Selective and Efficient Structural Elaboration of 2‐(Trifluoromethyl)quinolinones

Abstract

Keywords:Bromine-lithium exchange / Ethyl 4,4,4-trifluoroacetoacetate / Heterocycles / Hydrogen-lithium exchange / RegioselectivityThe acid-catalyzed cyclization-condensation between anilines and ethyl 4,4,4-trifluoroacetoacetate affords 1,4-dihydro-2-trifluoromethyl-4H-4-quinolinones (1), which can easily be converted into 4-bromo-2-(trifluoromethyl)quinolines. These undergo halogen/metal exchange, generating 2-trifluoromethyl-4-quinolyllithiums, when treated with butyllithium, and hydrogen/metal exchange, generating 4-bromo-2-trifluoromethyl-3-quinolyllithiums, when treated with Ethyl 4,4,4-trifluoroacetoacetate, technically manufactured by addition of trifluoroacetyl chloride to ketene, [1] is a most versatile component for condensation and cyclization reactions. From this building block, considerable numbers of 2-(trifluoromethyl)furans, [2] 2,5-dihydro-4-trifluoromethyl-2-furanones, [3] trifluoromethyl-substituted sugars [4,5] or cyclohexenones [6] and 4-trifluoromethyl-2-benzopyranones have been prepared. An even greater variety of five-and six-membered nitrogen heterocycles has also been made available in such a way: 3-(trifluoromethyl)pyrroles, [7,8] 5-(trifluoromethyl)pyrazoles, [9,10] 3-(trifluoromethyl)-5-pyrrolinones, [11Ϫ15] 1,4-dihydro-2,6-bis(trifluoromethyl)pyridines, [16] 2-hetero-substituted 4-trifluoromethyl-6-pyridinones, [17Ϫ19] 2-amino-substituted 4-(trifluoromethyl)pyrimidines [20,21] or -pyrimidones [22Ϫ25] and (trifluoromethyl)quinolinones. [25Ϫ29] The purpose of this report is to draw attention to the synergies which can be exploited when an electronegative [a]

Relay Propagation of Crowding: The Trifluoromethyl Group as Both an Emitter and Transmitter of Steric Pressure

“…[19] Meanwhile we have extended the investigation to additional model compounds. 4-Bromo-5,7-dimethyl-2-(trifluoromethyl)quinoline (6) and 2-bromo-5,7-dimethoxy-4-(trifluoromethyl)quinoline (8) were also found to be totally inert toward lithium diisopropylamide or LITMP.…”

Trifluoromethoxy Containing Azoles and Azines: Synthesis and Biological Activity

“…Similar reactions of β-ketoesters, such as 4,4,4-trifluoroacetoacetate, gave 2-trifluoromethyl-4( 1 H)-quinolinone 57, which could be readily converted into 4-quinoiine carboxylic acid 58 (Scheme 21) (36).…”

CF3‐Bearing Aromatic and Heterocyclic Building Blocks

“…Carboxylation of the intermediates produces 4-bromo-2-(trifluoromethyl)quinoline-3-carboxylic acids 52 and 2-(trifluoromethyl)quinoline-4-carboxylic acids 53, respectively, whereas the treatment of the organometallic species with water gives the unfunctionalized heterocycles 54 (Scheme 20). [64] The same ethyl 4,4,4-trifluoroacetoacetate and the same anilines can be put together differently by passing through an carboxanilide intermediate to afford the regioisomeric 4-trifluoromethyl-2(1H)quinolinones (Scheme 21). [65] In both series, the condensation and subsequent cyclization imply the loss of one molecule of water and one molecule of ethanol.…”