What Is Cope Elimination Reaction?
The Cope elimination reaction involves the elimination of nitrogen oxides to form olefins and is one of the methods for synthesizing olefins. Nitrogen oxides can be obtained by oxidation of amines (H2O2 or MCPBA). There are research reports showing that Cope elimination reaction can be carried out under mild conditions. In addition, Cope elimination reactions are increasingly becoming a useful tool for solid-phase synthesis and construction of compound libraries for active compound screening.
The Cope elimination reaction exhibits significant solvent effects, and aprotic polar solvents can increase the reaction rate by up to a million times. In aprotic solvents, the less polar, the faster the reaction rate. In protic solvents, hydrogen bonding between the amine oxide and the solvent results in a relative rate hysteresis of the amine oxide.
The Mechanism of Cope Elimination Reaction
The reaction mechanism of Cope elimination is Ei cis elimination through a planar five-membered ring transition state. Whether the Cope elimination reaction can proceed and its regioselectivity depend on whether a planar five-membered ring transition state can be formed.
To produce such a cyclic structure, the amino and β-hydrogen atoms must be on the same side, and when forming a five-membered ring transition state, the atomic groups on the α, β-carbon atoms are overlapping. Such a transition state requires a relatively small amount of space. It has high activation energy and is very unstable after formation, making it easy to undergo elimination reactions.
Fig 1. Cope elimination reaction and its mechanism. [1]
Stereoselectivity of Cope Elimination Reaction
Amine oxide functionalities with higher steric hindrance preferentially react with more accessible hydrogens and tend to have better selectivity in favor of less substituted alkenes. Therefore, for simple alkenes, the reaction follows Huffman's rules.
The following structures illustrate the stereochemical requirements for reaching the five-membered cyclic transition state and the influence of stereo-requiring groups on some cyclic compounds.
Fig 2. Structural examples of stereoselectivity of Cope elimination reaction.
Reverse Cope Elimination Reaction
In 1976, House discovered that when unsaturated hydroxylamine is heated, it can be cyclized in a synergistic manner to obtain nitrogen oxides, which can be further converted into hydroxylamine. This reaction is called reverse Cope elimination reaction (or reverse Cope cyclization reaction). [2]
The reverse Cope elimination reaction has become an important method for the synthesis of cyclic nitrogen oxides and has been applied in the synthesis of natural products. In addition, the tandem Cope elimination reaction and reverse Cope elimination reaction have been reported for the synthesis of nitrogen-containing heterocycles.
Fig 3. Reverse Cope elimination reaction and its application. [3]
Application Examples of Cope Elimination Reaction
- Example 1: A single pot dipolar cycloaddition reaction/Cope elimination sequence for the synthesis of a novel P2X7 antagonist (1,4,6,7-tetrahydro-5H-[1,2,3]triazolo [4,5-c]pyridine) with a chiral center. [4]
- Example 2: In the preparation process to obtain medium-sized lactams, cleavage of protecting groups can be achieved by a mild sequence combining N-oxidation and Cope elimination. [5]
Fig 4. Different synthesis examples via Cope elimination reaction.
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References
- Li, J.J. Name Reactions. Springer, Cham., Cope Elimination. 2021, pp 112-114.
- Ciganek E, et al. The Journal of Organic Chemistry, 1995, 60(18), 5795-5802.
- Henry N, et al. Tetrahedron letters, 2007, 48(10), 1691-1694.
- Chrovian C C, et al. Journal of Medicinal Chemistry, 2018, 61(1), 207-223.
- Hegmann N, et al. Organic letters, 2018, 20(24), 7825-7829.
