Synthesis Skraup

Quinaldine (or 2-methylquinoline) can be prepared by the Doebner.Miller Synthesis, which in some respects is closely similar to the Skraup Synthesis (p. 297) but has some significant differences. 

It is best now to proceed as in the Skraup Synthesis (p. 297) and warm the mixture over an asbestos-covered gauze with a Bunsen flame until the reaction starts, and have at hand a duster soaked in cold water so that when the reaction starts, the heating can be at once removed and the duster wrapped round the shoulders of the flask to aid condensation. 

Gyclization. Aniline, nitrobenzene, and glycerol react under acid catalysis (Skraup synthesis) to form quinoline [91-22-5] (27). 

By substituting paraldehyde for glycerol, 2-methylquinoline [27601-00-9] may be synthesized. The Skraup synthesis is regarded as an example of the broader Doebner-von Miller synthesis. In the case of the Skraup synthesis, the glycerol undergoes an acid-catalyzed dehydration to provide a small concentration of acrolein that is the reactive species. If acrolein itself is used as a reactant, it would polymerize. Crotonaldehyde is the reactive intermediate in the Doebner-von Miller synthesis (28). 

Both 5-hydroxyquiQoline [578-67-6] and S-hydroxyquiaoline [148-24-3] have been prepared ia good yields by the acid hydrolysis of the appropriate aminoquiaoline at temperatures of 180—235°C (124). The latter compound has been prepared ia several different ways, including sulfonation-fusion of quiaoline. Hydrolysis of 8-chloroquinoline [611-33-6] gives a 93% yield, whereas 80% is obtained ia a modified Skraup synthesis with o-aminophenol (125,126). 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

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). 

Benzo[/i]quinoIines hydrogenation, 2, 329 Skraup synthesis, 2, 467 structure, 2, 110 synthesis, 2, 468 from benzindoline, 2, 491 from propargyinaphthylamines, 2, 416 Benzoquinolinium cations metabolism, 1, 234 Benzoquinolinium salts Beyer synthesis, 2, 474 Benzoquinolinones synthesis, 2, 448... 

Naphtho[l,2-h]pyrylium salts, 5,6-dihydro-2,4-diphenyl-synthesis, 3, 869 Naphtho[2,l-h]pyrylium salts synthesis, 3, 866 Naphthoquinolines, tetrahydro-synthesis, 2, 469 N aphtho[ 1,2-7]quinolines Skraup synthesis, 2, 467... 

Quinoline, 2,4-bis(dimethylamino)-synthesis, 2, 419, 469 Quinoline, 3-bromo-bromination, 2, 319 oxidation, 2, 325 Skraup synthesis, 2, 467 Quinoline, 5-bromo-bromination, 2, 319 nucleophilic substitution, 2, 324 Quinoline, 6-bromo-nucleophilic substitution, 2, 324 Quinoline, 8-bromo-bromination, 2, 319 N-oxide... 

Skraup synthesis, 2, 466 synthesis from o-amidostyrenes, 2, 415 3-substituted... 

Quinolinium salts, l-(4-alkoxyphenyl)-2-methyl-synthesis, 2, 475 Quinolinium salts, aryl-Skraup synthesis, 2, 467 Quinolinium salts, 4-chloro-synthesis... 

Skraup synthesis starting from 4- and 5-aminobenzothiadiazole afforded only angularly annelated products thiadiazolo[5,4-/i]- and [4,5-/]quinoline, respectively. Attempts to cyclize 4-chloro-5-aminobenzothiadiazole failed (37LA38). 

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. ... 

For the Skraup synthesis, glycerol 2 is used as starting material in the presence of concentrated sulfuric acid (see scheme above) it is dehydrated to acrolein 6. Although it is assumed that the reactive carbonyl component in the Skraup reaction actually is acrolein, attempts to use acrolein directly, instead of glycerol, proved to be unsuccessful." ... 

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 ... 

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. 

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 )... 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

Iodoquinol Iodoquinol, 5,7-diiodo-8-quinolinol (37.2.2), is made by iodination of 8-oxyquinoline (37.2.1) using a mixture of potassium iodide/potassium iodate. The initial 8-hydroxyquinolin (37.2.1) is made from 2-aminophenol and glycerol in the presence of sulfuric acid and nitrobenzene (Skraup synthesis) [39,40]. 

The commonest approach is the Skraup synthesis. Here a mixture of glycerol (propane-1,2,3-triol), aniline (phenylamine), sulfuric acid, nitrobenzene and ferrous [iron(II)] sulfate are heated together (Scheme... 

The mechanism is similar to that of the Skraup synthesis (Problem 20.37) in that carbonyl O is protonated and the electrophilic C attacks the benzene ring in cyclization, to be followed by dehydration and oxidation. 

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