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Author: Subject: Selective methylation of phenol
1911
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[*] posted on 22-10-2011 at 04:04
Selective methylation of phenol


I have a problem methylating a phenolic oxygen without touching the primary amine in the same molecule. Is there a way to do that. If I prepare a phenoxide and react that with methyl iodide should the phenoxide group react faster than amine group or do I get a too many side reactions?
I tried googling 'selective methylation of phenols' but that didn't provide anything useful.
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AndersHoveland
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[*] posted on 22-10-2011 at 04:30


One option would be oxidizing the amine to a nitro group first. Then simply distill the phenol with conc H2SO4 and methanol. Lastly, reduce the nitro back to an amine.
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fledarmus
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[*] posted on 22-10-2011 at 05:40


You can also make the CBZ protected amine or if you're not using an acid, even the BOC protected amine. CBZ can be removed with mild catalytic hydrogenation and BOC by stirring in relatively dilute HCl/MeOH or in trifluoroacetic acid.

Usually if you can selectively deprotonate the phenol, you can selectively methylate it if you add the methyl iodide slowly and not in excess.
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smuv
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[*] posted on 22-10-2011 at 20:35


Generally, the amine will be alkylated preferentially, even if you pre-form the phenoxide. As stated, you need to protect the amine. If you show/explain the exact transformation you want to accomplish, maybe someone can give you a more specific answer



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[*] posted on 23-10-2011 at 00:53


Here is the desired reaction. Should the indolic nitrogen form another problem in the methylation step? I'm aware that there are other ways to synthesize the target chemical but I'm trying to find a theoretical way from 5-hydroxytryptophan.
Synthesis I.gif - 2kB
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smuv
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[*] posted on 23-10-2011 at 02:21


Indole should be OK but the primary amine is toast. You need to protect! But doing that OTC is easier said than done.



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[*] posted on 25-10-2011 at 06:53


I got an idea about using Kolbe electrolysis to decarboxylate the carboxylic group from 5-HTP and replace that with methyl group from acetate salt. When the amino acid is deprotonated and excess of base is used, that will deprotonate the phenolic oxygen too? When Kolbe electrolysis is applied with acetate salt in excess would the phenolic oxygen become methylated too from methyl radicals present?
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[*] posted on 25-10-2011 at 07:44


Quote: Originally posted by 1911  
Here is the desired reaction. Should the indolic nitrogen form another problem in the methylation step? I'm aware that there are other ways to synthesize the target chemical but I'm trying to find a theoretical way from 5-hydroxytryptophan.

Well, good luck. I can't remember having seen a convincing phenylalanine to amphetamine route and tryptamines are more sensitive than phenethylamines. Aiming high is laudable, but maybe chose a simpler target first?
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