Acyloin condensation is a reductive coupling of two carboxylic esters using metallic sodium to yield an α-hydroxyketone, also known as an acyloin. The reaction is most successful when R is aliphatic and saturated. The reaction is performed in aprotic solvents with a high boiling point, such as benzene and toluene in an oxygen free atmosphere of nitrogen. The use of protic solvents results in the Bouveault-Blanc reduction of the separate esters rather than condensation. Depending on ring size and steric properties, but independent from high dilution, the acyloin condensation of diesters favours intramolecular cyclisation over intermolecular polymerisation when diesters are used. To account for such cyclisation, it is suggested that the ends, where ester groups are present, are adsorbed, albeit weakly, at nearby sites on the sodium metal. Thus, the reactive ends are not available for polymerisation, thereby decreasing competition for the cyclisation process. Diesters possessing 10 or more carbons undergo cyclisation very easily.
Acyloin cyclization of diesters
The cyclization of diesters by intramolecular acyloin condensation is a classical approach for the synthesis of aliphatic ring systems. In general, compared to other cyclization reactions that proceed under basic conditions like the Ziegler-Thorpe and Dieckmann ring formation methods, the acyloin synthesis is suitable for more ring sizes, especially when the Rühlmann method is used to trap the cyclization product as the bisalkene. Although 3-membered rings are not accessible through the acyloin condensation, 5- and 6-membered rings form in high yield, 4-, 7-, 10-, and 11-membered rings form in moderate yield, 8- and 9-membered rings form in poor to modest yield, and finally, 12-membered and higher rings form in good to excellent yields. Although yields for 4-membered and medium-sized rings are poor to moderate, the acyloin condensation constitutes one of the earliest practical cyclization reactions to prepare these challenging ring sizes. In comparison, the Dieckmann method is practical only for 5- to 8-membered rings. The Thorpe method is more easily modified via high dilution to enable the synthesis of large rings, but 4-membered and 9- to 13-membered rings are still not accessible. Concentration is much less important a factor for obtaining high yields for the acyloin condensation, as the reaction occurs on the surface of the sodium metal. Although, the need for sodium metal limits the functional group tolerance of the reaction, compared to more modern cyclization reactions, the acyloin condensation continues to be used in the synthesis of complex natural products for the preparation of challenging ring systems.
Mechanism
The mechanism consists of four steps:
Variations
Rühlmann-method
The method according to Rühlmann employs trimethylchlorosilane as a trapping reagent; by this, competing reactions are efficiently subdued. Generally, yields increase considerably. The hydrolytic cleavage of the silylether gives the acyloin. To achieve a mild cleavage methanol can be used in several cases. Usually toluene, dioxane, tetrahydrofuran or acyclic dialkylethers are employed as solvents. Advantageously also N-methyl-morpholine has been used. It allowed in some cases a successful reaction, in which otherwise the reaction failed in less polar media.
