Conrad-Limpach quinoline

Some applications of the described reactions include the preparation of chloroquine, an important anti-malarial, which is made by reacting 4,7-dichloroquinoline with 4-diethylamino-l-methylbutylamine at 180 °C. 7-Chloro-4-hydroxyquinoline, a precursor of 4,7-dichloroquinoline, was routinely prepared by heating 3-chloroaniline with the ethyl ester of formylacetic acid, through the Conrad-Limpach quinoline synthesis. ... 

This reaction is related to the Camps Reaction, Conrad-Limpach Quinoline Synthesis, Doebner-Miller Reaction, Gould-Jacobs Quinoline Synthesis, Niementowski Reaction, and Skraup Reaction. 

Other references related to the Conrad-Limpach quinoline synthesis are cited in the literature. 

The reaction is related to the Combes Quinoline Synthesis and Conrad-Limpach Quinoline Synthesis. 

The last two decades of the 19th century proved to be an important era for the development of quinoline chemistry. It was during this time period that various methods for synthesizing quinolines, such as the Friedlander quinoline synthesis, Pfitzinger quinoline synthesis, Doebner-Miller quinoline synthesis, Conrad-Limpach quinoline synthesis, Combes quinoline synthesis, and Camps quinoline synthesis were first reported. In 1882, Friedlander showed that the condensation of 2-aminobenzaldehyde (4) with acetaldehyde (5) provided quinoline (6). ... 

An intramolecular ketene electrocyclization also seems to occur in the Conrad-Limpach quinoline synthesis. In the heating of the 6-anilinocrotonic acid ester in a high-boiUng solvent at 240-250 °C, the ketene 466 is generated, which undergoes inttamolecular cy-clization to form a quinoline derivative 467 ... 

The Conrad-Limpach reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with the ketone or aldehyde of a 3-ketoester or a-formylester 2 providing enamine 3, and (b) cyclization with loss of alcohol to yield 4-hydroxy-quinoline 4. 

The Conrad-Limpach reaction has been applied as a key step in the formation of pyrido[4,3-b]quinoline. Condensation of 3 different anilines 55 (R = H, Br, OMe) with keto-ester 56 provided the enamino-esters 57 in acceptable yields. Cyclization gave the desired quinolones 58 in good to moderate yield. ... 

A -acetyl groups attached to the aniline have been shown to withstand the Conrad-Limpach reaction. Phenols and alcohols also survived unless in proximity to a reactive center. Jaroszewski reported the formation of 64 by reaction of aniline 63 with ethyl acetoacetate (5). Cyclization under thermal conditions in paraffin gave a mixture of quinolone 65 and quinoline 66. 

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... 

Acid-catalyzed condensation of anilines and P-diketones to assemble quinolines. Cf. Conrad-Limpach reaction. 

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. 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

A few extensions of the Conrad-Limpach synthesis have been applied to the synthesis of 4,7-phenanthrolines. Unlike o-phenylenediamine, which gives a quinoxaline derivative, p-phenylenediamine reacts with excess of ethyl ethoxalylpropionate to give an intermediate bisanil, which cyclizes in hot diphenyl ether to afford 3,8-dicarboethoxy-l,10-dihydroxy-2,9-dimethyl-4,7-phenanthroline in high yield.237 With diethyl ethoxymethylenemalonate as condensing agent, 6-amino-8-methoxy-quinoline has been converted into 2-carboethoxy-l-hydroxy-6-methoxy-4,7-phenanthroline.238 A related condensation affording 1-... 

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. 

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. 

A modification of the known Conrad-Limpach synthesis of quinolines, using anilino-methylenemalonates instead of / -anilinocrotonates, has long been known290,291. 

The formation of quinolines and benzoquinolines by the condensation of primary aryl amines with P-diketones followed by an acid catalyzed ring closure of the Schiff base intermediate is known as the Combes quinoline synthesis. The closely related reaction of primary aryl amines with p-ketoesters followed by the cyclization of the Schiff base intermediate is called the Conrad-Limpach reaction and it gives 4-hydroxyquinolines as products. ... 

This sequence calls to mind an old, long-known reaction the thermal version of the Conrad-Limpach synthesis of quinoline-4-one derivatives by thermolysis of aryl-aminocrotonates110a arylaminomethylenemalonates1 lob c arylaminomethylene-cyanoacetates110d and related compounds111-114. ... 

A totally different approach from the Skraup and Conrad-Limpach syntheses of naphtho[2,1-f]quinoline from 2-aminophenanthrene involves expansion of the five-membered ring of a steroid to a six-membered heterocyclic ring. 

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