What Is Dieckmann Condensation?
Dieckmann condensation is an intramolecular Claisen condensation reaction of diesters which occurs in alkaline conditions leading to β-ketoester formation. The German chemist Walter Dieckmann first reported Dieckmann Condensation in 1900. Five- and six-membered ring formation occurs most frequently while medium and large rings with over seven members primarily undergo dimerization as a side reaction. Sodium ethoxide has historically served as the base in this reaction which takes place within an ethanol environment. Synthetic chemists now frequently employ sterically hindered bases with low nucleophilicity like t-BuOK, LDA, and LHMDS in aprotic solvents including tetrahydrofuran to perform reactions under lower temperature conditions which help in minimizing side reactions.
The reaction is widely employed in organic synthesis for constructing carbocyclic and heterocyclic frameworks, particularly in natural product (such as terpenoids and alkaloids) synthesis and medicinal chemistry (such as prostaglandin intermediates and macrolide antibiotics).
Reagents: Strong bases [e.g., sodium, sodium ethoxide, potassium ethoxide, potassium tert-butoxide (t-BuOK), sodium hydride, Lithium diisopropylamide (LDA), LHMDS, etc.].
- Reactants: α-Hydrogen diesters.
- Products: Cyclic β-keto esters or β-diketones (typically 5- or 6-membered rings).
- Reaction type: Intramolecular cyclization.
- Related reactions: Claisen condensation, Aza-Dieckmann condensation.
Fig 1. Dieckmann condensation reaction and its mechanism. [1]
Mechanism of Dieckmann Condensation
Dieckmann condensation follows a mechanism that resembles the Claisen condensation reaction. Through an α-proton extraction from one ester by the base an enolate ion forms which subsequently attacks the other ester resulting in a tetrahedral intermediate. The alkoxide ion is released and then forms a second base-mediated enolate ion. The final cyclic β-ketoester is obtained after acid treatment.
Experimental Tips
- If there are less than 4 carbon atoms between the two ester groups, the Dieckmann reaction cannot occur.
- The reaction is suitable for the formation of 5-8 membered rings. If a larger ring is synthesized, the yield of this reaction becomes lower, and other methods are suitable.
- Commonly used reaction solvents are: tetrahydrofuran (THF), benzene, toluene, ether, and anhydrous ethanol. Polar aprotic solvents (THF, DMF) enhance enolate stability, while non-polar solvents (toluene) may reduce side reactions.
- When one of the ester groups does not contain α-hydrogen, the reaction does not have a regioselectivity problem. The regioselectivity of the asymmetric ester reaction depends on the difference in the steric hindrance of the α-carbon of the two ester groups.
Application Examples of Dieckmann Condensation
- Example 1: In the total synthesis strategy of calyciphylline B-type alkaloids [(−)-Daphlongamine H and (−)-Isodaphlongamine H], the acyclic precursor intermediates treated with LiHMDS can successfully initiate Dieckmann condensation to give the brominated bicyclic with a yield of >74%. [2]
- Example 2: In the total synthesis route of halofuginone, Hua Xu et al. found that polar aprotic solvents may be a better choice for the Dieckmann condensation reaction of intermediate compound 8. Therefore, using t-BuONa as a base in THF, 5.44 kg of compound 9 was obtained in a single batch with an HPLC purity of 75%. [3]
Fig 2. Synthetic examples via Dieckmann condensation reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 162-165.
- Hugelshofer, Cedric L., et al. Journal of the American Chemical Society, 2019, 141(21), 8431-8435.
- Xu, Hua, et al. Organic Process Research & Development, 2019, 23(5), 990-997.
