Friedlander synthesis of quinolines

The Friedlander synthesis of quinolines has been adapted to give derivatives of compounds (279) and (280). The isomeric quinoline aldehydes (284) and (285) react with various ketones to give (286) and (287) (77CR(C)(284)459, 82JHC1289). Compound (286) has also been obtained starting from the Schiff s base derivative of (284) (81JHC925). 

In the simplest of these, jS-enaminones are synthesized (equation 129) by the addition of amines to 1,3-diketones or /3-ketoesters. The reaction has been apphed to the Friedlander synthesis of quinolines by condensation of the enaminone and other carbonyl present in the substrate. Substituted pyrroles in equation (130) can be obtained as well when a propargyl group is present, by addition of the enaminone to the triple bond. Alcohols, thiols, and secondary phosphines have been also tested as nucleophiles with good results. A particularly interesting case is found in the condensation of indoles with 1,3-diketones to give substituted indol derivatives in equation (131). ... 

In order to maximize yields and regioselectivity in the Friedlander synthesis of quinolines, the bicyclic pyrrolidine base l,3,3-trimethyl-6-azabicyclo[3.2.1]octane (TABO) was utilized to good effect. TTie reaction was carried out with unactivated methyl ketones <03JOC467>. The ratios of the two products were 86% 2-substituted and 14% 2,3-disubstituted. 

The Friedlander Synthesis of Quinolines Chia-Chung Cheng and Shou-Jen Yan... 

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. 

G. Karthikeyan, P.T. Perumal, A mild, effident and improved protocol for the friedlander synthesis of quinolines using lewis acidic ionic liquid, J. Heterocycl. Chem. 41 (2004) 1039-1041. 

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