Sciencemadness Discussion Board

Indole-3-Carbinol Oxidation

MethoxMan - 15-3-2007 at 02:42

Is it possible to oxidize Indole-3-Carbinol (Indole-3-Methanol) to Indole-3-carboxaldehyde without oxidative attack of the indole-nucleus?

If yes, which simple and not so exotic oxidant is suitable for this oxidation?

Thanks.

stoichiometric_steve - 15-3-2007 at 03:57

pyridinium chlorochromate.

Nicodem - 15-3-2007 at 10:43

EP658533 : with IBX (see example 34)

MethoxMan - 16-3-2007 at 06:35

Thank you very much Nicodem for this great reference!

But one thing confused me:

In Example 31 (the procedure for Example 34) they use 27.9 mmol oxidant for 2.79 mmol substrate. This is a 10xmolar excess! However in the other examples for this procedure (Examples 33-36) they use a little bit more than 1 oxidant equivalent for the oxidation.

Does this make sense to you?
I hope you can help me.
Thank you very much.

Nicodem - 16-3-2007 at 11:34

Only the procedure is said to be the same as for Example 31 and the amount of the oxidant is thus for the substrate 31. The amount for the Example 34 is indicated in the table (1.2 equivalents of the oxidant).

I tried this and this is what happened:

Monoamine - 1-6-2021 at 15:10

First off, since I didn't have dichloromethane, I used chloroform as my solvent.

(Also, one thing I notices is that if you heat Indole-3-carbinol too much (like about 70Co or dissolve it in THF, it forms this weird red condensation product, and the compound is basically destroyed...

I used 1.5 times the moles of PCC as I had Indole-3-carbinol and an excess of chloroform.

The Indole-3-carbinol dissolved in the chloroform no problem, but the PCC had a lot of trouble to properly dissolve. I had to crush it up and shake like mad until it finally (mostly) dissolved. At that point the PCC chloroform solution was a blood red colour.

I heated to reaction flask to about 30-40 Co and with vigorous stirring. The PCC was then added very slowly dropwise. This caused the the colour of the clear Indole-3-carbinol solution to change slowly and then dramatically after about half the PCC had been added. It turned from pink to a dark purple colour, almost black.

After letting it stirr for another 30 minutes or so, I tried to quench any remaining PCC by adding some ethanol and isopropanol. But this didn't produce any visible changes. (Btw, isopropanol probably isn't a great choice here, since all of these compounds are soluble in acetone, which the isopropanol would be converted to...). I guess you could try to boil it off, but you have to be very careful not to get hotter than 60 Co

Apparently the byproducts should then dissipate out of solution. If this was the case I could not see it however (everything was dark purple after all...).


So I decided to put it in the freezer overnight to see if that helps the byproducts crash out of solution.

If they do then great, if they don't then I think the best thing may be to let all the solvent evaporate off (gently and just to be safe I wouldn't heat the flask to more than about 50 Co). But once that's done, then just extract the impurities with water (since they should all be water soluble) and extract the Indole-3-carboxaldehyde (if there really is any...) with diethyl ether.

Another thing that could work to purify your compound would be to just add water to the solvents (which are all miscible in water) until the Indole-3-carboxaldehyde crashes out of solution, then you can probably just filter it off and wash it with cold water or something...

Whatever the outcome I'll definitely keep trying to do it. Also wonder how much of an effect swapping out the dichloromethane for chloroform mattered...

I'm also curious about this post.

[Edited on 1-6-2021 by Monoamine]

student - 1-6-2021 at 16:12

How about using manganese dioxide or barium manganate for the oxidation, to take advantage of the easily-oxidized benzylic nature of this alcohol?

zed - 2-6-2021 at 12:27

https://patents.google.com/patent/EP0658533A1/en

You have hints of a procedure that works; why not utilize it?

[Edited on 2-6-2021 by zed]

[Edited on 2-6-2021 by zed]

karlos³ - 2-6-2021 at 13:47

And IBX isn't hard to make at all, its actually quite straight forward from anthranilic acid(from available and OTC methyl anthranilate).
Just a sandmeyer followed by an oxidation with oxone, pretty OTC too.

Monoamine - 5-6-2021 at 03:04

Quote: Originally posted by Monoamine  
First off, since I didn't have dichloromethane, I used chloroform as my solvent.

(Also, one thing I notices is that if you heat Indole-3-carbinol too much (like about 40 Co or dissolve it in THF, it forms this weird red condensation product, and the compound is basically destroyed...

I used 1.5 times the moles of PCC as I had Indole-3-carbinol and an excess of chloroform.

The Indole-3-carbinol dissolved in the chloroform no problem, but the PCC had a lot of trouble to properly dissolve. I had to crush it up and shake like mad until it finally (mostly) dissolved. At that point the PCC chloroform solution was a blood red colour.

I heated to reaction flask to about 30-40 Co and with vigorous stirring. The PCC was then added very slowly dropwise. This caused the the colour of the clear Indole-3-carbinol solution to change slowly and then dramatically after about half the PCC had been added. It turned from pink to a dark purple colour, almost black.

After letting it stirr for another 30 minutes or so, I tried to quench any remaining PCC by adding some ethanol and isopropanol. But this didn't produce any visible changes. (Btw, isopropanol probably isn't a great choice here, since all of these compounds are soluble in acetone, which the isopropanol would be converted to...). I guess you could try to boil it off, but you have to be very careful not to get hotter than 60 Co

Apparently the byproducts should then dissipate out of solution. If this was the case I could not see it however (everything was dark purple after all...).


So I decided to put it in the freezer overnight to see if that helps the byproducts crash out of solution.

If they do then great, if they don't then I think the best thing may be to let all the solvent evaporate off (gently and just to be safe I wouldn't heat the flask to more than about 50 Co). But once that's done, then just extract the impurities with water (since they should all be water soluble) and extract the Indole-3-carboxaldehyde (if there really is any...) with diethyl ether.

Another thing that could work to purify your compound would be to just add water to the solvents (which are all miscible in water) until the Indole-3-carboxaldehyde crashes out of solution, then you can probably just filter it off and wash it with cold water or something...

Whatever the outcome I'll definitely keep trying to do it. Also wonder how much of an effect swapping out the dichloromethane for chloroform mattered...

I'm also curious about this post.

[Edited on 1-6-2021 by Monoamine]


Edit: Just realized that chloroform is actually not miscible with H20, which simplifies things a lot. Specifically, this means that all the impurities can simply be extracted with H20.

I did this, washing the organic layer with H20 five times until the aqueous layer was visibly clear.

I then tried to distill of the chloroform on the water bath at 60 Co. I noticed the smell of the Indole-3-carbinol condensation product, and so immediately removed the water bath and simply air dried the chloroform in the fume hood. Unfortunately, the solutes in the organic layer were identified as just being the Indole-3-carbinol condensation product - not indole-3-carboxaldehyde.

I think the experiment failed due to one or more of the following factors:

1) I likely didn't let the PCC react with the Indole-3-carbinol long enough (only about 1 hour).

2) It's possible that my quenching technique of adding excess isopropanol (which should be converted to acetone, could have led to the formation of the condensation product. A better way of quenching the reaction would likely be to wash the organic layer in a solution of Na2CO3 and sodium thiosulfate, to convert any remaining PCC into its trivalent oxidation state and it's sodium salt.

3) Since it seems that Indole-3-carbinol decomposes into its condensation product at around 40 Co, it means that the solvent cannot be evaporated by distillation, as the boiling point of. chloroform is 61.7 Co. So the only way to remove the solvent is to air dry it. (Kind of a waste of solvent, unfortunately...

I will definitely try this again though, using what I learned and report on the outcome.

Also, if anyone knows how long the reaction between PCC and an Aryl-carbinol should run in general, please let me know.

The current plan is to try to run the reaction for 24h at room temperature, and to add the PCC to the Indole-3-carbinol dropwise over the course of 1 or 2 hours.

Fingers crossed that this time it will work...

[Edited on 5-6-2021 by Monoamine]

zed - 5-6-2021 at 03:52

Fourteen years ago, a member suggested PCC might work. No reference.

Another member, suggested IBX does work and provided a reference.


The Aldehyde is readily produced from Indole.

Apparently, it can also be produced from the Carbinol via IBX.

Do you have a reference wherein someone achieved this oxidation via PCC?

Indoles are fussy about being oxidized. Really fussy.

I'm not saying you can't achieve your goal via PCC, but it might not actually be achievable.

If you don't have a reference, you could be headed for YEARS of failures.

mr_bovinejony - 5-6-2021 at 03:58

I have already tried this with PCC twice with no success, but I haven't seen any other trials so don't let that discourage you. I've also tried with bleach and GAA which gave the carboxylic acid. Each time I failed I got some purple product, the carbinol was meant as a vitamin so it probably had some unlisted ingredients, although even after recrystalization it still was purpleish. So who knows

karlos³ - 5-6-2021 at 05:51

You still got the indole-3-carboxylic acid?
Esterify and then 5,6-dibrominate it!

njl - 5-6-2021 at 05:54

To what end, karl? Just out of curiosity.

karlos³ - 5-6-2021 at 06:20

5,6-dibrominated tryptamines of course!
Here: https://doi.org/10.1039/C1OB05522D

mr_bovinejony - 5-6-2021 at 06:23

Yeah I still have them, but the color is stupid and two recrystalizations later helped none. It's a side project for now

njl - 5-6-2021 at 06:29

I think we all have a few "side projects" like that collecting dust :D

mr_bovinejony - 5-6-2021 at 06:43

I had some succes recrystallizing indole 3 aldehyde with dmf and water, maybe it'll work for indole 3 carboxylic acid too?

karlos³ - 5-6-2021 at 07:32

Have you tried salt formation first, in water, to make it polar and then remove all the impurities by extraction with a nonpolar solvent?

mr_bovinejony - 5-6-2021 at 07:47

Sure haven't! I'm going to run a tlc on these indoles I have now for practice

This might be worth a try. And it should be useful for oxidizing Ar-CH2-OH compounds in general.

Monoamine - 9-6-2021 at 18:10

This may be worth a shot as it uses relatively easy to obtain reagents and seems very straight forward to pull of.

Sorry, the pic below is a bit blurry...
Attachment: Reaction (82kB)
This file has been downloaded 317 times

According to the below paper, aromatic carbinols (aromatic methanols??) can be oxidized to aldehydes simply by adding them to a solution of one molar equivalent of 98% sulfuric acid in dimethyl sulfoxide and heating under reflux for 1-2 hours (which they claim gives a 93% yield!). They even claim that no byproducts are formed so depending on your product, you may even be able to recover all of your DMSO and H2SO4. Nice!

- I see two potential pitfalls with this method though:
1) Since the boiling point of DMSO is is 189oC, you need an apparatus that can achieve this heat.
2) For the particular problem of oxidizing Indole-3-carbinol, you may run into problems due to the fact that the melting point on Indole-3-carbinol is about 93oC and the melting point of Indole-3-carboxaldehyde is only about 4-5 degrees above the boiling point of DMSO.

In my experience, melting Indole-3-carbinol basically destroys it...

However, according to the paper, the reaction still works at lower temperatures, but with diminishing yields. So maybe you could do this at around 80%, but I wouldn't expect more than about 20% yield at that point...

In any case, I will most certainly be trying this out to see if it works and report back with the results.

Even if it doesn't work for this particular compound I can see it being useful for all sorts of other Ar-CH2-OH oxidations!

Download link for the PDF of the paper
Attachment: PDF of original paper (194kB)
This file has been downloaded 405 times

Purifying and recrystallizing OTC In-3-CH2-OH

Monoamine - 9-6-2021 at 18:22

Quote: Originally posted by mr_bovinejony  
Yeah I still have them, but the color is stupid and two recrystallizations later helped none. It's a side project for now


You can purify In-3-CH2-OH in two ways:
1) If you get yours from some health supplement capsules, then the easiest way to get rid of most additives is to dissolve the content in isopropanol (since the impurities generally aren't soluble in it) and then filter the impurities off. But... don't try to boil off the isopropanol, you'll ruin the dissolved Indole!. Either let the isopropanol air evaporate off, or...

2) Crystalize it from the isopropanol by slowly pouring in distilled H20 heated to about 40oC until you see the solute crash out of solution (the clear amber solution will turn a milky beige). At that point just let it sit for a few days until a crude crust of crystals forms.

Maybe there are better ways but this is probably one of the more straightforward ones and it uses relatively inexpensive and easily available materials.

[Edited on 10-6-2021 by Monoamine]

Naive question

Monoamine - 9-6-2021 at 18:35

One thing that has foiled most of my attempts to do this oxydation so far is the fact the In-3-CH2-OH seems to really like to react with itself and form some useless, blood red, smearly product that I've only been able to clean up with acetone.

It happens when it's heated to about 60C in isopropanol it happens when it's simply dissolved in acetone, it happens when it's dissolved in THF, it happens when it's heated to 40C in chloroform, it happens when it melts... Quite, quite, frustrating....

From the FTIR it looks like whatever it is, it still has on OH, but no carbonyl.

I'd be extremely curious to hear if anyone has an theory of what it could be or why In-3-CH2-OH is so prone to react with itself?

zed - 9-6-2021 at 22:09

It's a thing. https://en.wikipedia.org/wiki/Indigo_dye

Monoamine - 10-6-2021 at 13:22

Quote: Originally posted by zed  
It's a thing. https://en.wikipedia.org/wiki/Indigo_dye


The fact that the IR spectrum doesn't show a C=O bond peak would suggest that this annoying condensation product isn't indigo dye. Whatever it is, it still has an OH group in it.

Also, indigo is blue, this stuff is blood red.

[Edited on 11-6-2021 by Monoamine]

zed - 10-6-2021 at 21:32

I wasn't. suggesting it was Indigo. Just an example of an indolic dimerization.

Protection of the the indole nitrogen

Monoamine - 7-8-2021 at 07:36

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 277 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.

karlos³ - 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.

AvBaeyer - 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

AvB

zed - 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]