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Short Paper | Special issue | Vol 101, No. 2, 2020, pp.692-700
Published online, 29th August, 2019
DOI: 10.3987/COM-19-S(F)37
Selective Aromatic Nucleophilic Substitution of 4-Dimethylamino-2-methoxy-3-(trifluoroacetyl)quinoline with Alcohols – DFT Calculation Study

Norio Ota, Yusuke Harada, Yasuhiro Kamitori, and Etsuji Okada*

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan


The nucleophilic aromatic substitution proceeds exclusively at the 4-position of 4-dimethylamino-2-methoxy-3-(trifluoroacetyl)quinoline 1 by simple alcoholysis to give the corresponding N-O exchanged products solely, and no O-O exchange reactions at the 2-position are performed. Our DFT calculation study provides a rational explanation regarding this complete selectivity based on relative energies of the intermediates VII, VIII which are corresponding to the O-protonated Meisenheimer complexes at carbonyl oxygen in 3-trifluoroacetyl group. The reaction pathway for the present unique selective substitution with alcohols is elucidated by referring to the analogous selective substitutions on 1 with amines and thiols as nucleophiles.