6- Nitro-2-quinolone

N14.94% yel tufts (methanol, benz/pet eth), mp 96°, sol in benz. Prepd by heating sodiumr 8-nitro-quinolonate with ethyliodide at 150° Refs l)Beil 21, 309 2)H.Decker A. 

The case of i-methyl-4-quinolone is puzzling. The large proportion of the 3-nitro isomer formed in the nitration (table 10.3 cf. 4-hydroxyquinoline) might be a result of nitration via the free base but this is not substantiated by the acidity dependence of the rate of nitration or by the Arrhenius parameters. From r-methyl-4-quinolone the total yield of nitro-compounds was not high (table ro.3). 

More importantly, Peet and coworkers reported the reaction of o-nitroaniline 35 with acetylene dicarboxylate 32 to provide fumarate 36. Subsequent cyclization proved difficult under thermal conditions and only a 35% yield of quinolone 37 was isolated. Use of PPA for the cyclization improved the yield of 37 significantly. Using this modification allowed enamino-ester formation with a nitro-group attached to the arylamine. 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

The 8-nitro group in intermediate quinolone 225 can be easily displaced even with aliphatic oxygen nucleophiles. Starting compound 224 under various conditions provided directly tricyclic compound 226 and all attempts to isolate the expected intermediate 225 failed (Scheme 34) (91CCC1937). 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

The reaction of or//io-substituted anilines containing substituent groups, e.g., phenyl, cyano, and nitro, gives rise to simple enamine fumarates these in turn can be cyclized to the corresponding 4-quinolones. " Aromatic diamines such as o-phenylenediamine and 2,3-diaminonaphthalene, however, react with DMAD to give tetra-hydroquinoxaline derivatives (7) [Eq. (2)]. ° It has been suggested that these tetrahydroquinoxalines exist in tautomeric equilibrium between the imine and enamine forms and that the enamine form (7) is more favored in inert organic solvents. On the other hand, an iso-... 

N12.84% yel ndls (ale), mp 18i subl. Prepd by hitrating the parent, heating ethyliodide with. sodium -6Tnitro-2-quinolonate, or by the potassium ferri cyanide oxidation as with the 5-nitro compd... 

N-ethyl nitro qninolones 6 E328 N-ethyl-6-nitro-2-quinolonium nitrate 6 E328 N-ethyl-5 (-6 or -7)-trinitro-2-quinolone 6 E329... 

Very few synthetic compounds other than the sulfa drugs have shown useful activity against systemic bacterial infections, particularly those due to Gram-negative bacteria. Activity of this kind was discovered in a series of l-alkyl-4-quinolones (60BRP830832), but the most active of these, l,2-dimethyl-6-nitro-4-quinolone and l-methyl-6-nitro-4-quin-olone-3-carboxylic acid, produced eye damage (opacity of the lens) that precluded clinical trial. A closely related 1,8-naphthyridine derivative, nalidixic acid (255), was later found to be effective, and it is largely used for urinary tract infections. The quinolone oxolinic acid (256) is also used for this purpose. These compounds inhibit enzymes concerned in DNA synthesis. 

Figure 9.1-2. Reactions of organic compounds in high temperature H2O (a), saponification of esters [28] (b), selective reduction of nitro-aromatics [29] (c), the synthesis of quinolones [30].

Quinolines have also been prepared on insoluble supports by cyclocondensation reactions and by intramolecular aromatic nucleophilic substitution (Table 15.26). Entry 10 in Table 15.26 is an example of a remarkable palladium-mediated cycloaddition of support-bound 2-iodoanilines to 1,4-dienes. Reduction of the nitro group of polystyrene-bound 2-nitro-l-(3-oxoalkyl)benzenes with SnCl2 (Entry 11, Table 15.26) leads to the formation of quinoline /Y-oxides. These intermediates can be reduced to the quinolines on solid phase by treatment with TiCl3. 4-Quinolones have been prepared by thermolysis of resin-bound 2-(arylamino)methylenemalonic esters [311]. 

An analogous reaction took place with some 6-substituted-2-methyl-4-quinolones and [hydroxy(tosyloxy)iodo]benzene [162] and also between 5-nitro-7-hydroxyquinoline and (diacetoxyiodo)benzene [163]. Depending on the solvent or the presence of alkali, either the iodonium salt or the 1,4-dipole could be isolated. 

To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate. Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed the acid groups, and reduction with Fe(TT) and HC1 converted the nitro group into the amino group required for the quinolone synthesis. 

From or via o-substituted cinnamoyl derivatives. or/ -Substituted benzenes of type 93 (Z = 0, S, NH) can undergo ring closure (Scheme 61). Amines of type 93 (Z = NH), which usually cyclize spontaneously, are often prepared in situ by reduction of nitro compounds, e.g., o-nitrocinnamic acid with (NH4)2S gives 2-quinolone. 

A series of 4-hydroxy-3-nitro-2-quinolones (93 X = CH) has been synthesized from nitroacetic ester and isatoic anhydrides in the presence of sodium hydride [Eq. (29)].85 A similar reaction has produced the naph-thyridine derivatives 93 (X = N, R2 = H).86... 

Penicillin, the first natural antibiotic produced by genus Penicillium, discovered in 1928 by Fleming, as well as sulfonamides, the first chemotherapeutic agents discovered in the 1930s, lead a long list of currently known antibiotics. Besides 3-lactams (penicillins and cephalosporines) and sulfonamides, the list includes aminoglycosides, macrolides, tetracyclines, quinolones, peptides, polyether ionophores, ri-famycins, linkosamides, coumarins, nitrofurans, nitro heterocytes, chloramphenicol, and others. 

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