Friedlander synthesis Mechanism

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. 

Quinoline derivatives are of wide occurrence in natural products and medicinal drugs they also find applications in polymer chemistry, electronics, and optoelectronics for their excellent mechanical properties as well [200]. The Friedlander synthesis of quinolines is a classic method involving reduction of o-nitro aryl aldehyde as the first step followed by condensation of the reduced product with enolizable carbonyl compound in the presence of a Bronsted or Lewis acid catalyst [201]. To avoid the harsh reaction conditions, the use of ILs has recently gained considerable attention in the synthesis of quinoline derivatives. 

The basic synthesis of the simplest azaheterocyclic compounds is discussed first along with the basic mechanism of the Friedlander reaction after which a series of more and more complex azaheterocycles are covered. 

The mechanism for the Niementowski quinoline synthesis is presumably similar to that of the closely related Friedlander reaetion. The mechanism for the Friedlander reaction has been studied extensively" and two possible mechanistic pathways exist, as illustrated below. There is support for both pathways. Most of the evidence, however, tends to favor initial formation of the SchifTs base intermediate (13) followed by cyclization to give quinoline 15 however, the reaction conditions and structures of the reactants may influence the pathway by which the reaetion proeeeds. ... 

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