Synthesis of novel heterocyclic analogues of isoflavones

The primary aim of the project was to investigate various methodologies for the synthesis of aza-analogues of isoflavones, or 4-quinolones, and their reduced analogues with an oxygenated pattern that is present in naturally occurring flavonoids. A series of 3-aryl-5,7-dimethoxyquinolin-4-ones was synthesized by the reaction of 3,5-dimethoxyaniline with α-aryl-β-ketoesters, giving enamino esters which were then converted to the corresponding 4-quinolones by thermal cyclization. The reduced 2,3-dihydroquinolin-4-one analogues were synthesized by the reaction of 3,5-dimethoxyaniline with α-aryl-β-ketoesters in the presence of sodium cyanoborohydride, followed by amino group protection and ester hydrolysis. The resulting acids were then cyclized and deprotected to give the desired 2,3-dihydroquinolin-4-ones.The previously unreported 4-arylazaisoflavans were synthesized via two approaches. In the first approach, a Grignard reaction was performed on the carbonyl group of the 2,3-dihydroquinolin-4-ones, and the resulting alcohol was dehydrated and hydrogenated to give the fully reduced ring system, with a cis arrangement of substituents. In the other approach, the carbonyl group of 2,3-dihydroquinoline was reduced to an alcohol, which was then reacted with various nucleophiles. This approach gave the corresponding 4-aryl and 4-heteroarylazaisoflavan ring systems with a trans arrangement of substituents.The pyrrolo[3,2,1-ij]quinolin-6-one ring system was synthesized from 4-quinolones. The reaction of α-bromo-acetophenones with 4-quinolones gave the corresponding quinolinoketones which on acid catalyzed cyclization gave the desired pyrroloquinolin-6-one. Reduction of pyrroloquinolin-6-ones with lithium aluminium hydride yielded the corresponding dihydroquinolin-6-ones.Selective demethylation of the C5-methoxy group in the synthesized 4-quinolones, 2,3-dihydroquinolin-4-ones and pyrroloquinolones was performed using cerium chloride and sodium iodide. Similar reactions with borontribromide gave dihydroxy analogues of 2,3-dihydroquinolin-4-one but was found to only selectively demethylate 4-arylazaisoflavans at C5. Dimethoxyquinolones also underwent Mannich reaction at C8 with primary amines and amino acid esters to give quinazolones