Unexpected 5,6,7,8,9,10-Hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-Tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines from Skraup–Doebner–Von Miller Quinoline Synthesis and Their Implications for the Mechanism of That Reaction

• Published in: Journal of organic chemistry 2012-03, Vol.77 (6), p.2784-2790
• Main Authors: Fotie, Jean, Kemami Wangun, Hilaire V, Fronczek, Frank R, Massawe, Nancy, Bhattarai, Bijay T, Rhodus, Jessica L, Singleton, Thomas A, Bohle, D. Scott
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Kinetics and mechanisms; Molecular Structure; Noncondensed benzenic compounds; Organic chemistry; Phenanthridines - chemical synthesis; Phenanthridines - chemistry; Preparations and properties; Quinolines - chemical synthesis; Quinolines - chemistry; Reactivity and mechanisms
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo202681r

The real mechanism of the Skraup–Doebner–Von Miller quinoline synthesis remains controversial and not well understood despite several mechanistic studies reported on the matter. A series of unexpected and unusual 5,6,7,8,9,10-hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines have been obtained through the Skraup–Doebner–Von Miller quinoline synthesis. On the basis of these unexpected results and in agreement with some of the previously reported quinoline syntheses, an alternative mechanistic pathway is proposed for this variant of the reaction. It involves the formation of a Schiff base through a reaction between the ketone and the aniline derivative in the first step, followed by a cycloalkenylation at the ortho-position to the amine functional group of the aniline derivative, and an annulation in the final step to close the quinoline ring, leading to a dihydroquinoline derivative. To the best of our knowledge, this is the first report of such a mechanistic pathway being proposed for any variant of the Skraup–Doebner–Von Miller quinoline synthesis.