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

Abstract

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.

C–N Coupling of 1,2‐Dihydro‐2,2,4‐trimethylquinoline Derivatives via a Silver(I)‐Catalyzed Direct Functionalization of a C–H Bond

“…Furthermore, Nomura et al [30], using sodium persulfate in the presence of silver ions, were able to prepare 1,1 -bipiperidine (1) by oxidative coupling of piperidine, resulting in a direct formation of an intermolecular N,N-linkage. The dihydroquinoline derivatives used as starting materials were readily prepared from the corresponding aniline derivative through a Skraup-Doebner-Von Miller quinoline synthesis [33]. However, submitting 6-chloro-1,2-dihydro-2,2,4-trimethylquinoline (2a) and 6-ethoxy-1,2dihydro-2,2,4-trimethylquinoline (2b) to the same conditions did not yield the expected N,N-linked dimers.…”

“…Compounds 2a and 2b were readily prepared from 4-chloroanilne and 4-ethoxyaniline, respectively, at 160-165 • C for 72 h in the presence of 0.05 equiv of iodine and 5 equiv of acetone [33]. Compounds 1, 3a, and 3b were prepared in similar conditions by allowing the appropriate starting material, sodium hydroxide (2 equiv), silver nitrate (0.05 equiv), and water (15 mL) to stir for 15-20 min in an ice bath.…”

Synthesis and Crystal Structures of Methyl 3,4,5-Trimethoxybenzoate and 1,2-Dihydro-2,2,4-Trimethylquinoline Derivatives

“…We have recently discovered that some dihydroquinoline derivatives also display outstanding antitrypanosomal activities [23,24]. Through our continuous effort to optimize the antitrypanosomal activity of this family of compounds, we have synthesized 1,2-dihydro-8-methoxy-2,2,4-trimethylquinoline (3) and 6-chloro-1,2-dihydro-2,2,4-trimethylquinoline (4) as intermediates to some of our target molecules, through the Skraup-Doebner-Von Miller reaction [25] (see Scheme 2), and their crystal structures were also determined by single crystal X-ray diffraction.…”

Regioselective Synthesis of 1,2-Dihydroquinolines by a Solvent-Free MgBr2-Catalyzed Multicomponent Reaction

“…17 Analogous MCR catalyzed by transition metals used terminal acetylenes instead of ketones. 18 Recently, an Au/Ag-catalyzed cyclization of o-(hydroxyallyl)anilines under mild conditions was reported.…”

“…Due to the controversial nature of the mechanism for their formation, 17 the mechanistic pathway was also explored in an attempt to establish the possible species involved in such cascade reaction.…”