Sciencemadness Discussion Board

Methylation of indole?

White Yeti - 9-12-2012 at 09:20

I have a quick question about indoles, more specifically the reactivity of nitrogen atom. According to the wiki page, the nitrogen atom is not basic, owing to the nearby presence of an arene group. If the nitrogen is weakly basic, then it is relatively difficult to protonate.

Is the nitrogen in the indole heterocycle resistant to an Eschweiler-Clarke methylation?

smaerd - 9-12-2012 at 09:37

I would imagine it would be. Usually alkylation at the nitrogen or the '1 position' is done first by deprotonation of the nitrogen with a strong base. Edit - in some cases it seems advantageous to alkylate the nitrogen prior to the heterocycle formation.

See:
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0769

[Edited on 9-12-2012 by smaerd]

turd - 9-12-2012 at 09:49

Quote:
owing to the nearby presence of an arene group.

What do you mean with nearby presence? The indolic N is aromatic.
Quote:
Is the nitrogen in the indole heterocycle resistant to an Eschweiler-Clarke methylation?

It depends on the reaction conditions.
There's a review on reduction with STAB (and relatives) flying around on this board where the authors describe alkylation of the indolic N (by the acid) and even reduction to the indoline. On the other hand, there are success reports of people using STAB to dialkylate tryptamine in moderate yields.

PS: STAB may technically not be an Eschweiler-Clarke methylation (or is it?), but is preferred to the classic acidic route due to the Pictet-Spengler reaction.

zed - 11-12-2012 at 15:44

Yeah, under some circumstances....That 1- position is reactive.

On a different note.... http://wiredspace.wits.ac.za/bitstream/handle/10539/6619/The...

Nicodem - 12-12-2012 at 09:10

Indole is easily N-methylated. There are plenty of procedures available. It is most practical to use KOH as the base in DMSO where indole is easily deprotonated (no N-alkylation can occur without prior deprotonation). Also, a recent contribution in Prepublication gives a reference for the N-methylation of indoles with dimethyl carbonate.
Quote: Originally posted by White Yeti  
Is the nitrogen in the indole heterocycle resistant to an Eschweiler-Clarke methylation?

The Eschweiler-Clarke methylation can be used for the N-methylation of primary and secondary aliphatic and some aromatic amines (it does not work on aniline itself due to ring attack, but where electrophilic attack on the ring is inhibited by substitution or deactivation, N,N-dimethylation can proceed). See Organic reactions 5 for an excellent review.

Indole is not an amine, so in principle you can not apply the Eschweiler-Clarke methylation on it. However, it is an enamine and these can be reduced by the formic acid used in this reaction as the reducing reagent (UTFSE for info about reductions with formic acid). But it is a poorly reactive enamine (being part of aromatic system) that cannot be reduced by all general methods (it is easily reduced to indoline by the electrophilic hydrides like BH3.THF or AlH3, but not by any nucleophilic hydride like NaBH4 or LiAlH4).
There are problems though. Even if the indole would be reduced to indoline by formic acid under Eschweiler-Clarke methylation conditions (not impossible), the so formed aromatic amine (indoline) would unlikely be cleanly N-methylated to N-methylindoline for the same reasons as the reaction with aniline fails. More importantly, formaldehyde would C-alkylate the indole at the position 3, giving mostly bis(indol-3-yl)methane as the expected product. And so on.
In any case, formation of N-methylindole is impossible by the current understanding of synthesis theory.

If you want to experiment with indole and formic acid, then try refluxing indole in 85% formic acid. I did not bother checking the literature, but if you are lucky, you might get N-formylindoline as the main product. And if the reaction is not described in the literature (check first!), it would represent your first contribution to science.

zed - 12-12-2012 at 17:50

I would be reluctant to risk valuable indole by refluxing under acetic or harsh conditions. My concern being coupling or polymerization.

The unsubstituted indole ring is none too stable. Somethings it will tolerate, others it will not. I would prefer for others to discover what it will not tolerate.

Try something known to work.







[Edited on 13-12-2012 by zed]

CuReUS - 12-10-2014 at 03:26


yesterday i had a terrible thought:( could someone somehow how methylate indole in the 2 position first(like a Me-chibabin reaction) while simultaneously reducing it to get rid of the double bond and then methylate the N using methyliodide and then breaking the bond that connects the N with the benzene ring

if this is possible ,then some idiotic chemists are definitely going to have a field day:mad:

reimer tiemann on indole would give 3 -methylindole and chances of ring expansion to form Quinoline is also possible
also RT is messy and the yield is low

[Edited on 12-10-2014 by CuReUS]