Organic Chemistry Portal
Reactions >> Name Reactions

Further Information

Related Reactions
Synthesis of carbonyl compounds
Synthesis of β-hydroxy ketones

Corey-Seebach Reaction
Seebach Umpolung

The Corey-Seebach Reaction uses lithiated 1,3-dithianes as nucleophilic acylating agents.

Mechanism of the Corey-Seebach Reaction

The Corey-Seebach Reaction allows a reversal of the normal reactivity of acyl carbon atoms, which combine only with nucleophiles. The German term "Umpolung" is widely used for this inversion of reactivity.

The lithiated 1,3-dithiane can be viewed as an masked acyl anion that is able to react with various electrophiles.

The acidity difference of hydrogen atoms adjacent to divalent sulfur compared to oxygen stems from the greater polarizability of sulfur and the longer C-S-bond length; d-orbitals are not involved. In most cases treatment of dithianes with n-BuLi at temperatures of -30 °C is sufficient for the preparation of the lithio-derivatives. With pKA values of approximately 30, lithiated dithianes can react with aldehydes or ketones, epoxides and acid derivatives, but also with alkyl halides without competing elimination reactions.

Umpolung offers access to a wide range of products, especially 1,2-diketones and α-hydroxy ketones, products that cannot be obtained using the normal reactivity (for example through aldol addition).

Among the other thioacetals that could be used for Umpolung, metallated dithiolanes undergo fragmentation and disproportionate to ethene and dithiocarboxylates:

1,3-Dithianes are readily prepared from aldehydes (for an overview, see 1,3-dithianes as protecting group) and offer high stability towards acids and bases. Therefore, use of the S,S-acetal unit is especially useful in multistep synthesis. A crucial step is the hydrolysis of S,S-acetals, the difficulty of which is due to the excellent nucleophilicity of sulfur.

Only irreversible removal of the dithiol or of the solvolysis products can push the equilibrium to the right. Methods of choice are transacetalization to a highly reactive carbonyl derivative, alkylation to sulfide, oxidation of the thiol (for recent methods see deprotection of 1,3-dithianes) and formation of metal thiolates, for which mercury(II) salts are frequently used.

For a review on "Umpolung of the Reactivity of Carbonyl Compounds Through Sulfur-Containing Reagents" please check out a publication by Seebach (Synthesis 1977, 357. DOI).

Recent Literature

Alkylation of 2-Lithio-1,3-dithianes with Arenesulfonates of Primary Alcohols
D. Seebach, E.-M. Wilka, Synlett, 1976, 476-477.

Anion Relay Chemistry: An Effective Tactic for Diversity Oriented Synthesis
A. B. Smtih, III, M. Xiang, J. Am. Chem. Soc., 2006, 128, 66-67.

Trimethylene Dithioacetals of Carbohydrates, Part 6: C-C Coupling Reactions of Dilithiated N-Acetyl-D-glucosamine Trimethylene Dithioacetal Derivatives
Y.-L. Chen, R. Leguijt, H. Redlich, R. Fröhlich, Synthesis, 2006, 4212-4218.