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Fischer Indole Synthesis

Fischer indole synthesis   Named Reactions in Organic Synthesis
Reaction category:
Heterocycle formation


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During 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 acids is now known as the Fischer Indole Synthesis. Since its discovery it has remained the most important method of preparing substituted indoles.

The main features of the Fischer Indole synthesis include:

  • the indole formation can be carried out in one-pot as it is not necessary to isolate the intermediate arylhydrazones
  • Unsymmetrical ketones give two region-isomeric 2,3-disubstituted indoles with the region-selectivity dependant 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:

mechanism of Fischer indole synthesis

Often used in conjunction with the Fischer Indole synthes is the Japp-Klingemann reaction that involves coupling arydiazonium salts and 1,3-dicarbonyl compounds to generate the corresponding arylhydrazones.

The total synthesis of both (+_) –deethylibophyllidine and the indole alkaloid tryprostatin A utilized the Fischer Indole synthesis. In the latter the precursor arylhydrazone was prepared using the Japp-Klingemann reaction.



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Other reaction categories:

Electrophilic aromatic substitution

Nucleophilic substitution reactions

Transition Metal-Catalyzed Couplings

Oxidation

Reactions involving carbonyl compounds

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Some relevant Alfa Aesar products for the Fischer indole synthesis:
Ethyl 2-methylacetoacetate, 95%
Methyl 2-ethylacetoacetate, 97%
p-Toluenesulfonic acid monohydrate, 97%
p-Toluenesulfonic acid monohydrate, 98%
p-Toluenesulfonic acid monohydrate, ACS, 98.5+%
Polyphosphoric acid, ca 84% (as phosphorus pentoxide)
Pyridine hydrochloride, 98%
Zinc chloride, ACS, 97% min
Zinc chloride, anhydrous, 99.95% (metals basis)
Zinc chloride, ultra dry, 99.995% (metals basis)
Zinc chloride, 1.9M in 2-MeTHF
Zinc chloride, 1M in diethyl ether
Zinc chloride, 1M in diethyl ether, packaged under Argon in resealable ChemSeal™ bottles
Zinc chloride, 0.7M soln. in THF

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