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The reaction of a (substituted) phenyl[[hydrazine]] with a [[carbonyl]] (aldehyde or ketone) initially forms a [[phenylhydrazone]] which [[isomerization|isomerizes]] to the respective [[enamine]] (or 'ene-hydrazine'). After [[protonation]], a cyclic [[sigmatropic rearrangement|[3,3]-sigmatropic rearrangement]] occurs producing a [[diimine]]. The resulting diimine forms a cyclic [[aminoacetal]] (or ''aminal''), which under acid [[catalyst|catalysis]] eliminates [[Ammonia|NH<sub>3</sub>]], resulting in the energetically favorable aromatic indole. | The reaction of a (substituted) phenyl[[hydrazine]] with a [[carbonyl]] (aldehyde or ketone) initially forms a [[phenylhydrazone]] which [[isomerization|isomerizes]] to the respective [[enamine]] (or 'ene-hydrazine'). After [[protonation]], a cyclic [[sigmatropic rearrangement|[3,3]-sigmatropic rearrangement]] occurs producing a [[diimine]]. The resulting diimine forms a cyclic [[aminoacetal]] (or ''aminal''), which under acid [[catalyst|catalysis]] eliminates [[Ammonia|NH<sub>3</sub>]], resulting in the energetically favorable aromatic indole. | ||
[[File:Fischer Indole Mechanism.png|center|thumb|700x700px|The mechanism of the Fischer indole synthesis]] | [[File:Fischer Indole Mechanism.png|center|thumb|700x700px|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.<ref>{{Cite journal | doi = 10.1021/ja01244a033 | year = 1943 | last1 = Allen | first1 = C. F. H. | last2 = Wilson | first2 = C. V. | title = The Use of N<sup>15</sup> as a Tracer Element in Chemical Reactions. The Mechanism of the Fischer Indole Synthesis| journal = Journal of the American Chemical Society | volume = 65 | issue = 4 | pages = 611–612}}</ref><ref>{{cite journal |author1=Clusius, K. |author2=Weisser, H. R. | title = Reaktionen mit <sup>15</sup>N. III. Zum Mechanismus der Fischer'schen Indolsynthese|journal = Helvetica Chimica Acta | year = 1952 | volume = 35 | issue = 1 | pages = 400–406 | doi = 10.1002/hlca.19520350151}}</ref> | Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is incorporated into the resulting indole.<ref>{{Cite journal | doi = 10.1021/ja01244a033 | year = 1943 | last1 = Allen | first1 = C. F. H. | last2 = Wilson | first2 = C. V. | title = The Use of N<sup>15</sup> as a Tracer Element in Chemical Reactions. The Mechanism of the Fischer Indole Synthesis| journal = Journal of the American Chemical Society | volume = 65 | issue = 4 | pages = 611–612| bibcode = 1943JAChS..65..611A }}</ref><ref>{{cite journal |author1=Clusius, K. |author2=Weisser, H. R. | title = Reaktionen mit <sup>15</sup>N. III. Zum Mechanismus der Fischer'schen Indolsynthese|journal = Helvetica Chimica Acta | year = 1952 | volume = 35 | issue = 1 | pages = 400–406 | doi = 10.1002/hlca.19520350151}}</ref> | ||
==Buchwald modification== | ==Buchwald modification== | ||
Via a [[palladium]]-catalyzed reaction, the Fischer indole synthesis can be effected by cross-coupling aryl bromides and hydrazones.<ref>{{Cite journal | last1 = Wagaw| first1 = S. | last2 = Yang|first2 = B. H. | last3 = Buchwald | first3 = S. L. | title = A Palladium-Catalyzed Strategy for the Preparation of Indoles: A Novel Entry into the Fischer Indole Synthesis | journal = Journal of the American Chemical Society | year =1998 | volume = 120 | issue = 26 | pages = 6621–6622| doi = 10.1021/ja981045r}}</ref> 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. | Via a [[palladium]]-catalyzed reaction, the Fischer indole synthesis can be effected by cross-coupling aryl bromides and hydrazones.<ref>{{Cite journal | last1 = Wagaw| first1 = S. | last2 = Yang|first2 = B. H. | last3 = Buchwald | first3 = S. L. | title = A Palladium-Catalyzed Strategy for the Preparation of Indoles: A Novel Entry into the Fischer Indole Synthesis | journal = Journal of the American Chemical Society | year =1998 | volume = 120 | issue = 26 | pages = 6621–6622| doi = 10.1021/ja981045r| bibcode = 1998JAChS.120.6621W }}</ref> 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. | ||
[[File:Fischer_Indole_Buchwald_Modification_Scheme.png|center|500px|The Buchwald modification of the Fischer indole synthesis]] | [[File:Fischer_Indole_Buchwald_Modification_Scheme.png|center|500px|The Buchwald modification of the Fischer indole synthesis]] | ||
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==Application== | ==Application== | ||
*A variant of the Fischer indolization reaction, termed the interrupted Fischer indolization by [[Neil Garg|Garg]] and coworkers,<ref>{{Cite journal |last1=Susick |first1=Robert B. |last2=Morrill |first2=Lucas A. |last3=Picazo |first3=Elias |last4=Garg |first4=Neil K. |date=January 2017 |title=Pardon the Interruption: A Modification of Fischer's Venerable Reaction for the Synthesis of Heterocycles and Natural Products |journal=Synlett |language=en |volume=28 |issue=1 |pages=1–11 |doi=10.1055/s-0036-1588372 |issn=0936-5214 |pmc=5846481 |pmid=29540961}}</ref> has been used in the total synthesis of akuammiline natural products.<ref>{{Cite journal |last1=Picazo |first1=Elias |last2=Morrill |first2=Lucas A. |last3=Susick |first3=Robert B. |last4=Moreno |first4=Jesus |last5=Smith |first5=Joel M. |last6=Garg |first6=Neil K. |date=2018-05-23 |title=Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies |journal=Journal of the American Chemical Society |language=en |volume=140 |issue=20 |pages=6483–6492 |doi=10.1021/jacs.8b03404 |issn=0002-7863 |pmc=6085837 |pmid=29694031}}</ref><ref>{{Cite journal |last1=Moreno |first1=Jesus |last2=Picazo |first2=Elias |last3=Morrill |first3=Lucas A. |last4=Smith |first4=Joel M. |last5=Garg |first5=Neil K. |date=2016-02-03 |title=Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2( S )-Cathafoline, and (−)-Aspidophylline A |journal=Journal of the American Chemical Society |language=en |volume=138 |issue=4 |pages=1162–1165 |doi=10.1021/jacs.5b12880 |issn=0002-7863 |pmc=5154302 |pmid=26783944}}</ref><ref>{{Cite journal |last1=Smith |first1=Joel M. |last2=Moreno |first2=Jesus |last3=Boal |first3=Ben W. |last4=Garg |first4=Neil K. |date=2015-09-18 |title=Fischer Indolizations as a Strategic Platform for the Total Synthesis of Picrinine |url=https://pubs.acs.org/doi/10.1021/acs.joc.5b00872 |journal=The Journal of Organic Chemistry |language=en |volume=80 |issue=18 |pages=8954–8967 |doi=10.1021/acs.joc.5b00872 |pmid=26134260 |issn=0022-3263|url-access=subscription }}</ref><ref>{{Cite journal |last1=Smith |first1=Joel M. |last2=Moreno |first2=Jesus |last3=Boal |first3=Ben W. |last4=Garg |first4=Neil K. |date=2015-01-07 |title=Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201406866 |journal=Angewandte Chemie International Edition |language=en |volume=54 |issue=2 |pages=400–412 |doi=10.1002/anie.201406866 |pmid=25346244 |issn=1433-7851|url-access=subscription }}</ref> The method has also been used in medicinal chemistry.<ref>{{Cite journal |last1=Bilousova |first1=Tina |last2=Simmons |first2=Bryan J. |last3=Knapp |first3=Rachel R. |last4=Elias |first4=Chris J. |last5=Campagna |first5=Jesus |last6=Melnik |first6=Mikhail |last7=Chandra |first7=Sujyoti |last8=Focht |first8=Samantha |last9=Zhu |first9=Chunni |last10=Vadivel |first10=Kanagasabai |last11=Jagodzinska |first11=Barbara |last12=Cohn |first12=Whitaker |last13=Spilman |first13=Patricia |last14=Gylys |first14=Karen H. |last15=Garg |first15=Neil K. |date=2020-06-19 |title=Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease |journal=ACS Chemical Biology |language=en |volume=15 |issue=6 |pages=1671–1684 |doi=10.1021/acschembio.0c00311 |issn=1554-8929 |pmc=8297715 |pmid=32352753}}</ref> | *A variant of the Fischer indolization reaction, termed the interrupted Fischer indolization by [[Neil Garg|Garg]] and coworkers,<ref>{{Cite journal |last1=Susick |first1=Robert B. |last2=Morrill |first2=Lucas A. |last3=Picazo |first3=Elias |last4=Garg |first4=Neil K. |date=January 2017 |title=Pardon the Interruption: A Modification of Fischer's Venerable Reaction for the Synthesis of Heterocycles and Natural Products |journal=Synlett |language=en |volume=28 |issue=1 |pages=1–11 |doi=10.1055/s-0036-1588372 |issn=0936-5214 |pmc=5846481 |pmid=29540961}}</ref> has been used in the total synthesis of akuammiline natural products.<ref>{{Cite journal |last1=Picazo |first1=Elias |last2=Morrill |first2=Lucas A. |last3=Susick |first3=Robert B. |last4=Moreno |first4=Jesus |last5=Smith |first5=Joel M. |last6=Garg |first6=Neil K. |date=2018-05-23 |title=Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies |journal=Journal of the American Chemical Society |language=en |volume=140 |issue=20 |pages=6483–6492 |doi=10.1021/jacs.8b03404 |issn=0002-7863 |pmc=6085837 |pmid=29694031|bibcode=2018JAChS.140.6483P }}</ref><ref>{{Cite journal |last1=Moreno |first1=Jesus |last2=Picazo |first2=Elias |last3=Morrill |first3=Lucas A. |last4=Smith |first4=Joel M. |last5=Garg |first5=Neil K. |date=2016-02-03 |title=Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2( S )-Cathafoline, and (−)-Aspidophylline A |journal=Journal of the American Chemical Society |language=en |volume=138 |issue=4 |pages=1162–1165 |doi=10.1021/jacs.5b12880 |issn=0002-7863 |pmc=5154302 |pmid=26783944|bibcode=2016JAChS.138.1162M }}</ref><ref>{{Cite journal |last1=Smith |first1=Joel M. |last2=Moreno |first2=Jesus |last3=Boal |first3=Ben W. |last4=Garg |first4=Neil K. |date=2015-09-18 |title=Fischer Indolizations as a Strategic Platform for the Total Synthesis of Picrinine |url=https://pubs.acs.org/doi/10.1021/acs.joc.5b00872 |journal=The Journal of Organic Chemistry |language=en |volume=80 |issue=18 |pages=8954–8967 |doi=10.1021/acs.joc.5b00872 |pmid=26134260 |issn=0022-3263|url-access=subscription }}</ref><ref>{{Cite journal |last1=Smith |first1=Joel M. |last2=Moreno |first2=Jesus |last3=Boal |first3=Ben W. |last4=Garg |first4=Neil K. |date=2015-01-07 |title=Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.201406866 |journal=Angewandte Chemie International Edition |language=en |volume=54 |issue=2 |pages=400–412 |doi=10.1002/anie.201406866 |pmid=25346244 |issn=1433-7851|url-access=subscription }}</ref> The method has also been used in medicinal chemistry.<ref>{{Cite journal |last1=Bilousova |first1=Tina |last2=Simmons |first2=Bryan J. |last3=Knapp |first3=Rachel R. |last4=Elias |first4=Chris J. |last5=Campagna |first5=Jesus |last6=Melnik |first6=Mikhail |last7=Chandra |first7=Sujyoti |last8=Focht |first8=Samantha |last9=Zhu |first9=Chunni |last10=Vadivel |first10=Kanagasabai |last11=Jagodzinska |first11=Barbara |last12=Cohn |first12=Whitaker |last13=Spilman |first13=Patricia |last14=Gylys |first14=Karen H. |last15=Garg |first15=Neil K. |date=2020-06-19 |title=Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease |journal=ACS Chemical Biology |language=en |volume=15 |issue=6 |pages=1671–1684 |doi=10.1021/acschembio.0c00311 |issn=1554-8929 |pmc=8297715 |pmid=32352753}}</ref> | ||
*[[Indometacin]] preparation. | *[[Indometacin]] preparation. | ||
*[[Triptan]] synthesis | *[[Triptan]] synthesis | ||
Latest revision as of 02:26, 26 June 2025
Template:Short description Template:Reactionbox 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.
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.
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.
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
References
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