4‐(Trifluoromethyl)quinoline Derivatives

Under carefully controlled conditions, ethyl 4,4,4‐trifluoroacetoacetate (ethyl 4,4,4‐trifluoro‐3‐oxobutanoate) can be condensed with anilines and subsequently cyclized to give 4‐trifluoromethyl‐2‐quinolinones 1 although only in poor yield. Heating these products with phosphoryl tribromide affords 2‐bromo‐4‐(trifluoromethyl)quinolines 2 which can be converted into 4‐(trifluoromethyl)quinolines 3 by reduction, 4‐trifluoromethyl‐2‐quinolinecarboxylic acids 4 by permutational halogen/metal exchange followed by carboxylation, and 2‐bromo‐4‐trifluoromethyl‐3‐quinolinecarboxylic acids 5 by consecutive treatment with lithium diisopropylamide and dry ice. Debromination of acids 5 makes 4‐trifluoromethyl‐3‐quinolinecarboxylic acids 6 available. As at any time 2‐trifluoromethyl‐4‐quinolinones 9 may form instead of the expected isomers 1, the structures have to be assigned on the basis of unequivocal NMR spectral criteria. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)