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

• Published in: Magnetic resonance in chemistry 2020-04, Vol.58 (4), p.295-304
• Main Authors: Vasconcelos Vontobel, Pedro Henrique, Santos Fuscaldo, Rodrigo, Santos, Francisco Paulo, Sobieski da Costa, Jessie
• Format: Article
• Language: English
• Subjects: 1H─15N HMBC; bederocin; Deuteration; Ethoxylation; H/D exchange; NMR; NMR spectroscopy; Nuclear magnetic resonance; Quinoline; quinolines; quinolones; Selectivity; Synthesis
• ISSN: 0749-1581; 1097-458X
• DOI: 10.1002/mrc.4980

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 1H─15N 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 1H 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. 2‐Chloro‐4‐ethoxy‐quinoline, a building block for the synthesis of 2‐substituted‐quinolones, was regioselectively prepared and studied by NMR spectroscopy.