Miller reaction

Doebner-von Miller reaction is a variant of the Skraup reaction. Therefore, the mechanism for the Skraup reaction is also operative for the Doebner-von Miller reaction. An alternative mechanism shown below is based on the fact that the preformed imine (Schiff base) also gave 2-methylquinoline  

Skraup Doebner-von Miller Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 488-494. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 84, Springer-Verlag Berlin Heidelberg 2009 

Denmark, S. E. Venkatraman, S. J. Org. Chem. 2006, 71, 1668—1676. Mechamstic study using C-labelled a,P-unsaturated ketones. 

Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and aUcynes. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications DOI 10.1007/978-3-319-03979-4 91, Springer International Publishing Switzerland 2014 

Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium 

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Doebner-von Miller reaction Condensation of an aromatic amine with an aldehyde or ketone in the presence of hydrochloric acid to form a quinoline derivative. A general method, thus aniline and ethanal give 2-methyl-quinoline (quinaldine) and p-phenetidine. 

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. 

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. ... 

Classical Skraup/Doebner-von Miller reaction — Quinolines... 

The preparation of 3-alkyl quinolines by traditional Skraup/Doebner-von Miller reaction typically results in very low yields. When ethylacrolein (9) is condensed with m-toluidine (8) under typical Skraup/Doebner-von Miller conditions, the yield of 10 is only 25%, compared to 65% with di-acetyl acetal 11. 

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... 

The yields of Skraup/Doebner-von Miller reaction can be dramatically improved by running the reaction as a two-phase mixture. Reaction of crotonaldehyde with 30 in acidic ethanol provides only 10% of quinoline 31. However, when a toluene solution of crotonaldehyde is reacted with 30 (starting as the acetanilide) in 6M HCI at 100 °C for 2 h, quinoline 31 is isolated in 80% yield on 5kg scale. 

In addition to two-phase conditions, phase transfer catalysts have been used to improve the Skraup/Doebner-von Miller reaction.Condensation of 32 with 5 in a two-phase system of toluene/con HCI provides 33 in 47% yield. Addition of 5 mol% tetra- -butyl ammonium chloride increased the yield to 57%. 

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. 

Interestingly the Skraup/Doebner-von Miller reaction has been used to prepare a number of spiro-compounds. Aniline was reacted with enone 42 in the presence of iodine to yield dihydroquinoline 43 in acceptable yields. 

For an alternative mechanism, see that of the Doebner-von Miller reaction (page 547). 

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). 

Aldehydes are one of the most impotent synthons in organic chemistry. Many methods of preparation of formyl carboranes have been discussed previously (E. I. Rosemund method,14 Sonn-Miller reaction,14 reaction of dodecaborane with diacylal of propargyl aldehyde,14 Swem Oxidation15). Since oxazolines are rather good reagents for the preparation of aldehydes and nitriles, we developed a method of preparation of carboranyl oxazolines (Scheme 9). 

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. 

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