4- Amino-substituted quinolines

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. 

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. 

Ketones react with o-oxazoline-substituted anilines 187 and a catalytic amount of PTSA in dry n-butanol to form 4-amino-substituted quinolines 188 or 4-quinolones in fair to good yields (Scheme 39) (06T9365). 

Ana.lytica.1 Rea.gents, The chelating property of quinolines, eg, 8-hydroxy derivatives, make them useful in metal gravimetric appHcations however, few are any longer of practical importance. Amino- and sulfur-substituted quinolines have also been employed in metal analyses (105,106). 

The Friedlander quinoline synthesis combines an a-amino aldehyde or ketone (1) with another aldehyde or ketone with at least one methylene a to the carbonyl (2) to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat. 

The intramolecular Diels-Alder reaction of 1-amino substituted isobenzofiiran 62 leads to hydrobenzo[/i]quinolines 63 <95TL(36)8581>. 

The thermal cyclization of [(3-chloro-4-fluorophenyl)amino][4-methoxy-phenyl)methylthio]methylenemalonate (789, R = Cl, R1 = 4-MeOC6H4) in diphenyl ether at 250°C for 3 min gave 2-substituted quinoline-3-carbox-ylate (790, R = Cl, R = 4-MeOC6H4) in 66% yield (82EUP58392). 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

With mew-substituted amino ketones 19, a mixture of 5- and 7-substituted quinolines 20 and 21 are obtained, with the 7-substituted product 21 predominating in every case.18... 

The schemes presented below also illustrate the synthesis of various amides of substituted quinoline-and quinolonecarboxylic acids 212-214 by the reaction of isatins 7, 9, 54, and 180 with amides 215 [179], acylated amino acids 216 and isothiocyanates [182], and enamines 217 [183],... 

Ionic liquids (imidazolium salts) were utilized as green solvents in the Friedlander synthesis. Reactions of o-amino-substituted aromatic carbonyls with a variety of ketones (cyclic, acyclic, aromatic) result in the desired quinolines in uniformly high yield. Conditions are mild and no hazardous acids or bases are used <03JOC9371>. 

As part of their study on gastric (H+/K+)-ATPase inhibitors, Kang et al. developed a simple and convenient synthetic approach to 1,2,3-trisubstituted pyrrolo[3,2-c]quinolines by means of Pd-catalyzed heteroannulation of 4-amino-3-iodoquinoline derivatives with internal alkynes [76]. The following scheme shows an example of a reaction using 4-arylamino-3-iodoquinoline derivative 180 with alkyne 181 to provide 1-arylpyrrolo [3,2-c]quinoline 182, illustrating the possibility of introducing diverse substituents to 1-arylpyrrolo[3,2-c]quinolines. In addition, a Pd-catalyzed domino hydroarylation/ cyclization process was reported to form substituted quinolines [77]. Thus, 3-arylquino-lines were prepared in 56-74% yield when 3,3-diethyl-l-phenyl-1-propyne and aryl iodide were refluxed in ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate [(bmim)BF4 ],in the presence of HCO2H, EtjN, and palladium catalyst. Meanwhile,... 

Early work on the amination of quinoline and substituted quinolines showed that the parent compound gave only a 32% yield of 2-aminoquinoline (78) in aromatic hydrocarbons (20MI1). Many derivatives, including quinoline carboxylic acids and amides, formed amino products more readily. However, amino- and hydroxyquinolines do not participate in the Chichibabin reaction (78RCR1042). 

The SAR studies in 7-chloro-4-substituted aminoquinolines have been carried out by Bass et al. [17]. These authors used regression analysis of a large variety of 4-aminoquinolines and observed that their findings are in close resemblance with the model proposed by Hahn and Co-workers [18]. In a further probe to study the role of the 4-substituted amino function in evoking the antimalarial activity in quinolines, a number of 7-chloro-4-substituted quinolines (12) were prepared, but none exhibited noteworthy antimalarial activity [19-23]. Some bisquinolines of type 13-15 have also been synthesized, of which 14 and 15 have been shown to exhibit potent antimalarial activity [23-25]. 

Finally, Hitomi et al. recently presented a catalytic system based on the pentadentate H-dpaq ligand (dpaq = 2-[bis-(pyridine)-2-ylmethyl)]amino-A(-quinolin-8-yl-acetamidate, Scheme 10) [60]. The complex [Fe (dpaq)(H20)] was used in combination with various oxidants to show a metal-based oxidation mechanism suggested by the high alcohol/ketone (A/K) ratios obtained in the oxidation of cyclohexane, regardless of the oxidant employed. This catalyst presented a performance virtually identical to that of [Fe(pdp)(CH3CN)2](SbF6)2 in the oxidation of cw-4-methylcyclohexyl-l-pivalate and 1-substituted 3,7-dimethyl-octane without the addition of acetic acid. 

The standard Chichibabin amination of quinoline with sodium amide in DMA gives 2-aminoquinoline in a low 7% yield and 2-amino-3,4-dihydroquinoline in a 24% yield. Not until the introduction of the Chichibabin oxidative amination variant (e.g., in the presence of KMn04) were these yields improved. Regio-chemical outcome depends on reaction temperature (kinetic or thermodynamic control). 2-aminoquinoline (39) forms at -65 °C, i.e., the kinetic adduct, and is isolated in a 50-55% yield with no evidence of 4-amino adduct formation, whereas 4-aminoquinoline (40) forms in 60-65% yield at 15 °C, i.e., the thermodynamic adduct (oxidant added at -45 C), with 6-7% of 39. Substituted quinolines give various... 

Many heterocyclic compounds can be halogenated with H2O2/HX. Examples include tetra-iodination of pyrrole in 80% yield with H2O2 and KI at 45°C [270], monochlorination of 3-aminopyridine with H2O2/HCI at 80°C giving the 2-chloro-product [271], and of the more active 3-bromo-2,4-dihydroxypyridine at ambient temperature giving the 6-chloro-product. Several substituted quinolines have also been chlorinated, including 3-hydroxy [272], 8-hydroxy [273], 8-amino [274] and 8-methoxy-4-hydroxy [275]. 

Furthermore, selective monoarylation of 1-aminocyclopropane-l-carboxylic acid derivative 83 was achieved in the presence of alkoxy-substituted quinoline 85 in good yield (Scheme 23) [45]. Only one diastereomer of the unnatural amino acid derivative 84 was produced. 

The reaction between amino group (-NH2) and a carbonyl group (C=0) elsewhere in the same molecule has been used in the synthesis of many heterocyclic compounds. For example as shown in Equation 9.53, substituted quinolines can be produced by acid-catalyzed cyclization of the appropriate aminoketones (formed during the Friedlander synthesis, in this instance between propanone and ortho-aminobenzaldehyde, in an aldol-type reaction with loss of water this chapter, vide infra), and even more than one reaction can be induced to occur. Thus, in Equation 9.54,1,2-benzenediamine (ort/io-aminoaniline) undergoes acid-catalyzed addition to 2,3-butane-dione to produce 2,3-dimethyl-13-benzopyrazine (23-dime thy Iquinoxaline). ... 

The quinolin/4(l//)-one alkaloids with a linear aliphatic side chain at C-2 appear to be absent in fungi. Fungus Penicillium (Ascomycota phylum, Ascomycetes class, and Eurotiales order) has yielded a novel class of quinolin/ones [41], They are based on the combination of amino acids L-valine and L-isoleucine, anthranilic acid, and acetic acid [41] (Schemes 24.22, 24.23), or these amino acids and tryptamine [41] (Scheme 24.24). They constitute two small groups which can be considered as 2-substituted quinolin-4(l/f)-ones quinolactacins Al, A2, B, and C, quinolactacide and 2-substitued quinolines quinocitrinines A and B. Both are alkaloid types at present unknown from any other source. Thus, clearly fungi from Ascomycetes class deserve more attention in order to find new quinolactacins, since they showed interesting biological effect on tumor necrosis factor (TNF) [41]. 

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