On the Mechanism of the Skraup−Doebner−Von Miller Quinoline Synthesis

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.

Recent Advances in Metal-Free Quinoline Synthesis

“…One of the oldest and most enduring of such procedures is the Skraup reaction (A, Figure 2). In 1880, Czech chemist Zdenko Hans Skraup heated aniline and glycerol with an oxidant in concentrated sulfuric acid, a method that is still commonly used for the production of heteroring-unsubstituted quinolines [6]. The Doebner method (B), introduced by Oscar Doebner in 1887, combines aniline with an aldehyde and pyruvic acid to give 2-substituted quinoline-4-carboxylic acids.…”

“…However, to their surprise they isolated only the polyfluorinated benzo[f ]quinoline, a product of electrophilic substitution of fluorine in the 1-position ( Figure 6). The proposed mechanism for this annulation begins with the conjugate addition of naphthylamine to acrolein 7, the product of glycerol dehydration and generally presumed to be the active annulation partner in the Skraup reaction [6]. Cyclization then occurs through attack of the aromatic ring on the carbonyl group.…”

A Green, Solvent-Free One-Pot Synthesis of Disubstituted Quinolines via A3-Coupling Using 1 Mol% FeCl3

“…[35] by replacing the previously used glycerol, with α,β-unsaturated aldehydes and ketones 12 and heated with an aromatic amine 3 in the presence of an acid catalyst. [36] The first stage of the Döebner-Miller reaction is a crotonic condensation of two molecules of either an aldehyde or ketone, which results in the formation of an α,β-unsaturated compound (Scheme 4). [31] Scheme 4: Döebner-Miller quinoline synthesis.…”

Potential Applications for Solar Photocatalysis: From Environmental Remediation to Energy Conversion

“…Besides the application in order to minimize the environmental impacts of human action, via photocatalytic processes, semiconductor oxides have also been employed in producing chemical raw materials through specific chemical reactions (Kanai et al, 2001;Murata et al, 2003;Amano et al, 2006;Denmark & Venkatraman, 2006;Hakki et al,2009;Swaminathan & Selvam, 2011;Swaminathan & Krishnakumar, 2011), in the conversion of solar energy into electricity (Prashant, 2007;Patrocínio et al, 2010;Huang et al, 2011;Zhou et al, 2011) and production of hydrogen for subsequent generation of energy (Jing et al, 2010;Kim & Choi, 2010;Melo & Silva, 2011).…”