Quinolones => aniline

If the 1,3-dicarbonyl component is at the 1,3-keto acid oxidation level, then the product is a quinolone. Anilines and P-keto esters react at lower temperatures to give the kinetic product, a P-aminoacrylate, cyclisation of which gives a 4-quinolone. At higher temperatures, P-keto acid anilides are formed and cyclisation of these affords 2-quinolones. 

Kemp utilized a very similar oxo-diester 49. Not only was this ketone reactive enough to form an enamine using p-nitroaniline 48, but 49 underwent bis-addition of aniline 48, providing 50 in 64% yield. Intermediate 50 smoothly cyclized to provide quinolone 51 which was utilized to prepare a diacylaminoepindolidione, a template to study the folding of 3-pleated sheets. 

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. 

In the first step of what is considered to be a fairly straightforward mechanism, the anilinic nitrogen reacts with the ester group of the 3-ketoester 5 to provide the anilide 3. The latter can either be isolated or carried on directly. Upon warming in the presence of acid, the acetanilide cyclizes with subsequent loss of water to yield the quinolone product 9. ... 

A related reaction has been described for the synthesis of 2-quinolones, reacting substituted secondary anilines with malonic acid derivatives. The reaction was carried out neat under microwave irradiation at 290 °C for 15 min. These harsh conditions were reqiured for the elimination of two... 

One frequently used method for synthesizing 2-quinolones is to react anilines with malonic esters. This reaction can be difficult to accomphsh by conventional methods [48,49] since high temperatures (250-350 °C) are required for the generation of an o -oxoketene intermediate 12 (Fig. 6). In a recent example of this type of reaction, Stadler et al. synthesized 4-hydroxyquinolin-2(lH)-ones by using a microwave-assisted procedure (Scheme 5) [50]. 

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... 

A novel reaction for the synthesis of 4-amino-substituted quinolines 80 or 4-quinolones 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted anilines 84 and 85 in the presence of a catalytic amount of /Mol ucncsul tonic acid (p-TSA) in dry w-butanol led to 80 and 81, respectively <06T9365>. To the authors surprise, the reaction of acetophenones 82 lead to a different outcome than that of the cyclic or acyclic ketones 83 containing more than one carbons a to the ketone. 

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-... 

The enamine adducts formed in the reaction of aromatic amines with DMAD have been found to undergo cyclization leading to heterocyclic compounds, and the mode of these reactions is to a considerable extent influenced by the reaction conditions, the catalyst employed, and also the nature of the functional groups present in the starting amine. The reaction of aniline with methyl propiolate in presence of cuprous acetate, for example, is reported to give a mixture of 2(lH)-quinolone (1) and 4(l//)-quinolone (2) [Eq. (1)]." On the other hand, dimethyl anilinofumarate (3), formed from aniline with DMAD, undergoes... 

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-... 

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. 

Quinolones are obtained in the Conrad-Limpach-Knorr synthesis, which is subject to either kinetic or thermodynamic control, when aniline is reacted with a 3-keto ester (Scheme 3.11a). At room temperature the more reactive keto group combines with the aniline nitrogen atom, leading to an enamino ester the kinetic product. Cyclization of this product to a 4-quinolone requires heating at 250 C. 

The same scheme affords a true quinolone when applied to an aniline. Condensation of piperonylamine (38-7) with EMME followed by cyclization of... 

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 insertion of alkynes into arylpalladium complexes might also be accompanied by the insertion of carbon monoxide into the resulting vinylpalladium intermediate. The carbonylative annulation of TV-protected 2-iodoanilines and internal alkynes under an ambient pressure of carbon monoxide resulted in the formation of 2-quinolones (4.14.), The protection of the nitrogen atom in the aniline is crucial to the success of the reaction. 

In another synthesis of quinolines involving imine intermediates, o-oxazoline-substi-tuted anilines (6) react with ketones in dry butanol reflux to give 4-amino-substituted quinolines [e.g. (7)], or 4-quinolones, using tosic acid as catalyst.18 A mechanism involving ketoimine formation with subsequent tautomerization to give an enamine which attacks the oxazoline ring is discussed. 

In many cases N-substitued anilines or azomethines (resp. enamines) react with two equivalents of diethyl malonate to give pyrono derivatives of 2-quinolones or 2-pyridones in good yield [84JHC1881] [89JHC1555] [88TH000] [90THO00], Chlorination of these compounds with sulfuryl chloride and aqueous work up yields dichloroacetyl derivatives of quinolones and pyridones which in turn react with sodium azide to afford a variety of diazidoacetyl derivatives of type 38. 

A 1,3-dipolar cycloaddition using oxime derivatives yielded the tetrahydroquinoline derivative 25 (Equation 58) <2005S3423>. It was advantageous that the product precipitated out of the aqueous reaction medium in excellent yield. Carbenoid-insertion reactions have been demonstrated to produce the ring-extended quinolone structure 26 from simple substituted anilines (Equation 59) <2003TL7433>. The C-H insertion onto the aromatic ring can vary. 

Non-hemiterpenoid Quinolines.—New sources of the simple quinolines 4-methoxy-l-methyl-2-quinolone and its 8-methoxy-derivative (folimine) have been reported the former was isolated from Myrtopsis sellingii9 and from Zanthoxylum cuspidatum,16 and folimine was shown to be a constituent of Haplophyllum perforatum.5 The latter species also contains foliosidine (9), previously isolated from H. foliosum. The micro-organism Pseudomonas aertiginosa has been shown to contain 2-(hept-l-enyl)-4-quinolone (12).10 The structure of the alkaloid was established by n.m.r. and mass spectroscopy and by its synthesis from aniline and the j3-keto-ester Me(CH2)4CH=CHC0CH2C02Me. 

Hydroxy-l-methyl-3-prenyl-2-quinolones, cf. (22), are key intermediates in the synthesis of quinoline alkaloids, and usually are prepared in one stage from an N-methyl-aniline and diethyl prenylmalonate. Interesting new methods beginning with N-methylisatoic anhydrides, cf. (20), have been explored and briefly repor-... 

Quinolones also come from anilines by cyclization to an ortho position... 

Zewge et al. discovered that Eaton s reagent could be used to efficiently promote the cyclization of aniline derivatives to give substituted 4-quinolones <07JOC4276>. As shown below, aniline derivative 105 can be treated with Eaton s reagent at 50 °C for 2 h to provide 4-quinolone 106. 

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