Journal of Organic Chemistry 2006-02-17

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

Scott E Denmark, Srikanth Venkatraman

Index: J. Org. Chem. 71(4) , 1668-76, (2006)

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Abstract

The mechanism of the formation of substituted quinolines from anilines and alpha,beta-unsaturated ketones has been studied by the use of 13C-labeled ketones in cross-over experiments. In the reaction of doubly labeled 13C(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.