Sciencemadness Discussion Board

Protecting weak secondary amines - driving me crazy!

hexabio - 13-11-2017 at 12:12

I am trying to BOC protect tryptophol and this is driving me crazy.
I have tried pyridine, triethylamine and naoh catalysts with no luck (along with BOCoA)
Have also tried different molar eqs of each.
Does anyone have advice on BOC protecting stubborn secondary amines?

DJF90 - 13-11-2017 at 12:36

What you're referring to is not a secondary amine, but an indole. Two quite separate things.

I'd suggest NaH then Boc2O (what is BOCoA?) for protection of indole nitrogen. In your case (tryptophol) you've got a chemoselectivity issue due to the primary alcohol that is also present. I'll let you do your homework on that one.

clearly_not_atara - 13-11-2017 at 13:53

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. Anhydrous KOH in DMSO is sometimes recommended as a superbasic system. Sodium ethoxide is more soluble and might react more quickly, though. Acetonitrile or DMF might be replacements for DMSO if the latter is unavailable.

hexabio - 13-11-2017 at 15:30

Quote: Originally posted by DJF90  
What you're referring to is not a secondary amine, but an indole. Two quite separate things.

I'd suggest NaH then Boc2O (what is BOCoA?) for protection of indole nitrogen. In your case (tryptophol) you've got a chemoselectivity issue due to the primary alcohol that is also present. I'll let you do your homework on that one.


From what I understand, Boc2O is more selective toward the indole than the primary alcohol unless a strong catalyst is used, I was avoiding the use of DMAP catalyst for this reason, once you introduce it, it will become reactive with the primary alcohol.

hexabio - 13-11-2017 at 15:34

Quote: Originally posted by DJF90  
What you're referring to is not a secondary amine, but an indole. Two quite separate things.

I'd suggest NaH then Boc2O (what is BOCoA?) for protection of indole nitrogen. In your case (tryptophol) you've got a chemoselectivity issue due to the primary alcohol that is also present. I'll let you do your homework on that one.


I have never seen NaH used in BOC protections, can you tell me more about this?

solo - 13-11-2017 at 16:22

......here is a source where you can investigate such combination of protection of said compound,

Amino Acids, Peptides and Proteins in Organic Chemistry: Volume 4 - Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis (Amino Acids, Peptides and Proteins in Organic Chemistry (VCH))

Andrew B. Hughes





http://libgen.io/ads.php?md5=3E9CD888F1BD614C66E2320D3124FEA...

[Edited on 14-11-2017 by solo]

CuReUS - 13-11-2017 at 18:36

Quote: Originally posted by hexabio  
I am trying to BOC protect tryptophol and this is driving me crazy.
I have tried pyridine, triethylamine and naoh catalysts with no luck (along with BOCoA)
Quote: Originally posted by hexabio  
I was avoiding the use of DMAP catalyst for this reason, once you introduce it, it will become reactive with the primary alcohol.

You have to use DMAP to protect the N,the solvent being CH2Cl2,RT for 20 minutes AFTER you protect the OH(with OTBS or something else)

hexabio - 14-11-2017 at 08:09

Quote: Originally posted by CuReUS  
Quote: Originally posted by hexabio  
I am trying to BOC protect tryptophol and this is driving me crazy.
I have tried pyridine, triethylamine and naoh catalysts with no luck (along with BOCoA)
Quote: Originally posted by hexabio  
I was avoiding the use of DMAP catalyst for this reason, once you introduce it, it will become reactive with the primary alcohol.

You have to use DMAP to protect the N,the solvent being CH2Cl2,RT for 20 minutes AFTER you protect the OH(with OTBS or something else)


I thought the DMAP acts as a strong base not a transprotecting group.
I am trying to run this without protecting the OH position by controlling reaction conditions carefully.

DJF90 - 14-11-2017 at 09:24

Quote: Originally posted by hexabio  
I have never seen NaH used in BOC protections, can you tell me more about this?


Use the NaH to deprotonate the indole and then add the Boc2O. As mentioned above you'll need to make provision for your hydroxyl group, whether that be by protective group or otherwise.
Quote: Originally posted by CuReUS  

You have to use DMAP to protect the N,the solvent being CH2Cl2,RT for 20 minutes AFTER you protect the OH(with OTBS or something else)


You don't have to use DMAP if you preform the anion first with a strong base.
Quote: Originally posted by hexabio  
I thought the DMAP acts as a strong base not a transprotecting group.
I am trying to run this without protecting the OH position by controlling reaction conditions carefully.


DMAP is not a strong base at all, and not a "transprotecting group" either (whatever that is supposed to mean). It is a nucleophilic catalyst - it reacts with the Boc2O faster than indole, to form an active species that will acylate indole faster than Boc2O itself would

hexabio - 14-11-2017 at 10:05

Quote: Originally posted by DJF90  
Quote: Originally posted by hexabio  
I have never seen NaH used in BOC protections, can you tell me more about this?


Use the NaH to deprotonate the indole and then add the Boc2O. As mentioned above you'll need to make provision for your hydroxyl group, whether that be by protective group or otherwise.
Quote: Originally posted by CuReUS  

You have to use DMAP to protect the N,the solvent being CH2Cl2,RT for 20 minutes AFTER you protect the OH(with OTBS or something else)


You don't have to use DMAP if you preform the anion first with a strong base.
Quote: Originally posted by hexabio  
I thought the DMAP acts as a strong base not a transprotecting group.
I am trying to run this without protecting the OH position by controlling reaction conditions carefully.


DMAP is not a strong base at all, and not a "transprotecting group" either (whatever that is supposed to mean). It is a nucleophilic catalyst - it reacts with the Boc2O faster than indole, to form an active species that will acylate indole faster than Boc2O itself would



NaH is a pretty brutal reagent just for depronating indole, isnt triethylamine, pyridine or NaOH usually used for that?

Is there anything else other than NaH which would have the same effect? I have to admit I have been treating the indole as a cyclic amine in my research.

The transprotecting approach is sometimes used to replace a smaller protecting group with a stronger one, which is what my intuition says happens here.

Any help will be appreciated as OH protection is not an option.

DJF90 - 14-11-2017 at 10:47

Quote: Originally posted by hexabio  
NaH is a pretty brutal reagent just for depronating indole, isnt triethylamine, pyridine or NaOH usually used for that?

Triethylamine and pyridine aren't strong enough bases to deprotonate indole (look at the pKas). NaH is a convenient means of deprotonating the indole quantitatively before addition of an electrophile (it is commonly used for deprotonation of -OH, -NH and -SH species).

Quote: Originally posted by hexabio  
Is there anything else other than NaH which would have the same effect? I have to admit I have been treating the indole as a cyclic amine in my research.

I'm sure other strong non-nucleophilic bases would do an equally good job; LDA or KHMDS for example. I'm not saying this approach is the only way to do it (or even if it would work given your specific substrate and its chemoselectivity issues) , but it is one route that you can research further. Why don't you look at "Protecting groups in organic synthesis" for a summary of other methods?
Quote: Originally posted by hexabio  
The transprotecting approach is sometimes used to replace a smaller protecting group with a stronger one, which is what my intuition says happens here.

Thats not what you're doing here. You're moving the protecting group from one species (the DMAP catalyst) to another (substrate).

Quote: Originally posted by hexabio  
Any help will be appreciated as OH protection is not an option.

Perhaps you can share your synthetic route so that we can see why this is a problem?

[Edited on 14-11-2017 by DJF90]

hexabio - 14-11-2017 at 12:54

I appreciate all the insights, I had this backwards in my head.
On TLC I am seeing some type of BOC protection, two separate products depending on how I optimize.

Since I am using a weak base (not strong enough to deprotonate the amine) with BOC, would you assume one of the products is O-Boc and the other C3-Boc?

Sigmatropic - 14-11-2017 at 14:57

C3 Bocylation seems unlikely to me as the product loses aromaticity in the indole ring. Of course this could rearrange and give you something but I doubt that.
I would attempt to either protect the alcohol first (silyl, acyl or trityl) then protect the nitrogen followed by O-deprotection. Or create the O, N, double anion and selectively protect the more basic indole nitrogen.
I'm with DFJ90, without knowing your synthetic route we cannot know or even begin to think about what procedures are called for. If it's going where I think you are going then you don't need to worry about (self) alkylation of the indole nitrogen. (look up some conditions for alkylation the indole nitrogen and you'll see why). But all this is conjecture without knowing your route and or target.

CuReUS - 15-11-2017 at 01:50

Quote: Originally posted by hexabio  

I am trying to run this without protecting the OH position by controlling reaction conditions carefully.

I don't think you can do that in tryptophol.Generally N is much more willing to share electrons than O,so you can selectively react it with your reagent.But in this case,the lone pair of N is in resonance with the indole ring,making it less juicy and relatively making the OH more attractive to react with;)
If you could tell your target compound,maybe another route could be suggested which would completely bypass the need for protection:)

hexabio - 15-11-2017 at 05:13

Quote: Originally posted by Sigmatropic  
C3 Bocylation seems unlikely to me as the product loses aromaticity in the indole ring. Of course this could rearrange and give you something but I doubt that.
I would attempt to either protect the alcohol first (silyl, acyl or trityl) then protect the nitrogen followed by O-deprotection. Or create the O, N, double anion and selectively protect the more basic indole nitrogen.
I'm with DFJ90, without knowing your synthetic route we cannot know or even begin to think about what procedures are called for. If it's going where I think you are going then you don't need to worry about (self) alkylation of the indole nitrogen. (look up some conditions for alkylation the indole nitrogen and you'll see why). But all this is conjecture without knowing your route and or target.



So you are saying that depronating the indole hydrogen (using NaH or something) is not enough for a chemioselective BOC protection on the N position of the indole?

I need to go further and form the double anion which will be more basic and make this BOC protection chemioselective?

Sigmatropic - 15-11-2017 at 09:20

What I'm saying is that, based on pKa values, one equivalent of NaH gets you the O-anion which when treated with boc anhydride gives you the O-boc compound. Treating with 2 or better yet an excess of NaH gives you the N, O-dianion which you may then be able to chemoselectively protect at the nitrogen.

To give you an idea, most literature methods do O-protection, N functionalization, O-deprotection. Although the O,N-double anion is encountered quite commonly in the case of alkylation.

[Edited on 15-11-2017 by Sigmatropic]

Attachment: reaxys_anonymous_20171115_173954_541.pdf (275kB)
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DJF90 - 15-11-2017 at 09:31

Quote: Originally posted by Sigmatropic  
What I'm saying is that, based on pKa values, one equivalent of NaH gets you the O-anion which when treated with boc anhydride gives you the O-boc compound. Treating with 2 or better yet an excess of NaH gives you the N, O-dianion which you may then be able to chemoselectively protect at the nitrogen.


My thoughts exactly, but wanted the OP to work for the answer a little more. They don't seem to have a particularly good grasp on organic chem, so why they'd be messing around with something like Tryptophol is beyond me (I have a pretty good idea actually: DMT).

karlos³ - 17-11-2017 at 08:54

Use tosyl chloride and pyridine, that works for a great leaving group.

zed - 17-11-2017 at 17:08

Original poster. Hey, just exactly what are you trying to make?

Collectively, the guys know much of what there is to know.

Possibly, they can just tell you how to get to where you want to go.

So, where do you want to go?

hexabio - 23-11-2017 at 05:35

I found a reference which uses poly(4-vinylpyridine) and BOC2o to selectively protect indoles in the presence of alcohol groups. They have one or two examples of indoles in the reference although it is geared toward other amine groups.

https://www.researchgate.net/publication/257806822_Poly4-vin...

Is there any reason this wont work for my substrate?

CuReUS - 23-11-2017 at 05:57

Quote: Originally posted by hexabio  
Is there any reason this wont work for my substrate?

I don't see why not:) good find:o

karlos³ - 23-11-2017 at 14:43

@OP, I concur with zed, could you please be so kind to tell us more about what you´re up to produce?
I´ve worked with tryptophol(and tosylate) in the past too, so your ambitions and goal would be very interesting to know.

hexabio - 23-11-2017 at 18:04

I had a custom synthesis request for N-boc protected tryptophol and I am trying to avoid the O protection/deprotection.

The previously posted paper looks very promising, two indole compounds were protected in high yields and alcohol groups are not touched, the only thing that blows my mind is how the hell a polymer causes such chemioselectivity and reactivity with BOC, apparently the mechanism is unknown, it just works.

Can anyone take a look at the paper and tell me if its nonesense? Its from Iran, not sure what their academic reputation is but from what I know, they make great scientists.

DJF90 - 24-11-2017 at 05:22

So you're on a forum for amateur science asking for advice/solutions to your commercial problems? Do us all a favour - go and hire yourself a consultant (a good one - you need all the help you can get).

Sigmatropic - 24-11-2017 at 10:07

Using TMS as a transient protecting group would still fall under the general scheme of O-protection, N-functionalization followed by O-deprotection.
The fact they use a recoverable bronsted base catalyst does not change this fact nor does it make the mechanism unknown. All that does is make it 'novel' and thus publishable. What I would call a prime example of denovation resulting from the publish or perish culture at universities. What I mean to say is, there are better, cheaper and faster ways. But maybe if this polyvinylpyridine becomes as available as polystyrene sulfonate (aka amberlite, amberlyst, dowex) it may actually have its uses. But until then I will just employ the cheap as shit pyridine or its cousin DMAP.

[Edited on 24-11-2017 by Sigmatropic]

hexabio - 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.

zed - 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

clearly_not_atara - 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.

DJF90 - 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.

clearly_not_atara - 26-11-2017 at 11:26

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

Cryolite. - 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.]

hexabio - 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.

zed - 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]

CuReUS - 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]

clearly_not_atara - 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]