Combes quinoline synthesis

It involves the condensation of unsubstituted anilines (1) with β-diketones (2) to form substituted quinolines (4) after an acid-catalyzed ring closure of an intermediate Schiff base (3).

One modification to the generic Combes quinoline synthesis was the use of a mixture of polyphosphoric acid (PPA) and various alcohols (Sloop used ethanol in his experiment).

The mixture produced a polyphosphoric ester (PPE) catalyst that proved to be more effective as the dehydrating agent than concentrated sulfuric acid (H2SO4), which is commonly used in the Combes quinoline synthesis.

The study concludes that the interaction of steric and electronic effects leads to the preferred formation of 2-CF3-quinolines, which provides us with some information on how to manipulate the Combes quinoline synthesis to form a desired regioisomer as the product.

The synthesis of quinoline derivatives has been prevalent in biomedical studies due to the efficiency of the synthetic methods as well as the relative low-cost production of these compounds, which can also be produced in large scales.