Fischer indole synthesis template

Acetone phenylhydrazone tautomerises to the ene-hydrazine. After N-protonation a [3,3]-sigmatropic shift makes the new C–C bond and breaks the N–N bond; rearomatisation, attack of the aniline nitrogen on the iminium ion and loss of ammonia give 2-methylindole.

Mechanism step by step

An aryl hydrazone and acid give an indole: [3,3] shift, ring closure, loss of NH₃

1. Phenylhydrazone – Condensation with the ketone (acid catalysed)
2. Ene-hydrazine – Acid-catalysed tautomerisation, like imine → enamine
3. N-Protonation – The N next to the alkene takes a proton
4. [3,3]-Sigmatropic shift – Key step: the new C–C bond forms as the weak N–N bond breaks
5. Rearomatisation – Tautomerisation (C–H → N–H) restores the benzene ring
6. Ring closure – The aniline N attacks the iminium carbon: a cyclic aminal
7. Proton transfer – H⁺ moves from the ring N to NH₂, making NH₃⁺ a good leaving group
8. Loss of NH₃ – The ring N lone pair pushes out ammonia
9. Deprotonation – Loss of a C–H proton gives the aromatic indole

Key points

• Accepted mechanism (Robinson): ene-hydrazine, [3,3]-sigmatropic shift, ring closure, loss of NH₃; ¹⁵N labelling shows the N next to the ketone carbon is the one lost.
• The ketone needs an α-CH₂ or CH₃; unsymmetrical ketones can give two indoles, depending on which ene-hydrazine forms. Cyclohexanone gives tetrahydrocarbazole.
• Brønsted (H₂SO₄, AcOH, PPA) or Lewis acids (ZnCl₂, BF₃) catalyse it; acetaldehyde fails, so indole itself is made another way.
• Used for tryptamines and the triptan anti-migraine drugs (e.g. sumatriptan).

Drawn with 227 atoms, 22 arrows, 15 shapes – every one editable in MolDraw.

Sources

• Kürti & Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier 2005, Fischer indole synthesis Textbook
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012, ch. 30 Textbook