Displacement quinolone

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

Alternatively, HC(OC2H )3 may be used in step 1. The appioptiate group is attached by a second nucleophilic displacement to give the desired quinolone. 

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). 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

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]. 

The product from the formal replacement of the benzimidazolone function in itasetron (57-6, Chapter 10) by a quinolone has been reported to display much the same serotonin antagonists activity of the former. In the absence of a specific reference to the synthesis, the starting quinolone is speculatively formed by reaction of cyclo-hexylaniline (50-1) with EMME to produce the enamide (50-2) from displacement... 

Tetrabenzo[a,c,g,i]fluorene has been used to selectively link synthetic intermediates to charcoal, for the purpose of their purification. In polar solvents, the tetrabenzo-fluorene is strongly adsorbed by charcoal this enables efficient separation of the intermediate from reagents. After centrifugation and washing, the intermediate is displaced from the charcoal and released into solution by addition of a non-polar solvent, and a new synthetic operation in solution can be conducted (Figure 3.43). Tetrabenzo-fluorene has also been used for the purification of peptides [849] and oligonucleotides [850], and for the synthesis of quinolones [851]. 

The synthesis of the important quinolone antibiotic 6.33 is shown. The key stages are the Gould-Jacobson quinolone synthesis to give 6.32, and the displacement reaction to afford 6.33. What are the mechanisms of these reactions ... 

Allyl and crotyl ethers were prepared from 3-propyl-4-quinolones by two different approaches. Displacement of 4-chloro-3-propyl-quinoline by the sodium salt of the two alcohols gave the ethers (1) as clean products, whereas reacting 3-propyl-4-hydroxyquinoline with allyl bromide in the presence of sodium ethoxide afforded not only the allyl ether but also the 1-allylquinolone (2). The products were well-characterized by their ultraviolet spectra and infrared bands. Rearrangement of the ethers at 200° without solvent gave quantitative yields of the corresponding l-allyl-3-propyl-4-quinolones (2). 

The cyclization to a quinolone (95) in this case is effected with sodium hydride. Treatment of this intermediate with the spiro diamine (96) leads to displacement of fluorine and formation of alkylation product 97. Deprotection by acid-catalyzed cleavage of the t-BOC group flowed by saponification yields the quinolone antibacterial agent 98. ... 

A popular method to prepare haloquinolines is the halogenation of quinolones using oxyphosphorus halides, most notably POCI3. The carbonyl can be located either at the C(2) or the C(4) positions. As depicted in Scheme 1, the C(2) position of quinolone 4 was chlorinated with POCI3 to give 6-bromo-2-chloroquinoline (5) [1]. The subsequent S Ar displacement of the chlorine substituent on 5 with sodium methoxide led to 6-bromo-2-methoxyquinoline. Analogously, chlorination at the C(4) position of quinolones is exemplified by transformations 6 7 [2] and 8 9 [3]. 

P-Aminoacrylates, for cyclisation to 4-quinolones, are also available via the addition of anihnes to acetylenic esters ° ° or by displacement of ethoxy from ethoxymethylenemalonate (Et0CH=C(C02Et)2. ... 

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