Choline Chloride/Acetic Acid Deep Eutectic Solvent for the Doebner–von Miller Synthesis of 2-Arylquinolines and Their Reduction to 2-Aryl-1,2,3,4-tetrahydroquinolines
- 1Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Consorzio CINMPIS, via E. Orabona 4, 70125 Bari, Italy
Abstract
Quinolines constitute privileged N-heterocyclic scaffolds with widespread applications in medicinal and synthetic chemistry, yet classical Doebner–von Miller (DvM) synthesis generally relies on harsh acidic conditions, volatile organic solvents, and, in many cases, external oxidants. Herein, we report a DvM protocol based on the deep eutectic solvent (DES) choline chloride/acetic acid (ChCl/AcOH, 1:2), which serves as reaction medium while providing the Brønsted-acidic environment required for the condensation of substituted anilines with cinnamaldehydes under aerobic conditions. A broad range of functionalized 2-arylquinolines was obtained in moderate to good isolated yields, and the methodology proved readily scalable to the multigram level. The ChCl/AcOH eutectic mixture could also be reused over multiple reaction cycles while maintaining satisfactory efficiency. Mechanistic investigations of the model reaction between aniline and cinnamaldehyde revealed the formation of the corresponding conjugated imine, supporting its possible involvement as an intermediate in an alternative annulation pathway. Finally, in a separate set of experiments, freshly prepared ChCl/AcOH of the same composition was successfully employed as the reaction medium for the NaBH3CN reduction of selected isolated quinolines at room temperature, providing the corresponding 2-aryl-1,2,3,4-tetrahydroquinolines in essentially quantitative yields.
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BibTeX
@article{paparella2026choline,
title = {{Choline Chloride/Acetic Acid Deep Eutectic Solvent for the Doebner–von Miller Synthesis of 2-Arylquinolines and Their Reduction to 2-Aryl-1,2,3,4-tetrahydroquinolines}},
author = {Andrea Nicola Paparella and Luciana Cicco and Francesco Ostuni and Filippo Maria Perna and Vito Capriati},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203591},
url = {https://www.mdpi.com/1420-3049/31/20/3591},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Choline Chloride/Acetic Acid Deep Eutectic Solvent for the Doebner–von Miller Synthesis of 2-Arylquinolines and Their Reduction to 2-Aryl-1,2,3,4-tetrahydroquinolines
AU - Andrea Nicola Paparella
AU - Luciana Cicco
AU - Francesco Ostuni
AU - Filippo Maria Perna
AU - Vito Capriati
PY - 2026
DA - 2026/10/09
JO - Molecules
DO - 10.3390/molecules31203591
UR - https://www.mdpi.com/1420-3049/31/20/3591
AB - Quinolines constitute privileged N-heterocyclic scaffolds with widespread applications in medicinal and synthetic chemistry, yet classical Doebner–von Miller (DvM) synthesis generally relies on harsh acidic conditions, volatile organic solvents, and, in many cases, external oxidants. Herein, we report a DvM protocol based on the deep eutectic solvent (DES) choline chloride/acetic acid (ChCl/AcOH, 1:2), which serves as reaction medium while providing the Brønsted-acidic environment required for the condensation of substituted anilines with cinnamaldehydes under aerobic conditions. A broad range of functionalized 2-arylquinolines was obtained in moderate to good isolated yields, and the methodology proved readily scalable to the multigram level. The ChCl/AcOH eutectic mixture could also be reused over multiple reaction cycles while maintaining satisfactory efficiency. Mechanistic investigations of the model reaction between aniline and cinnamaldehyde revealed the formation of the corresponding conjugated imine, supporting its possible involvement as an intermediate in an alternative annulation pathway. Finally, in a separate set of experiments, freshly prepared ChCl/AcOH of the same composition was successfully employed as the reaction medium for the NaBH3CN reduction of selected isolated quinolines at room temperature, providing the corresponding 2-aryl-1,2,3,4-tetrahydroquinolines in essentially quantitative yields.
SN - 1420-3049
ER -