Quinolones, alkylation

Secondary enamino ketones such as - -octahydro-7-quinolone (64) furnish a mixture of N- and C-alkylated bases, 120 and 121, respectively, on treatment with ethyliodide (168). Alkylation of tertiary enamino ketones as, for example, 101 proceeds exclusively on the oxygen-atom, forming product 122 (206). 

Various l-alkyl-4-(benzotriazol-l-yl)-l,2,3,4-tetrahydroquinolines have been prepared by condensation of V-alkylaniline with two equivalents of an aldehyde and one equivalent of benzotriazole <95JOC(60)7631>. Quinolones 66 were simply prepared in good yield by heating a mixture of the appropriate vinylogous amide 65 and NaHCOj in the presence of a catalytic amount of palladium(II) acetate and triphenylphosphine in DMF under a carbon monoxide atmosphere <96CC2253>. 

Alkylation of a series of 4-quinolones under basic two-phase conditions yields a mixture of the O- and A-alkylated derivatives [65], The ratio of the two isomers depends on the substituents. A-Alkylation is predominant (N 0 ratio = ca. >4 1) for most compounds but, somewhat surprisingly, the presence of a methyl group at either the 2- or 8-position results in a higher, or sometimes exclusive, yield of the N-alkylated product, irrespective of other substituents on the system. 

It has been reported that alkylation of 2-pyridone and 2-quinolone and other related potentially tautomeric azinones under solid-liquid phase-transfer catalytic conditions generally produces the A-alkylated derivatives exclusively in 65-90% yield [58], although it has been suggested that the yield of the O-alkylated derivative can be increased by the use of long-chain quaternary ammonium salts and when bulky alkylating agents are used [69]. 

Hamasaki N, Ishii E, Tominaga K, Tezuka Y, Nagaoka T, Kadota S, Kuroki T, Yano 1. (2000) Highly selective antibacterial activity of novel alkyl quinolone alkaloids from a Chinese herbal medicine, Gosyuyu (Wu-Chu-Yu), against Helicobacter pylori in vitro. Microbiol Immunol 44 9-15. 

The Gould-Jacobs sequence (Scheme 4.1) commences with an addition-elimination reaction between aniline 30 and substituted ethylenemalonate derivative 31 to yield malonic ester 32. Subsequent intramolecular cychzation delivers the 4-hydroxy-3-carboalkoxy-quinolone 33. In the presence of an alkylating agent, 33 is converted to 34. Saponfication of the ester affords quinolone core 35. 

Quinolinium salts react similarly to pyridinium compounds when oxidized. N-Alkylated salts 142, for example, yield only 2-quinolones 143 after Decker oxidation. 4-Quinolones 144 cannot be isolated (1892CB443 70HCA1903). 

The hydroxyquinoline (39-2) provides the starting material for a quinolone that incorporates a hydrazine function. Reaction of (39-2) with 2,4-dintrophenyl O-hydroxylamine ether (41-1) in the presence of potassium carbonate leads to a scission of the weak N-O hydroxylamine bond by the transient anion from the quinolone the excellent leaving character of 2,4-dinitrophenoxide adds the driving force for the overall reaction, resulting in alkylation on nitrogen to form the hydrazine (41-2). The primary amine is then converted to the formamide (41-3) by reaction with the mixed acetic-formic anhydride. Alkylation of that intermediate with methyl iodide followed by removal of the formamide affords the monomethylated derivative (41-4). Chlorine at the 7 position is then displaced by A-methylpiperazine and the product saponified. There is thus obtained amifloxacin (41-6) [48]. 

Evodia rutaecarpa (Juss.) Berth Wu Zhu Yu (Evodia) (fruit) Alkyl methyl quinolone alkaloids, evodiamine, limonin, evocarpine, rutaecarpine, N-methyl anthranilic acid, evodol, hydroxyevodiamine, N-methylanthranflamide, N,N-dimethyl-5 -methoxytryptamine, dehydroevodiamine.32,33,237 Antiemetic, analgesic, lower blood pressure, antibacterial. 

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. 

Alkylation of 83 (R = OH) takes a variety of paths including alkylation of the NOH to give 1-alkoxyisatins, alkylation of the NOH and the carbonyl group to give 1,2-dialkoxyindoles, alkylation at the hydrazone group, and ring expansion to 2-quinolones.301 The course of the reaction depends upon the nature of the substituent in the side chain. 

Hadjeri, M. Mariotte, A.-M. Boumendjel, A. Alkylation of 2-phenyl-4-quinolones synthetic and structural studies. Chem. Pharm. Bull. 2001, 49,1352-1355. 

In a model reaction used to support the structure identification of a neutral polyaza cleft for enolate complexations, the disubstituted dihydropyrrolo[2,3-/i]quinoline (51) was prepared by alkylation of 7-bromo-5,6,7,8-tetrahydro-8-quinolone with ethyl 3,3-diamino-2-propenoate (Equation (24)) <91JA9687>. The regioisomeric residence of the two substituents in this product was supported by 13C—13C shift-correlated NMR spectroscopy. 

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