Synthesis of INDOLES

(By the method of disconnections)

The indole ring system has been found in many natural compounds of great chemical and biochemical interest, which is why it is said to be the most abundant in nature. Thus, tryptophan is an essential amino acid, indigo is a dye, and indolyl-3-acetic acid is a plant growth hormone. On the other hand, interest in these molecules arises from their pharmacological use, examples being sumatriptan (antimigraine) and frovatriptan, also an antimigraine.

Indole is a colorless crystalline solid with a mp 52°C, easily soluble in most organic solvents and crystallizes from water, has a pleasant odor and is therefore also used as a perfume base.

It was first prepared in 1866 by heating oxindole with zinc dust and has become an important commercial product. Baeyer in 1869 proposed the following synthesis:


The classical synthesis methods for indoles are those of Fischer, Bischler, Reissert and Leimgruber-Batcho, Bartoli, Larock, Gassman, Sugasawa, Fukuyama, Hegedus, and Dobbs.

1.       FISCHER synthesis

It consists of heating phenylhydrazones of ketones or aldehydes, with anhydrous zinc chloride, boron trifluoride, polyphosphoric acid, or some other acid catalyst, to produce indoles. An acid-catalyzed rearrangement of a phenylhydrazone occurs with elimination of water and NH 3 . Electrodonor groups favor cyclization and electroattractors hinder it.


With asymmetric ketones, the intramolecular cyclization of the hydrazone can lead to two isomeric indoles in different proportions depending on the conditions used; in strongly acidic media, the less substituted indole can predominate.

When there are meta substituents, with respect to the hydrazone nitrogen, cyclization can take place in two positions, leading to two isomeric indoles:


If the substituent G is electro-withdrawing, the two isomers (4- and 6-) are formed in approximately the same proportion. On the other hand, if G is an electron-donating substituent, the 6-substituted isomer is formed mainly. The retrosynthetic analysis of the indole formed by the Fischer synthesis can be considered as follows:


Propose a synthesis plan for the following molecules:

MOb 119


MOb 120


MOb 119. Retrosynthetic analysis. The fundamental disconnection in the indoles that are supposed to be formed by the Fischer synthesis corresponds to a retro-transposition, which is shown in the disconnection of the MOb 119. The disconnection that occurs generates a precursor derived from phenylhydrazine.


Synthesis : From ortho-nitrotoluene, the intermediate derivative of phenylhydrazine is generated, necessary in the synthesis of Fischer indoles, the imine is formed with a cyclopentanone, and by heating   the MOb. 119


MOb 120. Retrosynthetic analysis.   The retro-transposition of the mob 120, allows to see the structures of the ketone and the phenylhydrazine derivative, used in its synthesis.


Synthesis. The OH of the starting molecule is protected, forming a cyclic acetal and the nitro group is reduced to later diazotize the amino.

The reduction of the diazo compound formed with sodium sulfite, allows obtaining the phenylfidrazine derivative, which is combined with cyclohexanone, which then leads to the   MOb 120


1.       BISCHLER synthesis

It consists of an acid-catalyzed cyclization of an α-arylaminoketone, which is prepared from an aniline and an α-halocarbonyl. Using N-acylated α-aminoketones, the cyclization is more controllable and allows obtaining substituted indoles in the heterocyclic ring


Propose a synthesis design for the following molecules :

MOb 121


MOb 122


MOb 121 . Retrosynthetic analysis. the MOb 3-phenyl-1H-indole, can be carried by two IGFs towards a structure, disconnectable by a CC bond, as proposed by the Bischler synthesis. Aniline is a good starting molecule for the synthesis of the mob 121


Synthesis.   Starting from aniline, the required amide can be obtained, which will then react with α-bromo benzophenone, to form a molecule that cyclizes with PPA. The application of a base such as KOH and heat, forms the mob 121


MOb 122 . Retrosynthetic analysis.   the MOb 122, 1,2-diethyl-1H indole is disconnected as predicted by a Bischler synthesis. what drives   to aniline as a simple and affordable starting material.


Synthesis. Again, the synthesis of the mob 122, with aniline and according to the Bischler synthesis of indoles   is used later   an alpha-bromo butanal


2.       REISSERT synthesis

In this method it is essential that the hydrogens of the substituent in the ortho position to the nitro group are acidic enough, and therefore the nucleophile is guaranteed in its formation, to combine with a carbonyl compound.


Propose a synthesis plan

for the following molecules:

MOb 123


MOb 124


MOb 123 . Retrosynthetic analysis. the MOb It is a derivative of the indole, which can be considered its disconnection, taking into account the synthesis of Reissert indoles. In this way, one arrives   to p-xylene as starting material.


Synthesis. p-xylene is transformed into a nitroderivative, as the required intermediate, to cyclize,   decarboxylate and thus form the mob 123.


MOb 124 . Retrosynthetic analysis.   the MOb you begin to disconnect according to the strategy that best suits you, to link it with the synthesis of   Reissert.


Synthesis. The starting material proposed for the synthesis of the MOb 124, can be prepared from benzene.


3.       LEIMGRUBER-BATCHO synthesis

As in the previous method, the acidity of the substituent in the ortho position to the nitro group must be guaranteed, the electrophile that is required is provided by the aminodiacetal.


Propose a synthesis plan for the following molecules:

MOb 125


MOb 126


MOb 125. Retrosynthetic analysis.   The disconnection strategy that emerges from the Leimgruber-Batcho synthesis is used to the mob 125,


Synthesis. The intermediate 2,4-dimethyl-1-nitrobenzene can be prepared from benzene and continue with the reactions provided for in the Leimgruber-Batcho method, for the synthesis of the mob 125.


MOb 126 . Retrosynthetic analysis. The methyl group at C2 of the indole forces the disconnections to be linked to the presence of an acetylenic group, which will eventually combine with the amino group. The MOb 126, can thus be synthesized from 1-bromo-2-nitrobenzene.


Synthesis. To introduce the acetylene group into benzene, an organomagnesium is reacted with acetylene.   The cyclization is produced by a reaction of the amino group with the triple bond. The following reactions make it possible to form the mob 126.


Other syntheses of indoles, also of importance, are the following:

HEGEDUS synthesis :


FUKUYAMA synthesis :


SUGASAWA synthesis :


Gassman's synthesis :


BARTOLI synthesis:


DOBBS synthesis :


CASTRO synthesis:


LAROCK Synthesis: