Conrad–Limpach synthesis

The Conrad–Limpach synthesis is the chemical reaction of anilines (1) with β-ketoesters (2) to form 4-hydroxyquinolines (4) via a Schiff base (3).^[1][2][3] The overall reaction type is a combination of both an addition reaction as well as a re-arrangement reaction. Both Manske and Rietsma have published reviews.^[4][5]

The Conrad-Limpach synthesis

Mechanism

EDited picture of Conrad-Limpach Syn

The mechanism begins with an attack of aniline on the keto group of the β-ketoester to form a tetrahedral intermediate. The newly formed oxide is then twice protonated to form the Schiff base, which then undergoes keto-enol tautomerization before an electrocyclic ring closing. The mechanism concludes with the removal of an alcohol and a series of proton transfers to form a 4-hydroxyquinoline, the final product of the Conrad-Limpach Synthesis.

Perhaps the most important step (and the rate-determining step) in the reaction mechanism is the annulation of the molecule via an electrocyclic ring closing. For this step, the Schiff base must be heated to around 250°C for the ring closure to occur. Furthermore, the type of solvent used is very important to ensuring high yields of the 4-hydroxyquinoline product. In the early work, the cyclization was accomplished by heating the Schiff Base without a solvent and the yields were very moderate (below 30 percent). Limpach reported many years later that the yields in the cyclization were raised to 95 percent in many cases when an inert solvent, such as mineral oil or paraffin oil, was used for the reaction.

The Conrad-Limpach reaction mechanism also involves multiple keto-enol tautomerizations, all of which are catalyzed through the use of a strong acid, often HCl or H2SO4.

References

1. ^ Conrad, M.; Limpach, L. Ber. 1887, 20, 944.
2. ^ Conrad, M.; Limpach, L. Ber. 1891, 24, 2990.
3. ^ Reynolds, G. A.; Hauser, C. R. Org. Syn., Coll. Vol. 3, p. 593 (1955); Vol. 29, p. 70 (1949). (Article)
4. ^ Manske, R. H. Chem. Rev. 1942, 30, 113. (Review)
5. ^ Reitsema, R. H. Chem. Rev. 1948, 43, 43. (Review)

See also

• Combes quinoline synthesis
• Doebner reaction