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. [Fischer, E.; Jourdan, F. "Ber." 1883, "16", 2241.] [Fischer, E.; Hess, O. "Ber." 1884, "17", 559.] The reaction was discovered in 1883 by Hermann Emil Fischer. Today antimigraine drugs of the triptan class are often synthesized by this method.

The choice of acid catalyst is very important. Bronsted acids such as HCl, H₂SO₄, and polyphosphoric acid have been used successfully. Lewis acids such as boron trifluoride, zinc chloride, iron chloride, and aluminium chloride are also useful catalysts.

Several reviews have been published. [Van Orden, R. B.; Lindwell, H. G. "Chem. Rev." 1942, "30", 69-96. ( [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cr60095a004 Review] )] [Robinson, B. "Chem. Rev." 1963, "63", 373-401. ( [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cr60224a003 Review] )] [Robinson, B. "Chem. Rev." 1969, "69", 227-250. ( [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cr60258a004 Review] )]

Reaction mechanism

The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After protonation, a cyclic [sigmatropic rearrangement| [3,3] -sigmatropic rearrangement] occurs producing an imine. The resulting imine forms a cyclic aminoacetal (or "aminal"), which under acid catalysis that eliminates NH₃, 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. [Allen, C. F. H.; Wilson, C. V. "J. Am. Chem. Soc." 1943, "65", 611.] [Clusius, K.; Weisser, H. R. "Helv. Chim. Acta" 1952, "35", 400.]

Buchwald modification

Using palladium chemistry developed at MIT by Stephen Buchwald, the Fischer indole synthesis can be completed using aryl bromides as starting materials. [Buchwald, S. L. "et al." "J. Am. Chem. Soc." 1998, "120", 6621-6622. (DOI|10.1021/ja981045r)] Note that this also gives evidence to the fact that hydrazones are potential intermediates in the classical Fischer indole synthesis.

Methanesulfonic acid can be used as the acid catalyst in this reaction.

References

ee also

* Bartoli indole synthesis
* Japp-Klingemann indole synthesis
* Leimgruber-Batcho indole synthesis