Proline-Catalyzed Friedländer Synthesis of Quinolines

Significance

Reported is the proline-catalyzed Friedländer synthesis of 4-trifluoromethyl quinoline derivatives. The proline-catalyzed reaction shows excellent regioselectivity for the condensation of a variety of unsymmetrical ketones as well as acetone. In case of the latter compound, the reaction temperature could be left ambient; however, reactions of bulkier ketones necessitated a temperature increase to 50 ˚C. When an N-triphenylmethylene-protected aniline was used as starting material, an intermediate arising from aldol condensation was isolated. This strongly indicates that an aldol condensation mechanistic pathway is followed in the Friedländer reaction when proline is used as base. To the credit of the authors, extension of this mechanistic conclusion to other catalysts was not made.