Doebner-Miller reactions

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

Quinoline derivatives may be synthesised by heating aii aromatic amine with an aldehyde or a mixture of aldehydes in the presence of concentrated hydrochloric or sulphuric acid this synthesis is known as the Doebner - Miller reaction. Thus aniline and paraldehyde afford 2-methylquinohne or quinaldine. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

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. 

Dauphinee, G. A., Forrest, T. P. Sequential intermediates in the Doebner-Miller reaction. J. Chem. Soc., Chem. Commun. 1969, 327. 

Doebner-Miller reaction (Beyer method for quinolines). Synthesis of quinolines from primary aromatic amines and a,(3-unsaturated carbonyl compounds in acid catalysis. The carbonyl compounds may be prepared in situ from two molecules of aldehyde or an aldehyde and methyl ketone. The latter is known as the Beyer method. 

Reaction of a primary aromatic amine (such as aniline) with a carhonyl compound such as acetaldehyde, in the presence of acid, also generates a 2-alkylquinoline in the Doebner-Miller reaction. Reaction of aniline with acetaldehyde gave 262, but a subsequent aldol condensation with the imine derived from acetaldehyde (sec. 9.4.F.i) led to 263.1 Friedel-Crafts cyclization was followed by loss of aniline to give 264, and aromatization gave 2-methylquinoline (265). 

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

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... 

Other references related to the Doebner-Miller reaction are cited in the literature.-... 

Dimroth Rearrangement Doebner Modification Doebner Reaction Doebner-Miller Reaction Doering-LaFlamme Allene Synthesis Dotz Reaction... 

Michael Reaction Michaelis-Arbuzov Reaction Miescher Degradation Mignonac Reaction Milas Hvdroxvlation of Olefins Miller (see Doebner-Miller Reaction)... 

Doebner-Miller Reaction Beyer Method for Quinolines... 

Synthesis of Quinaldines and Lepidines by a Doebner-Miller Reaction Under Thermal and Microwave Irradiation Conditions... 

Alternatively, several new methods were unfolded which eventirally became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and p-diketones (b) Conrad-Limpach synthesis employing anilines and P-ketoesters (c) Doebner-Miller reaction involving anilines and a,P-unsatmated carbonyl compotmds (d) Friedlander synthesis using 2-amino-benzaldehyde and acetaldehyde (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Al-... 

Shivaprasad G, Rajesh R, Perumal PT (2006) Synthesis of quinaldines and lepidines by a Doebner-Miller reaction under thermal and microwave irradiation conditions using phospho-tungstic acid. Tetrahedron Lett 47 1783-1785... 

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