On the mechanism of the Skraup-Doebner-Von Miller quinoline synthesis

The mechanism of the formation of substituted quinolines from anilines and alpha,beta-unsaturated ketones has been studied by the use of C-13-labeled ketones in cross-over experiments. In the reaction of doubly labeled C-13(2,4) mesityl oxide, a 100% scrambling of the label in the quinoline product was observed, whereas only a small (5-10%) amount of the starting mesityl oxide showed scrambling of the label. Similarly, the reaction of triply labeled pulegone clearly shows that the label in the product is 100% scrambled, whereas the label in the starting pulegone is retained. On the basis of these studies, a mechanistic pathway for the Skraup quinoline synthesis is proposed that involves a fragmentation-recombination mechanism. The aniline component condenses with the alpha,beta-unsaturated ketone initially in a conjugate fashion, followed by a fragmentation to the corresponding imine and the ketone itself. These fragments recombine to form the quinoline product.