Fischer indole synthesis

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

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

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.

The mechanism of the Fischer indole synthesis

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

Buchwald modification

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

Application

• 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

• Bartoli indole synthesis
• Japp–Klingemann indole synthesis
• Leimgruber–Batcho indole synthesis
• Larock indole synthesis

Related reactions

• Madelung synthesis
• Reissert synthesis
• Gassman synthesis
• Nenitzescu synthesis

References

1. Fischer, E.; Jourdan, F. (1883). "Ueber die Hydrazine der Brenztraubensäure". Berichte der Deutschen Chemischen Gesellschaft. 16 (2): 2241–2245. doi:10.1002/cber.188301602141.
2. Fischer, E.; Hess, O. (1884). "Synthese von Indolderivaten". Berichte der Deutschen Chemischen Gesellschaft. 17 (1): 559–568. doi:10.1002/cber.188401701155.
3. van Order, R. B.; Lindwall, H. G. (1942). "Indole". Chemical Reviews. 30 (1): 69–96. doi:10.1021/cr60095a004.
4. Robinson, B. (1963). "The Fischer Indole Synthesis". Chemical Reviews. 63 (4): 373–401. doi:10.1021/cr60224a003.
5. Robinson, B. (1969). "Studies on the Fischer indole synthesis". Chemical Reviews. 69 (2): 227–250. doi:10.1021/cr60258a004.
6. 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.
7. 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.
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 (26): 6621–6622. doi:10.1021/ja981045r.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.