4-Hydroxy-2-quinolones. 97. Simple synthesis of the esters of 4-halo-substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acids

Abstract

Keywords: 4-amino-2-oxo-1,2-dihydroquinolines, enamines, ethyl esters of 4-halo-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, hydrolysis, decarboxylation.The ability of enamines to form carbonyl compounds under acid-catalyzed hydrolysis conditions has been known for a long time and is used widely in organic chemistry as a method of indirect C-alkylation or acylation of aldehydes and ketones inclined to selfcondense in the presence of strong bases [2].We previously studied the acid hydrolysis of 4-benzylamino-3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolines. In this was noted the ease of N-debenzylation and the relative stability of the ester grouping. As a result the investigation proved to be a convenient method of obtaining ethyl esters of 1-R-2-oxo-1,2-dihydroquinoline-3-carboxylic acids with a primary amino group in position 4 of the quinoline nucleus [3].On going over to tertiary enamines, which are similar in structure, different hydrolysis products must be expected, and typical for this type of reaction are the initial carbonyl compounds and amines. In reality short term (30 min) boiling of the ethyl ester of 4-morpholino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (1) in concentrated hydrochloric acid causes breakdown of this enamine to morpholine and 3-ethoxycarbonyl-4-hydroxy-2-oxo-1,2-dihydroquinoline, which under the experimental conditions is also hydrolyzed, decarboxylated, and converted finally into 4-hydroxy-1H-quinolin-2-one (2). Reducing the time of treatment to 1-2 min we unexpectedly discovered that, with retention of the ester grouping, the residue of morpholine has time to be substituted not by a hydroxyl group, as the mechanism of the hydrolysis reaction of enamines requires [4], but by a chlorine atom. This reaction occurs analogously with hydrobromic and hydriodic acids and leads to the ethyl ester of the corresponding 4-halo-substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acids 3a-c in

A Practical Method for Preparation of 4-Hydroxyquinolinone Esters

“…A variety of synthetic methods exist which allow access to highly functionalized 4-hydroxyquinolinone esters, facilitating library synthesis and drug discovery (Figure ). For example, substituted anilines 2 can be directly converted into 4-hydroxyquinolinone esters 1 by heating in the presence of methanetricarboxylates (Route A) . Difluorobenzonitriles 3 can be elaborated to 4-hydroxyquinolinone esters via a double S N Ar pathway (Route B) 7a.…”

BiCl3-catalyzed green synthesis of 4-hydroxy-2-quinolone analogues under microwave irradiation

“…Due to their wide range of biological applications, many synthetic routes leading to 4-hydroxy-2-quinolones and related analogues have been reported in the literature, 22,36 including classical methods using different catalysts, such as hydrogen chloride, 37 sodium hydride, 28 polyphosphoric acid PPA, 38–40 phosphorus pentoxide methanesulfonic acid solution or Eaton's reagent, 41,42 TiCl 4 , 43 AgNO 3 , 44 and Pd/C. 45 Microwave irradiation was also used in the synthesis of various 4-hydroxy-2-quinolones from the condensation of anilines and other reagents comprising diethylmalonate, 46 malonic acid, 47 and activated arylmalonate.…”

Amine‐Promoted Asymmetric (4+2) Annulations for the Enantioselective Synthesis of Tetrahydropyridines: A Traceless and Recoverable Auxiliary Strategy

“…To our surprise, neither product 5 a nor catalyst 4 e were detected, even when the reaction mixture was stirred at room temperature for 15 days. This observation may be attributed to the fact that enamine intermediate 6 is so stable that its hydrolysis is sluggish under these conditions, [12] which may be an intrinsic obstruction to the development of an optimal catalytic version. However, simple treatment of the reaction mixture with aqueous hydrochloric acid (6 n) allowed the isolation of 5 a in 72 % yield with 90 % ee.…”