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Author: Subject: Protecting weak secondary amines - driving me crazy!
hexabio
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[*] posted on 24-11-2017 at 15:20


I am trying to do this without O protection/deprotection, the paper suggested that PVP will work with BOC to make it amine selective, it wont touch OH groups, I was asking this forum if anyone has insights into it working on my substrate, there are examples in the paper of it working with indole type compounds selective for the N group but not indole itself.
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zed
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[*] posted on 25-11-2017 at 16:46


Indole is not an amine. And, it's reactions are not typically those of an Amine.

Technically, you could consider it an enamine. It being the internal condensation product of O-Amino-Phenylacetaldehyde.

Generally speaking, the 1-position of indole, does not need protecting.

Tryptophol N-protection, could be done via ketene, followed by hydrolysis of the resulting ester.

Cheaper too.

https://www.google.com/patents/US2810723
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clearly_not_atara
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[*] posted on 25-11-2017 at 18:05


I know that esters sometimes react with amines -- could you e.g. just react tryptophol with excess dibenzyl carbonate at room temperature for a few days? This should avoid any possibility of attacking the alcohol or indole and happens in one step.

More generally, it seems to me that trying to selectively attack nitrogen is going to be easier than trying to selectively protect anything.




[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 26-11-2017 at 07:58


Quote: Originally posted by clearly_not_atara  
I know that esters sometimes react with amines...

The indole nitrogen does not display reactivity of a typical aromatic or aliphatic amine. It reacts quite similarly to pyrrole, but (generally) regioselectiviy is different due to the fused benzene ring.
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clearly_not_atara
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[*] posted on 26-11-2017 at 11:26


I thought we were trying to selectively protect the amine nitrogen on tryptophol? Otherwise yeah I'm confused.



[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 26-11-2017 at 12:44


Selective protecting the ring nitrogen of tryptophol ( (3-indolyl)-2-ethanol to clear up ambiguity) is very difficult: the indolic nitrogen's lone pair is delocalized by aromaticity and therefore exhibits extremely low nucleophilicity. However, this delocalization means that the N-H bond in the indole core is reasonably acidic, and can therefore be pulled off by a strong base like NaH (or even KOH under PTC conditions). Note that this reactivity is very different from normal amines, and so the standard protection conditions for those do not apply here. One of the better ways I've seen to protect indole nitrogens in the literature is to deprotonate with sodium hydride and then treat with tosyl chloride to form an n-tosylindole. These can be subsequently deprotected by mild base, if I remember correctly. You may end up tosylating the alcohol as well, but that is potentially what you want anyways.

[Edited on 26-11-2017 by Cryolite.]
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[*] posted on 26-11-2017 at 16:02


Quote: Originally posted by Cryolite.  
Selective protecting the ring nitrogen of tryptophol ( (3-indolyl)-2-ethanol to clear up ambiguity) is very difficult: the indolic nitrogen's lone pair is delocalized by aromaticity and therefore exhibits extremely low nucleophilicity. However, this delocalization means that the N-H bond in the indole core is reasonably acidic, and can therefore be pulled off by a strong base like NaH (or even KOH under PTC conditions). Note that this reactivity is very different from normal amines, and so the standard protection conditions for those do not apply here. One of the better ways I've seen to protect indole nitrogens in the literature is to deprotonate with sodium hydride and then treat with tosyl chloride to form an n-tosylindole. These can be subsequently deprotected by mild base, if I remember correctly. You may end up tosylating the alcohol as well, but that is potentially what you want anyways.

[Edited on 26-11-2017 by Cryolite.]


This is very helpful, thank you so much. I didnt realize the indole character was initially acidic, I was thrown off by the fact that you can still form the HCL salt but I realize now that happens at C2 not the N group.

So in the normal BOC/DMAP procedure, the DMAP-boc intermediate attacks the indole without a depronation step beforehand.

It looks like the BOC/PVP method I referenced earlier can do the same without also attacking the primary OH group? That is the question I am trying to answer as I need BOC at the N position but I can not utilize the normal OH protection/deprotection method as a limitation, so I am trying to find a way to protect only the indole N in one step with BOC specifically.

It looks like my only hope is to somehow optimize DMAP/BOC reaction to have decent yields on N-Boc proted tryptophol with N,O product being a side product I could recycle through deprotection. OR possibly the BOC/PVP really is specific to indoles and the OH group wont be protected at all since the have indole nitrogens in the examples that work selectively at high yields.
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zed
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[*] posted on 27-11-2017 at 19:01


Which is why I suggested the N-acetylation via ketene. Ketene of course, is a deadly gas.

So, if you aren't skilled in its use, and/or you don't have the right safety gear....Don't consider using it.

The patent authors, are not acetylating tryptophol, but another molecule. So your results might vary. The expected product would be N-Acetyl-Tryptophol acetate. And, if their results hold true (not a certainty). The product might be hydrolysed to N-Acetyl-Tryptophol, via mildly acetic conditions. The product is stable to dilute acid conditions, but not strongly basic conditions.

Your N- would be protected, but by not by BOC.

https://www.google.com/patents/US2810723

Now, this information may be of no use to you whatsoever. But, it is what it is.
If you really have to have BOC, you have to have BOC. Just not sure how to get there.

[Edited on 28-11-2017 by zed]

[Edited on 28-11-2017 by zed]
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CuReUS
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[*] posted on 28-11-2017 at 08:20


Quote: Originally posted by Cryolite.  
You may end up tosylating the alcohol as well, but that is potentially what you want anyways.

That's exactly what the OP does NOT want
Quote: Originally posted by hexabio  
I had a custom synthesis request for N-boc protected tryptophol and I am trying to avoid the O protection/deprotection.

Quote: Originally posted by hexabio  
I didnt realize the indole character was initially acidic, I was thrown off by the fact that you can still form the HCL salt but I realize now that happens at C2 not the N group.

Are you sure ? I thought you needed metal cations to be able to react with carbanions ?

[Edited on 28-11-2017 by CuReUS]
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clearly_not_atara
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[*] posted on 28-11-2017 at 11:51


Me, last page:

Quote: Originally posted by clearly_not_atara  
In water, the pKa of ethanol and indole are roughly equal, both about 16. But in DMSO, the pKa of indole is 17 while the pKa of ethanol is 30. So the solvent has a large effect.


In order to attack the indole nitrogen and not the alcohol oxygen, you need to deprotonate one without deprotonating the other. The different groups have different pKas in different solvents. DMSO seems to have the desired properties.

[Edited on 28-11-2017 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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