Reactions Skraup

The synthesis can be carried out with most aromatic amines and is usually termed the Skraup reaction. The nitrobenzene is frequently replaced by arsenic acid, as in the prep)aration of 8-nitroquinoline from o-nitroanUine ... 

If the approximate water content of commercial glycerol is known, the above dehydration may be avoided by adding sufficient SO, in the form of oleum to the concentrated sulphuric acid employed in the Skraup reaction to combine with all the water present. 

Hydroxyquinoline ( oxine ). The technique adopted in this preparation is based upon the fact that, in general, the reactants glycerol, amine, nitro compound and sulphuric acid can be mixed with temperature control, and then maintained at any convenient temperature below 120° without any appreciable chemical reaction taking place. A pre-mix of the amine, glycerol and sulphuric acid, maintained at a temperature which keeps it fluid (60-90°), is added in portions to a reaction vessel containiug the nitro compound and warmed with stirring to 140-170° at which temperature the Skraup reaction takes place. 

This important oxidation - reduction indicator is readily prepared by a double Skraup reaction (compare Section V,l) upon o-phenylenediamine ... 

In view of the high reactivity and sensitivity to oxidation of o-phenylone-diamine, the normal experimental conditions of the Skraup reaction are modified the condensation is carried out hi the presence of glycerol, arsenic acid solution and dilute sulphuric acid. 

Pinacol-pinacolone rearrangement Prileschajew epoxidation reaction Reformataky reaction Reimer-Tiemanii reaction Rosenmund reduction Sandmeyer reaction Schiemaim reaction Schmidt reaction or rearrangement Schotten-Baumann reaction Skraup reaction Sommelet reaction. ... 

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. 

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. ... 

However, attempts to prepare 3-iiitro-l,8-iiaphthyridiiie (11) by the Skraup reaction—heating of 2-amino-5-nitropyridine with glycerol in the presence of an oxidant— were not successful (74YZ1328). 

The first thiazoloquinolines, namely angularly annelated 2-methyl-thiazolo [4,5-/]quinoline 19 and linearly annelated 2-methyl-thiazolo[4,5-g]quinoline 20, were prepared in 1937 in poor yield using the Skraup reaction and exploiting the blockage of position 4 in 5-amino-2-methylbenzothiazole with a chlorine atom, as shown in Scheme 10 (37LA60). 

Thiazolo[5,4-/]quinoline 23 was prepared in 1949 starting from 6-aminobenzo-thiazole using Skraup reaction conditions glycerol, sodium 3-nitrobenzenesulfo-nate, and 78% sulfuric acid and heating at 110°C for 12 hours. Angular ring fusion... 

The isomeric triazolo[4,5-/]quinoline 145 was synthetized by the Skraup reaction from 5(6)-aminobenzotriazole (34CB213). 

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." ... 

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. 

The traditional unpredictably violent nature of the Skraup reaction (preparation of quinoline and derivatives by treating anilines with glycerol, sulfuric acid and an oxidant, usually nitrobenzene) is attributed to lack of stirring and adequate temperature control in many published descriptions [1], A reaction on 450 1 scale, in which sulfuric acid was added to a stirred mixture of aniline, glycerol, nitrobenzene, ferrous sulfate and water, went out of control soon after the addition. A 150 mm rupture disk blew out first, followed by the manhole cover of the vessel. The violent reaction was attributed to doubling the scale of the reaction, an unusually high ambient temperature (reaction contents at 32°C) and the accidental addition of excess acid. Experiment showed that a critical temperature of 120°C was attained immediately on addition of excess acid under these conditions [2],... 

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 ... 

Primaquine Primaquine, 8-[(4-amino-l-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.4), is made from 6-methoxy-8-nitroquinoline (37.1.2.1), which is synthesized in a Skraup reaction from 4-methoxy-2-nitroaniline and glycerol in the presence of sulfuric acid. The nitro group in this compound is reduced to make 6-methoxy-8-aminoquinoline (37.1.2.2). Alkylating the amino group with 4-bromo-l-phthalimidopentane gives 8-[(4-phthalimido-l-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.3), the hydrazi-nolysis of which removes the phthalimide protection, giving primaqnine [28,29]. 

The difference in direction of closure which was observed in the Skraup reaction of 9-ethyl-3-aminocarbazole that produced 156 and in the... 

Combes synthesis with pentan-2,4-dione that led to 157, was ascribed to unfavorable steric hindrance in the alternative orientation in the Combes synthesis. 2-Amino-l,4-dimethylcarbazole underwent the Skraup reaction in the only orientation available to it. Finally, the carbazol-1-yIhydrazone of ethyl pyruvate underwent normal Fischer indolization giving 158 its 3-isomer gave an indole by cyclization at C-4 producing 159. ... 

---