Doebner Von Miller Research Articles

LB794 Synthesis and biological evaluation of a small molecule library identifies novel anti-skin cancer agents

Treatment of melanoma (MSC) and non-melanoma skin cancers (NMSCs, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)), affecting one-fifth of the US population, is hampered by drug resistance, side effects, and low bioavailability. Owing to low molecular weight and the ability to enter cells, small molecules are gaining ground towards enhancing bioavailability and minimizing some of the side effects associated with classical cancer drugs. Herein, we synthesized a mini-library of 86 compounds via C-N/C-C coupling, direct substitution on the aromatic ring, or a modified Skraup–Doebner–von Miller approach, and their solubility and biological properties were characterized.

Recent advances in the synthesis of biologically and pharmaceutically active quinoline and its analogues: a review.

Recently, quinoline has become an essential heterocyclic compound due to its versatile applications in the fields of industrial and synthetic organic chemistry. It is a vital scaffold for leads in drug discovery and plays a major role in the field of medicinal chemistry. Nowadays there are plenty of articles reporting syntheses of the main scaffold and its functionalization for biological and pharmaceutical activities. So far, a wide range of synthesis protocols have been reported in the literature for the construction of this scaffold. For example, Gould–Jacob, Friedländer, Pfitzinger, Skraup, Doebner–von Miller and Conrad–Limpach are well-known classical synthesis protocols used up to now for the construction of the principal quinoline scaffold. Transition metal catalysed reactions, metal-free ionic liquid mediated reactions, ultrasound irradiation reactions and green reaction protocols are also useful for the construction and functionalization of this compound. The main part of this review focuses on and highlights the above-mentioned synthesis procedures and findings to tackle the drawbacks of the syntheses and side effects on the environment. Furthermore, various selected quinolines and derivatives with potential biological and pharmaceutical activities will be presented.

Mesoporous HBeta zeolite obtained via zeolitic dissolution–recrystallization successive treatment for vapor-phase Doebner–Von Miller reaction to quinolines

Mesoporous HBeta zeolite was obtained via zeolitic dissolution–recrystallization successive treatment, and exhibited enhanced selectivity to Q, anti-alkylation ability and stability in the vapor-phase Doebner–Von Miller reaction.

Synthesis of fluorine-containing 1,10-phenanthrolines using mild versions of Skraup and Doebner-von Miller reactions

A versatile route for the synthesis of new 1,10-phenanthroline derivatives with fluorine-containing groups is described. Skraup reactions were performed with yields of 19 up to 48% and overall yields of 5 up to 13% based on different fluorinated anilines as starting materials. Ten formerly unknown derivatives were synthesized and characterized by NMR spectroscopy (1H, 13C, 19F), ESI mass spectrometry and elemental analysis.

Recent Advances in Metal-Free Quinoline Synthesis.

The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner–Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring-unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns.

ChemInform Abstract: Quinoline Synthesis by Improved Skraup—Doebner—Von Miller Reactions Utilizing Acrolein Diethyl Acetal.

A robust synthetic method has been developed as an improvement to the venerable Skraup–Doebner–Von Miller reaction providing access to various quinoline products. The straightforward procedure utilizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic, organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be compatible with the reaction conditions and the corresponding quinoline products are isolated in moderate to good yields.

Quinoline synthesis by improved Skraup–Doebner–Von Miller reactions utilizing acrolein diethyl acetal

A robust synthetic method has been developed as an improvement to the venerable Skraup–Doebner–Von Miller reaction providing access to various quinoline products. The straightforward procedure utilizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic, organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be compatible with the reaction conditions and the corresponding quinoline products are isolated in moderate to good yields.

A Systematic Study on the Synthesis of n‐Butyl Substituted 8‐Aminoquinolines

A systematic study on the synthesis of 8‐aminoquinoline derivatives with an n‐butyl group at each alternate position of the quinoline ring was carried out. Skraup Reaction and its Doebner–von Miller variation were used to obtain most of the quinoline ring except for the 2‐butyl‐8‐aminoquinolines and 4‐butyl‐8‐aminoquinolines where the commercially available methylquinoline derivatives were used as precursors. The structures of the synthesized compounds were characterized by FTIR, 1H‐NMR, COSY, 13C‐NMR and HRMS spectra.

Recent Applications of Doebner, Doebner-von Miller and Knoevenagel-Doebner Reactions in Organic Syntheses

Quinolines as one of the most important classes of heterocyclic compounds are widely present as key structural motifs in many natural products, particularly in alkaloids and numerous bioactive drugs. Various name reactions for the syntheses of quinolines such as Skraup, Camps, Combes, Conrad-Lympach, Knorr, Gould-Jacobs, Povarov, Doebner and Doebner-von Miller, Pfitzinger and Niementowski, and Friedländer have already been discovered and extensively developed and modified. This review covers the most recent applications of Doebner and Doebner-von Miller reactions in organic syntheses. In addition the developments of the Knoevenagel- Doebner reaction in the synthesis of α,β-unsaturated carboxylic acids were demonstrated. In this paper we provide extensive compilation of the development of the Doebner reaction and variations for the synthesis of quinolines published from 2006 to 2013. Keywords: Doebner reaction, doebner-von miller, heterocyclic syntheses, Knoevenagel reaction, quinolines.

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

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.

Unusual open chain quinolinyl peroxol and its alcohol counterpart obtained through a modified Skraup–Doebner–Von Miller quinoline synthesis: theoretical studies and complete 1H‐ and 13C‐NMR assignments

Because of their extreme instability, it is generally difficult to synthesize and fully characterize open chain peroxides, also known as peroxols. In our attempt to investigate the mechanism of the Skraup-Doebner-Von Miller quinoline synthesis, we were able to obtain an unusual open chain peroxy-quinoline, namely, 4-(8-ethoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)butane-1-peroxol (1), and its alcohol counterpart, namely 4-(8-ethoxy-2,3-dihydro-1H-cyclopenta[c]quinolin-4-yl)butan-1-ol (2) obtained as a side product during the same reaction. Although structurally similar, these two compounds appeared to display some very distinct physical and spectroscopic characteristics. This work reports detailed NMR studies and full (1) H and (13) C NMR assignments for these two compounds. These assignments are based upon the analysis of the NMR spectra of these compounds including (1) H, (13) C, COSY, gHSQC and gHMBC. The effect of the peroxide functional group on the chemical shift of neighboring carbons and protons was also investigated by comparing the NMR data of these two compounds. Furthermore, the effects of potential hydrogen bondings in 1, 2, and possible 1-1 dimer, 2-2 dimer and in prototypical model systems, as well as the stability of these compounds, were investigated computationally. The computed dissociation energies and NMR data support the interpretation of the experimental data.

ChemInform Abstract: Synthesis of Mono‐Substituted Derivatives of 6‐Aminoquinoline.

Abstract6‐Aminoquinolines are available as potential intermediates in drug design using p‐chloroaniline as an optimal oxidant in the Skraup—Doebner—von Miller reaction.

Ruthenium-catalysed synthesis of 2- and 3-substituted quinolines from anilines and 1,3-diols

A straightforward synthesis of substituted quinolines is described by cyclocondensation of anilines with 1,3-diols. The reaction proceeds in mesitylene solution with catalytic amounts of RuCl(3)·xH(2)O, PBu(3) and MgBr(2)·OEt(2). The transformation does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy and chloro substituents as well as naphthylamines were shown to participate in the heterocyclisation. In the 1,3-diol a substituent was allowed in the 1- or the 2-position giving rise to 2- and 3-substituted quinolines, respectively. The best results were obtained with 2-alkyl substituted 1,3-diols to afford 3-alkylquinolines. The mechanism is believed to involve dehydrogenation of the 1,3-diol to the 3-hydroxyaldehyde which eliminates water to the corresponding α,β-unsaturated aldehyde. The latter then reacts with anilines in a similar fashion as observed in the Doebner-von Miller quinoline synthesis.

Synthesis of mono-substituted derivatives of 6-aminoquinoline

Abstract Several 6-aminoquinoline derivatives, which could be used in drug design, have been synthesized. The reaction conditions were comparatively studied, and the p -chloroaniline was used as optimum oxidant in Skraup–Doebner–Von Miller reaction. The nitro group was reduced effectively by SnCl 2 with no halo-removed occurred.

Synthesis of novel annelated systems based on the interaction and reactivity estimation of amino‐1,5‐benzodiazepin‐2‐ones with dimethyl‐2‐oxoglutaconate

Abstract magnified image A number of substituted tetracyclic 4H‐[1,4]diazepino[3,2,1‐hi]pyrido[4,3,2‐cd]indole and tricyclic 1H‐[1,4]diazepino[2,3‐g] or [2,3‐h]quinoline derivatives were prepared from 7‐ (or 8, or 9)amino‐1,5‐benzodiazepin‐2‐ones by the Doebner–von Miller quinoline synthesis. The structure of the cyclized products depends on the position of the primary amino group and on the substituents of the diazepine ring of the starting compounds. The regiochemical outcome of the reaction was estimated by calculating average local ionization energies on the molecular surface at the Density Functional Theory (DFT) level of theory. J. Heterocyclic Chem., (2009).

Skraup—Doebner—Von Miller Quinoline Synthesis Revisited: Reversal of the Regiochemistry for γ‐Aryl‐β,γ‐unsaturated α‐Ketoesters.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Quinoline-2,4-dicarboxylic acids: Synthesis and evaluation as inhibitors of the glutamate vesicular transport system

Twenty-six quinoline-2,4-dicarboxylic acids (QDC's) were synthesized by a modified Doebner-von Miller pathway and tested as inhibitors against the glutamate vesicular transport (GVT) protein. The QDC's were active as inhibitors with the most potent QDC's found to contain halogens at the 6-/8-position, a hydroxyl at the 8-position, or a tethered aromatic moiety at the 6- or 7-position of the quinoline.

An unusual product in a Doebner-von Miller quinoline synthesis

In an attempt to synthesize an aza pyrroloquinolinequinone isomer, Doebner-von Miller quinoline synthesis from an aminoindole resulted in an unexpected product, formed by reaction at an electronrich benzenoid carbon with the unsaturated carbon atom β to the ketone of dimethyl trans-2-oxoglutaconate. This observation suggests an alternative mechanistic possibility for Doebner-von Miller reaction with some electron-rich aromatic amines.

Synthesis of Isomeric Analogues of Coenzyme Pyrroloquinoline Quinone (PQQ)

Three isomeric analogues 2-4 of the redox-active coenzyme 4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid (1, PQQ, methoxatin) were synthesized from methoxynitroanilines 8, 9 and 10a, respectively. Reaction of the diazonium salts of each of the starting compounds with ethyl α-methylacetoacetate gave the corresponding substituted phenylhydrazones of ethyl pyruvate. These intermediates underwent acid-catalyzed Fischer indolization and gave the esters 13, 17 and 25, respectively. Reduction to the corresponding aminoindoles with hydrogen over Pd/C, followed by Doebner-von Miller quinoline synthesis with dimethyl trans-2-ketoglutaconate, oxidation of the intermediate methoxy compound to the o-quinone, and hydrolysis of triester products gave 2, 3, and 4, respectively. These isomers will serve as authentic examples to define their possible formation in nature and will also serve as isosteric probes to define the binding of PQQ at active sites in PQQ-requiring quinoproteins.

Syntheses dans le domaine des composes polycycliques aromatiques—XXIII : Quinoléines et méthylquinoléines polycondensées

Four new (VIII, IX, X and XI) and six known polycondensed quinolines as well as two new (IVa and VIa) and one known polycondensed methylquinolines, have been prepared by modified Skraup and Doebner-von Miller reactions, using polycyclic aromatic acetamides as starting material. Yields of 40–80% were obtained in all but one case (X:10 %). The UV spectra of the new products have been recorded in cyclohexane (Figs. 2, 3, 4 and 5).