The Friedländer Synthesis of Quinolines

Cheng, Chia-Chung; Yan, Shou-Jen


Friedländer prepared quinoline in 1882 by the condensation of o-aminobenzaldehyde with acetaldehyde in the presence of sodium hydroxide. This type of reaction has since been extensively explored and, in its most general form, can be defined as an acid- or base-catalyzed condensation followed by a cyclodehydration between an o-amino-substituted aromatic aldehyde, ketone, or derivative thereof with an appropriately substituted aldehyde, ketone, or other carbonyl compound containing a reactive α-methylene group. Some quinolines can also be prepared simply by heating a mixture of the reactants with or without a solvent.

Because both reactants contain a carbonyl group, certain quinolines can be prepared from a single starting compound. Of historic interest is the formation of the dye flavaniline from acetanilide. When acetanilide is heated with zinc chloride, the acetyl group of some molecules migrates to the ortho position, and that of others migrates to the para position. The resulting mixture of o-acetylaniline and p-acetylaniline then undergoes Friedländer condensation to form flavaniline.

Two related quinoline syntheses, the Pfitzinger reaction and the Niementowski reaction, can be considered as extensions of the Friedländer synthesis. The Pfitzinger reaction uses an isatic acid or isatin and the Niementowski reaction uses an anthranilic acid for condensation to form a 4-quinolinecarboxylic acid and a 4-hydroxyquinoline, respectively.

Several other related reactions, such as the Combes quinoline synthesis, the Doebner–Miller quinoline synthesis, and the Skraup quinoline synthesis, use different types of starting compounds. It is of interest that all of the six aforementioned syntheses of quinolines were discovered within a period of 14 years in the latter part of the nineteenth century, undoubtedly reflecting many scientific interests and commercial activities at that time, including the isolation of quinolines from coal tar, the manufacture of dyes, and studies of natural products such as alkaloids.