Fischer indole synthesis

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.

The Fischer indole synthesis

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

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

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

Application

• A variant of the Fischer indolization reaction, termed the interrupted Fischer indolization by Garg 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).

See also

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

Related reactions

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