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Author: Subject: OTC Amine protection?
thors.lab
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[*] posted on 15-2-2021 at 15:38
OTC Amine protection?


Hi,

I'm looking for a way to protect an amino acid's amine from forming an amide. Unfortunately the textbook protecting groups (Boc, Cbz) seem a bit hard to get ahold of if one doesn't have chlorination reagents (to make BocCl or CbzCl or Boc Anhydride for example).

Are there any OTC amine protection methods I could employ here?

Thanks,




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EverythingAl2O3
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[*] posted on 15-2-2021 at 17:51


Are trying to protect a primary or secondary amine? What conditions will your reactant undergo? If it is a secondary it might be possible to protect it with a benzyl group via Sn2 with benzyl chloride. I don't know how reversible benzyl groups with hydrolysis of amines, but they tend to be willing to form carbocations and have the double bonds to help push off the positively charged amine salt. Though that is just conjecture for what might be more available option, because you'd just need benzyl alcohol and HCl to form benzyl chloride. My reasoning for mentioning it is this statement from benzylamine wikipedia
Quote:

Benzylamine is used as a masked source of ammonia, since after N-alkylation, the benzyl group can be removed by hydrogenolysis

So hydrogenolysis would probably work here, but again I don't know if there would be an easier method.
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thors.lab
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[*] posted on 15-2-2021 at 18:54


Quote: Originally posted by EverythingAl2O3  
Are trying to protect a primary or secondary amine? What conditions will your reactant undergo? If it is a secondary it might be possible to protect it with a benzyl group via Sn2 with benzyl chloride. I don't know how reversible benzyl groups with hydrolysis of amines, but they tend to be willing to form carbocations and have the double bonds to help push off the positively charged amine salt. Though that is just conjecture for what might be more available option, because you'd just need benzyl alcohol and HCl to form benzyl chloride. My reasoning for mentioning it is this statement from benzylamine wikipedia
Quote:

Benzylamine is used as a masked source of ammonia, since after N-alkylation, the benzyl group can be removed by hydrogenolysis

So hydrogenolysis would probably work here, but again I don't know if there would be an easier method.


Sorry I should have been more specific -- I'm trying to protect lysine's amines. The end goal is an amide bond to lysine. That might be a good idea if deprotection won't destroy my final product -- I'd have to think about that.




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karlosĀ³
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[*] posted on 15-2-2021 at 20:03


Quote: Originally posted by thors.lab  
Quote: Originally posted by EverythingAl2O3  
The end goal is an amide bond to lysine. That might be a good idea if deprotection won't destroy my final product -- I'd have to think about that.

Making lisdexamfetamine or similar analogues is far harder than it might seems on the first glance.
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thors.lab
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[*] posted on 16-2-2021 at 00:24


Quote: Originally posted by karlosĀ³  
Quote: Originally posted by thors.lab  
Quote: Originally posted by EverythingAl2O3  
The end goal is an amide bond to lysine. That might be a good idea if deprotection won't destroy my final product -- I'd have to think about that.

Making lisdexamfetamine or similar analogues is far harder than it might seems on the first glance.


First I should mention that lisdexamfetamine isn't my desired final product here, nor is my final product a scheduled substance, and nor do I plan on distributing it. My purposes here are purely investigative.

Second, I wouldn't say the chemistry here is particularly difficult. Without using coupling reagents like DCC etc, it should be as easy as 1. protecting the amine groups, 2. esterifying the lysine to produce a good LG, 3. react to form amide, and 4. deprotecting. What is difficult is the aquisition of the required reagents here. And I should note that it's not difficult to aquire these reagents due to any sort of DEA restrictions, but because the average person has little use for amine protection reagents.

[Edited on 16-2-2021 by thors.lab]

[Edited on 16-2-2021 by thors.lab]




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Boffis
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[*] posted on 16-2-2021 at 06:18


Are you trying to make lysinamide as an intermediate? If so you don't need to protect the amino group, you can esterify the lysine with alcohol + HCl gas and then treat the ester hydrochloride with excess ammonia I am pretty sure I have seen this method described somewhere when I was looking into the preparation of hydantoin and thiohydantoin.
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thors.lab
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[*] posted on 16-2-2021 at 07:59


Quote: Originally posted by Boffis  
Are you trying to make lysinamide as an intermediate? If so you don't need to protect the amino group, you can esterify the lysine with alcohol + HCl gas and then treat the ester hydrochloride with excess ammonia I am pretty sure I have seen this method described somewhere when I was looking into the preparation of hydantoin and thiohydantoin.


No, I was planning on going to the hydroxy succinamide ester (CAS #34404-36-9). But there's a thought!




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Triflic Acid
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[*] posted on 2-3-2021 at 07:29


Have you looked into the TosCl? That can be made pretty easily from toluene and sulfurly chloride(sulfur dioxide and chlorine). It doesn't seem like a bad protecting group to me.
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clearly_not_atara
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[*] posted on 2-3-2021 at 13:03


^refs for prep of TsCl from SO2Cl2 and PhMe?

OP's problem is quite subtle: he wants to protect lysine's amines in such a way that they won't be attacked by an acylating agent, and he wants to deprotect them without cleaving his amide bond. karlos3 is right; you should listen to him. This is not an easy problem.

One possible strategy is to try to form the cyclic sulfur diimide (specifically, a 2,1,3-thiodiazocane) by reaction of a lysine ester with SCl2. If successful, this should allow for a fully orthogonal deprotection by reduction, and there are plenty of people here who have made SCl2 from OTC materials. Beware of H2S! :P




[Edited on 04-20-1969 by clearly_not_atara]
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Triflic Acid
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[*] posted on 4-3-2021 at 08:30


Oh, I got that synthesis from Ullmann's Encyclopedia of Industrial Chemistry. On page ten of the section on benzenesulfonic acid derivatives, it says that
Quote:

Other chlorinating agents, such as phosgene, thionyl chloride, sulfuryl chloride, or phosphorus pentachloride, can be used instead of chlorosulfuric acid.


[Edit: If anyone needs some information from Ullmann's, PM me and I'll send you my pdf]

[Edited on 4-3-2021 by Triflic Acid]
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[*] posted on 6-3-2021 at 10:18


Don't know what your product is. But, Carlos may be on the right track. Benzylamines can be cleaved by hydrogenation. Not much chance, peptide linkages will be damaged.

Got an interesting alanine protection, I first saw yesterday. Probably useless, but interesting.

https://erowid.org/references/texts/show/6516docid6045

You can't easily buy any of those Chlorinating Agents, but some can be made. At least, they can be easily made if you have SCl2... Which Doug's Lab, has provided instructions for making. https://www.youtube.com/watch?v=oYw89ieffa4&t=23s

Oh, yeah. One of our members has posted a procedure for Thionyl Chloride. Top of the page.

https://www.sciencemadness.org/whisper/viewthread.php?tid=78...

[Edited on 6-3-2021 by zed]

[Edited on 6-3-2021 by zed]

[Edited on 6-3-2021 by zed]

[Edited on 6-3-2021 by zed]
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