Quinolone, formation

While the 2-quinolone formation is due to an SgAr process analogous to a Combes synthesis, the 4-quinolone formation is thought to be the result of an electrocyclization. The Konrad-Limpach synthesis is very flexible with regard to the arylamine and P-keto ester substituents, as well as to the use of alkoxymethylene malonic esters and dianilides of malonic aicid... 

While 2-quinolone formation can be understood in terms of an intramolecular SeAt process (in 98) analogous to the Combes mechanism, the 4-quinolone formation from 99 is thought to result from a 67t-electrocycHzation followed by sigmatropic (l,3)-H-shift and concluded by EtOH elimination. 

In the synthesis of Win 57,273 the attachment of the group, a 2,6-dimethylpytidinyl group, involves formation of a carbon-carbon bond rather than a carbon-nitrogen bond. The method for the attachment of this group is a palladium mediated coupling reaction (77,78) of 4-tributylstarmyl-2,6-dimethylpyridine [122033-61 -8] with a 7-halo quinolone (26). 

Ca.ta.lysts, A small amount of quinoline promotes the formation of rigid foams (qv) from diols and unsaturated dicarboxyhc acids (100). Acrolein and methacrolein 1,4-addition polymerisation is catalysed by lithium complexes of quinoline (101). Organic bases, including quinoline, promote the dehydrogenation of unbranched alkanes to unbranched alkenes using platinum on sodium mordenite (102). The peracetic acid epoxidation of a wide range of alkenes is catalysed by 8-hydroxyquinoline (103). Hydroformylation catalysts have been improved using 2-quinolone [59-31-4] (104) (see Catalysis). 

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 Conrad-Limpach reaction has been applied as a key step in the formation of pyrido[4,3-b]quinoline. Condensation of 3 different anilines 55 (R = H, Br, OMe) with keto-ester 56 provided the enamino-esters 57 in acceptable yields. Cyclization gave the desired quinolones 58 in good to moderate yield. ... 

A -acetyl groups attached to the aniline have been shown to withstand the Conrad-Limpach reaction. Phenols and alcohols also survived unless in proximity to a reactive center. Jaroszewski reported the formation of 64 by reaction of aniline 63 with ethyl acetoacetate (5). Cyclization under thermal conditions in paraffin gave a mixture of quinolone 65 and quinoline 66. 

The methods described for synthesizing 2-quinolones has so far been dependent upon the formation of the intermediate o -oxoketene 12 (Fig. 5). There are, however, other methods for the formation of 2-quinolones. One... 

The synthesis of this aminoquinoline starts with one of the standard sequences for preparation of 4-hydroxyquinolines, i.e., with the formation of the Shiff base (5) from the appropriately substituted aniline and diethyl oxaloacetate. Thermal cycliza-tion gives the quinolone (6) this then spontaneously tautomerizes to the enol form (7). Saponification followed by decarboxylation gives the desired quinolol... 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Reaction of these antibiotics with chlorine mostly generated chlorinated and OH-substituted by-products [86, 87]. Unlike fluroquinolones, whose quinolone ring is left mostly intact, disinfection with CIO2 may diminish the antibiotic capacity of tetracyclines because it leads to cleavage of the tetracyclines ring system [86,88]. On the other hand, oxidation of p-lactam antibiotics such as penicillin, amoxicillin, and cefadroxil with CIO2 leads to the formation of hydroquinone and a wide range of substituted phenols [89]. 

The influence of a C-2 substituent upon the reaction course has been investigated. If only a 2-aryl group is present, as in 145 (R = H), then 4-quinolones 146 are formed (85H2375). But ferricyanide oxidation of 2,4-diphenyl derivatives resulted in the release of the 2-phenyl group and formation of the quinolones 147 instead of the exptected indole derivatives (83CCC2965). 

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