The Cope elimination reaction involves the stereoselective syn elimination of tertiary amine oxides, which are typically prepared by the oxidation of tertiary amines with a peroxide.
- The Cope elimination promotes the intramolecular elimination of an alkyl N-oxide to yield an alkene and a hydroxylamine.
- Amine oxides are easily prepared by the oxidation of the tertiary amine with a peroxide. Common peroxides include hydrogen peroxide and peroxycarboxylic acids such as m-CPBA.
- The Cope elimination is a one-pot reaction. Isolation of the tertiary amine oxide is not required. The amine is mixed with the oxidizing agent and heated.
- Typically, a tertiary amine is oxidized to yield a zwitterionic N-oxide, which can then abstract a β proton upon heating at 120–150 °C with solvents typically employed for high-temperature reactions, such as DMF and DMSO.
- The reaction is extraordinarily sensitive to solvent effects; million-fold rate increases can be obtained in going from protic to aprotic solvents. Even among aprotic solvents increasing polarity significantly reduces the reaction rate.
- N-oxides can undergo spontaneous Cope elimination at room temperature in polar aprotic solvents (see example 1).Â
Reaction mechanism of Cope elimination
The Cope elimination reaction is concerted and proceeds via a planar five-membered transition state involving the syn hydrogen. The mechanism features a syn periplanar elimination. For more details, see J. Am. Chem. Soc. 2006, 128, 6141.
The Cope elimination involves the thermal decomposition of an amine oxide by a five-membered cyclic transition state. J. Org. Chem. 1973, 38, 1742.
Examples and experimental procedures of Cope elimination
Example 1: Angew. Chem. Int. Ed. 2018, 57, 1991.
To a round-bottom flask equipped with a magnetic stir bar, the racemic amine (0.32 mmol, 1.0 equiv) and DCM (3.10 mL) were added. The solution was cooled in a dry ice/acetone bath and stirred at this temperature for 10 min before the addition of m-CPBA (1.0 equiv) as a solution in DCM. The m-CPBA solution was added dropwise to maintain a consistent temperature. Upon completion of the addition, basic alumina, Al2O3, (0.66 g per mmol), was added to the solution and stirred 20 seconds at this temperature before the solution quickly passed through a plug of basic alumina. Concentration and purification of the filtrate via flash column chromatography afforded the racemic alkene.
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