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Fischer indole synthesis

From Wikipedia, the free encyclopedia

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 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, polyphosphoric acid and
p-toluenesulfonic 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.[3][4][5]

Contents
1 Reaction mechanism
2 Buchwald modification
3 References
4 See also

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 [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.

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

Buchwald modification
Using palladium chemistry developed at MIT by Stephen Buchwald, the Fischer indole synthesis can be
completed using aryl bromides as starting materials.[8] 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
1. ^ Fischer, E.; Jourdan, F. (1883). "Ueber die Hydrazine der Brenztraubensäure". Berichte der deutschen
chemischen Gesellschaft 16: 2241. doi:10.1002/cber.188301602141 (http://dx.doi.org
/10.1002%2Fcber.188301602141) .
2. ^ Fischer, E.; Hess, O. (1884). "Synthese von Indolderivaten". Berichte der deutschen chemischen Gesellschaft 17:
559. doi:10.1002/cber.188401701155 (http://dx.doi.org/10.1002%2Fcber.188401701155) .
3. ^ Van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chemical Reviews 30: 69. doi:10.1021/cr60095a004
(http://dx.doi.org/10.1021%2Fcr60095a004) .
4. ^ Robinson, B. (1963). "The Fischer Indole Synthesis". Chemical Reviews 63: 373–401. doi:10.1021/cr60224a003
(http://dx.doi.org/10.1021%2Fcr60224a003) .
5. ^ Robinson, B. (1969). "Studies on the Fischer indole synthesis". Chemical Reviews 69: 227–250.
doi:10.1021/cr60258a004 (http://dx.doi.org/10.1021%2Fcr60258a004) .
6. ^ Allen, C. F. H.; Wilson, C. V. (1943). Journal of the American Chemical Society 65: 611.
doi:10.1021/ja01244a033 (http://dx.doi.org/10.1021%2Fja01244a033) .
7. ^ Clusius, K.; Weisser, H. R. Helv. Chim. Acta 1952, 35, 400.
8. ^ Wagaw, S.; Yang, B. H.; Buchwald, S. L. (1998). "A Palladium-Catalyzed Strategy for the Preparation of
Indoles: A Novel Entry into the Fischer Indole Synthesis". Journal of the American Chemical Society 120: 6621.
doi:10.1021/ja981045r (http://dx.doi.org/10.1021%2Fja981045r) .

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See also
Bartoli indole synthesis
Japp-Klingemann indole synthesis
Leimgruber-Batcho indole synthesis
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Categories: Indole forming reactions | Name reactions

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