Regioselective preparation and NMR spectroscopy study of 2-chloro-4-ethoxy-quinoline for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one.

Herein, we describe the C4-ethoxylation of 2,4-dichloroquinoline to prepare 2-chloro-4-ethoxy-quinoline (3), which is a prominent intermediate used for the synthesis of 2-substituted quinolones. To achieve this goal, we studied different conditions for the reaction between 2,4-dichloroquinoline and sodium ethoxide. We discovered that the use of 18-crown-6 ether as an additive and dimethylformamide as the reaction solvent allowed us to obtain the desired product 3 in very good yield and selectivity. In addition, a definitive distinction between the C2 and C4 ethoxylation products was achieved using (HN)-H-1-N-15 heteronuclear multiple bond correlation. Compound 3 is an intermediate used for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one, which displays peculiar behavior during H-1 nuclear magnetic resonance analysis, such as the broadening of the H8 singlet and unexpected deuteration at the C8-position. Effort has been dedicated to understand these findings.