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The Fischer indole synthesis is a 
This reaction can be catalyzed by Brønsted acids such as HCl, H2SO4,
Isotopic labelling studies show that the aryl nitrogen (N1) of the starting phenylhydrazine is incorporated into the resulting indole.
chemical reaction
A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...
that produces the aromatic
In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...
indole
Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
from a (substituted) phenylhydrazine
Phenylhydrazine is the chemical compound with the formula . It is often abbreviated as . It is also found in edible mushrooms.
Properties
Phenylhydrazine forms monoclinic prisms that melt to an oil around room temperature which may turn yellow ...
and an aldehyde
In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
or ketone
In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
under acid
An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...
ic conditions. The reaction was discovered in 1883 by Emil Fischer
Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and List of Nobel laureates in Chemistry, 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fisch ...
. Today antimigraine drugs of the triptan
Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...
class are often synthesized by this method.
This reaction can be catalyzed by Brønsted acids such as HCl, H2SO4, polyphosphoric acid
In chemistry, a phosphoric acid, in the general sense, is a phosphorus acid, phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is chemical bond, bonded to four oxygen (O) atoms, one of them through a double b ...
and p-toluenesulfonic acid or Lewis acid
A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any ...
s such as boron trifluoride
Boron trifluoride is the inorganic compound with the formula . This pungent, colourless, and toxic gas forms white fumes in moist air. It is a useful Lewis acid and a versatile building block for other boron compounds.
Structure and bonding
The g ...
, zinc chloride
Zinc chloride is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula ZnCl2·''n''H2O, with ''n'' ranging from 0 to 4.5, forming water of hydration, hydrates. Zinc chloride, anhydrous and its hydrates, are colo ...
, and aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms a hexahydrate with the formula , containing six water molecules of hydration. Both the anhydrous form and the hexahydrate are col ...
.
Several reviews have been published.
Reaction mechanism
The reaction of a (substituted) phenylhydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly hazardous unless handled in solution as, for example, hydraz ...
with a carbonyl
In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...
(aldehyde or ketone) initially forms a phenylhydrazone which isomerizes to the respective enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the r ...
(or 'ene-hydrazine'). After protonation
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), usually denoted by H+, to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brø ...
, a cyclic ,3sigmatropic rearrangement occurs producing a diimine
Diimines are organic compounds containing two imine (RCH=NR') groups. Common derivatives are 1,2-diimines and 1,3-diimines. These compounds are used as ligands, but they are also precursors to other organic compounds.
Preparation
Diimines are ...
. The resulting diimine forms a cyclic aminoacetal (or ''aminal''), which under acid catalysis
Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
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.
Buchwald modification
Via apalladium
Palladium is a chemical element; it has symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1802 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas (formally 2 Pallas), ...
-catalyzed reaction, the Fischer indole synthesis can be effected by cross-coupling aryl bromides and hydrazones. 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, has been used in the total synthesis of akuammiline natural products. The method has also been used in medicinal chemistry. *Indometacin
Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of ...
preparation.
*Triptan
Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...
synthesis
* Iprindole synthesis (phenylhydrazine
Phenylhydrazine is the chemical compound with the formula . It is often abbreviated as . It is also found in edible mushrooms.
Properties
Phenylhydrazine forms monoclinic prisms that melt to an oil around room temperature which may turn yellow ...
+ suberone → 2,3-Cycloheptenoindole).
See also
* Bartoli indole synthesis * Japp–Klingemann indole synthesis * Leimgruber–Batcho indole synthesis * Larock indole synthesisRelated reactions
* Madelung synthesis * Reissert synthesis * Gassman synthesis * Nenitzescu synthesisReferences
{{Reflist Indole forming reactions Name reactions Emil Fischer