Reactions Doebner-Von Miller

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. 

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). 

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). 

Doebner-von Miller reaction is a variant of the Skraup quinoline synthesis (page 545). 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 gives 2-methylquinoline ... 

Imidazoquinolines 71 have been synthesized in good yield by coupling benzimidazole 70 with dimethyl fraws-2-ketoglutaconate under Doebner-Von Miller reaction conditions in dichloromethane (Scheme 15). The compound 71 was demethylated using hydrobromic acid in glacial acetic acid, re-esterifed with methanolic hydrochloric acid, and oxidized to afford benzimidazole quinone 72 [59]. 

Transition metal catalyzed hetero-annulation provides a useful and convenient tool for the construction of N-heterocycles [1]. Quinolines are of special interest in that they display attractive applications in pharmaceuticals and are synthetic building blocks [2, 3]. Catalytic processes employing palladium [4—6], rhodium [7-9], ruthenium [10-14], and iron [15] have been studied and developed to synthesize quinoline skeletons. There are five common methods used to prepare substituted quinolines the Skraup reaction [16], the Doebner-Von Miller reaction [17], the Conrad-Limpach reaction [18], the Friedlaender reaction [19, 20], and the Pfitz-inger reaction [21, 22]. All five of the reactions require environmentally unfriendly acids or bases, high temperatures, or harsh conditions. Quinoline yields are usually low due to numerous side reactions. Even though much work has been done to find catalytic routes to quinolines, the use of non-precious metals remains an active area of research. 

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. 

Usually, the reaction is low yielding depending on the substituents either on the aromatic ring or on the unsaturated aldehyde reaction partner. The low yields are also correlated with the general difficulty to work up and isolate the desired products from the reaction mixture. An improved method was reported lately from Matsugi, et al. using a biphasic system as reaction media for the Doebner-von Miller reaction. The method proved to be advantageous in terms of yield and easy work-up process. Other modifications concern the use of different Lewis acids as promoters for the later cyclization process (InCL, lanthanides, etc.). ... 

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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