Fischer indole synthesis

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Fischer indole synthesis
Named after Hermann Emil Fischer
Reaction type Ring forming reaction
Identifiers
Organic Chemistry Portal fischer-indole-synthesis
RSC ontology ID RXNO:0000064

The Fischer indole synthesis is a chemical reaction that produces the aromatic heterocycle indole from a (substituted) phenylhydrazine and an aldehyde or ketone under acidic conditions. [1] [2] The reaction was discovered in 1883 by Emil Fischer. Today antimigraine drugs of the triptan class are often synthesized by this method.

Contents

The Fischer indole synthesis Fischer indole reaction scheme.svg
The Fischer indole synthesis

This reaction can be catalyzed by Brønsted acids such as HCl, H2SO4, polyphosphoric acid and p-toluenesulfonic acid or Lewis acids such as boron trifluoride, zinc chloride, and aluminium chloride.

Several reviews have been published. [3] [4] [5]

Reaction mechanism

The reaction of a (substituted) phenylhydrazine with a carbonyl (aldehyde or ketone) initially forms a phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After protonation, a cyclic [3,3]-sigmatropic rearrangement occurs producing a diimine. The resulting diimine forms a cyclic aminoacetal (or aminal), which under acid catalysis eliminates NH3, resulting in the energetically favorable aromatic indole.

The mechanism of the Fischer indole synthesis Fischer Indole Mechanism.png
The mechanism of the Fischer indole synthesis

Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is incorporated into the resulting indole. [6] [7]

Buchwald modification

Via a palladium-catalyzed reaction, the Fischer indole synthesis can be effected by cross-coupling aryl bromides and hydrazones. [8] This result supports the previously proposed intermediacy as hydrazone intermediates in the classical Fischer indole synthesis. These N-arylhydrazones undergo exchange with other ketones, expanding the scope of this method.

The Buchwald modification of the Fischer indole synthesis Fischer Indole Buchwald Modification Scheme.png
The Buchwald modification of the Fischer indole synthesis


Application

See also

Related Research Articles

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References

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  2. Fischer, E.; Hess, O. (1884). "Synthese von Indolderivaten". Berichte der Deutschen Chemischen Gesellschaft. 17 (1): 559–568. doi:10.1002/cber.188401701155.
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