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The Fischer indole synthesis is a 
This reaction can be catalyzed by Brønsted acids such as
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 chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
that produces the aromatic
In chemistry, aromaticity is a chemical property of cyclic (ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to sat ...
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 chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
indole
Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environme ...
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 () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...
or ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...
under acidic 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 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...
. Today antimigraine
Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.
Treatment of acute symp ...
drugs of the triptan
Triptans are a family of tryptamine-based 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 headaches, th ...
class are often synthesized by this method.
This reaction can be catalyzed by Brønsted acids such as HCl HCL may refer to:
Science and medicine
* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia
* Harvard Cyclotron Laboratory, from 1961 to 2002, a proton accelerator used for research and development
* Hollow-cathode lamp, a s ...
, H2SO4, polyphosphoric acid
A phosphoric acid, in the general sense, is a phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is bonded to four oxygen (O) atoms, one of them through a double bond, arranged as the corners of a tetrahedron. ...
and p-toluenesulfonic acid
''p''-Toluenesulfonic acid (PTSA or ''p''TsOH) or tosylic acid (TsOH) is an organic compound with the formula CH3 C6H4 SO3H. It is a white extremely hygroscopic solid that is soluble in water, alcohols, and other polar organic solvents. The CH3 ...
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 sp ...
s such as boron trifluoride
Boron trifluoride is the inorganic compound with the formula BF3. 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 bondin ...
, zinc chloride
Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic and e ...
, iron chloride Iron chloride may refer to:
* Iron(II) chloride (ferrous chloride, iron dichloride), FeCl2
* Iron(III) chloride
Iron(III) chloride is the inorganic compound with the formula . Also called ferric chloride, it is a common compound of iron in the + ...
, and aluminium chloride
Aluminium chloride, also known as aluminium trichloride, is an inorganic compound with the formula . It forms hexahydrate with the formula , containing six water molecules of hydration. Both are colourless crystals, but samples are often contam ...
.
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 toxic unless handled in solution as, for example, hydrazin ...
with a carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containin ...
(aldehyde or ketone) initially forms a phenylhydrazone
Hydrazones are a class of organic compounds with the structure . They are related to ketones and aldehydes by the replacement of the oxygen =O with the = functional group. They are formed usually by the action of hydrazine on ketones or aldehydes. ...
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 ...
(or 'ene-hydrazine'). After protonation
In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...
, a cyclic ,3sigmatropic rearrangement occurs producing an imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
. The resulting imine forms a cyclic aminoacetal
In organic chemistry, an aminal or aminoacetal is a functional group or type of organic compound that has two amine groups attached to the same carbon atom: . (As is customary in organic chemistry, R can represent hydrogen or an alkyl group). A ...
(or ''aminal''), which under acid catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycl ...
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 with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself nam ...
-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
*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 pros ...
preparation.
*Triptan
Triptans are a family of tryptamine-based 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 headaches, th ...
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
The Bartoli indole synthesis (also called the Bartoli reaction) is the chemical reaction of ortho-substituted nitroarenes and nitrosoarenes with vinyl Grignard reagents to form substituted indoles.
The reaction is often unsuccessful without s ...
* Japp–Klingemann indole synthesis
* Leimgruber–Batcho indole synthesis
*Larock indole synthesis
The Larock indole synthesis is a heteroannulation reaction that uses palladium as a catalyst to synthesize indoles from an ortho-iodoaniline and a disubstituted alkyne. It is also known as Larock heteroannulation. The reaction is extremely versati ...
Related reactions
* Madelung synthesis * Reissert synthesis * Gassman synthesis * Nenitzescu synthesisReferences
{{Reflist Indole forming reactions Name reactions Emil Fischer