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Author: Subject: Indole-3-Carbinol Oxidation
zed
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[*] posted on 10-6-2021 at 21:32


I wasn't. suggesting it was Indigo. Just an example of an indolic dimerization.
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[*] posted on 7-8-2021 at 07:36
Protection of the the indole nitrogen


I've been thinking about this a bit more lately, and I'm starting to suspect that the nitrogen in the indole ring may be responsible for the lack of success so far.

It may be worth deprotonating and subsequently protecting the indole nitrogen with an acetamide protecting group (or if you can make it, a t-butyl carbamate protecting group). (Check out this page with various protecting groups for amines, since it also contains references to the original sources)

Amine protecting groups

If we only want an acetamide protecting group, then this can be done via a relatively simple procedure (no need for forming acid-halides or SOCl2 reagents) using the approach in (Sharley and Williams, 2017, Attachment: Acetal_amine_protection_procedure_(Sharley_2017.pdf (1.5MB)
This file has been downloaded 91 times)

The one issue with this approach is that any base that is strong enough to deprotonate the indole nitrogen will also deprotonate the OH of the carbinol group, so you'd probably create some esther there, unless you somehow protect it first. (Maybe react the OH with acetic acid to form an ester and the simply cleave the ester once the indole OH has been protected?)

But let me stress that this is only speculation at this point. The only thing I'm quite sure about is that if the indole nitrogen is protected from reaction, it should be much less likely to get these annoying side reactions when attempting to oxidize the carbinol to a carboxaldehyde)



Reference: Sharley, D.D.S. and Williams, J.M., 2017. Acetic acid as a catalyst for the N-acylation of amines using esters as the acyl source. Chemical Communications, 53(12), pp.2020-2023.

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[*] posted on 7-8-2021 at 13:54


Quote:
Quote: Originally posted by Monoamine  

The one issue with this approach is that any base that is strong enough to deprotonate the indole nitrogen will also deprotonate the OH of the carbinol group, so you'd probably create some esther there, unless you somehow protect it first. (Maybe react the OH with acetic acid to form an ester and the simply cleave the ester once the indole OH has been protected?)

First, who is Esther?

Second, thats not true, just use a PTC if you want to deprotonate the pyrrole N with aqueous lye, as I said in another thread.


Quote: Originally posted by Monoamine  

But let me stress that this is only speculation at this point. The only thing I'm quite sure about is that if the indole nitrogen is protected from reaction, it should be much less likely to get these annoying side reactions when attempting to oxidize the carbinol to a carboxaldehyde)

Whats the issue with IBX, with its 98% yield on that specific oxidation, and its easy preparation from anthranilic acid, it sounds like there aren't any side reactions or obstacles to achieve that?

Just whip some IBX up and stop to worry.
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[*] posted on 7-8-2021 at 18:45


What is missing here is the realization that indole-3-carbinol is a vinylog of a N-hydroxymethyl aniline. There should be little expectation that the carbinol will react like a "normal" benzylic alcohol. If you "push the arrows" from the indole nitrogen to the 3-position you will see that the OH group can be readily eliminated, hence the high reactivity/sensitivity of indole-3-carbinol. Once (or if) the carbinol group is oxidized to a formyl group, you have a vinylog of N-formylaniline, a very stable compound. Indole-3-carboxylic acid is a relatively stable compound but will easily decarboxylate on heating. It is the vinylog of N-carboxyaniline.

A discussion of what I am talking about can be found in

R.J. Sundberg, "The Chemistry of Indoles," pp39ff

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[*] posted on 9-8-2021 at 00:36


Do some library research and find a procedure. Indole isn't an Amine, and it doesn't usually react like one.

A decent procedure for 1-acetalation does exist however.

Scully, in his synthesis of an LSD analog, utilized the reaction of ketene with Lysergic Acid. The resultant 1-Acetyl Indole, proved pretty stable.

[Edited on 9-8-2021 by zed]
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