Skraup and Doebner-Miller quinoline synthesis

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. 

heat m-nitrobenzene sulfonic acid Na-salt 

The synthesis of the antimalarial 5-fluoroprimaquine by P.M. O Neil and co-workers involved a Doebner-Miller reaction of 5-fluoro-4-methoxy-2-nitroaniline with acrolein.In this modified procedure 80% phosphoric acid, acrolein and arsenic acid were employed to allow a shorter reaction time and lower temperature than in the original procedure. 

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. 

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Skraup and Doebner-Miller quinoline synthesis Condensation of enones with substituted anilines to afford isoquinolines. 414... 

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) ... 

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... 

A very large group of syntheses in which the /3,y-bond is formed are those in which a side chain electrophile attacks the benzene ring. These include the Skraup and Doebner-von Miller syntheses (dealt with in Section 2.08.2.2.3(ii)), the Knorr, Conrad-Limpach and Combes syntheses of quinolines (dealt with here), the Pomerantz-Fritsch synthesis of isoquinolines, and many syntheses of phenanthridines and of acridines. 

This reaction is related to the Camps Reaction, Conrad-Limpach Quinoline Synthesis, Doebner-Miller Reaction, Gould-Jacobs Quinoline Synthesis, Niementowski Reaction, and Skraup Reaction. 

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. 

A second similar synthesis, due to Doebner and Miller, leads to the formation of substituted quinolines. The simplest example is the production of quinaldine from aniline and paraldehyde by heating with concentrated hydrochloric acid. The course of the reaction is closely related to that of the Skraup synthesis by route II. There the aniline reacts with acrolein, here with crotonaldehyde, which is easily formed under the conditions which prevail ... 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

The Doebner-von Miller reaction was used as a method of choice for the synthesis of several biological active quinoline compounds. The anti-malarial drug primaquine, which acts against the hepatic stage of plasmodia infection, was synthesized by a Skraup reaction fi om 4-methoxy-2-nitroaniline and glyceron in the presence of sulfiiric acid. The nitro group was then reduced and alkylated with 4-bromo-l-phthalimidopentane to provide the protected primaquine, which was deprotected by using hydrazine. ... 

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