Corey-Seebach Reaction

Theory and Defination :

The Corey-Seebach Reaction uses lithiated 1,3-dithianes as nucleophilic acylating agents
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
Umpolung or polarity inversion in organic chemistry is the chemical modification of a functional group with the aim of the reversal of polarity of that group
Concept was introduced by D. Seebach (hence the German word umpolung for reversed polarity) and E.J. Corey.

General Reaction :

Mechanism :

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 stabilizability 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 aldehyde 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.