chloro group is rapidly (10 min) displaced in boiling aqueous acid (cf. Table XI, p. 338). 

Kinetic studies of pyrolysis of azides, giving oxadiazole A-oxides in near-quantitative yields, showed that the 5-azido-6-nitroquinoline pyrolyzed in acetic acid 27.6 times faster than did 5-azidoquinolines, because of the -M effect of the group adjacent to the azide group (85AJC1045). 

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. 

The proportion of oxadiazoloquinolines compared to aminonitroquinolines decreases from the 5-, to the 8-, to the 7-nitro series it is smallest for 6-nitroquinolines (73YZ1019, 73YZ1024). 

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. 

The key intermediate for the preparation of the 8-aminoquin-oline antimalarial agents is obtained by condensation of the substituted aniline, 90, with "dynamite-grade" glycerol in concentrated sulfuric acid. (The reaction may well follow some scheme such as that depicted below.) Ihe nitroquinoline obtained from... 

Likewise with 2-nitronaphthalcne (6), 1 //-2-benzazepin-l -yl phosphonates 7 are formed in good yields, and the method can also be used to synthesize pyridoazepines from nitroquinolines (see Section 3.2.1.4.1.5.). The reaction fails, however, with 2-substituted 1-nitronaphthalenes. 

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). 

Electronegative groups do not invariably prevent nuclear bromination, but reaction conditions must be much more severe, and the orientation of substitution may be affected by the substituent. Thus 6-nitroquinoline was brominated in sulfuric acid at 100°C to give the 8-bromo product (71) in 51% yield 8-methyl-5-nitroquinoline gave a 69% yield of the 7-bromo derivative (72) under similar conditions, whereas 7-chloroquinoline was transformed into the 5-bromo product (93%) (88CHE892) (Scheme 35). In a sealed tube reaction with bromine, 8-nitroquinoline gave a mixture... 

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