Pd-catalyzed thioester coupling
Fukuyama coupling
How the Fukuyama coupling works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: R–C(=O)SEt, R′ZnI, cat. Pd(0) (PdCl₂(PPh₃)₂ or Pd/C). Conditions: THF or toluene, 25 °C. Bonds formed: C(acyl)–C bond (ketone); bonds broken: C(acyl)–S, C–Zn. Stereochemistry: None at carbonyl; retains α-stereocentres. Rate and selectivity: Oxidative addition into C–S is facile; tolerates esters, aldehydes, halides.
At a glance
Step 1: Oxidative addition into C–S
Pd(0) oxidatively adds a thioester's C–S bond — a weaker, more reactive bond than a typical ester's C–O, making thioesters unusually good oxidative-addition partners despite looking like ordinary acyl compounds.
Step 2: Transmetalation with organozinc
An organozinc reagent performs transmetalation onto the resulting acyl-palladium species, transferring its organic group and displacing the thiolate.
Step 3: Reductive elimination
Reductive elimination forms a new ketone directly — this lets a thioester serve as a mild, bench-stable acylating agent for building ketones under conditions gentle enough to leave many other functional groups untouched.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- Ar
- Aryl group. Any aromatic ring substituent such as phenyl.
- THF
- Tetrahydrofuran. Cyclic ether solvent; its oxygen lone pairs solvate Li⁺/Mg²⁺ so organometallics stay dissolved and reactive.
- Pd/C
- Palladium on carbon. Heterogeneous hydrogenation catalyst.
- PPh3
- Triphenylphosphine. Nucleophilic phosphine; forms very strong P=O bonds, driving Wittig, Appel and Mitsunobu reactions.
- L2
- Ligand set. Spectator ligands on the metal that tune its reactivity.
How it compares with related reactions
| Fukuyama coupling | Buchwald-Hartwig amination | Buchwald-Hartwig etherification | |
|---|---|---|---|
| Reagents | R–C(=O)SEt, R′ZnI, cat. Pd(0) (PdCl₂(PPh₃)₂ or Pd/C) | ArBr, R₂NH, Pd₂(dba)₃ / bulky phosphine (XPhos, BINAP), NaOtBu | ArBr, ROH, Pd₂(dba)₃ or Pd(OAc)₂ / bulky biaryl phosphine (RockPhos, tBuBrettPhos), Cs₂CO₃ or NaOtBu |
| Conditions | THF or toluene, 25 °C | Toluene or dioxane, 80–110 °C | Toluene or dioxane, 80–100 °C |
| Stereochemistry | None at carbonyl; retains α-stereocentres | No new stereocentre; retention of aryl geometry | No new stereocentre; aryl geometry retained |
| Rate / selectivity | Oxidative addition into C–S is facile; tolerates esters, aldehydes, halides | Bulky, electron-rich ligand speeds oxidative addition and C–N reductive elimination | C–O reductive elimination is slow, so very bulky ligands are needed |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Fukuyama coupling?
R–C(=O)SEt, R′ZnI, cat. Pd(0) (PdCl₂(PPh₃)₂ or Pd/C). Conditions: THF or toluene, 25 °C.
Which bonds are formed and which are broken?
Formed: C(acyl)–C bond (ketone). Broken: C(acyl)–S, C–Zn.
What is the stereochemical outcome?
None at carbonyl; retains α-stereocentres
What controls the rate or the selectivity?
Oxidative addition into C–S is facile; tolerates esters, aldehydes, halides
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam