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

Abstract

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.

Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

“…The 1 H‐ 15 N HMBC NMR spectra of compounds 13 – 17 (O‐alkylation adducts) also indicate that there is a systematic shift upfield of the δ N value of the alkoxypyridinium nitrogen of these compounds relative to the δ N value of the starting material N ‐oxide nitrogen (Table entries (x)–(xiii)). A three‐bond coupling interaction is shown to exist for each of these compounds between the alkoxypyridinium nitrogen and the methyl group C H 3 protons or benzhydryl C H proton by correlations in the 1 H‐ 15 N HMBC NMR spectra of the compounds , …”