Skraup synthesis of quinolines

In the Skraup synthesis of quinoline the principal difficulty has always been the violence with which the reaction generally takes place it occasionally proceeds relatively smoothly, but in the majority of cases gets beyond control, with consequent loss of material through the condenser. By the addition of ferrous sulfate, which undoubtedly functions as an oxygen carrier, the reaction is extended over a longer period of time. It is thus possible to work with much larger quantities of material when ferrous sulfate is employed. 

The classical Skraup synthesis of quinolines is exemplified by the reaction of aniline 6.3 with glycerol 6.4 under acidic/oxidative conditions to produce quinoline 6.1. 

Arsenic pentoxide, AsjOs, functions as an oxidant in the Skraup synthesis of quinolines [480]. 

As yet unexplained is the use of ferrous sulfate as moderator to control the otherwise stormy reaction of aniline, glycerol, nitrobenzene, and concentrated sulfuric acid in the Skraup synthesis of quinoline. ... 

It is well known that acrolein is an intermediate in the Skraup synthesis of quinoline, so the use of other a/3-unsaturated carbonyl compounds can be considered at this point. Russian workers12 reported that methyl vinyl ketone reacted with 2-aminothiophene double salt to give 4-methylthieno[2,3-6 pyridine (Eq. (1)1 but later Klemm13 showed that a... 

The Skraup Synthesis of Quinolines R. H. F. Manskc and Marshall Kulka... 

Ranu et al. (2000) reported that the reaction time for the Skraup synthesis of quinolines by microwave irradiation was reduced to a few min (5-12 min) with high yield of the product (80-87%). 

The Skraup reaction involves the synthesis of quinoline 3 from the reaction of aniline 1 and glycerol 2 in the presence of a strong acid and an oxidant. 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

The Skraup-Doebner-Von Miller synthesis of quinolines - involving condensation of an aniline with an ,/i-unsalurated ketone - has been investigated using 13C-labelled ketones in cross-over experiments a complex fragmentation-recombination mechanism involving imine intermediates is indicated.17... 

Scheme 1 Synthesis of quinoline, starting from acrolein and aniline (Skraup synthesis) [7]...

This dyestuff is prepared by heating -nitroalizarin with glycerine and sulphuric acid. It is peculiar in so far that it possesses the lake-forming properties characteristic of the alizarin dyes, and is at the same time a weak base. Alizarin blue was discovered by Prud homme [28], and the determination of its constitution by Graebe [29] led to the synthesis of quinoline by Skraup from glycerine, nitrobenzene, and aniline. 

An improved Skraup synthesis of benzo[h]quinolines from 1-naphthylamine and an unsaturated carbonyl compound utilises a mixture of fuming sulphuric acid and nitrobenzene (Sulfo-mix), iron(II) sulphate and boric acid (Y. Hamada and I. Takeuchi, J.org.Chem., 1977, 42. 4209). 

Homologues of quinoline have been prepared by replacing aniline by its substitution-products in the Skraup synthesis. A third synthesis of quinoline is also of interest. When... 

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) ... 

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 is related to the Skraup Reaction, but is used for the synthesis of quinolines bearing substitutents in the pyridinoid ring. This reaction is also related to the Gould-Jacobs Quinoline Synthesis and Knorr Quinoline Synthesis. 

Bose et al. were also able to successfully achieve the microwave-assisted synthesis of quinoline (72) and dihydroquinoline (73) derivative under solvent-free condition via Skraup synthesis. They demonstrated that 25 mol% of KjCoW,20 q (PDTC) was effective for one-pot reaction of aniline with alkyl vinyl ketones as shown in Scheme 6.28. This reagent was also demonstrated to be an effective catalyst for the Friedlander synthesis [67]. 

Scheme 6.28 Microwave-assisted synthesis of quinoline (72) and dihydroquinoline (73) derivative under solvent-free eondition via Skraup synthesis...

On the other hand, molybdenum species, due to their Lewis acidity, should mainly catalyse the condensation reaction, similar to those proposed in the Skraup s synthesis of quinolines from aldehydes and aniline (Scheme 15) ... 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

The Friedlander quinoline synthesis is particular useful for the preparation of 3-substituted quinolines, which are less accessible by other routes. A drawback however is the fact that the required o-atninobenzaldehydes or o-aminoarylketones are not as easy to prepare as, e.g., the anilines that are required for the Skraup synthesis. 

By reaction of a primary aromatic amine—e.g. aniline 1—with glycerol 2, and a subsequent oxidation of the intermediate product 4, quinoline 5 or a quinoline derivative can be obtained.As in the case of the related Friedlander quinoline synthesis, there are also some variants known for the Skraup synthesis, where the quinoline skeleton is constructed in similar ways using different starting materials. ... 

The Skraup reaction is of wide scope for the synthesis of substituted quinolines. Certain primary amines, bearing a cyano, acetyl or methyl group, may however be subject to decomposition under the usual reaction conditions. 

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 ... 

Skraup synthesis org chem A method for the preparation of commercial synthetic quinoline by heating aniline and glycerol in the presence of sulfuric acid and an oxidizing agent to form pyridine unsubstituted quinolines. skraup sin-tha-sas slaked lime See calcium hydroxide. slakt iTm )... 

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