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:
- A. William Johnson and Robert B. LaCount. J. Am. Chem. Soc. 1961, 83(2), 417-423.
- E. J. Corey and Michael Chaykovsky. J. Am. Chem. Soc. 1965, 87(6), 1353-1364.
Popular Applications:
- Catalytic Asymmetric Synthesis of 2,2-Disubstituted Terminal Epoxides via Dimethyloxosulfonium Methylide Addition to Ketones. J. Am. Chem. Soc. , 130(31), 10078-10079.
- Diastereoselective Synthesis of α-Quaternary Aziridine-2-carboxylates via Aza-Corey-Chaykovsky Aziridination of N-tert-Butanesulfinyl Ketimino Esters. Org. Lett. 2015, 17(22), 5614-5617.
Related Products:
- Trimethylsulfonium iodide, 97% (CAS 2181-42-2)
- Trimethylsulfoxonium iodide, 98% (CAS 1774-47-6)
- Sodium hydride, for synthesis, 60% (CAS 7646-69-7)
- Dimethyl sulfoxide, 99% (CAS 67-68-5)
