Friedländer synthesis explained

The Friedländer synthesis is a chemical reaction of 2-aminobenzaldehydes^[1] with ketones to form quinoline derivatives.^{[2] [3]} It is named after German chemist Paul Friedländer (1857–1923).

This reaction has been catalyzed by trifluoroacetic acid,^[4] toluenesulfonic acid,^[5] iodine,^[6] and Lewis acids.^[7]

Several reviews have been published.^{[8] [9] [10]}

Mechanism

Two viable reaction mechanisms exist for this reaction. In the first mechanism 2-amino substituted carbonyl compound 1 and carbonyl compound 2 react in a rate-limiting step to aldol adduct 3. This intermediate loses water in an elimination reaction to unsaturated carbonyl compound 4 and then loses water again in imine formation to quinoline 7. In the second mechanism the first step is Schiff base formation to 5 followed by Aldol reaction to 6 and elimination to 7.^[11]

The Pfitzinger reaction and the Niementowski quinoline synthesis are variations of the Friedländer reaction.

See also

• Doebner-Miller reaction
• Povarov reaction
• Skraup reaction

Notes and References

1. [Organic Syntheses]
2. Friedländer, P. . Chemische Berichte. 1882. 15. 2572–2575. 10.1002/cber.188201502219. Ueber o-Amidobenzaldehyd. 2.
3. Friedländer, P. . Gohring, C. F. . Ber.. 1883. 16. 1833–1839. 10.1002/cber.18830160265. Ueber eine Darstellungsmethode im Pyridinkern substituirter Chinolinderivate. 2.
4. Shaabani, A. . Soleimani, E. . Badri, Z. . 10.1080/00397910601055230. Triflouroacetic Acid as an Efficient Catalyst for the Synthesis of Quinoline. 2007. Synthetic Communications. 37. 4. 629–635. 98625429 .
5. Jia, C.-S. . Zhang, Z. . Tu, S.-J. . Wang, G.-W. . Org. Biomol. Chem.. 2006. 4. 104–110. 10.1039/b513721g. 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. 1 . 16358003 .
6. Wu, J. . Xia, H.-G. . Gao, K. . Org. Biomol. Chem.. 2006. 4. 126–129. 10.1039/b514635f. Molecular iodine: A highly efficient catalyst in the synthesis of quinolines via Friedländer annulation. 1 . 16358006 .
7. Varala, R. . Enugala, R. . Adapa, S. R. . Synthesis. 2006. 3825–3830 . 10.1055/s-2006-950296 . 2006 . 22 . Efficient and Rapid Friedlander Synthesis of Functionalized Quinolines Catalyzed by Neodymium(III) Nitrate Hexahydrate.
8. Manske, R. H. . Chem. Rev.. 1942. 30. 113–144. 10.1021/cr60095a006. The Chemistry of Quinolines.
9. Bergstrom, F. W. . Chem. Rev.. 1944. 35. 77–277. 10.1021/cr60111a001. Heterocyclic Nitrogen Compounds. Part IIA. Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline. 2.
10. Book: Cheng, C.-C. . Yan, S.-J. . 10.1002/0471264180.or028.02. The Friedländer Synthesis of Quinolines. Organic Reactions. 2004. 0471264180.
11. Jose Marco-Contelles . Elena Perez-Mayoral . Abdelouahid Samadi . Marıa do Carmo Carreiras . Elena Soriano . Recent Advances in the Friedlander Reaction. 10.1021/cr800482c. 2009. Chemical Reviews. 109. 6. 2652–71. 19361199.