4- Amino-substituted quinolines synthesis

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. 

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 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... 

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>. 

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). ... 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-6]quinolin-5(6//)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-l//-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). 

Eswaran et al. [16] reported the successful synthesis of new 5-(4-amino substi-tuted-8-(trifluoromethyl)quinolin-3-yl)-4-(un)substituted phenyl-4//-1,2,4-triazole-3-thiols (iv) carrying biologically active groups. 

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