Knorr quinoline reaction / synthesis

The Knorr quinoline synthesis refers to the formation of a-hydroxyquinolines 4 from P-ketoesters 2 and aryl amines 1. The reaction usually requires heating well above 100°C. However, some cases do exist when the cyclization takes place in the presence of a catalytic amount of mineral acid at temperatures as low as -10 °C. The intermediate anilide 3 undergoes cyclization by dehydration with concentrated sulfuric acid. The reaction is conceptually close to the Doebner-Miller and Gould-Jacobs reactions. ... 

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

The lower temperature variation of this reaction initially forms an imine or an enamine. Friedel Crafts cyclization gives the 4-hydroxyquinoline in what is called the Conrad-Limpach reaction. xhis reaction generally gives the opposite regioisomeric product to that obtained by the Knorr quinoline synthesis. The initially formed product is usually the enamine (as in the formation of 248 from aniline and ethyl acetoacetate). 3 Under acidic conditions the iminium salt is formed and cyclized with the aromatic ring. A more efficient method simply heated 248 to 250°C in mineral oil, giving a 90% yield of 249. A variety of other functional groups can be tolerated in the molecule when this procedure is used. 

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. 

This reaction is related to the Doebner-von Miller Quinoline Synthesis and Knorr Quinoline Synthesis. 

This reaction was first reported by Knorr in 1886. It is the synthesis of 2-hydroxyquinolines via the cyclization and dehydration of an anilide intermediate condensed from )0-ketoesters and anilines at a relatively high temperature. Right after this report, Conrad and Limpach also reported a similar reaction between anilines and )0-ketoesters but at low temperatures, which resulted in the formation of 4-hydroxy quinolines from the intermediate of alkyl crotonate. Thus this reaction is known as the Knorr synthesis, Knorr-Limpach method, Knorr cyclization, Conrad-Limpach-Knorr reaction, or Knorr quinoline synthesis. It has been reported that the formation of an alkyl crotonate intermediate is favored at moderate or low temperature in the presence of iodine or an acid catalyst, whereas intermediate anilide is formed at high temperatures. ... 

Quinolin-2-one, 3-cyano-4-hydroxy-synthesis, 2, 428 Quinolin-2-one, 3,4-dialkyl-Knorr synthesis, 2, 425 Quinolin-2-one, dihydro-Camps synthesis, 2, 418 synthesis, 2, 402 from benzazepinones, 2, 506 from indanone oxime, 2, 487 from indanones, 2, 488 by intramolecular Friedel-Crafts reactions, 2, 421... 

Conrad-Limpach-Knorr Synthesis. When a /1-kcto ester is the carbonyl component of these pathways, two products are possible. Aniline reacts with ethyl acetoacetate below IOO"C to form 3-anilinocrotonate, which is converted to 4-hydroxy-2-methylquinoline by placing it in a preheated environment at 250°C. If die initial reaction lakes place at 160 C, acetoacetanilide forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoltne. This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents. 

On the other hand, the high importance of Knorr reaction in drug design is highlighted in the synthesis of quinine. Reaction of jp-anisidine and acetoacetic ester in the presence of sulfuric acid provides 6-methoxylepidine. Substitution of hydroxyl group with chloride and subsequent reduction provides the 2-unsubstituted quinoline. Condensation and oxidation affords a quininic ester, which is just three steps away from the synthesis of strong anti-malarial compound quinine. ... 

The Simonis chromone synthesis and the Pechmann-Duisberg reaction can be considered as O-analogs of the Conrad-Limpach and Knorr reactions for the preparation of quinolines from the corresponding aniline. ... 

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