The Corey–Chaykovsky reaction transfers a one-carbon methylene unit from a DMSO-derived sulfoxonium salt to aldehydes, ketones, and enones, producing epoxides and cyclopropanes. DMSO is both the reaction medium and the structural parent of the ylide reagent, which makes it the standard solvent for this transformation in pharmaceutical manufacturing.
R2C=O + (CH3)2S(O)=CH2NaH, DMSO/THF, 0–25 °C→epoxide (oxirane) + (CH3)2SO
Reaction 1: Corey–Chaykovsky epoxidation — carbonyl compound to epoxide
Where Corey–Chaykovsky in DMSO Is Used
The dominant industrial application is steroid API production. Eplerenone and related aldosterone antagonists are built on a steroid framework whose side-chain and lactone construction relies on methylene-transfer chemistry; a steroidal ketone is epoxidized with trimethylsulfoxonium iodide and NaH in a DMSO/THF mixture, and canrenone-type intermediates are elaborated by the same route.
Beyond steroids, the reaction converts aldehydes and ketones to epoxides that are difficult to obtain by alkene epoxidation, and cyclopropanates electron-poor alkenes without any transition-metal catalyst. Its compatibility with esters, amides, and ethers makes it a late-stage methylene-transfer tool in multi-step medicinal-chemistry sequences.
More Industrial Applications
The reaction is chosen wherever a strained three-membered ring must be installed on a sensitive molecule. Fine-chemical epoxides that cannot tolerate alkene epoxidation conditions are prepared this way, and electron-poor enones are cyclopropanated without palladium, which avoids residual-metal contamination in API chains.
The mechanism proceeds through deprotonation of trimethylsulfoxonium iodide by NaH to form dimethylsulfoxonium methylide, a stabilized ylide whose sulfoxide oxygen is inherited from DMSO. The ylide adds to the carbonyl carbon to give a betaine intermediate, which collapses with displacement of dimethyl sulfoxide to close the epoxide ring. For enones, conjugate addition followed by intramolecular displacement yields cyclopropanes instead.
| Product | Industry | DMSO Step |
|---|---|---|
| Eplerenone | Cardiovascular API | Steroidal ketone → spiro-epoxide |
| Canrenone / spironolactone intermediates | Steroid API | Enone cyclopropanation, methylene transfer |
| Fine-chemical epoxides | Pharma R&D | Carbonyl → epoxide, metal-free |
Table 1: Representative industrial Corey–Chaykovsky processes using DMSO
Why DMSO Rather Than THF or Amide Solvents
DMSO is not interchangeable here: it is the medium in which NaH deprotonates trimethylsulfoxonium iodide at 0–25 °C, and the sulfoxide oxygen in that very salt stabilizes the ylide carbanion. A mixed DMSO/THF blend dissolves the inorganic salt and base while THF moderates the rate and exotherm, which gives a manageable, room-temperature generation rather than the cryogenic conditions required for the sulfonium analogue.
The alternative dimethylsulfonium methylide needs low-temperature generation in THF or liquid ammonia, which is why the sulfoxonium route in DMSO has become the production standard. DMSO also avoids the high-temperature decomposition seen in DMF and the REACH reproductive-toxin classification attached to NMP, so the same solvent suits both laboratory route scouting and plant-scale methylene transfer.
References
- Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc., 1962, 84(5), 867–868.
- Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev., 1997, 97(7), 2341–2372.