Corey–Seebach Reactive

The Corey–Seebach reaction, also known as the Seebach Umpolung reaction, is a classic reaction that achieves nucleophilic acylation of carbonyl carbon atoms through a "polarity reversal" (Umpolung) strategy. In this reaction, an aldehyde (or ketone) first reacts with 1,3-propanedithiol to form a 1,3-dithiane intermediate, which is then lithiated under the action of a base (such as n-butyllithium) to yield a lithiated 1,3-dithiane. This lithiated product can be regarded as a "masked acyl anion" and can react with various electrophiles (such as alkyl halides, aldehydes, etc.) to ultimately form ketones.

The reaction is named after its discoverers, Elias J. Corey and Dieter Seebach. It was the first systematic realization of "nucleophilic inversion" of carbonyl carbons and is highly useful for constructing complex carbon-carbon molecular frameworks.

Reagents: 1,3-Propanedithiol, base (e.g., n-butyllithium), solvent, mercury salts
Reactants: Aldehyde, electrophiles (e.g., alkyl halides, aldehydes, ketones, etc.)
Products: Ketones
Reaction Type: Coupling reaction

Experimental Tips:
The lithiated 1,3-dithiane can undergo alkylation reactions with a variety of electrophiles, including alkyl halides, epoxides, ketones, acyl halides, and iminium salts. The resulting dithioacetal intermediates can be hydrolyzed under acidic conditions to yield valuable compounds such as ketones, β-hydroxy ketones, α-hydroxy ketones, 1,2-diketones, and α-amino ketones (see figure below). It is worth emphasizing that the α-hydroxy ketone and 1,2-diketone structures are typically inaccessible via conventional aldehyde reaction pathways (e.g., aldol condensation).

The lithiated 1,3-dithiane reacts with various electrophiles to undergo alkylation.

Reaction Mechanism:

Original Literature:
Corey, Elias James; Seebach, Dieter. Angewandte Chemie International Edition. 1965, 4(12), 1077-1078.

Popular Applications:

• Synthesis of α-Silyl Ketones via 1,3-Dithianes. J. Am. Chem. Soc. 1967, 89 (2), 434-436.

• d-Glucosamine trimethylene dithioacetal derivatives: formation of six- and seven-membered ring amino carbasugars. Synthesis of (–)-calystegine B3. Org. Biomol. Chem., 2007, 5, 3330-3339.

• β-Selective C-Glycosylation and its Application in the Synthesis of Scleropentaside A. Angew. Chem. Int. Ed., 2019, 58 (15), 5110-5113.