Skraup/Doebner-von Miller Reaction

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. 

Moore, A. 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). 

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. 

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... 

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