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An Improved Access to 4‐Trifluoromethyl‐2(1 H )‐quinolinones: The “Watering Protocol”
Author(s) -
Marull Marc,
Lefebvre Olivier,
Schlosser Manfred
Publication year - 2004
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200300531
Subject(s) - trifluoromethyl , chemistry , condensation , organic chemistry , distillation , medicinal chemistry , alkyl , physics , thermodynamics
Condensation of anilines with ethyl 4,4,4‐trifluoroacetoacetate ( 7 ) to afford the corresponding 4,4,4‐trifluoro‐3‐oxobutaneanilides ( 10 ), precursors to 4‐(trifluoromethyl)‐2‐quinolinones ( 11 ), can be favored and the competing condensation to produce the ethyl 4,4,4‐trifluoro‐3‐(phenylimino)butanoate, the precursor to 2‐(trifluoromethyl)‐4‐quinolinones, avoided if water is occasionally added to the reaction mixture while ethanol is continuously removed by distillation. The anilides 10 also form selectively when 4,4,4‐trifluoroacetoacetyl chloride ( 6 ) is allowed to react with anilines. The cyclization of the anilides has to be accomplished under carefully controlled conditions. The resulting 4‐(trifluoromethyl)‐2‐quinolinones ( 11 ) can be converted into 4‐(trifluoromethyl)quinolines ( 13 ), 4‐(trifluoromethyl)‐2‐quinolinecarboxylic acids ( 14 ), and 2‐bromo‐4‐(trifluoromethyl)quinolines ( 12 ), the last of which may in turn be converted into 2‐bromo‐4‐(trifluoromethyl)‐3‐quinolinecarboxylic acids ( 15 ) and eventually 4‐trifluoromethyl‐3‐quinolinecarboxylic acids ( 16 ). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)