Diketones, acid catalyzed with amines

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. ... 

The first step in the Combes reaction is the acid-catalyzed condensation of the diketone with the aromatic amine to form a Schiff base (imine), which then isomerizes to the corresponding enamine. In the second step, the carbonyl oxygen atom of the enamine is protonated to give a carbocation that undergoes an electrophilic aromatic substitution. Subsequent proton transfer, elimination of water and deprotonation of the ring nitrogen atom gives rise to the neutral substituted quinoline system. 

The most important general methods for enaminone preparation are (i) direct condensations of ammonia or amines with 1,3-diketones or 3-ketoesters, (ii) nucleophilic reactions of lactams or related compounds with vinylogous acid chlorides, (iii) transformations catalyzed by organopalla-dium complexes, and (iv) the reactions of active methylene compounds with formamide acetals. This last method (iv) has been reviewed in detail... 

Pyrrole 38 was generated from nitrobenzene and a 1,4-diketone with indium metal in acetic acid. The reductive conditions convert nitrobenzene to aniline in situ cyclization then occurs with the dione in moderate to excellent yield (40-98%, 21 examples) (13T6698). A Pd(OCOCF3)2-catalyzed cascade furnished tetrasubstituted pyrrole 39 from 1,3-dicarbonyl compounds and primary amines in good yield (13CC4667). 

Reaction of Alkyl Amines Copper-catalyzed cross-coupling of aliphatic amines with aryl halides has made considerable progress. Several methods have used Ctil with p-amino alcohols L58 [42], amino acids L59, L60 [43], Al,Al-diethyl saUcylaldehyde L61 [44], or p-diketones L62-L65 [45] (Fig. 20.3). Among these, the protocol using p-diketones exhibited the superior results catalyzing the reaction even at room temperature (Scheme 20.19). 

S)-proline-catalyzed reaction is not sufficient therefore, a large number of (S)-proline-derived secondary amine catalysts have been developed. Primary amine catalysts derived from natural amino acids and cinchona alkaloids have also emerged as highly versatile and powerful catalysts [25]. For example, in the intramolecular 6-endo aldol reaction of diketone 43, quinine-derived primary amine 44 in acetic acid affords the cyclic ketone (S)-46 in 94% yield with 90% ee (Scheme 28.3) (S)-prohne gives the cycUzation product in low yield with moderate ee. In addition, the pseudo-enantiomeric quinidine-derived primary amine 45 deUvers the opposite product, the (R)-enantiomer 46, with similar yield and enantioselectivity [26]. 

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