Sciencemadness Discussion Board

Protecting groups for tertiary amines

Monoamine - 6-7-2021 at 11:13

Greetings!

I was wondering if any of you have some input about a problem for a synthesis I'm facing atm.

Basically, I want to use this compound (Figure 1)

Figure 1) Starting_Material.png - 41kB

to make this compound (Figure 2)

Product.png - 49kB

Basically this is just an ether synthesis, but the problem is that the molecule also contains a tertiary amine and so should be protected to avoid over alkylation to a quaternary ammonium ion.

I have been looking at Wuts "Protective groups for organic synthesis" extensively, but the problem is that the protective groups shown there are all basically derivatives of acetic anhydride, which is a schedule 1 precursor (I think cartels use it to acetylate morphine or something...). In any case, this would mean that the standard protecting groups are off the table for me unfortunately (not judging what others choose to do, just saying).

I have noticed however, that when converting a quaternary ammonium ion to a tertiary amine, the alkyl substituent that is expelled is the most substituted of the four. So maybe a strategy would be to first "over alkylate" the amine by adding a t-butyl group onto it, forming the ether, and then removing the redundant "protective" alkane from the amine.

Unfortunately, I couldn't find any consistent sources on how to turn a quaternary ammonium ion into a tertiary amine.

If any of you know how to do this (or if the proposed method even has a chance of succeeding I would love to hear from you! If you know of other, less restrictive protecting groups that might work here, the I'd be super curious to learn about those too!

Below is the proposed synthesis (Figure 3)

Proposed_synthesis.png - 448kB

References:
Wuts, Peter GM, and Theodora W. Greene. Greene's protective groups in organic synthesis. John Wiley & Sons, 2006.






[Edited on 7-7-2021 by Monoamine]

karlos³ - 6-7-2021 at 11:49

Boil it in ethanolamine to dequaternise.

zed - 6-7-2021 at 11:57

Find a reference for the procedure.

Need for a protecting group is not certain.

Some alkylating agents might attack that tertiary amine, and some might not.

Jenks - 6-7-2021 at 12:14

A very similar structure is ibogaine. Here is a patent where its methyl ether is converted into an ethyl ether while the tertiary nitrogen is protected by temporarily converting it into a lactam.

Monoamine - 6-7-2021 at 16:24

Amazing! Thank you for all the helpful replies!
Time to hit the books :D

Monoamine - 6-7-2021 at 16:44

Quote: Originally posted by Jenks  
A very similar structure is ibogaine. Here is a patent where its methyl ether is converted into an ethyl ether while the tertiary nitrogen is protected by temporarily converting it into a lactam.


Out of curiosity: Do you happen to know if the compounds in the patent you linked ever made it to pre-clinical trials and if their in vitro pharmacology was ever studied? In particular, was their affinity for the human HERG channel ever investigated?

Dr.Bob - 6-7-2021 at 17:48

You could also oxidize the tert amine to the N-oxide and that would stable and then reduce it back later.

Jenks - 6-7-2021 at 19:38

Quote: Originally posted by Monoamine  
Quote: Originally posted by Jenks  
A very similar structure is ibogaine. Here is a patent where its methyl ether is converted into an ethyl ether while the tertiary nitrogen is protected by temporarily converting it into a lactam.


Out of curiosity: Do you happen to know if the compounds in the patent you linked ever made it to pre-clinical trials and if their in vitro pharmacology was ever studied? In particular, was their affinity for the human HERG channel ever investigated?

The patent is from 1959 and I haven't found any other reference to O-ethyl-noribogaine, except as a way of derivitizing noribogaine for HPLC analysis. But ibogaine and noribogaine have been extensively studied.
Quote: Originally posted by karlos³  
Boil it in ethanolamine to dequaternise.

This seems like the easiest method if it works. If ethyl is too bulky, the amine could be methylated, then the phenol ethylated, then the amine demethylated with ethanolamine or a thiolate. Still one pot.

[Edited on 7-7-2021 by Jenks]

Monoamine - 11-7-2021 at 20:04

Quote: Originally posted by Jenks  
Quote: Originally posted by Monoamine  
Quote: Originally posted by Jenks  
A very similar structure is ibogaine. Here is a patent where its methyl ether is converted into an ethyl ether while the tertiary nitrogen is protected by temporarily converting it into a lactam.


Out of curiosity: Do you happen to know if the compounds in the patent you linked ever made it to pre-clinical trials and if their in vitro pharmacology was ever studied? In particular, was their affinity for the human HERG channel ever investigated?

The patent is from 1959 and I haven't found any other reference to O-ethyl-noribogaine, except as a way of derivatizing noribogaine for HPLC analysis. But ibogaine and noribogaine have been extensively studied.
Quote: Originally posted by karlos³  
Boil it in ethanolamine to dequaternise.

This seems like the easiest method if it works. If ethyl is too bulky, the amine could be methylated, then the phenol ethylated, then the amine demethylated with ethanolamine or a thiolate. Still one pot.

[Edited on 7-7-2021 by Jenks]


Indeed, Ibogaloids are a fascinating class of compounds, and we're probably only scratching the surface of their potential. Still, it would be nice to find a compound possessing all of Ibogaine's therapeutic effects, but without blocking the HERG channel, which can cause cardiac arrhythmias at extremely high doses in some people.

Noribogaine - the major, active metabolite of Ibogaine - which contributes to the total effects significantly, has an even higher affinity for the HERG channel unfortunately.

But... I'm confident that much progress will be made in that area in the years to come.

I'm curious to hear what your thoughts are?

Another possible way to for protection:

Monoamine - 11-7-2021 at 20:21

Just saw this: (https://www.organic-chemistry.org/protectivegroups/amino/tol...).
It seems that under the above conditions even a tosyl group can be used for protection of amines.

Screen Shot 2021-07-11 at 9.06.21 PM.png - 16kB

Not though, that protecting tertiary amines creates ammonium cations.



Reference:
A facile and efficient indium-catalyzed sulfonylation of amines allows the synthesis of a wide range of sulfonamides in excellent yields. The method showed a generality for substrates including less nucleophilic and sterically hindered anilines, and it is also applicable for preparing sulfonic esters from sulfonyl chlorides and alcohols.
J. Yan, J. Li, D. Cheng, Synlett, 2007, 2442-2444.

SWIM - 11-7-2021 at 21:08

Wouldn't the ethyl bromide have to attack the tertiary amine via an SN2 pathway because of the relatively mild conditions that would be used to form a phenol ether?
And wouldn't this be impossible because of the rigidity of the structure?

Not sure about this, but it looks like that nitrogen would have trouble doing the 'umbrella blown inside out' thing that is required for an SN2.


Disclaimer:
If this opinion is gibberish, I blame the dexamethasone and lenalidomide.
It's a combo that kinda sneaks up on you.


Oxy - 11-7-2021 at 21:58

Quote: Originally posted by SWIM  
Wouldn't the ethyl bromide have to attack the tertiary amine via an SN2 pathway because of the relatively mild conditions that would be used to form a phenol ether?
And wouldn't this be impossible because of the rigidity of the structure?

Not sure about this, but it looks like that nitrogen would have trouble doing the 'umbrella blown inside out' thing that is required for an SN2.



I think in this case it would be in an other way around. Nitrogen's lone pair of electrons (exposed a bit due to structure and very basic due to 3 alkyl substituents) will attack ethyl bromide as nucleophile and substitute bromine.
That means there is no need and place for any structural inversion here.

Jenks - 12-7-2021 at 04:43

Quote: Originally posted by Monoamine  

Indeed, Ibogaloids are a fascinating class of compounds, and we're probably only scratching the surface of their potential. Still, it would be nice to find a compound possessing all of Ibogaine's therapeutic effects, but without blocking the HERG channel, which can cause cardiac arrhythmias at extremely high doses in some people.

Noribogaine - the major, active metabolite of Ibogaine - which contributes to the total effects significantly, has an even higher affinity for the HERG channel unfortunately.

But... I'm confident that much progress will be made in that area in the years to come.

I'm curious to hear what your thoughts are?

I agree with you that the structure-activity relationships of structures like ibogaine are a wide open and potentially highly helpful area. The few analogs that have been promoted (noribogaine, 18-methoxycoronaridine (18-MC), anything else?) have not shown better properties for treating addiction than ibogaine, as far as I am aware. The main "feature" of noribogaine is supposed to be that it doesn't produce visionary effects, so as not to frighten the decision makers that might approve its use. But a lot of people who have been treated for addiction with ibogaine credit the visions they had for helping them understand the causes of their addiction and live differently. Addiction is extremely complicated and animals aren't a very good screen. For example, voacangine (16-carbomethoxy-ibogaine) was able to prevent withdrawal in rats, but mainly causes gastrointestinal distress in humans, maybe due to a difference in metabolism of this difficult-to-hydrolyze ester. That wasn't discovered by some clinical trial though - it was found by volunteers at an unregulated addiction treatment provider, the voacangine being available because it is the main precursor to ibogaine. And that doesn't bode well for 18-MC, having the same ester group, which still hasn't started clinical trials for treating addiction despite being developed as a candidate for that purpose in 1996.

Everything about ibogaine is an uphill battle. Drug addicts have been the group for the media to hate for a century, to the point where there is even an insurmountable stigma against helping them. Howard Lotsof, the one who discovered ibogaine's anti-addictive effects in 1962, once asked a representative at a pharmaceutical company why they would not develop ibogaine as a medication. Their candid reply was that the stigma of even helping drug addicts would cause so much loss in sales of their other product lines that it would not be profitable. This is why, to this day, almost all addiction treatment with ibogaine is provided by self-selected, unregulated providers - many of them former addicts themselves - trying to fly below the radar in countries like Mexico. So as interesting as the chemistry and pharmacology of ibogaine is, the main problem with developing it remains psychological, even spiritual, affecting the attitude of people throughout the world.

As far as promising analogs, Tabernanthe iboga itself contains ibogaline, ibogamine and tabernanthine, in order of amount, in addition to ibogaine. These probably have properties similar to ibogaine, differing only in number and position of aryl methoxy groups, and any one might have a better pharmacological profile (which, in my mind, mainly means less chance of causing cardiac arrhythmia). Another place to start is derivatization of the ibogamine skeleton, as was done with 18-MC, an isomer of voacangine. Also, the methyl group on ibogaine could be replaced with other alkyl groups as we discussed. Finally, it may be possible to find Friedel-Crafts conditions that would selectively functionalize the benzene ring in ibogaine, based on a reverse Friedel-Crafts alkylation of voacamine into voacangine that was recently published. This paper also described the isolation of voacristine from Voacanga africana, which allows analogs similar to 18-MC, and its de-esterified derivatives, to be made. It is also possible to functionalize the carbon on ibogaine where voacangine has its ester group. There are also a few other ibogamine derivatives available from Tabernaemontana species which could be derivatized. The difficulty here is that the species would have to be cultivated, requiring both a farmer and a chemist.

[Edited on 12-7-2021 by Jenks]

Texium - 12-7-2021 at 05:42

Quote: Originally posted by Monoamine  
Just saw this: (https://www.organic-chemistry.org/protectivegroups/amino/tol...)
Stop posting multiple threads on the same subject.

Triflic Acid - 12-7-2021 at 05:50

Maybe try using diethyl carbonate. It seems that carbonates are unable to form quaternary ammoniums. You could make diethyl carbonate by heating diethyl oxalate up so it breaks down to diethyl carbonate and carbon monoxide. Or, if you want to buy it, U2U me. I know a member with a large stock he can sell.
[Edit: He has dimethyl carbonate, not diethyl. My bad.]

[Edited on 12-7-2021 by Triflic Acid]

EverythingAl2O3 - 17-7-2021 at 06:20

Is there anything stopping you from doing an acid catalyzed ether synthesis? So you could use H2SO4 and ethanol to get your phenethoxy group and avoid the overalkylation?

njl - 17-7-2021 at 06:32

Or deprotonate and perform William ether synthesis

Triflic Acid - 17-7-2021 at 06:54

But the Williamson ether needs an alkyl halide, which will destroy the amine. Assuming you don't add a protecting group like the OP said.

njl - 17-7-2021 at 07:02

I think the phenolate will react much more quickly compared to the amine.

Monoamine - 20-7-2021 at 09:46

Quote: Originally posted by karlos³  
Boil it in ethanolamine to dequaternise.


Thank you for the tip! (So just to clarify, this is done to deprotect the amine later?)

Monoamine - 20-7-2021 at 09:51

Quote: Originally posted by njl  
Or deprotonate and perform William ether synthesis


Ahhh... you mean because a deprotonated OH (ie O-) will be far more likely to react with with the Br-Alkyl, than the weaker (lewis?) base which is the lone pair on the amine.

I will try this for sure, if it works it'll definitely make thinks a lot easier!

Thanks!

njl - 21-7-2021 at 05:11

Quote: Originally posted by Monoamine  
Quote: Originally posted by karlos³  
Boil it in ethanolamine to dequaternise.


Thank you for the tip! (So just to clarify, this is done to deprotect the amine later?)


Not exactly to deprotect, this method just accepts the quaternization and deals with it after the reaction rather than preventing it in the first place.
Quote:

Ahhh... you mean because a deprotonated OH (ie O-) will be far more likely to react with with the Br-Alkyl, than the weaker (lewis?) base which is the lone pair on the amine.


Yes. Although the nitrogen lone pair will probably be more nucleophilic than other tertiary amines due to the molecules geometry.

clearly_not_atara - 21-7-2021 at 06:12

Quote: Originally posted by njl  
I think the phenolate will react much more quickly compared to the amine.

It depends on the solvent conditions. A phenolate is more reactive than an amine. But in a less polar solvent, the phenol will be neutral (protonated) and the amine will react first.

So first you must ensure the phenol is deprotonated.

You can also use weaker alkylating agents like diethyl oxalate, which should only attack the phenol here.

This seems like a pretty straight forward way to make acetal protected amines

Monoamine - 30-7-2021 at 18:04

This may be a bit late, but it seems pretty useful, so I'll post this here anyay:

Attachment: Acetal_amine_protection_procedure_(Sharley_2017.pdf (1.5MB)
This file has been downloaded 284 times

Basically, the authors have a way to apply pretty much any acetal protecting group to (secondary or primary) amines. The cool thing about this seems to be that they only use relatively common reagents for all this. (No need for acid-halides etc...)

The only drawback that I can see is that there doesn't seem to be a very cleary way to determine how much catalyst (acetic acid) has to be used. The amount can range from 0.1 eqiv to 2.5 equiv!! Also the reaction takes about 20h.

But still, unless you have some acetic anhydride or SOCl2 lying around, this definitely seems like a decent alternative, considering how general it is.

Sharley, Daniel D. Sanz, and Jonathan MJ Williams. "Acetic acid as a catalyst for the N-acylation of amines using esters as the acyl source." Chemical Communications 53, no. 12 (2017): 2020-2023.

Monoamine - 30-7-2021 at 18:13

Quote: Originally posted by clearly_not_atara  
Quote: Originally posted by njl  
I think the phenolate will react much more quickly compared to the amine.

It depends on the solvent conditions. A phenolate is more reactive than an amine. But in a less polar solvent, the phenol will be neutral (protonated) and the amine will react first.

So first you must ensure the phenol is deprotonated.

You can also use weaker alkylating agents like diethyl oxalate, which should only attack the phenol here.


Thank you for the tip! Would the solvent also have to be protic or would e.g. DMSO work. (Or would the Br-Et react with the alpha carbon of the thionyl of DMSO?

zed - 30-7-2021 at 22:20

As stated previously. Under some circumstances a protecting group is not required.

The molecule you are trying to synthesize bears some structural similarity to Codeine, and Chemists did spend many years perfecting that synthesis via the etherization of Morphine.

Eventually, they simply utilized a Quaternary Ammonium Salt, as the Methylating agent. Such a reagent will preferentially Methylate the hydroxy group.

https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bu...

I'll dig a little bit more. Yeah, I'm imagining Ethylation is not more difficult than Methylation, but I do not have a procedure.

The Ethyl Ether of Morphine (an analog to Codeine) is named Dionine. It is particularly useful for application to the eyes.
The preferred use of the Ethyl Ether rather than the Methyl Ether, might have to do with the toxic effect Methanol has on the optic nerve. I do not know that with any certainty though.

Dionine/Ethyl Morphine synthesis.... https://www.sciencedirect.com/science/article/abs/pii/S00959...

Sorry. No can open it, myself!

[Edited on 31-7-2021 by zed]

[Edited on 31-7-2021 by zed]

Triflic Acid - 31-7-2021 at 07:24

Ethanol should work as a solvent. If you have more than one go at this, try both ways. The diethyl oxalate/carbonate way, and the protecting group + EtBr way.

njl - 31-7-2021 at 11:14

Acetic acid catalyzed ester aminolysis

Monoamine - 7-8-2021 at 07:20

Quote: Originally posted by EverythingAl2O3  
Is there anything stopping you from doing an acid catalyzed ether synthesis? So you could use H2SO4 and ethanol to get your phenoxy group and avoid the overalkylation?


I'm not too familiar with this approach, but if this works for armatic OH groups, then of course this would solve the problem. Let me look into the exact reaction mechanism for this kind of ether-synthesis.

Thanks for the tip!

Monoamine - 13-8-2021 at 22:49

Quote: Originally posted by zed  
As stated previously. Under some circumstances a protecting group is not required.

The molecule you are trying to synthesize bears some structural similarity to Codeine, and Chemists did spend many years perfecting that synthesis via the etherization of Morphine.

Eventually, they simply utilized a Quaternary Ammonium Salt, as the Methylating agent. Such a reagent will preferentially Methylate the hydroxy group.

https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bu...

I'll dig a little bit more. Yeah, I'm imagining Ethylation is not more difficult than Methylation, but I do not have a procedure.

The Ethyl Ether of Morphine (an analog to Codeine) is named Dionine. It is particularly useful for application to the eyes.
The preferred use of the Ethyl Ether rather than the Methyl Ether, might have to do with the toxic effect Methanol has on the optic nerve. I do not know that with any certainty though.

Dionine/Ethyl Morphine synthesis.... https://www.sciencedirect.com/science/article/abs/pii/S00959...

Sorry. No can open it, myself!

[Edited on 31-7-2021 by zed]

[Edited on 31-7-2021 by zed]


Very interesting that it contains a similar 3D moiety as Codeine! Just looked up the structure and there really is a similar one, but smaller, than that of the above compound. But as someone pointed out it also bears a semblance to noribogaine, the active metabolite of ibogaine, both of which are used to cure opiate addiction. But I guess in retrospect it isn't a surprise that a medication that addresses the symptoms of opiate withdrawal would have a similar structure to the later...

As for the difficulty of methylation vs. ethylation, I would actually imagine that ethylation is easier (if you're using an alkyl halide) since MeBr is a gas while EtBr isn't, so it's much easier to control the amount of reagent introduced to the reaction. (I'd guess that more than one molar equivalent of EtBr would inevitably lead to the formation of side products, where the amine is also alkylated).

Maybe you could use a tosylated methanol if you want to do a methylation? But honestly, I don't remember if that would even work for an ether synthesis. I'll look into it.