TheFischer indole synthesis is achemical reaction that produces thearomaticheterocycleindole from a (substituted)phenylhydrazine and analdehyde orketone underacidic conditions.^[1][2] The reaction was discovered in 1883 byEmil Fischer. Todayantimigraine drugs of thetriptan class are often synthesized by this method.

This reaction can be catalyzed byBrønsted acids such asHCl,H₂SO₄,polyphosphoric acid andp-toluenesulfonic acid orLewis acids such asboron trifluoride,zinc chloride, andaluminium chloride.

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

The reaction of a (substituted) phenylhydrazine with acarbonyl (aldehyde or ketone) initially forms aphenylhydrazone whichisomerizes to the respectiveenamine (or 'ene-hydrazine'). Afterprotonation, a cyclic[3,3]-sigmatropic rearrangement occurs producing adiimine. The resulting diimine forms a cyclicaminoacetal (oraminal), which under acidcatalysis eliminatesNH₃, resulting in the energetically favorable aromatic indole.

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

Via apalladium-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. TheseN-arylhydrazones undergo exchange with other ketones, expanding the scope of this method.

• A variant of the Fischer indolization reaction, termed the interrupted Fischer indolization byGarg and coworkers,^[9] has been used in the total synthesis of akuammiline natural products.^{[10][11][12][13]} The method has also been used in medicinal chemistry.^[14]
• Indometacin preparation.
• Triptan synthesis
• Iprindole synthesis (phenylhydrazine +suberone → 2,3-Cycloheptenoindole).

• Bartoli indole synthesis
• Japp–Klingemann indole synthesis
• Leimgruber–Batcho indole synthesis
• Larock indole synthesis

• Madelung synthesis
• Reissert synthesis
• Gassman synthesis
• Nenitzescu synthesis

• Indole forming reactions
• Name reactions
• Emil Fischer

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• Short description matches Wikidata