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Fischer Indole Synthesis

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The most widely applied method for indole formation, the Fischer indole synthesis, has been shown on solid support. Following a report of the ability of tetramethylguanidine to promote palladium catalyzed coupling and cyclization in the solution phase one pot synthesis of 2-unsubstituted benzofurans, this methodology was used in the synthesis of a number of indoles on solid support with high yields and under mild reaction conditions. 

A veru well known Fischer indole synthesis is a two step sequence consisting of the formation of a hydrazone followed by a [3,3]-sigmatropic rearrangement and is still a standard method for the synthesis of IND core. The Fischer indole synthesis was developed in 1883, yet still remains a useful method for laboratory and large scale and pharmaceutical preparations. It proceeds via the protic or Lewis acid assited sigmatropic rearrangement of a phenylhydrazone, which is formed from the condensation of a phenylhydrazine and an aldehyde or ketone.

Mechanism

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The Fischer indole synthesis continues to be used extensively; for example, sumatripan and related compounds were prepared by this method.

Fischer indole synthesis was used as part of a synthetic scheme towards the marine alkaloid eudistomidin:

Fischer Indole Synthesis Mechanism

A classical method to synthesize indoles is the Fischer indolization involving the cyclization of aryl hydrazonesin the presence of strong acids. The microwave induced Fischer indole synthesis was performed on montmorillonite K10 clay modified with zinc chloride, providing the desired indoles within a relatively short time frame.

The most commonly used catalyst for the reaction is zinc chloride, which is often used in stoichiometric or greater amounts in a solvent at 150oC or higher temperatures but choice of catalyst, solvent and temperature for optimum yields of indoles depends very much on the structure of the substrate.

The mechanism of Fischer Indole Synthesis is shown below:

Fischer Indole Synthesis Mechanism Example

The synthesis is a simple and practicable one but the mechanism is not so straightforward, since one of the two nitrogen atoms of the hydrazone is lost. It has been established that the nitrogen atom which is retained is the one attached to the sryl group in the hydrazone. 

The key substitution step can be regarded as an internal electrophilic substitution or perhaps better as a [3,3] sigmatropic shift in which a weak (N-N) bond is broken and a strong (C-C) bond is created.

Procedure

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Indole itself has a benzene ring fused with pyrrole ring, both sharing one double bond.
It is aromatic system with 10 electrons. The resonance energy of indole is 200kJ/mol.
 

Fischer Indole Synthesis Procedure

The most important method for the synthesis of indoles involves the reaction of phenyl hydrazine with an aldehyde or ketone in the presence of acid (either mineral acid or Lewis acid). This method was discovered in 1883 by Emil Fischer and known as Fischer indole synthesis. Indole itself cannot be obtained from acetaldehyde by this reaction. 

Fischer Indole Synthesis Procedure Example

Though the Fischer indole synthesis remains one of the most employed routes to indole, it limits itself to a certain type of substrates. The Fischer indole synthesis the most widely used of all indole synthesis has also been adapted to the solid phase. In an early approach only one point of diversity was introduced by reaction of phenylhydrazins except in the cases of the electron deficient. A more practical traceless indole synthesis introducing two points of diversity based on the FIscher indole rearrangement has been established by Waldmann et al.