Earlier in this series we talked about heterocycles, and one important aromatic heterocycle is
the indole, a bicyclic structure involving benzene fused with pyrrole.
Indoles are widespread in nature, acting as common subunits of bioactive molecules.
Here are some examples of biologically relevant compounds featuring indoles, such as tryptophan,
an amino acid, strychnine, an alkaloid found in certain plants, and serotonin, a neurotransmitter.
Due to their prevalence in nature, their synthesis has been the object of much attention.
A very important route to indoles is the Fischer synthesis, which was discovered in 1882 by
the famous German chemist Emil Fischer, who was a Nobel prize winner in 1902.
Here we see the reaction illustrated for the simple case of phenyl hydrazine and acetone,
however it works generally for all aryl hydrazines and ketones.
So let’s talk about each of these steps in a bit of detail.
It is well known that one can condense an aryl hydrazine with a ketone, involving the
elimination of water.
This is usually done with acid catalysts, where the removal of water will drive the
equilibrium forward.
This yields aryl hydrazones like this one, which are often crystalline compounds.
These hydrazones can be treated with strong Bronsted-Lowry acids like hydrochloric, phosphoric,
or sulfuric acid, and even Lewis acids like alumnium trichloride, to yield indoles.
We can probably identify the atoms from each of the starting materials in the product,
but we will also notice that we start with two nitrogen atoms, and we end up with only
one.
So the mechanism must account for the loss of one nitrogen atom.
As it turns out, the mechanism for this second step is quite complex, but let’s take a
look at it.
Here is the result of the first step, involving phenyl hydrazine and some ketone of at least
four carbons.
Now we begin with the acid catalysis and shuffling of protons.
First this nitrogen is protonated, it being more basic, since its lone pair is not tied
up in resonance with the neighboring ring, like the other nitrogen.
Then a proton is lost at this beta position, putting a pi bond here and neutralizing the
nitrogen, to yield this ene-hydrazine.
Protonation occurs again, at the same nitrogen as the first time.
This is where something interesting happens.
We talked about sigmatropic shifts a little earlier in the series, so if that term is
unfamiliar, you may want to refresh your memory with that tutorial.
Otherwise, this intermediate will undergo a 3,3 sigmatropic shift which generates the
crucial carbon-carbon bond at the ortho position of the benzene ring.
This species isomerizes immediately to the more stable aniline form, thereby restoring
the aromaticity of the ring.
Then the nitrogen from the aniline moiety attacks the iminium ion in intramolecular
fashion to secure the five-membered ring.
At this point, one of these protons is lost, and then acid catalyzes the elimination of
ammonia.
And there we have the indole, with the mechanism understood.
Now the situation is more complex when the ring is substituted.
We can look at the 3,3 shift as a reaction in which the ortho-carbon of the electron-rich
aniline attacks the electron-poor alkene.
Thus, the more electron rich the aniline, the faster the reaction.
Therefore, if electron-donating substituents are present on the ring, the reaction is accelerated.
If electron-withdrawing substituents are present, the reaction is hindered, and in extreme cases
it just does not occur.
But when introducing substitution, there is another complicating issue, that of the resulting
site selectivity.
It is the case that if the aryl hydrazine is para-substituted, given the symmetry of
the molecule, the substituent can only end up at the C-5 position of the indole.
When numbering indoles, the nitrogen is always position 1, then we number around the five-membered
ring, and then continuing to the other, skipping the two carbons involved in both rings.
If the hydrazine is ortho-substituted, the substituent will always end up at the C-7
position, because one of the carbons that could close the second ring is occupied.
However, if the substituent is meta, two possible products exist, because there are two carbons
that are free to be involved in the cyclization, resulting in the C-4 and C-6 substituted products.
Here we look at the specific substituent to know which will predominate.
If R is electron releasing, para attack is usually favored, although not completely,
and the major product is the one where R is at C-6.
If R is electron withdrawing, selectivity is very poor, and one can expect both C-4
and C-6 substitution, unless R is very bulky, in which case the C-6 substitution tends to
prevail.
Of course, with the presence of more than one substituent, the situation becomes highly
complex.
So far we have used acetone, a symmetrical ketone where the two sides are equivalent,
but there are many other types of ketones that could be involved, some of which could
yield multiple products.
If only one side of the ketone can enolize, then this is the one taking part in the sigmatropic
shift, and only one product can form, such as when using this ketone involving a phenyl
group.
The situation becomes more complex for nonsymmetrical ketones in which both sides can enolize.
In this case, two products will arise.
When using strong acids like methanesulfonic acid, enolization tends to occur at the less
substituted side of the ketone.
In this case, let us assume we are dealing with an alkyl methyl ketone.
Enolization at the methyl group will yield the major product, and enolization at the
other side will give the minor product.
The exact ratios depend on the identity of R, of course, and on the reaction conditions,
with the preference eroding if weaker acids are used as catalysts.
However, the trend we have just discussed is quite consistent.
So that’s some information on this name reaction.
In the case of complications with this synthesis, there are other approaches to forming indoles.
Nevertheless, the Fischer synthesis is a classic in organic synthesis, and is usually the one
that comes to mind first when one is planning to make an indole.