Knorr quinoline 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.  

The first cyclization of acetanilide was carried out by Knorr in 1883 who subsequently demonstrated that the reaction was also applicable to acetoacylated aryl amines that have a vacant ortho position.  

In the first step of what is considered to be a fairly straightforward mechanism, the anilinic nitrogen reacts with the ester group of the 3-ketoester 5 to provide the anilide 3. The latter can either be isolated or carried on directly. Upon warming in the presence of acid, the acetanilide cyclizes with subsequent loss of water to yield the quinolone product 9.  

In their general synthesis of quinoline-2,5,8(lf/)-triones, Avendano and coworkers use this modified protocol to access the key 2,5-dimethoxyanilide systems 11 required in their synthetic plan. For more examples, see reference 11 and references cited within. 

The Knorr synthesis is a venerable process that has found a number of useful synthetic 

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KNORR Quinoline Synthesis Quinoline synthesis by cyclization of acetoacetanilides. 

The Knorr quinoline synthesis has been nicely extended by Hodgkinson and Staskun to include P-ketoesters that do not have protons at the 2 position of the starting keto-ester. 2,2 -dichloroanilides of type 14 can cyclize to provide quinolines such as 15 and 16 in good respective yields. ... 

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... 

KNORR Pyrazole synlheais 206 KNORR Quinoline synthesis 206 Knorr 209,284 Knowtes 180... 

Knorr quinoline synthesis. Formation of a-hydroxyquinolines from (3-ketoesters and aryla-mines above 100C. The intermediate anilide undergoes cyclization by dehydration with concentrated sulfuric acid. 

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. ... 

Other references related to the Knorr quinoline synthesis are cited in the literature. ... 

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