Heterocycle synthesis — sigmatropic
Fischer indole synthesis
How the Fischer 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: Phenylhydrazine, ketone (acetone), acid (ZnCl₂, PPA, H₂SO₄, AcOH). Conditions: 80–180 °C, Brønsted or Lewis acid. Bonds formed: C–C (aryl–CH₂); C–N (ring); aromatic indole; bonds broken: N–N; C=O; C–NH₂. Stereochemistry: None in product; regiochemistry from ene-hydrazine formation. Rate and selectivity: [3,3]-shift is rate-limiting and irreversible.
At a glance
Step 1: Hydrazone, then ene-hydrazine
A phenylhydrazine condenses with a ketone, losing water to form a phenylhydrazone; acid then tautomerizes it to the more reactive ene-hydrazine form.
Step 2: [3,3]-sigmatropic shift
This ene-hydrazine undergoes a [3,3]-sigmatropic rearrangement — the same concerted, closed-loop arrow-pushing pattern as the Claisen and Cope rearrangements you already know — forming a new C–C bond directly to the aromatic ring.
Step 3: Rearomatise, cyclise, lose NH₃
Loss of ammonia and ring closure (an intramolecular condensation) aromatizes the five-membered ring, giving an indole — a core scaffold found throughout natural products and pharmaceuticals.
Abbreviations and terms
- AcOH
- Acetic acid. Weak acid and polar protic solvent.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- Lewis acid
- Lewis acid. Electron-pair acceptor (AlCl₃, BF₃, TiCl₄…) that activates carbonyls and halides.
- H2SO4
- Sulfuric acid. Strong acid and dehydrating agent.
How it compares with related reactions
| Fischer indole synthesis | Bischler indole synthesis | Bischler-Napieralski reaction | |
|---|---|---|---|
| Reagents | Phenylhydrazine, ketone (acetone), acid (ZnCl₂, PPA, H₂SO₄, AcOH) | Aniline (excess), α-haloketone (PhCOCH₂Br) | β-Arylethylamide, POCl₃ (or P₂O₅, Tf₂O) |
| Conditions | 80–180 °C, Brønsted or Lewis acid | Step 1: 25–80 °C; step 2: acid (or aniline·HBr), 150–200 °C | Toluene or MeCN, reflux |
| Stereochemistry | None in product; regiochemistry from ene-hydrazine formation | None | Product is a 3,4-dihydroisoquinoline; none created |
| Rate / selectivity | [3,3]-shift is rate-limiting and irreversible | Cyclisation (high T) is slow; SN2 alkylation is fast | Nitrilium formation then SEAr; electron-rich arenes react best |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Fischer indole synthesis?
Phenylhydrazine, ketone (acetone), acid (ZnCl₂, PPA, H₂SO₄, AcOH). Conditions: 80–180 °C, Brønsted or Lewis acid.
Which bonds are formed and which are broken?
Formed: C–C (aryl–CH₂); C–N (ring); aromatic indole. Broken: N–N; C=O; C–NH₂.
What is the stereochemical outcome?
None in product; regiochemistry from ene-hydrazine formation
What controls the rate or the selectivity?
[3,3]-shift is rate-limiting and irreversible
Study guides that help with this reaction
- Pericyclic reactions explained: cycloadditions, electrocyclisations and sigmatropic shifts
- Stereochemistry in mechanisms: inversion, retention, syn and anti