Pd-catalyzed heteroannulation
Larock indole synthesis
How the Larock indole synthesis 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: o-iodoaniline, internal alkyne, Pd(OAc)₂, PPh₃. Conditions: Na₂CO₃ or K₂CO₃, LiCl, DMF, 100 °C. Bonds formed: Aryl–C (C3) and C–N (N1–C2) bonds; bonds broken: Ar–I; N–H. Stereochemistry: Regioselective: the larger alkyne substituent ends at indole C2. Rate and selectivity: Oxidative addition and alkyne insertion are the key steps; Pd(0) regenerated.
At a glance
Step 1: Oxidative addition into Ar–I
Pd(0) oxidatively adds an ortho-iodoaniline's C–I bond, forming an aryl-palladium species with a free amine positioned nearby, ready to participate later in the same molecule.
Step 2: Alkyne insertion (Heck-type)
An internal alkyne coordinates to palladium and undergoes migratory insertion into the Ar–Pd bond — the same insertion chemistry used in the Heck reaction — forming a new C–C bond and a vinyl-palladium species with the amine now positioned right next to the metal.
Step 3: C–N bond formation closes the ring
The nearby amine displaces palladium in a final reductive-elimination-like C–N bond-forming step, closing the five-membered ring and releasing a fully substituted indole — this single Pd-catalyzed cycle builds both new bonds of the indole ring (C–C and C–N) from two simple, easily varied starting materials.
Abbreviations and terms
- Ar
- Aryl group. Any aromatic ring substituent such as phenyl.
- Ph
- Phenyl. –C₆H₅.
- OAc
- Acetoxy. –OC(=O)CH₃, an acetate group.
- DMF
- N,N-Dimethylformamide. Polar aprotic solvent – dissolves ionic nucleophiles but does not H-bond to them, speeding SN2 and SNAr.
- K2CO3
- Potassium carbonate. Mild inorganic base.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- PPh3
- Triphenylphosphine. Nucleophilic phosphine; forms very strong P=O bonds, driving Wittig, Appel and Mitsunobu reactions.
- Pd(OAc)2
- Palladium(II) acetate. Pd(II) pre-catalyst, reduced in situ to Pd(0).
- L2
- Ligand set. Spectator ligands on the metal that tune its reactivity.
How it compares with related reactions
| Larock indole synthesis | Buchwald-Hartwig amination | Buchwald-Hartwig etherification | |
|---|---|---|---|
| Reagents | o-iodoaniline, internal alkyne, Pd(OAc)₂, PPh₃ | 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 | Na₂CO₃ or K₂CO₃, LiCl, DMF, 100 °C | Toluene or dioxane, 80–110 °C | Toluene or dioxane, 80–100 °C |
| Stereochemistry | Regioselective: the larger alkyne substituent ends at indole C2 | No new stereocentre; retention of aryl geometry | No new stereocentre; aryl geometry retained |
| Rate / selectivity | Oxidative addition and alkyne insertion are the key steps; Pd(0) regenerated | 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 Larock indole synthesis?
o-iodoaniline, internal alkyne, Pd(OAc)₂, PPh₃. Conditions: Na₂CO₃ or K₂CO₃, LiCl, DMF, 100 °C.
Which bonds are formed and which are broken?
Formed: Aryl–C (C3) and C–N (N1–C2) bonds. Broken: Ar–I; N–H.
What is the stereochemical outcome?
Regioselective: the larger alkyne substituent ends at indole C2
What controls the rate or the selectivity?
Oxidative addition and alkyne insertion are the key steps; Pd(0) regenerated
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam