Fischer Indole synthesis – a heterocycle formation reaction

In 1883, E. Fischer and F. Jourdan treated pyruvic acid 1-methylphenylhydrazone with alcoholic hydrogen chloride and generated 1-methylindole-2-carboxylic acid. Preparing indoles by heating the arylhydrazones of either aldehydes or ketones in the presence of a protic or Lewis acid is now known as the Fischer indole synthesis. Since its discovery, it has remained the most important method of preparing substituted indoles.

Main features of the Fischer indole synthesis:

  • The indole formation can be carried out as a one-pot synthesis, as it is not necessary to isolate the intermediate arylhydrazones
  • Unsymmetrical ketones give two region-isomeric 2,3-disubstituted indoles, with the region-selectivity dependent on acidity of the medium, substitution of the hydrazine, and steric effects
  • 1,2-diketones can give both mono and bis-indoles, the mono-indoles usually forming with strong acid catalysts in refluxing alcohols

Mechanism of the Fischer indole synthesis

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