An Efficient Synthesis of 1-Alkyl-2-phenyl-4-quinolones from 2-Halobenzoic Acids

Abstract

1-Methyl-2-phenyl-4-quinolones are naturally occurring alkaloids isolated from the leaves and stems of the plant family Rutaceae. They have drawn considerable interest because of their potent pharmacological activities that include antifungal and antitumor activity, inhibition of acetylcholinesterase (AChE), and antimutagenic effect. Several methods have been developed to synthesize 1alkyl-2-phenyl-4-quinolones from 2'-substituted acetophenones, anilines, and 2-halobenzoyl chlorides as starting materials. The reaction of N-methylisatoic anhydride with the lithium enolate of an 4'-methoxyacetophenone afforded the 1-methyl-2-phenyl-4-quinolone in a short sequence, but the yield was low. N-(2-Acetylphenyl)benzamides, prepared by Friedel-Crafts acylation of N-phenyl benzamides with acetyl chloride or benzoylation of 2'-aminoacetophenones with benzoyl chlorides, were cyclized with potassium tbutoxide to yield 2-aryl-4-quinolones, which were further alkylated with alkyl iodides to give 1-alkyl-2-aryl-4-quinolones. However, acylation was accompanied by formation of the regioisomer and alkylation yielded a mixture of Nalkylquinolones as the main products together with 4alkoxyquinolines as minor products. On the other hand, Nmethylated (2-acetylphenyl)benzamides, prepared from 2'(N-methylamino)acetophenones and benzoyl chlorides, could be cyclized with sodium hydride in DMF to afford the 1-methyl-2-phenyl-4-quinolones in moderate yields. 2'-(N-Alkylamino)chalcones, prepared by aldol condensation of 2'-aminoacetophenones and benzaldehydes followed by N-alkylation with alkyl halides, upon treatment with polystyrene-supported selenenyl bromide in the presence of ZnCl2 afforded 2,3-dihydro-3-polystyrene-supported selenenyl-4-quinolones. These compounds were subsequently oxidized with H2O2 and eliminated to give 1-alkyl-2-phenyl4-quinolones. Palladium-catalyzed carbonylative coupling of 2-iodo-N-ethylaniline with phenylacetylene occurred smoothly to give a mixture of the corresponding enamine and the desired cyclic quinolone. Further cyclization of the enamine intermediate with sodium hydride in refluxing THF led to 1-ethyl-2-phenyl-4-quinolone. Palladium-catalyzed tandem amination of 2-bromoalkynones, obtained by Sonogashira cross-coupling of arylacetylenes and 2-bromobenzoyl chlorides, with arylamines in refluxing dioxane was effective for the synthesis of 1-aryl-2-phenyl-4-quinolones. Similarly, treatment of 2-halophenyl alkynones with arylamines afforded the corresponding 3-(N-arylamino) α,βunsaturated ketones by conjugate addition. These compounds were then cyclized with K2CO3 in refluxing DMF for 52 h 13