What Is Corey-Chaykovsky Reaction?
The Corey-Chaykovsky reaction is a formal [1+2] cycloaddition of sulfur ylides 1 or 2 with electrophilic (carbon hetero, carbon carbon) double bonds to obtain three-membered ring compounds, which are most commonly used in the synthesis of epoxides and cyclopropanes. When sulfur ylide 2 is used under n-BuLi/THF conditions, a significant byproduct β-hydroxymethyl sulfide will be generated. Sulfur ylides 1 or 2 can be formed by salt formation with MeI by DMSO or Me2S, respectively, and then deprotonated with strong base (NaH or n-BuLi).
In recent years, substituted sulfur ylides have been successfully developed for the catalytic asymmetric synthesis of epoxides. Its synthetic utility lies in its ability to construct strained three-membered rings with high stereochemical control, making it indispensable in organic synthesis, natural product chemistry, and pharmaceutical research.
- Reagents: Sulfur ylides (generated in situ from sulfonium salts, e.g., trimethylsulfonium iodide, or sulfoxonium salts); strong bases (e.g., NaH, KOH, LDA, n-BuLi).
- Reactants: Carbonyl compounds [aldehydes, ketones (for epoxide formation); α,β-unsaturated carbonyl systems: enones, enals (for cyclopropanation); imines (for aziridine synthesis)].
- Products: Epoxides; cyclopropanes; aziridines.
- Reaction type: Cyclization reaction (heterocyclic).
- Related reactions: Wittig reaction, Johnson-Corey reaction, HWE reaction, Doyle-Kirmse reaction.
- Tips:
Compared with sulfur ylide 2, 1 is less active and can be prepared under heating; while the relatively active 2 can only be prepared and reacted in situ at lower temperatures. There are also some other differences in the chemical properties of the two, such as 1 selectively attacks the double bond of unsaturated ketones while 2 attacks the carbonyl group; when reacting with cyclohexanone derivatives, 1 stereospecifically forms carbon-carbon flat bonds while 2 stereoselectively forms carbon-carbon upright bonds, which makes their synthetic utilization very complementary.
Fig 1. Corey-Chaykovsky reaction and its mechanism. [1]
Mechanism of Corey-Chaykovsky reaction
Although concerted methylene transfer is not excluded, the generally accepted reaction mechanism is as follows:
Sulfur ylide nucleophilically adds to the substrate to form a zwitterionic intermediate (rate-determining step), which then undergoes electron transfer and simultaneously leaves DMSO or Me2S to generate a three-membered ring compound (using cyclopropane and epoxide as examples.
Application Examples of Corey-Chaykovsky Reaction
The small ring units (especially epoxides and cyclopropanes) synthesized using sulfur ylides 1 or 2 have certain tension and are easy to undergo ring-opening reactions to obtain valuable intermediates, which are widely used in the total synthesis of natural products. For example, 1 was used to obtain the epoxide required for the synthesis of tetracyclic diterpene (+)-methyl gummiferolate with high stereoselectivity. For another example, sulfur ylide 2 reacts with steroidal derivatives to stereoselectively obtain epoxides, which are then opened with different nucleophiles to establish a small molecule library. The following are some recently reported application examples of Corey-Chaykovsky reaction:
- Example 1: Spirocyclic indoles have attracted great research enthusiasm due to their unique structures and diverse but target-specific pharmacological properties. Saumen Hajra et al. developed a sequential Corey-Chaykovsky reaction of isatin, spiroepoxy or spiroaziridine oxindoles with sulfur ylide, realizing a convenient and direct one-pot reaction mode to obtain a series of spirocyclopropyl oxindoles. [2]
- Example 2: Dmytro V. Yarmoliuk et al. optimized the key Corey–Chaykovsky reaction conditions to construct two isomeric methanoazepane frameworks with a yield of 55–65%, reaching the multi-gram level. [3]
Fig 2. Synthetic examples via Corey-Chaykovsky reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 128-130.
- Hajra, Saumen, et al. Organic letters, 2018, 20(15), 4540-4544.
- Yarmoliuk, Dmytro V., et al. Tetrahedron Letters, 2018, 59(52), 4611-4615.
