Paal-Knorr Furan Synthesis
The acid-catalyzed cyclization of 1,4-dicarbonyl compounds known as the Paal-Knorr synthesis is one of the most important methods for the preparation of furans. As many methods for the synthesis of 1,4-diones have recently been developed, the synthetic utility of the Paal-Knorr reaction has improved.
Mechanism of the Paal-Knorr Furan Synthesis
A comparison of the cyclizations of meso- and dl-3,4-diethyl-2,5-hexanediones showed that these compounds cyclize at unequal rates, and that the stereochemical configuration of unchanged dione is preserved during the reaction. These findings are at odds with the commonly accepted mechanism shown here that involves the ring closure of a rapidly formed monoenol.
The rate of acid-catalyzed enolization is known not to be very sensitive to the structure of the ketone. Since the rate-determining step would be the same for both substrates, the differences in the reaction rate cannot be explained by this mechanism.
A mechanism in which the substituents would interfere differently in the rate-determining step is shown below. The ease of achieving a suitable conformation for the cyclization is not the same for both molecules:
A more detailed description can be found in the work by Amarath and Amarath, and references cited therein (J. Org. Chem., 1995, 60, 301).
Microwave-Assisted Paal-Knorr Reaction - Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes
G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288.