Doebner-Miller synthesis

Quinaldine (or 2-methylquinoline) can be prepared by the Doebner.Miller Synthesis, which in some respects is closely similar to the Skraup Synthesis (p. 297) but has some significant differences. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehyde. The mechanism is probably similar to that given for the Doebner-Miller synthesis of quinaldine (Section V,2), involving the intermediate formation of a dihydroqulnoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

A new synthesis was developed by Y. Kashman et al. for the preparation of the parent pyrido[2,3,4-/c/]acridine skeleton utilizing the Doebner-Miller synthesis. In the first step, 3-aminoacetanilide was reacted with vinyl phenyl ketone in the presence of m-nitrobenzenesulfonic acid sodium salt and acetic acid to afford the corresponding 4-phenylquinolines. The acetamide group was then converted to the corresponding aryl azide, which underwent intramolecular nitrene insertion upon thermolysis to give the desired heterocyclic skeleton. 

The short and convenient synthesis of novel naphthopyranoquinolines from naphthopyran chloroaldehydes via the Doebner-Miller synthesis was developed in the laboratory of J.K. Ray. The chloroaldehydes were treated with 2.5 equivalents of a substituted aniline in ethanol in the presence of 2N HCI to afford enaminoimine hydrochlorides in good yield. These hydrochloride salts were exposed to heat at a temperature slightly above their melting point, resulting in ring-closure and elimination of one equivalent of arylamine hydrochloride. 

Matsugi, M., Tabusa, F., Minamikawa, J.-l. Doebner-Miller synthesis in a two-phase system practical preparation of quinolines. 

Unsaluraled aldehydes or ketones also condense with the amines in an acidic [2569, 2364, 3012] or basic [2361] medium some of these reactions are known by the names of their discoverers, for example, the Doebner-Miller synthesis [2364) or the Doebner quinoline synthesis [3214]. The latter needs neither acid nor base. 

The use of an enone confirms the mechanism, showing that interaction of the aniline amino gronp with the carbonyl group is not the first step, and this variation is known as the Doebner-Miller synthesis. 

In the Skraup and Doebner-Miller synthesis of quinoline, primary arylamines with an unsubstituted ortho position react with a,p-unsaturated carbonyl compounds in an acid medium in the presence of an oxidizing agent (nitroarene, AS2O5) ... 

The Skraup synthesis consists of the reaction with acrolein which is formed in situ from glycerine/H2S04. The Doebner-Miller synthesis was originally limited to the reaction with crotonaldehyde to give quinaldines, but is increasingly used as a generic term for this reaction. 

Doebner-Miller Synthesis, Doebner-von Miller Quinoline Synthesis, Skraup-Doebner-von Miller Quinoline Synthesis)... 

This reaction was initially reported by Doebner and von Miller in 1881 as a modification of the original Skraup Reaction, and it was subsequently modified by Beyer in 1886 It is an acidic condensation between primary aromatic amines (e.g., anilines) and Q ,j8-unsaturated carbonyl compounds (mostly o ,y3-unsaturated aldehydes) to give 2,3-disubstituted quinolines. Therefore, this reaction is generally known as the Doebner-Miller reaction, or Doebner-Miller synthesis." In addition, this reaction is also referred to as the Doebner-von Miller quinoline synthesis, Skraup-Doebner-von Miller reaction, Skraup-Doebner-von Miller quinoline synthesis, Doebner-Miller condensation, and Doebner-Miller Quinaldine Synthesis. For comparison, the modification from Beyer, known as the Beyer method for quinoline, is an acidic condensation between anilines and Q ,j8-unsaturated carbonyl compounds generated in situ from aldehyde or aldehyde and methyl ketone to afford 2,4-disubstituted quinolines." The optimal condition of this reaction is to heat the mixture of aniline/aldehyde (1 2) at 100°C for 6 h with hydrochloric acid and zinc chloride in addition, an oxidizing reagent is also needed in this reaction, such as nitrobenzene. However, it has been reported that A -alkylanilines are also formed in this reaction. The nature and... 

Some of the classical quinoline syntheses utilize intramolecular ring-closing SnAr reactions. Among them, the Combes synthesis and the Skraup-Doebner-Miller synthesis are of general relevance. 

Dakin-West reaction 172 Darzens reaction 21 Dilthey synthesis (pyrylium ion) 302 Dimroth rearrangement 261 Doebner-Miller synthesis (isoquinoline) 400... 

Sandmeyer synthesis (isatin) 145 Schmidt-Druey synthesis (pyridazine) 461 Schollkopf synthesis (oxazole) 173 Sharpless-Katsuki epoxidation 24 Shaw synthesis (pyrimidine) 468 Skraup-Doebner-Miller synthesis (quinoline) 400 Smiles rearrangement 446 Sommelet-Hauser rearrangement 136 Staudinger reaction 53 Steglich reagent (DMAP) 348 Stork isoxazole annelation 191... 

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