Skraup and Doebner-Miller

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) ... 

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. 

Eisch, J. J., DIuzniewski, T. Mechanism of the Skraup and Doebner-von Miller quinoline syntheses. Cyclization of -unsaturated N-aryliminium salts via 1,3-diazetidinium ion intermediates. J. Org. Chem. 1989, 54, 1269-1274. 

The initial Michael addition results in products whose orientation is the reverse of that obtained in Skraup and Doebner-von Miller syntheses of quinoline (cf. Houben-Weyl, Vol. E7a, p 362). This is opposite to the rules stated previously in this section.219... 

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... 

The Skraup, Doebner-Miller, and Gould-Jacobs reactions for the syntheses of quinolines, quinaldines, and 4-hydroxyquinolines, respectively, were applied to 5-aminotropolone derivatives (e.g., 208, Scheme 50) to get pyridotropolones 209-211 (59NKZ75 68NKZ620) and other derivatives [52CI(L)471 60NKZ295]. These reactions illustrate the behavior of 5-aminotropolones as typical aromatic amines (55CRV9,... 

In 1880, Skraup synthesized quinolines by reaction of aniline and glycerol in a solution of sulfuric acid and an oxidizing reagent. What Skraup discovered was generalized one year later by Doebner and von Miller by using a,P-unsaturated aldehydes instead of glycerol in order to prepare substituted quinolines. 

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. 

Likewise regiocomplementary to the traditional Skraup-Doebner-Miller approach is the Rh-catalyzed formation of quinohnes 113 from a,P-unsaturated ketones and (2-amino)phenylboronates (or boronic acids) proceeding in basic medium [180] ... 

Many people view the Skraup/Doebner-von Miller reaction as the worst witch s brew of all the heterocyclic syntheses. The reaction can be violently exothermic. A variety of oxidizing reagents and additives have been added in an effort to improve yields, including iron (III) and tin (IV) salts, nitrobenzenes, iodine and various acids such as boric and arsenic. Cohn s conditions for the Skraup reaction using an iron salt and boric acid in concentrated sulfuric acid are frequently employed. ... 

One of the drawbacks of the Skraup/Doebner-von Miller reaction is the isolation of the desired product from the starting aniline and co-formed alkyl anilines and 1,2,3,4-tetrahydroquinaldine. Isolation can be simplified greatly by addition of one equivalent of zinc chloride at the end of the reaction all of the basic products were precipitated. Washing the brown solids with 2-propanol removed all impurities and left the desired quinoline as a 2 1 complex with zinc chloride in yields of 42-55%. 

A variety of oxidants have been used in the Skraup/Doebner-von Miller reaction between anilines and a, 3-unsaturated aldehydes. For example, aniline 23 was reacted... 

Recently, solvent-free Skraup/Doebner-von Miller reactions have been developed under microwave radiation. For example, aniline 34 and enone 35 are reacted in the presence of silica gel impregnated with indium trichloride to give the corresponding quinoline 36 in good yield. It was subsequently shown that both electron-rich and electron-poor anilines undergo cyclization in a similar fashion. 

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 ... 

In practical terms, the major advantage of the Doebner-von Miller and Skraup syntheses is the wide range of o- and p-substituents in the aniline which are tolerant of the acid conditions. Thus, 6- and 8-substituted quinolines can be made where the substituent is an... 

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