Fischer Indole Synthesis - ..
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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, H 2 SO 4 , 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 NH 3 , resulting in the energetically favorable aromatic indole. Fischer indole synthesis - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Fischer_indole_synthesis 1 of 3 12-09-2010 20:39
Transcript of Fischer Indole Synthesis - ..
Fischer indole synthesisFrom 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 wasdiscovered in 1883 by Hermann Emil Fischer. Today antimigraine drugs of the triptan class are oftensynthesized by this method.
The choice of acid catalyst is very important. Bronsted acids such as HCl, H2SO4, polyphosphoric acid andp-toluenesulfonic acid have been used successfully. Lewis acids such as boron trifluoride, zinc chloride, ironchloride, and aluminium chloride are also useful catalysts.
Several reviews have been published.[3][4][5]
Contents
1 Reaction mechanism2 Buchwald modification3 References4 See also
Reaction mechanism
The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a phenylhydrazonewhich isomerizes to the respective enamine (or 'ene-hydrazine'). After protonation, a cyclic [3,3]-sigmatropicrearrangement occurs producing an imine. The resulting imine forms a cyclic aminoacetal (or aminal), whichunder 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 intothe resulting indole.[6][7]
Buchwald modification
Using palladium chemistry developed at MIT by Stephen Buchwald, the Fischer indole synthesis can becompleted using aryl bromides as starting materials.[8] Note that this also gives evidence to the fact thathydrazones are potential intermediates in the classical Fischer indole synthesis.
Methanesulfonic acid can be used as the acid catalyst in this reaction.
References^ Fischer, E.; Jourdan, F. (1883). "Ueber die Hydrazine der Brenztraubensäure". Berichte der deutschenchemischen Gesellschaft 16: 2241. doi:10.1002/cber.188301602141 (http://dx.doi.org/10.1002%2Fcber.188301602141) .
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^ 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) .
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^ Van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chemical Reviews 30: 69. doi:10.1021/cr60095a004(http://dx.doi.org/10.1021%2Fcr60095a004) .
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^ Robinson, B. (1963). "The Fischer Indole Synthesis". Chemical Reviews 63: 373–401. doi:10.1021/cr60224a003(http://dx.doi.org/10.1021%2Fcr60224a003) .
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^ 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) .
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^ 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) .
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^ Clusius, K.; Weisser, H. R. Helv. Chim. Acta 1952, 35, 400.7.^ Wagaw, S.; Yang, B. H.; Buchwald, S. L. (1998). "A Palladium-Catalyzed Strategy for the Preparation ofIndoles: 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 synthesisJapp-Klingemann indole synthesisLeimgruber-Batcho indole synthesis
Retrieved from "http://en.wikipedia.org/wiki/Fischer_indole_synthesis"Categories: Indole forming reactions | Name reactions
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