The Corey-Chaykovsky Reaction

What the Corey-Chaykovsky reaction does

A sulfur ylide is a carbanion sitting right next to a positively charged sulfur: a nucleophilic carbon carrying a built-in leaving group. Point it at a carbonyl and something clever happens. The carbanion adds to the C=O carbon exactly like any nucleophile, generating an alkoxide. But now the alkoxide oxygen and the sulfonium sulfur sit two atoms apart — perfectly placed for an intramolecular S_N2. The alkoxide swings back onto the CH₂, kicks out neutral dimethyl sulfide, and closes an epoxide.

The net transformation is a one-carbon homologation that leaves behind a strained three-membered ring:

    R₂C=O  +  (CH₃)₂S⁺-CH₂⁻   ──→   R₂C—CH₂   +  (CH₃)₂S
                                        \ /
                                         O        (an epoxide / oxirane)

Swap the reagent for the sulfoxonium ylide and aim it at an α,β-unsaturated carbonyl (an enone), and the same methylene unit lands on the C=C instead of the C=O — giving a cyclopropane. Same one-carbon donor, two completely different rings, controlled entirely by which sulfur reagent you reach for.

The mechanism, arrow by arrow

Take the epoxide-forming case with dimethylsulfonium methylide and a ketone. Three steps:

1. Deprotonate to make the ylide. Trimethylsulfonium iodide, [(CH₃)₃S]⁺ I⁻, has acidic methyl protons (a C–H next to S⁺). A strong base — n-butyllithium or NaH — removes one proton to give the ylide (CH₃)₂S⁺–CH₂⁻. The lone pair on carbon is stabilized by the adjacent positive sulfur.
2. Nucleophilic addition to the carbonyl. The ylide carbanion attacks the electrophilic carbonyl carbon. The C=O π electrons fold up onto oxygen. You now have a betaine: a zwitterion with an alkoxide (O⁻) on one carbon and a sulfonium (S⁺) two atoms away.
3. Intramolecular displacement — ring closure. The alkoxide oxygen's lone pair attacks the carbon bearing sulfur (a backside S_N2), forming the C–O bond of the epoxide and simultaneously expelling neutral dimethyl sulfide as the leaving group. Aromaticity is not involved — the driving force is a good neutral leaving group plus formation of two new strong σ bonds.

  step 1:  [(CH₃)₃S]⁺ I⁻  +  n-BuLi  →  (CH₃)₂S⁺-CH₂⁻  +  BuH  +  LiI

  step 2:      O                     O⁻
               ‖                      |
           R — C — R'   +  ⁻CH₂-S⁺Me₂ →  R — C — CH₂ — S⁺Me₂     (betaine)
                                              |
                                              R'

  step 3:     O⁻                     O
              |          SN2         / \
          R — C — CH₂-S⁺Me₂  ──→   R-C — CH₂   +   :S(CH₃)₂
              |                        |
              R'                       R'          (epoxide + dimethyl sulfide)

The sulfoxonium version follows the identical logic, except the leaving group that departs in step 3 is dimethyl sulfoxide, (CH₃)₂S=O, instead of the sulfide. On a plain aldehyde or ketone, both ylides therefore deliver an epoxide.

Reagents, bases and conditions

• Dimethylsulfonium methylide (the reactive one). Made from trimethylsulfonium iodide (or the tetrafluoroborate) with n-BuLi in THF at −20 to 0 °C, or with NaH in DMSO. It is thermally unstable and is generated and used in situ, typically at 0 °C or below. Highly reactive, non-stabilized, adds irreversibly.
• Dimethylsulfoxonium methylide (the stable one). Made from trimethylsulfoxonium iodide, [(CH₃)₃S(O)]⁺ I⁻, with NaH in DMSO/THF, or with KOtBu. The sulfinyl group stabilizes the carbanion, so this ylide is more robust, can be handled near room temperature, and adds reversibly.
• Base. NaH is the workhorse for both salts; n-BuLi is used when you need faster, lower-temperature generation of the sulfonium ylide.
• Solvent. DMSO, THF, or DMSO/THF mixtures. DMSO doubles as a proton shuttle and stabilizing medium.
• Stoichiometry. Usually 1.1–2.0 equivalents of ylide per carbonyl. Excess salt and base are common because ylide generation is not perfectly clean.
• Workup. Aqueous quench; the volatile dimethyl sulfide (bp 38 °C, notoriously smelly) or DMSO washes out. Epoxides are isolated by extraction and chromatography.

Scope, selectivity and stereochemistry

The reaction is broad: aldehydes, ketones, and enones are all fair game, and it tolerates many functional groups that the Wittig or Grignard would attack. Three selectivity handles matter:

• 1,2- vs 1,4-selectivity (the headline). On an enone, the sulfonium ylide adds 1,2 to the carbonyl (kinetic, irreversible) → vinyl epoxide. The sulfoxonium ylide adds 1,4 to the β-carbon (thermodynamic, reversible) → cyclopropane. This is the single most useful rule of the method.
• Diastereoselectivity on epoxides. Because addition is often reversible for the sulfoxonium reagent, the more hindered but thermodynamically favored trans epoxide tends to dominate; the fast, irreversible sulfonium reagent can give the cis (less hindered approach) product. Reagent choice thus also tunes epoxide diastereochemistry.
• Chemoselectivity. An aldehyde reacts faster than a ketone, and a ketone faster than an ester (esters are essentially inert). This lets you epoxidize an aldehyde in the presence of an ester without protection.
• Asymmetric versions. Chiral sulfide catalysts (Aggarwal's camphor-derived sulfides) or chiral sulfonium/sulfoximine ylides deliver enantioenriched epoxides and aziridines, making the reaction a genuine tool for asymmetric synthesis rather than just a racemic curiosity.

Sulfonium vs sulfoxonium ylide

	Dimethylsulfonium methylide	Dimethylsulfoxonium methylide
Structure	(CH₃)₂S⁺-CH₂⁻	(CH₃)₂S(=O)⁺-CH₂⁻
Salt precursor	Trimethylsulfonium iodide	Trimethylsulfoxonium iodide
Base	n-BuLi or NaH	NaH or KOtBu
Stability	Unstable, generate at −20–0 °C, use immediately	Stable, handle near RT
Reactivity	Very reactive, adds irreversibly	Milder, adds reversibly
Control regime	Kinetic	Thermodynamic
Leaving group expelled	Dimethyl sulfide, (CH₃)₂S	Dimethyl sulfoxide, (CH₃)₂S=O
Plain aldehyde / ketone	Epoxide	Epoxide
Enone (α,β-unsaturated)	1,2-addition → vinyl epoxide	1,4-addition → cyclopropane
Epoxide diastereopreference	Often cis (kinetic)	Often trans (thermodynamic)

Worked example: benzaldehyde → styrene oxide

Turn benzaldehyde into styrene oxide (phenyloxirane) with the sulfonium ylide.

  [(CH₃)₃S]⁺ I⁻  +  NaH  ──DMSO, 0 °C──→  (CH₃)₂S⁺-CH₂⁻  (dimethylsulfonium methylide)

  Ph-CHO  +  (CH₃)₂S⁺-CH₂⁻  ──DMSO/THF, 0→25 °C──→   Ph-CH—CH₂   +   (CH₃)₂S
                                                          \ /
                                                           O         (styrene oxide)

• Reagents. Trimethylsulfonium iodide (1.5 equiv), NaH (1.5 equiv), benzaldehyde (1.0 equiv).
• Conditions. Generate the ylide in DMSO at 0 °C, add benzaldehyde, warm to 25 °C, 1–2 h.
• Workup. Quench into water, extract into ether, wash away DMSO and the dimethyl-sulfide odor, distill or chromatograph.
• Result. Styrene oxide in good yield, with the extra CH₂ supplied by the ylide — a clean one-carbon ring-forming step that a Grignard or a Wittig could not do.

Now contrast the enone case: react cyclohexenone with dimethylsulfoxonium methylide and you do not get the vinyl epoxide — you get bicyclo[4.1.0]heptan-2-one, the cyclopropane-fused ketone, because the stabilized ylide adds 1,4 to the β-carbon and the enolate closes onto the added methylene.

Real applications

• Terminal epoxides as building blocks. A terminal epoxide made this way opens regioselectively with nucleophiles (amines, azide, cyanide, Grignards) to give β-substituted alcohols — a standard way to install a two-carbon, oxygen-bearing chain.
• Steroid and terpenoid synthesis. Corey's original demonstrations included methylenation of steroidal ketones; the reaction is still used to spiro-epoxidate rigid polycyclic ketones where a Wittig would be sluggish.
• Cyclopropane pharmacophores. The sulfoxonium-ylide cyclopropanation of enones and enoates builds the strained three-membered rings found in many drugs and agrochemicals, where a cyclopropane locks conformation and blocks metabolism.
• Aggarwal's asymmetric epoxidation and aziridination. Using chiral sulfides catalytically (regenerated in a diazo-based cycle), the Corey-Chaykovsky framework delivers enantiopure epoxides and — with imines instead of carbonyls — aziridines, on scales relevant to process chemistry.
• Homologation logic. Because it adds exactly one carbon and installs a reactive ring, the reaction is a favorite retrosynthetic disconnection: "epoxide → carbonyl + CH₂" or "cyclopropane → enone + CH₂."

Limitations and side reactions

• The sulfonium ylide is fussy. It decomposes on standing and above ~0 °C, so timing and temperature control matter. Slow addition to a cold, freshly made ylide is standard.
• Enolizable ketones. A basic ylide can deprotonate an acidic α-CH instead of adding, returning starting material and consuming reagent. Use excess ylide, or the milder sulfoxonium reagent, for base-sensitive substrates.
• Sterically hindered ketones add slowly; the reversible sulfoxonium ylide can stall on very congested carbonyls.
• Stench and toxicity. Dimethyl sulfide is powerfully malodorous (detectable at ppb levels), and the sulfide/DMSO byproducts plus the iodide salts create real waste-handling considerations at scale.
• Not for esters or amides. These carbonyls are too unreactive; the ylide simply won't add. The method is for aldehydes, ketones, and Michael acceptors only.

Discovery: Corey and Chaykovsky, 1962-65

Elias James Corey and his postdoctoral associate Michael Chaykovsky introduced these ylides at Harvard in the early 1960s, publishing communications in 1962 and a definitive full paper in the Journal of the American Chemical Society in 1965 (J. Am. Chem. Soc. 1965, 87, 1353). They deliberately contrasted the two reagents, establishing the reactive-vs-stabilized dichotomy that still defines the method. The work sits within Corey's broader program of rational synthetic methodology and retrosynthetic analysis, for which he received the 1990 Nobel Prize in Chemistry. Sulfur ylides had been known since Ingold and others, but Corey and Chaykovsky turned them into a predictable, selective tool for building small rings.