Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones

Abstract

Eight substituted phenacyl anthranilates have been prepared by reaction of sodium anthranilate with substituted phenacyl halides in dimethylformamide in the yields from 31 to 93%. The phenacyl esters were cyclized in polyphosphoric acid or by mere heating to give the respective substituted 2-aryl-3-hydroxyquinolin-4(1H)-ones in the yields from 77 to 98%. All the compounds prepared have been characterized by their 1 H and 13 C NMR spectra.Phenacyl bromides belong among very reactive substances and their reaction with sodium salts of lower organic acids giving the corresponding phenacyl esters is well known and has been employed for identification of these acids 1,2 . The direct reaction of anthranilic acid with bromomethyl phenyl ketone has also been described 2,3 . In boiling ethanol in the absence of base, alkylation at amino group predominated to give N-phenacylanthranilic acid 3 . In the presence of base, phenacyl N-phenacylanthranilate was formed 2,3 . Phenacyl anthranilates were prepared by reactions of 2-nitrobenzoic acid with bromomethyl aryl ketones and subsequent reduction of the phenacyl 2-nitrobenzoates formed with hydrogen on palladium 4,5 . The rates of reactions of bromomethyl aryl ketones with nucleophiles are strongly affected by the solvent used. If amides are used as the reaction medium, the reaction is smooth even at room temperature and is exothermic 6 . When these conditions were adopted for the reactions of bromomethyl phenyl ketones I with salts of anthranilic acid, the alkylation predominantly took place at the oxygen atom to give phenacyl anthranilates II mostly in high yields (Scheme 1). The substances prepared were identified by their 1 H and 13 C NMR spectra (Tables I and II). Although quinolines represent an extensively studied class of heterocyclic compounds, only few basic representatives of 2-aryl-3-hydroxyquinolin-4(1H)-ones have been described in literature. The described method of preparation starting from the 2-nitrophenylethylene oxide prepared by the Darzens reaction 7,8 is laborious and the yields of whole synthesis are low. The method given by us for preparation of 3-hydroxyquinolin-4(1H)-ones III was discovered during cyclizations of phenacyl anthranilates (Scheme 1). Literature 4,5 describes their cyclizations in polyphosphoric acid to give the respective 2-aryl-3H-benz[e][1,4]oxazepin-5-ones IV which are converted into the more stable Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones

In vitro cytotoxicity, DNA cleavage and SOD-mimic activity of copper(II) mixed-ligand quinolinonato complexes

“…2-Phenyl-3-hydroxy-4(1H)-quinolinone (Hqui) was synthesized following the formerly reported procedure [36] and characterized by elemental analysis and FTIR (see Appendix A. Supplementary material).…”

Efficient Solid-Phase Synthesis of 2-Substituted-3-Hydroxy-4(1H)-Quinolinone-7-Carboxamides with Two Diversity Positions

“…After optimization of all steps, the entire synthetic sequence, including isolation of products, can be accomplished in 2 days using commercially available synthons. Preparation of N-derivatized carboxamides a a Reagents: (i) amine, 10% AcOH/DMF, overnight, NaBH(OAc) 3 , 5 h; (ii) 1-methyl-2-aminoterephtalate, DIC, HOBt, DCM, DMF, rt,overnight; (iii) TMSOK, THF, rt, 7 h; (iv) 2-bromo-4′-methyl-acetophenone, TEA, DMF, rt, 2 h; (v) 50% TFA, DCM, 30 min; (vi) TFA, 80 °C, 2 h. Six amines for the first diversity position. Bromoketones used for the synthesis of 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxylic acid propylamides (12).…”

Synthesis of N‐amino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone

“…For synthesis of the desired derivative we tried to use a modification of the widely explored cyclization reaction of anthranilic acid phenacylesters [9]. Because cyclization also takes place in phenacylesters with substituted amino groups e.g.…”

“…The incorporation of the mentioned protective group was achieved via diazotation of anthranilic acid phenacylester 1, prepared by a synthesis already described [9] and subsequent coupling reaction with malondinitrile, diethylmalonate, ethylcyanoacetate and ethyl-2-methylacetoacetate under neutral or slightly basic conditions (Scheme 1).…”