SYNTHESIS OF BIOLOGICALLY ACTIVE HETEROCYCLIC COMPOUNDS USING KETONIC MANNICH BASES

Abstract

Nitrogen-containing heterocycles such as pyridines, quinolines, acridines, and their derivatives have great synthetic interest because of their importance in both the synthetic organic and the medicinal chemistry. Therefore new approaches for the synthesis of these heterocycles remain a topic of current interest. In this study, one-pot three-component reaction of ketonic Mannich base as an enone precursor with enolizable ketones and ammonium acetate under environmentally-friendly conditions are used for the synthesis of a variety of nitrogen containing heteroaraomatics. K-10 catalyzed reaction of ketonic Mannich base with active methylene and ammonium acetate in water successfully furnished a series of 2,3,6-trisubstituted pyridines and 2,3-disubstituted 5,6,7,8- tetrahydroquinolines in moderate to excellent yields. The introduced method is employed for the metal-free synthesis of new and known 2-aryl substituted quinolin-5-ones and 3,4,5,6,7,8-hexahydroacridin-1(2H)-ones. Reaction of ketonic Mannich bases, cyclic -dicarbonyl compounds and ammonium acetate provided 2-aryl substituted quinolin-5-ones and 3,4,5,6,7,8- hexahydroacridin-1(2H)-ones in the presence of glacial acetic acid in moderate to high yields.The presented work is extended to the reaction of the keto-bis base dihydrochloride derived from cyclohexanone or cyclopentanone with an acyclic active methylenes and ammonium acetate to indicate the scope of introduced synthetic methods. The reaction of keto-bis base dihydrochloride with cyclic dicarbonyl instead of an acyclic active methylenes furnished new exo-cyclic methylene tethered cyclopenta[b]quinolin-8-ones and 3,4,5,6,7,8- hexahydroacridin-1(2H)-ones and new methyl substituted cyclopenta[b]quinolin-8- ones and 3,4,5,6,7,8-hexahydroacridin-1(2H)-ones. In the last part of the work, the biological activities of synthesized new methylene tethered tetrahydroquinolines (THQs), cyclopenta[b]pyridines, methylene tethered cyclopenta[b]quinolin-8-ones and methyl substituted cyclopenta[b]quinolin-8-ones were evaluated. Exo-cyclic methylene tethered tetrahydroquinolines (THQs) showed high cytotoxicity towards C6, MCF-7, PC3, SH-SY5Y cancer cell lines and a normal cell line (L929). New exo-cyclic methylene tethered cyclopenta[b]quinolin-8-one showed anti-tumor activities against T98G, MG-63, HUVEC and hDPSC cell lines. All synthesized compounds were purified by chromatographic methods and their structures were identified by 1H NMR, 13C NMR, 31P NMR, 19F NMR, DEPT-135 and HRMS techniques.