Friedlander and Pfitzinger Syntheses

The methods cited so far for the preparation of quinoline frameworks suffer from the mixtures obtained usually when weto-substituted anilines are used. The Friedlander quinoline synthesis avoids this problem by using an ortho-acylaniline derivative in reaction with enolizable carbonyl compounds.  

The reaction can be catalyzed either by acidic or basic conditions, or just by heating the reaction mixture. The outcome of the condensation was found to be dependent on the type of the catalyst used, with acid catalysis leading predominantly to formation of the thermodynamic product, whereas the base driving mostly to the kinetic. 

Despite the fact that Friedlander synthesis of quinolines has been known for more than a century, the reaction is still not completely understood. Two possible mechanisms are still debated. The first involves preformation of a Schiff base, while the other a Claisen condensation as the initial step. In either case, the intermediates are cyclodehydrated to form the quinoline core. Evidences for both mechanisms have been reported based on the isolation of formed intermediates. We have to point out that none of the described intermediates have been isolated from the exact conditions following the one-step Friedlander synthesis, providing a lot of space for doubt for the mechanism of the original reaction. 

The Friedlander reaction is quite versatile and can be used either by electron-rich or electron-poor aromatic components. The only limitation is the sustainability of the orf/ro-acylaniline for self condensation. In this logic, protected anilines and imines in some cases are used to avoid the undesired self condensation of the starting anilines. On the other hand, the Friedlander condensation is applicable to the aldehydes, ketones, carboxylic acids, esters, amides, nitriles, and aldoximines that have an adjacent enolizable group. In 

Two related reactions of quinoline construction, the Pfitzinger and Niementowski reaction, can be considered as extensions of the Friedlander synthesis. Niementowski reaction uses anthranilic acid for the synthesis of 4-hydroxy quinolines, and Pfitzinger reaction applies substituted isatins as precursors for ort/io-aminophenylglyoxylic acid, which is used as the condensation component with carbonyl compounds to produce 4-carboxylic acid quinolines. 

---