Claisen Condensation

What Is Claisen Condensation?

The reaction in which carboxylic acid esters condense to form β-keto esters under the action of a base (such as sodium ethoxide) is called Claisen condensation.

The α-hydrogen of alkyl-substituted esters is weakly acidic, and a stronger base than sodium ethoxide, such as triphenylmethyl sodium, must be used to make the reaction proceed. Grignard reagents with large steric hindrance can also be used as bases.

It is worth noting that the self-condensation of two molecules of ester only forms one β-keto ester, but the condensation of two molecules of different esters can form a mixture of four β-keto esters, which is called cross-ester condensation, which is not very meaningful in preparation.

Reaction Mechanism

• The first step of Claisen condensation is that C₂H₅ONa captures the α-hydrogen in the ester molecule to form a carbon anion.
• Then, the carbon anion attacks the carbonyl group of another ester molecule to form a negative oxygen ion, which loses C₂H₅O- to form ethyl acetoacetate (β-keto ester).
• Then, C₂H₅O- captures the more acidic active hydrogen in the β-keto ester to shift the equilibrium toward the product.
• Finally, protonation is performed to obtain ethyl acetoacetate.

Fig 1. Claisen condensation reaction and its mechanism. [1]

Development of Claisen condensation

In order to make cross-ester condensation valuable for preparation, many practical methods have been developed from the perspective of activating carbonyl groups and selecting suitable condensing agents. Among them, the method using imidazole and its derivatives as carbonyl activators and Lewis acid/base promotion can achieve high cross-condensation selectivity.

However, the most common method is to pre-protonate the component to be used as a nucleophile with a strong base (such as LDA) to form a preformed enolate anion or enol silyl ether, and then react with the component to be used as a nucleophile or its activated form. This method was used in the synthesis of the alkaloid (-)-secodaphniphylline.

Application Examples of Claisen Condensation

• Example 1: Solvent-free Claisen condensation. In the presence of potassium tert-butoxide, benzyl acetate or n-octyl acetate was subjected to solvent-free Claisen condensation to effectively obtain benzyl acetoacetate or n-octyl ester with a yield of 51% or 68%, respectively. [2]
• Example 2: Intramolecualar Claisen condensation. In the total synthesis route of the biologically active natural product Amorfrutin A, the key step involves a tandem Michael addition-intramolecular Claisen condensation reaction. Compound 7 is predicted to be formed from acrylic ester 4 and ethyl acetoacetate in NaOEt via Michael addition followed by intramolecular Claisen condensation to afford substituted 1,3-cyclohexanediketone 3 in a one-pot reaction. [3]
• Example 3: Vinylogous Claisen condensation. In the total synthetic strategy for pyrrolobenzenes and Campyrones A-C, key steps include vinylogous Claisen condensation to achieve fragment coupling and dioxinone thermolysis/cyclization cascade to form the α-pyrone ring. [4]

Fig 2. Synthetic examples via Claisen condensation.

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References

1. Li, Jie Jack. Name Reactions: A Collection of Detailed Reaction Mechanisms, 2006, 89-90.
2. Iida, Katsumi, et al. J. Labelled Compd. Radiopharm., 2008, 51(3), 167-169.
3. Song, Yao Yao, et al. Tetrahedron Letters, 2013, 54(21), 2658-2660.
4. Reber, Keith P., et al. Journal of natural products, 2018, 81(2), 292-297.