[schen]

I am working on the SAR study of the Indole molecule. I have trouble with the deprotonation of the Hydrogen attached to the Indole Nitrogen. I have tried using NaH with Ar protection, lower temperature and also room temperature. I've also used K2CO3. But both of them don't work for my compound. But the reference shows that it is a simple step. I emailed the author of the paper requesting supplementary information. But haven't heard back.

Has anyone worked on similar reaction? Can you walk me through this.

[camptzak]

I have never done this personally, but it sounds like you need a stronger base. maybe butyl lithium or something like that

[schen]

The reason I did not use butyl lithium yet is because it is a very strong base and I am afraid it will degrade the Starting material in my reaction, as it has amide substituent. It also requires very low temperature, around -78 Centigrade and Nitrogen gas protection. I am not sure if I can try using Butyl Lithium. But if nothing else works, I may try using it.

Thank you for the suggestion!

[TwistedConf]

I have tried using NaH with Ar protection,

What do you mean by this?

NaH will deprotonate indole.

[schen]

My compound is not core Indole ring, it has an amide bond with a proton attached to the Nitrogen and a teristary amino group as substituents.

[Benzene]

Could you show us the compound?

[schen]

Attached is the structure of my compound

[schen]

Sorry ignore the above structure. This is the compound I am working on

[camptzak]

maybe try deiethyimide? something bulky and very basic. I would take care not to break the amide bond.

[Dan]

Two questions:

1. I assume you are trying to do something with the deprotonated indole - what is the reaction you are trying to do? An alkylation?

2. How do you know the indole was not deprotonated?

[schen]

@camptzak, I am trying to do acylation reaction. If I use the diethylimide, it may react with benzylchloride.

@dan,  I am trying to do acylation. I monitor the reaction using TLC and base on the TLC and NMR results, I can still see the starting material and several other small spots in TLC and many impurity peaks in the spectrum. So I assume the deprotonation did not take place and that is the reason the assumed product did not form.

Is there any way I can monitor the reaction and know that the indole was deprotonated?

[Dan]

@dan,  I am trying to do acylation.

Acylation of indoles is commonly achieved with with triethylamine/DMAP or other N bases - I would check the literature and try that. Reagents like BuLi or LDA are not usually required.

You could also try something more sophisticated, like this.

it may react with benzylchloride

Benzyl chloride is an alkylating agent (installs a benzyl group) - do you mean benzoyl chloride?

[Doc Oc]

Reactions with indole nitrogens are very challenging.  The lone pair of the nitrogen is involved in the aromaticity of the ring and is therefore highly non-nucleophilic.  Alkylations and acylations more often occur at the C-3 position.

http://en.wikipedia.org/wiki/Indole#Chemical_reactions_of_indole

As for your dilemma, I'm sorry but I don't have any suggestions.  Can you proceed forward without acylating it knowing now that it's not very reactive?  You'd just need to watch out for reaction at the C-3.

[camptzak]

Reactions with indole nitrogens are very challenging.  The lone pair of the nitrogen is involved in the aromaticity of the ring and is therefore highly non-nucleophilic.  Alkylations and acylations more often occur at the C-3 position.

http://en.wikipedia.org/wiki/Indole#Chemical_reactions_of_indole

As for your dilemma, I'm sorry but I don't have any suggestions.  Can you proceed forward without acylating it knowing now that it's not very reactive?  You'd just need to watch out for reaction at the C-3.

I hope I am not confusing things but if you deprotonate the nitrogen, won't one electron pair be involved in the aromaticity and one pair not be involved in the aromaticity?

[TwistedConf]

The lone pair of the nitrogen is involved in the aromaticity of the ring and is therefore highly non-nucleophilic.

Irrelevant since we're talking about derivatizing the anion.

Alkylations and acylations more often occur at the C-3 position.

Not if you generate the sodium (NaH) anion, as mentioned in the article you linked.  I've never had a problem alkylating an indole nitrogen this way.