Conrad-Limpach-Knorr synthesis

Conrad-Limpach-Knorr synthesis, of quinolines, 21 189 Conrad recycling process, 21 455 Conradson carbon test method, 11 705, 721 Consensus materials standards, 15 743 Consent decree protocols, in the United States, 11 692-694 Consent decrees, 11 689-690 Consequence analysis, 21 860-861 Consequence modeling, 13 165-166 Conservation applications, high performance fibers in, 13 398 Conservation of energy, 21 290 Conservation of mass, 11 737, 738-739 Conservation, of resources, 24 164-167 Conservation scientists, 11 398-399 Consistent force field, 16 744 Consolidants, in fine art examination/ conservation, 11 410... 

Quinolones are obtained in the Conrad-Limpach-Knorr synthesis, which is subject to either kinetic or thermodynamic control, when aniline is reacted with a 3-keto ester (Scheme 3.11a). At room temperature the more reactive keto group combines with the aniline nitrogen atom, leading to an enamino ester the kinetic product. Cyclization of this product to a 4-quinolone requires heating at 250 C. 

ANTIPARASITICAGENTS - ANTIMYCOTICS] (Vol3) Conrad-Limpach-Knorr synthesis... 

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. 

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. ... 

A very large group of syntheses in which the /3,y-bond is formed are those in which a side chain electrophile attacks the benzene ring. These include the Skraup and Doebner-von Miller syntheses (dealt with in Section 2.08.2.2.3(ii)), the Knorr, Conrad-Limpach and Combes syntheses of quinolines (dealt with here), the Pomerantz-Fritsch synthesis of isoquinolines, and many syntheses of phenanthridines and of acridines. 

The synthesis of 1,8-naphthyridines using adaptations of quinoline syntheses (Knorr, Conrad-Limpach, Combs, Chichibabin, Doebner, and Doebner-Miller) has been discussed by Hauser and Weiss104 and the reader is referred to this work for details. 

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. 

Primary arylamines and p-ketoesters react in the presence of strong acid to provide 2-quinolones (Knorr reaction), whereas their thermal reaction yields 4-quinolones (Conrad-Limpach reaction). These reactions present a typical example of kinetic versus thermodynamic control, which has been employed in the synthesis of many quinolone derivatives for more than a century. 

Different reaction mechanisms are postulated for die synthesis of 2-or 4-quinolone derivatives. The Knorr reaction involves a nucleophilic attack of aniline nitrogen on the ester of P-ketoester component, providing anilide, which undergoes Friedel-Crafls cyclization followed by dehydration with sulfuric acid to yield 2-quinolones. On die other hand, a completely different pathway is involved in the case of Conrad-Limpach reaction. Condensation of aniline derivative with P-ketoester provides the corresponding enamino-ester. Enolization was followed by a 67c-electrocyclization reaction to form a 4-quinolone. A postulated alternative reaction padiway invokes the formation of an iminoketene prior to the cyclization step. 

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. ... 

---