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.
| 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.
Reaction mechanism
editThe 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.
Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is incorporated into the resulting indole.[6][7]
Buchwald modification
editVia 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.
Application
edit- 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
edit- Bartoli indole synthesis
- Japp–Klingemann indole synthesis
- Leimgruber–Batcho indole synthesis
- Larock indole synthesis
Related reactions
editReferences
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.
- ^ Susick, Robert B.; Morrill, Lucas A.; Picazo, Elias; Garg, Neil K. (January 2017). "Pardon the Interruption: A Modification of Fischer's Venerable Reaction for the Synthesis of Heterocycles and Natural Products". Synlett. 28 (1): 1–11. doi:10.1055/s-0036-1588372. ISSN 0936-5214. PMC 5846481. PMID 29540961.
- ^ Picazo, Elias; Morrill, Lucas A.; Susick, Robert B.; Moreno, Jesus; Smith, Joel M.; Garg, Neil K. (2018-05-23). "Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies". Journal of the American Chemical Society. 140 (20): 6483–6492. doi:10.1021/jacs.8b03404. ISSN 0002-7863. PMC 6085837. PMID 29694031.
- ^ Moreno, Jesus; Picazo, Elias; Morrill, Lucas A.; Smith, Joel M.; Garg, Neil K. (2016-02-03). "Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2( S )-Cathafoline, and (−)-Aspidophylline A". Journal of the American Chemical Society. 138 (4): 1162–1165. doi:10.1021/jacs.5b12880. ISSN 0002-7863. PMC 5154302. PMID 26783944.
- ^ Smith, Joel M.; Moreno, Jesus; Boal, Ben W.; Garg, Neil K. (2015-09-18). "Fischer Indolizations as a Strategic Platform for the Total Synthesis of Picrinine". The Journal of Organic Chemistry. 80 (18): 8954–8967. doi:10.1021/acs.joc.5b00872. ISSN 0022-3263. PMID 26134260.
- ^ Smith, Joel M.; Moreno, Jesus; Boal, Ben W.; Garg, Neil K. (2015-01-07). "Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis". Angewandte Chemie International Edition. 54 (2): 400–412. doi:10.1002/anie.201406866. ISSN 1433-7851. PMID 25346244.
- ^ Bilousova, Tina; Simmons, Bryan J.; Knapp, Rachel R.; Elias, Chris J.; Campagna, Jesus; Melnik, Mikhail; Chandra, Sujyoti; Focht, Samantha; Zhu, Chunni; Vadivel, Kanagasabai; Jagodzinska, Barbara; Cohn, Whitaker; Spilman, Patricia; Gylys, Karen H.; Garg, Neil K. (2020-06-19). "Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease". ACS Chemical Biology. 15 (6): 1671–1684. doi:10.1021/acschembio.0c00311. ISSN 1554-8929. PMC 8297715. PMID 32352753.