Fischer indole synthesis
From Wikipedia the free encyclopedia
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 |
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](http://upload.wikimedia.org/wikipedia/commons/thumb/4/47/Fischer_indole_reaction_scheme.svg/400px-Fischer_indole_reaction_scheme.svg.png)
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[edit]
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.
![](http://upload.wikimedia.org/wikipedia/commons/thumb/e/e6/Fischer_Indole_Mechanism.png/700px-Fischer_Indole_Mechanism.png)
Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is incorporated into the resulting indole.[6][7]
Buchwald modification[edit]
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](http://upload.wikimedia.org/wikipedia/commons/thumb/9/9b/Fischer_Indole_Buchwald_Modification_Scheme.png/500px-Fischer_Indole_Buchwald_Modification_Scheme.png)
Application[edit]
- Indometacin preparation.
- Triptan synthesis
- Iprindole synthesis (phenylhydrazine + suberone → 2,3-Cycloheptenoindole).
See also[edit]
- Bartoli indole synthesis
- Japp–Klingemann indole synthesis
- Leimgruber–Batcho indole synthesis
- Larock indole synthesis
Related reactions[edit]
References[edit]
- ^ Fischer, E.; Jourdan, F. (1883). "Ueber die Hydrazine der Brenztraubensäure". Berichte der Deutschen Chemischen Gesellschaft. 16 (2): 2241–2245. doi:10.1002/cber.188301602141.
- ^ Fischer, E.; Hess, O. (1884). "Synthese von Indolderivaten". Berichte der Deutschen Chemischen Gesellschaft. 17 (1): 559–568. doi:10.1002/cber.188401701155.
- ^ van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chemical Reviews. 30 (1): 69–96. doi:10.1021/cr60095a004.
- ^ Robinson, B. (1963). "The Fischer Indole Synthesis". Chemical Reviews. 63 (4): 373–401. doi:10.1021/cr60224a003.
- ^ Robinson, B. (1969). "Studies on the Fischer indole synthesis". Chemical Reviews. 69 (2): 227–250. doi:10.1021/cr60258a004.
- ^ Allen, C. F. H.; Wilson, C. V. (1943). "The Use of N15 as a Tracer Element in Chemical Reactions. The Mechanism of the Fischer Indole Synthesis". Journal of the American Chemical Society. 65 (4): 611–612. doi:10.1021/ja01244a033.
- ^ Clusius, K.; Weisser, H. R. (1952). "Reaktionen mit 15N. III. Zum Mechanismus der Fischer'schen Indolsynthese". Helvetica Chimica Acta. 35 (1): 400–406. doi:10.1002/hlca.19520350151.
- ^ 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 (26): 6621–6622. doi:10.1021/ja981045r.