What Is the Corey-Fuchs Reaction?
The Corey-Fuchs reaction refers to the reaction of aldehydes with CBr4 and PPh3, which undergoes one-carbon homologation to form dibromoolefins, which are then treated with n-BuLi to obtain terminal alkynes. Compared with the early preparation methods of dibromoolefin derivatives, the addition of Zn powder promotes the formation of ylide intermediates, thereby reducing the amount of Ph3P, making separation easier and yielding higher. For sensitive substrates (such as epoxy aldehydes), Et3N is required to replace Zn to achieve good results. As early as 2000, the industry had developed an equivalent synthesis method for CCl3CO2H, which solved the problem of difficult handling of Ph3P(O) in large-scale synthesis and could achieve 300~400g scale preparation.
Mechanism of Corey-Fuchs Reaction
The generally accepted reaction process currently includes: PPh3 nucleophilically attacks CBr4, and the intermediate formed is then nucleophilically attacked by bromoform anion to form dibromomethylene phosphorus ylide. Then, similar to the Wittig reaction, the amphoteric intermediate formed by the addition of the aldehyde carbonyl group is cyclized to form an oxaphosphine, which is further fragmented into triphenylphosphine oxide and dibromoolefin. The latter undergoes trans-HBr elimination with n-BuLi to obtain a bromoalkyne, which is then exchanged with a second molecule of n-BuLi for Br-Li, and finally quenched with acid to obtain an alkyne with one carbon added.
Fig 1. Schematic diagram of the Corey-Fuchs reaction and its mechanism. [1]
Application Examples of Corey-Fuchs Reaction
- Example 1: The alkyne functional group obtained by the Corey-Fuchs reaction can undergo many subsequent transformations, such as metal-catalyzed coupling reactions and nucleophilic addition reactions to carbonyl groups, and has been effectively used in the total synthesis of natural products. For example, the monoalkyne cyclohexylcarboxaldehyde is converted into a dialkyne by this reaction, and then the ten-membered macrocyclic alkene diyne skeleton of the antitumor dynemicin is constructed by the Stille reaction. [2] Williams used the Corey-Fuchs reaction to convert vanillin into an aromatic acetylene Grignard reagent, which then underwent diastereoselective nucleophilic addition with α-bromoketone. The resulting alcohol can be used to obtain a class of diterpene alkaloid skeletons through several steps of reaction. [3]
- Example 2: Mohan Dumpala et al. first reported a stereoselective total synthesis strategy for distaminolyne A, which combines the key steps of Corey-Fuchs alkyne formation reaction, Cardiot-Chodkiewicz cross coupling and subsequent Wittig olefination reaction. The preparation of terminal alkynes as Sonogashira precursors was successfully achieved through the Corey-Fuchs reaction. [4]
- Example 3: Jacek Martynow et al. improved the Corey-Fuchs method for synthesizing alkynes from aldehydes and achieved production-scale synthesis of alkynes with batch sizes close to 100 grams. This work demonstrates that the synthesis of the dibromo-methylene intermediate (S)-{4-[3-chloro-5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-methyl-butyl}-carbamic acid benzyl ester using P(OCH3)3/CBr4 in toluene can be used to synthesize target substituted aromatic alkyne (S)-[4-(3-chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]-carbamic acid benzyl ester under conditions suitable for scale-up. [5]
Fig 2. Different synthesis examples via Corey-Fuchs reaction.
Related Products
References
- Li, J.J. Name Reactions. Springer, Cham., Corey-Fuchs Reaction. 2021, pp 131-133.
- Danishefsky S J, et al. The Journal of Organic Chemistry, 1996, 61(1), 16-44.
- Williams C M, et al. Organic Letters, 2003, 5(19): 3499-3502.
- Dumpala M, et al. Tetrahedron Letters, 2017, 58(13), 1273-1275.
- Martynow J, et al. Organic Process Research & Development, 2019, 23(5), 1026-1033.
