Synthesis of Novel 2,3-Dihydro-2-phenylquinolone Dimers Using β-Ketoester and N-Alkylaniline

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New dimer, N,N'-dialkyl-2,2',4'-trihydroxy-4-oxo-2,2',3,3'tetrahydro-2,2'-diphenyl-4,4'-diquinolones were synthesized for the development of new candidates for anticancer drug through coupling of N-alkylanilines and ethyl benzoylacetate. A series of dimers was synthesized using an acid-catalyzed one-pot reaction involving condensation, cyclization, and dimerization. The formation of dimers was accomplished using p-toluenesulfonic acid (p-TSA) at 90-110 C in toluene for 3.5-9 h in a Dean-Stark apparatus. The N-alkylation of secondary amines with β-keto ester is not only important for the synthesis of tertiary amines, but is also essential for the preparation of a number of pharmaceuticals. Many reports have been published on the N-mono and N,N-dialkylation of anilines. Even though synthetic pathways for 2-phenyl-4-quinolones were developed by Li et al., Kuo et al., Watterson et al., Xia et al., and for 2,3-dihydro-2-phenyl-4-quinolones by Park et al., the synthesis of the dimers of 2,3-dihydro-2-phenyl-4-quinolones has not been reported until now. We applied a general method of preparing amines from a secondary amine and ketones and a synthetic one-pot operation to produce dihydroquinolone, and previously described a catalytic method that allows the 2-phenylquinolones. 2-Phenylquinolones have been extensively studied as potential antitumor compound. In our continuing study on the application of 2,3-dihydro2-phenyl-4-quinolones, we examined N-alkylanilines as secondary amines in order to discover of novel compound and N-alkylanilines were effective to coupling with ethyl benzoylacetate to give the corresponding dimers. Here, we present our results concerning the coupling of N-alkylated anilines by βketo ester, which provide access to quinolone dimers. N-Alkylated anilines 2 were synthesized from various anilines 1 through selective N-monoalkylation using alkyl halide and triethylamine. Quinolones 3a-n were prepared by coupling of N-alkylated anilines and ethyl benzoylacetate in toluene (Scheme 1). We previously reported the synthesis of 2.3-dihydro-2phenyl-4-quinolone using primary aniline. The 2,3-dihydro-2phenyl-4-quinolone derivatives were synthesized through dehydration, dealcoholation and hydration of related primary anilines and ethyl benzoylacetate. But we synthesized the dimers of quinolones without any monomer derivatives from related secondary anilines and ethyl benzoylacetate. In the formation of dimers, the monomers were not observed on the TLC monitoring. The proposed reaction mechanism for the formation of the final product involves cyclization between N-alkylated anilines and ethyl benzoylacetate (EBA) and intermolecular coupling between two quinolone molecules. When a β-keto ester is treated with a secondary amine in the presence of catalyst, reductive alkylation of the amine takes place to produce the ester intermediate. Ester was continuously converted to the appropriate quinolone by the removal of ethanol. The intermolecular reaction