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

Reaction Mechanism

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, a series of proton transfers, and a keto/enol tautomerization 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, 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.

Mechanism Note: With much of the literature on the synthesis of quinolines, there is some discrepancy on whether a substituted 4-hydroxyquinoline or a substituted 4-quinolone is the final product of the Conrad-Limpach Synthesis. Although the reaction product is often shown as a hydroxyquinoline (the enol form), it's believed that the quinolone (keto form) predominates. For the purposes of this page and based on the reaction mechanism as it is shown in Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications by Ji Jack Li, the product is shown as a hydroxyquinoline.

Regioselectivity of β-ketoester: Knorr Variation

In the reaction of aniline with a β-ketoester, there are two possible sites of attack for the aniline nitrogen atom: the very reactive keto group, or the less reactive ester group. When Conrad and Limpach first observed this reaction in 1887, it was run at room temperature, and gave high yields of β-aminoacrylate: the kinetic product. The reaction then continued to give the final product of 4-hydroxyquinoline. However, chemist Ludwig Knorr observed that under higher temperatures (approx. 140°C) the aniline would actually attack the ester group of the β-ketoester, leading to the thermodynamically preferred β-keto acid anilide product (albeit in less than ideal yields). Continuation of this reaction using the Conrad-Limpach mechanism led to the synthesis of 2-hydroxyquinoline. The initial synthesis of 2-hydroxyquinoline from a β-ketoanilide was reported in 1886 as the Knorr Quinoline Synthesis. For his contributions, many actually dub this overall reaction the “Conrad-Limpach-Knorr Reaction”.

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