Friedländer synthesis reaction

The Friedländer synthesis refers to the reaction between o-aminoaryl aldehydes or ketones and another molecule of an aldehyde or ketone to produce quinolines and their derivatives. This reaction was discovered by German chemist Paul Friedländer and is named after him.

The Friedländer synthesis is a classical method for constructing quinoline ring systems. It is valued for its operational simplicity and the easy availability of starting materials. This reaction has significant applications in pharmaceutical synthesis, natural product synthesis, and the development of fluorescent materials. Since the quinoline structure is widely present in biologically active compounds, the Friedländer synthesis is also an indispensable tool in heterocyclic chemistry.

• Reagents: Acids, bases

• Reactants: o-Aminoaryl aldehydes/ketones, aldehydes/ketones

• Products: Quinoline derivatives

• Reaction Type: Condensation reaction, intramolecular cyclization reaction

Experimental Tips:

• Acid catalysts (e.g., acetic acid, hydrochloric acid, sulfuric acid) or base catalysts (e.g., sodium hydroxide, pyridine) can promote the condensation;

• The carbonyl compound (i.e., the other aldehyde or ketone) should contain an α-active hydrogen to enable ring formation;

• Common solvents include ethanol (EtOH), methanol (MeOH), DMF, etc.; reaction temperatures are typically under reflux (80–120 °C).

Reaction Mechanism

Friedländer Synthesis Reaction Mechanism

Original Literature:
Paul Friedlaender. Berichte der deutschen chemischen Gesellschaft. 1882, 2572–2575.

Notable References:

• Environmentally Friendly Nafion-Mediated Friedländer Quinoline Synthesis under Microwave Irradiation: Application to One-Pot Synthesis of Substituted Quinolinyl Chalcones. Synthesis, 2020, 52 (12), 1779–1794.

• Ruthenium-catalysed oxidative cyclisation of 2-aminobenzyl alcohol with ketones: modified Friedlaender quinoline synthesis. Chem. Commun., 2001, 2576–2577.

• Rapid and efficient synthesis of poly-substituted quinolines assisted by p-toluene sulphonic acid under solvent-free conditions: comparative study of microwave irradiation versus conventional heating. Org. Biomol. Chem., 2006, 4 (37), 104–110.