Quinoline ring Conrad-Limpach

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,... 

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. ... 

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. 

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. 

Synthetic pharmaceuticals based on the quinoline ring are numerous. During World War II when supplies of the highly important antimalarial quinine became scarce, research was conducted in many laboratories to find a synthetic substitute. From this research came the dmg chloro-quine (9.103) and many related highly active compounds. Chloroquine is still in use today in the treatment of malarial infections. It is synthesized by a modification of the Conrad-Limpach synthesis as shown in Scheme 9.52. 

The great majority of quinolines and isoquinolines have been prepared by ring construction, instead of transformation of preexisting derivatives. They are obtained by variants of two main routes. The first route involves the cyclization of mono-substituted benzene rings, usually A-substituted anilines (Skraup, Doebner-von Miller, Knorr, Conrad-Limpach), and the second route involves the intramolecular condensation of o-disubstituted benzenes for the formation of the requisite pyridine ring (Friedlander, Pfitzinger reaction, etc.). 

Moore and MitchelH prepared soluble poly(enaminoester) (X) from a.a -bis(carbomethoxy) diacetyl benzene and aromatic diamines. The polymers were subsequently thermally cyclized (Conrad-Limpach reaction) to poly(quinolines) (XI), which is analogous to the conversion of poly(amic acids) to polyimides in terms of converting a soluble prepolymer to a stable polymer of cyclized, rigid ring structures with the formation of volatile by-products. The cyclized product however, was infusible and insoluble. 

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