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Synthesis, Reactions and Medicinal Uses of Indole

With a catalyzed vapor phase reaction, aniline and ethylene glycol produce indoles.

Indole

Synthesis

With a catalyzed vapor phase reaction, aniline and ethylene glycol produce indoles.


Fischer – indole synthesis - Indoles can be made by adding two or three substitutes to this molecule. An arylhydrazine is heated with an aldehyde or ketone, then the resulting arylhydrazone is rearranged with acid to give an indole with a loss of ammonia.


leimgruber – Batcho indole synthesis - To produce enamines, N, N-dimethyl formamide dimethyl acetal (DMFDMA) reacts with o-nitrotoluence. An indole is obtained by reductive cyclization of this enamine.


Reissert synthesis - When sodium ethoxide is present on a benzene ring, the methyl group ortho to the nitro becomes acidic enough to condense on diethyl oxalate. Indoles are obtained by reductive cyclization of the resulting acid.


Bichler synthesis - α-arylaminoketone is produced by treating arylamine with a 2-halo ketone and cyclizing it with strong acid or zinc chloride.


Bartoli synthesis - The method involves applying three moles equivalents of vinyl magnesium bromide to nitrobenzene to produce 7-substituted indoles.


Nenitzescu synthesis - This method was first described by Costin Nenitzescu in 1929. This method involves reacting benzoquinone with the β-aminocrotonic ester to produce 5-hydroxyindole derivatives.


Sugasawa synthesis - To produce 2-amino chloroacetophenone, nitrile and boron trifluoride are used as Friedel-Crafts acylators.


The intermediate is then reductively cyclized using NaBH4 to yield 2-unsubstituted indole derivatives. A strong electron-withdrawing substituent in an aniline makes this reaction unsuitable.

Reactions

Protonation


Alkylation - A sextet of six lone electrons are available on ring N-atoms; none of them are free. Indoles do not react at room temperature with alkyl halides. In DMF, indole reacts with methyl iodide to form 3-methyl indole at about 80°C. In the presence of a rising temperature, 1, 2, 3, trimethyl-3H-in dolium iodide is formed.


Nucleophilic substitution - Nucleophilic substitution reactions occur very rarely in Indoles. The direct displacement of ring-bound substituents does not occur in indoles. Initially, n-BuLi, which is a readily displaceable nucleophilic reagent, deprotonates the indole. Displacing the Li-atom then allows the nucleophile to attack at C-2.


Reactions with aldehydes and ketones - In acid-catalyzed reactions with aldehydes and ketones, the indole forms indol-3-ylcarbinols.



Mannich reaction - Using dimethylamine and formaldehyde in acetic acid, Mannich bases are prepared.



Diazo – coupling and nitrosation - Nitrosating agents and indoles undergo base-catalyzed reactions that result in N-nitroso- and 3-nitroso indoles.





Oxidation - When indole is exposed to air and light, it auto-oxidizes into a resinous substance. Through cleavage of the indole 2,3-double bond, methyl substituents at C3-position stabilize the ring, giving o-form amino acetophenone. If oxygen, ozone, sodium hypoiodate, or perbenzoic acid is used to oxidize 3-methyl indole.


Reduction - Benzenoid or heterocyclic rings can be selectively reduced by the indole ring. For instance, zinc/HCl can convert indole to indoline. An acidic medium also results in this type of conversion when indole is catalyzed.



Benzene ring is the only one reduced by lithium/liquid ammonia.


Medicinal Uses

There are indole structures in substances such as serotonin (neurotransmitter, neurotoxin), vinblastine (anti-cancer), indomethacin (NSAIDs), besipirdine (as an anti-Alzheimer's remedy), fendosal (NSAID), ondansetron (antiemetic in cancer chemotherapy), brasserie (anti-cancer), melatonin (hormone), and others.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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