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Topic: Decarboxylation to hydroxyindole mechanism  (Read 10234 times)

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Offline Fireredburn1

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Decarboxylation to hydroxyindole mechanism
« on: May 12, 2014, 10:15:31 AM »
hi i have some problem with some organic synthesis question. i do not have a clue how TFMS can result in cyclisation to form the five-membered ring containing nitrogen as well as the lactone. my only knowledge is that TBS acts as protecting groups for alcohol but again i do not see how it leads to formation of a lactone?



my second question is to ask if the mechanism drawn for decarboxylation leading to 6-hydroxyindole is correct?


Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #1 on: May 12, 2014, 01:31:50 PM »
Re Q2, you cannot break the C-H and C-O bond. This will leave a C(2+). Use the electrons from the nitrogen to release the CO electrons and loss of CO2.
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Offline critzz

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #2 on: May 12, 2014, 04:43:39 PM »
For the formation of the lactone a hint: transesterification

The other cyclization seems kinda like a Friedel-Crafts acylation but instead of an acyl chloride it's an amide?
The para methoxy-group would help to activate the benzene ring. After the attack of benzene to the amide a
hemi-aminal is formed which eliminates water in the presence of TFMS.

This would be my intuition, but I need someone to correct/confirm.  :P



Offline Fireredburn1

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #3 on: May 12, 2014, 10:08:39 PM »
Re Q2, you cannot break the C-H and C-O bond. This will leave a C(2+). Use the electrons from the nitrogen to release the CO electrons and loss of CO2.

i'm stuck at the breaking of C-O bond... i don't think i got it right yet ???


Offline Dan

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #4 on: May 13, 2014, 02:36:31 AM »
You are making fundamental mistakes with your curly arrows - you need to review this area.

In addition, the enolisation you propose is very unlikely (see Bredt's rule).
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Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #5 on: May 13, 2014, 06:29:56 AM »
If you were to explicitly write the hydrogens, you would find there is a hydrogen alpha to the carbonyl. If it is removed, it will not be present in the product. The initial protonation is correct, but I suggest you use the nitrogen in the next step to do the decarboxylation, no other reactions, just loss of CO2. Then you can tautomerize to make it aromatic. If you need to, try drawing this in every way possible if you are not realizing my hint.
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Offline zsinger

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #6 on: May 13, 2014, 03:32:24 PM »
I have have almost no success with these types of reactions (perhaps its me?).  Very finicky conditions, and sometimes they just don't work!!!  Thats organic chemistry for ya!
                      -Zack
"The answer is of zero significance if one cannot distinctly arrive at said place with an explanation"

Offline Fireredburn1

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #7 on: July 21, 2016, 02:43:45 AM »
Bumping this thread because I still have no success drawing the mechanism. In the original question,  it stated that there was lost of CO2 and H+. comparing between the original reactant and the product, i find that there is only loss of CO2, no lost of H+ as the qn indicated.

Also have no success of pushing the lone pair of electrons from nitrogen all the way to break the C-O bond. Is the qn flawed in any way? Would appreciate any help.

Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #8 on: July 21, 2016, 10:43:32 AM »
Concerning the cyclization on the isoindolin-1-one to the piperadine, I think you drew the final structure incorrectly. I drew a corrected structure after following the most logical cyclization mechanism (attached).

The structure you drew had two methylene carbons budding off of the aromatic ring at two positions. The two methylene carbons bud off of a single position on the aromatic ring.

Offline orgopete

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #9 on: July 21, 2016, 07:53:42 PM »
Re decarboxylation reaction

If I start working with the protonated ketone, the first structure, I would use the indole nitrogen to kick out CO2 and end with the enol-imium salt. Deprotonation and electron shift I think gives the product.
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Offline Fireredburn1

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #10 on: July 21, 2016, 10:08:02 PM »
Re decarboxylation reaction

If I start working with the protonated ketone, the first structure, I would use the indole nitrogen to kick out CO2 and end with the enol-imium salt. Deprotonation and electron shift I think gives the product.

Sorry but to clarify in order to expel CO2 I presume we will have to start breaking the C - O bond first in the ester group and not the other Carbon-Carbonyl carbon bond in the same ester right? What I see myself doing is to push the indole nitrogen lone pair through a series of double bonds to form a C=C bond at the bridge and forcing the C-O bond to leave before proceeding to decarboxylation.

I can see how the electron from nitrogen can be pushed to form an enol - iminium salt. (through the double bonds right) but unfortunately I still can't get the breaking of C-O bond quite right.

Unless you're talking about breaking the Carbon-Carbonyl carbon bond on the other side of the ester. But that is sort of an unusual way of doing decarboxylation

Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #11 on: July 21, 2016, 11:37:21 PM »

I can see how the electron from nitrogen can be pushed to form an enol - iminium salt. (through the double bonds right) but unfortunately I still can't get the breaking of C-O bond quite right.

Unless you're talking about breaking the Carbon-Carbonyl carbon bond on the other side of the ester. But that is sort of an unusual way of doing decarboxylation

I think you've hit the nail right on the head here.

Draw it out.

Offline Fireredburn1

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #12 on: July 22, 2016, 02:10:55 AM »
I think I got the mechanism



Well I think this is an unusual carboxylation. Don't decarboxylation normally start from the other oxygen before the lone pair joins the carbonyl oxygen like the case here?

http://mcat-review.org/decarboxylation.gif

Offline orthoformate

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #13 on: July 22, 2016, 10:25:56 AM »
I would say your drawing is accurate.

The link you have provided is what students are used to seeing for decarboxylation reactions, so in that sense it is unusual. This problem required you to think more, which you did, good work.

Offline lb2

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Re: Decarboxylation to hydroxyindole mechanism
« Reply #14 on: July 22, 2016, 04:43:52 PM »
Hi Fireredburn1,

Good, you seem to be working hard on this problem! Keep it up!

You're answer is essentially backwards... Your system is almost exactly the same as the one in the MCAT example you showed, which involves the decarboxylation of a beta-ketoacid, but in your system there is an added double bond between the keto and carboxylate groups. So your arrows should go in exactly the same direction as in that example. The way that you have CO2 being pushed off in your mechanism is really not how CO2 is lost in decarboxylation reactions: overall, you need to reverse the direction of the arrows.

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