What Is Corey-Kim Oxidation?
The Corey-Kim oxidation, developed by Elias James Corey and Chong Un Kim in 1972, stands as a valuable tool in the organic chemist's arsenal for converting primary and secondary alcohols to their corresponding aldehydes and ketones. Corey-Kim oxidation reaction refers to the reaction of dimethylchlorosulphonium ion generated by N-chlorosuccinimide/dimethyl sulfide (NCS/DMS) with alcohols, which can be oxidized to aldehydes or ketones by alkali treatment.
In addition, this reaction has a significant solvent effect. The reaction is generally carried out in toluene. Using a more polar solvent (dichloromethane/dimethyl sulfoxide) will lead to the production of methyl sulfide (ROCH2SCH3) as a by-product. For propanol and benzyl alcohol, this reaction affords the corresponding chlorides in high yields.
- Reagents: N-chlorosuccinimide and dimethyl sulfide (NCS/DMS).
- Reactants: primary and secondary alcohols .
- Products: aldehyde or ketone.
- Reaction type: oxidation reaction.
- Related reactions: Swern oxidation.
Fig 1. Corey-Kim oxidation reaction and its mechanism. [1]
Advantages and Limitations
Compared to traditional oxidation methods like chromic acid oxidation or Swern oxidation, the Corey-Kim oxidation offers several advantages. It is milder, exhibits higher functional group tolerance, and avoids the use of hazardous chromium-based reagents. However, the reaction does not efficiently oxidize tertiary alcohols and may not be suitable for substrates sensitive to basic conditions.
Mechanism of Corey-Kim Oxidation
The mechanism of the Corey-Kim oxidation reaction is similar to that of the Swern oxidation. First, DMS attacks the N-Cl bond in NCS to form the Corey-Kim zwitterion 1. This intermediate is thermally unstable and easily decomposes, and must be prepared in situ at low temperature to generate an electrophilic dimethylchlorosulphonium ion 2, which is attacked by the alcohol nucleophilically to obtain the intermediate 3. Subsequently, Et3N captures the proton on the C-O bond, eventually generating an aldehyde or ketone and releasing DMS.
Application Examples of Corey-Kim Oxidation
- Example 1: Since the reagents used are cheap and readily available, it has been applied in the industry, such as the synthesis of the the ketolide antibiotic ABT-773 (cethromycin, >300kg scale). As shown in Scheme, the oxidation of the C-3 hydroxyl of compound 2 provided the ketone 3 as the final isolated intermediate. Final deprotection of the benzoate group in 3 completed the synthesis of ABT-773. [2]
- Example 2: Selective oxidation of specific alcohol functional groups plays a crucial role in the synthesis of complex natural products. Corey-Kim oxidation has been used to prepare various bioactive molecules, such as the antitumor agent paclitaxel, the diterpene natural product ingenol, and the alkaloid cephalotaxine. In the final stage of the total synthesis of the alkaloid cephalolaxine, the ortho-diol intermediate needs to be oxidized to α-diketone. Except for the Corey-Kim oxidation reaction, other methods (Swern, PCC, etc.) were unsuccessful. [3]
Fig 2. Synthetic examples via Corey-Kim oxidation reaction.
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References
- Li, Jie Jack, et al. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Fifth Edition, 2014, 176-177.
- Cink, Russell D., et al. Organic process research & development, 2007, 11(2), 270-274.
- Kuehne, Martin E., et al. The Journal of Organic Chemistry, 1988, 53(15), 3439-3450.
