View source for Chemistry:Fischer indole synthesis

{{Short description|Chemical reaction}}
{{Reactionbox
| Name = Fischer indole synthesis
| Type = Ring forming reaction
| NamedAfter = Hermann Emil Fischer
| Section3 = {{Reactionbox Identifiers
 | OrganicChemistryNamed = fischer-indole-synthesis
 | RSC_ontology_id = 0000064
}}
}}
The '''Fischer indole synthesis''' is a [[Chemistry:Chemical reaction|chemical reaction]] that produces the aromatic [[Chemistry:Heterocyclic compound|heterocycle]] [[Chemistry:Indole|indole]] from a (substituted) [[Chemistry:Phenylhydrazine|phenylhydrazine]] and an [[Chemistry:Aldehyde|aldehyde]] or [[Chemistry:Ketone|ketone]] under [[Chemistry:Acid|acid]]ic conditions.<ref>{{Cite journal | doi = 10.1002/cber.188301602141 | title = Ueber die Hydrazine der Brenztraubensäure | year = 1883 | last1 = Fischer | first1 = E. | last2 = Jourdan | first2 = F. | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 16 | issue = 2 | pages = 2241–2245| url = https://zenodo.org/record/1425301}}</ref><ref>{{Cite journal | doi = 10.1002/cber.188401701155 | title = Synthese von Indolderivaten | year = 1884 | last1 = Fischer | first1 = E. | last2 = Hess| first2 = O. | journal = Berichte der Deutschen Chemischen Gesellschaft | volume = 17 | issue  = 1| pages  = 559–568| url = https://zenodo.org/record/1425321}}</ref> The reaction was discovered in 1883 by [[Biography:Emil Fischer|Emil Fischer]]. Today antimigraine drugs of the [[Chemistry:Triptan|triptan]] class are often synthesized by this method.

[[File:Fischer indole reaction scheme.svg|center|400px|The Fischer indole synthesis]]

This reaction can be catalyzed by Brønsted acids such as HCl, [[Chemistry:Sulfuric acid|H<sub>2</sub>SO<sub>4</sub>]], polyphosphoric acid and p-toluenesulfonic acid or [[Chemistry:Lewis acid|Lewis acid]]s such as [[Chemistry:Boron trifluoride|boron trifluoride]], [[Chemistry:Zinc chloride|zinc chloride]], and [[Chemistry:Aluminium chloride|aluminium chloride]].

Several reviews have been published.<ref>{{Cite journal | doi = 10.1021/cr60095a004 | title = Indole | year = 1942 | last1 = van Order | first1 = R. B. | last2 = Lindwall  | first2 = H. G. | journal = Chemical Reviews | volume = 30 | issue  = 1| pages = 69–96}}</ref><ref>{{Cite journal | doi = 10.1021/cr60224a003 | title = The Fischer Indole Synthesis | year = 1963 | last1 = Robinson | first1 = B. | journal = Chemical Reviews | volume = 63 | issue = 4| pages = 373–401}}</ref><ref>{{Cite journal | last1 = Robinson | first1 = B. | title = Studies on the Fischer indole synthesis | journal = Chemical Reviews | year = 1969 | volume = 69 | issue = 2 | pages = 227–250| doi = 10.1021/cr60258a004}}</ref>

==Reaction mechanism==
The reaction of a (substituted) phenyl[[Chemistry:Hydrazine|hydrazine]] with a carbonyl (aldehyde or ketone) initially forms a phenylhydrazone which [[Chemistry:Isomerization|isomerizes]] to the respective [[Chemistry:Enamine|enamine]] (or 'ene-hydrazine'). After [[Chemistry:Protonation|protonation]], a cyclic [3,3]-sigmatropic rearrangement occurs producing a [[Chemistry:Diimine|diimine]]. The resulting diimine forms a cyclic aminoacetal (or ''aminal''), which under acid [[Chemistry:Catalyst|catalysis]] eliminates [[Chemistry: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]]
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>

==Buchwald modification==
Via a [[Chemistry:Palladium|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.

[[File:Fischer_Indole_Buchwald_Modification_Scheme.png|center|500px|The Buchwald modification of the Fischer indole synthesis]]

<!--[[Chemistry:Methanesulfonic acid|Methanesulfonic acid]] can be used as the acid catalyst in this reaction.
 Need better reference: *Minard et al.  Penn State University. 1992.  The buchwald paper is highly cited -->

==Application==
*[[Chemistry:Indometacin|Indometacin]] preparation.
*[[Chemistry:Triptan|Triptan]] synthesis
*[[Chemistry:Iprindole|Iprindole]] synthesis ([[Chemistry:Phenylhydrazine|phenylhydrazine]] + suberone → 2,3-Cycloheptenoindole).

==See also==
*[[Chemistry:Bartoli indole synthesis|Bartoli indole synthesis]]
*[[Chemistry:Japp–Klingemann reaction|Japp–Klingemann indole synthesis]]
*[[Chemistry:Leimgruber–Batcho indole synthesis|Leimgruber–Batcho indole synthesis]]
*[[Chemistry:Larock indole synthesis|Larock indole synthesis]]

===Related reactions===
*[[Chemistry:Madelung synthesis|Madelung synthesis]]
*[[Chemistry:Reissert indole synthesis|Reissert synthesis]]
*[[Chemistry:Gassman indole synthesis|Gassman synthesis]]
*[[Chemistry:Nenitzescu indole synthesis|Nenitzescu synthesis]]

==References==
{{Reflist}}

[[Category:Name reactions]]

{{Sourceattribution|Fischer indole synthesis}}