Reactions Conrad-Limpach

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 first condensation is conducted selectively on a variety of 3-ketoesters and a-formylesters. The first step works well on most simple anilines even when sterically congested and is mostly affected by basicity. Formation of intermediate 3 is problematic when strong electron-withdrawing groups (EWG) are attached to the aniline (e.g., nitro). The cyclization step is promoted thermally in inert solvents as well as using acidic solvents at elevated temperature. When there exists an opportunity to form isomers on cyclization (e.g., m-substituted anilines) a mixture of the 5- and 7-substituted quinolines usually results. 

In 1887, Conrad and Limpach described the condensation of ethyl acetoacetate 5 with aniline 1 to provide enamine 6. Subsequent warming of the mixture provided quinoline 7. Limpach reported several years later that the yield of the cyclization step was improved when an inert solvent (e.g., mineral oil) was employed. While the cyclization step was normally quite facile at 240-280 °C, the physical properties and the methods described for the preparation of enamino-esters were inconsistent. 

These early contradictions were eventually resolved and led to the correction by Knorr of his initially proposed structure. While Conrad and Limpach described the reaction of aniline 1 with ethyl acetoacetate 5 which ultimately yielded 4-hydroxy-2-methylquinoline (7) via initial reaction of the amine with the ketone, Knorr described 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

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General Conditions for each step and selectivity of m-substituted anilines As previously mentioned, Hauser and Reynolds reported on factors governing the first step of the Conrad-Limpach reaction but they tvere by no means exhaustive. Other than the conditions reported above for the first step, HClAleOH, CHCI3 or CHCI2 (neat or with acid catalyst), PhMe or PhH with removal of water with or without acid catalyst, or EtOH/AcOH/CaS04 were reported to provide the desired enamino-ester from an aryl amine and 3-keto-ester. Hauser and Reynolds also noted that o-nitroaniline and o-nitro-p-methoxyaniline failed to form the desired enamino-ester under conditions which they reported. 

Brassard " applied the Conrad-Limpach reaction as an approach to the A-B ring system of Phomazarin. While the overall yield was only 23%, he showed that a methoxy group was an acceptable substituent on enamino-ester 46 and for the subsequent cyclization to quinolone 47. 

Various heterocyclic compounds have been used as substrates for the Conrad-Limpach reaction. Amino-isoquinoline 52 was converted into 54 in 36% overall yield. ... 

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. 

Although phenols have not participated in the Conrad-Limpach reaction under certain conditions thiophenols were not as innocent. Lee and coworkers reported mixtures of thiochromenones and quinolones from reactions of amino-thiophenols with ethyl benzoyl acetate. Amino-thiophenol 67 reacted with ethyl benzoylacetate 68 in PPA to give a mixture of thiochromenone 70 and quinolone 69 in which the quinolone predominated. 

This information coupled with the proposed mechanism of the Conrad-Limpach reaction, reasonably lead to the below proposed mechanisms. Conjugate addition of aniline and elimination of alcohol provides the P-anilinoacrylate 14, which upon heating to 180-320 °C gives species, like 34a,b, which undergo 6n-electrocyclization to 35 or 36, respectively. Loss of ethanol from 36 gives 35 and tautomerization provides 4-... 

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

Curran, T. T. Conrad-Limpach Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 398-406. (Review). 

Amino-9-ethylcarbazole and its 6-methyl-homolog underwent the Conrad-Limpach reaction with ethyl acetoacetate, closure occurring at C-4 giving 185 (R = H or Me). 1-Aminocarbazole condensed with diethyl ethoxymethylenemalonate to give 186, which was thermally cyclized... 

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,... 

Aminoquinolines, therefore, remain the starting materials of choice for the synthesis of 1,10-phenanthrolines. Numerous modifications, extensions, and variations of the Skraup and Conrad-Limpach reactions have been developed, particularly by Case and his colleagues starting from 8-aminoquinolines.38,96 98,166 176,196-221 Attempts to apply... 

The Conrad-Limpach reaction has been applied successfully to 7-aminoisoquinoline using acetoacetic ester as condensing agent. In this way 8-methyl-10-hydroxy-2,7-phenanthroline was obtained.181... 

Applications of the Conrad-Limpach reaction to the synthesis of 1-hydroxy-4,7-phenanthrolines or, more correctly, l-oxo-l,4-dihydro-4,7-phenanthrolines, from p-phenylenediamine or 6-aminoquinolines continue to be reported. l,10-Dihydroxy-3,8-dimethyl-4,7-phenanthroline has again been prepared from p-phenylenediamine,234 hot diphenyl ether being used to effect the cyclization. Other examples include the new or improved preparations of l-hydroxy-3-methyl-, 10-amino-l-hydroxy-3-methyl-,232 2-(y-chlorocrotonyl)- l,10-dihydroxy-3,8-dimethyl-, and 2,9-bis (y- chlorocrotonyl)-1,10- dihydroxy - 3,8 - dimethyl - 4,7 - phenanthro-lines.235 Compounds prepared in this way have been patented as antiasthmatic agents.178 A closely related synthesis employing poly-phosphoric acid as cyclizing agent has yielded l-hydroxy-3-phenyl-4,7-phenanthroline.236... 

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. ... 

Conrad-Limpach reaction. Thermal condensation of arylamines with (3-ketoesters followed by cyclization of the intermediate Schiff bases to 4-hydroxyquinolines. 

Aminobenzopyran-2-ones 279 undergo the Conrad-Limpach reaction with 2-ethoxycarbonylcyclohexanone 278 to give anils 280, which, on heating in diphenyl ether at reflux, give cyclized products 281 (Scheme 49) (83JHC775). 

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. 

The Conrad-Limpach reaction, which employs )8-anilinocrotonates, is also a valued method for 4-quinolone synthesis (1887CB944 48CRV53 52HC38), and a recent example is included in Table V (entry 6). 

Transition metal catalyzed hetero-annulation provides a useful and convenient tool for the construction of N-heterocycles [1]. Quinolines are of special interest in that they display attractive applications in pharmaceuticals and are synthetic building blocks [2, 3]. Catalytic processes employing palladium [4—6], rhodium [7-9], ruthenium [10-14], and iron [15] have been studied and developed to synthesize quinoline skeletons. There are five common methods used to prepare substituted quinolines the Skraup reaction [16], the Doebner-Von Miller reaction [17], the Conrad-Limpach reaction [18], the Friedlaender reaction [19, 20], and the Pfitz-inger reaction [21, 22]. All five of the reactions require environmentally unfriendly acids or bases, high temperatures, or harsh conditions. Quinoline yields are usually low due to numerous side reactions. Even though much work has been done to find catalytic routes to quinolines, the use of non-precious metals remains an active area of research. 

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