indole molecular model

The indole presents an acidic hydrogen on the nitrogen atom, with pKa= 17. Using strong bases it can be deprotonated, forming the indolium anion.

indole acidity 01

Reaction of indolium with different electrophiles:

a) Rental:

indole alkylation

b) Opening of epoxides:

opening indole epoxides

c) Attack to a,b -unsaturated:

indole unsaturated ab attack

The attack on the electrophiles occurs from position 3, because the pyrrole ring is richer in charge density than the carbocycle. Said attack is favored by the transfer of the lone pair of nitrogen.

electrophile substitution indole 01

a) Nitration:

The indole is nitrated with the nitric mixture in acetic anhydride.

indole 02 electrophile substitution

The 3-substituted indoles add the electrophile to position 3, rearranging it to position 2 at a later stage.

indole 07 electrophile substitution

a) Leaving groups near the ring

Indole throws out to the outgoing groups located in the neighboring situation to a ring. In addition, it is necessary that the chain that has the leaving group is located in position 3 of the ring.
indole derivatives 01

The indole is converted to quinoline by reaction with a carbene generated by a 1,1 elimination from chloroform. The carbene undergoes a cyclopropanation reaction on the double bond of the pyrrole ring, opening the cyclopropane generated at a later stage, to generate the final quinoline.

indole ring expansion

We can selectively reduce either the carbocycle or the pyrrole ring.

indole ring reduction

It is one of the most important synthesis of indole. Part of phenylhydrazine and a carbonyl with alpha hydrogens, which generate a hydrazone. After a tautomerism, a sigmatrope is produced that yields the indole after cyclization.

fischer indole synthesis 01

The hydrazone formation step has a well-known mechanism (the same one that forms imines) and we are not going to comment on it. We will focus on the steps that convert hydrazone to indole.

Stage 1. Tautomerism.

fischer indole synthesis 02

The Madelung synthesis is based on the formation of a benzylic carbanion that cyclizes on an amide substituent.

madelung 01


Step 1. Deprotonation of the amide

madelung 02