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Topic: Double methylation in one shot?  (Read 2659 times)

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Offline Urbanium

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Double methylation in one shot?
« on: November 05, 2014, 08:36:45 PM »
In relation to my previous question on cysteine, I would like to thank everyone for answers.

However, it seems unfortunately that I'll have to protect the acid and the thiol in Cys also. Is anyone familiar with some procedure I could use to methylate both the acid and thiol in one shot?

I checked some examples on SciFinder, there were conversions of acid to methyl ester (with SOCl2 in MeOH). However, all the examples were aminoacids without thiol, including some unnatural ones - would the thiol also undergo alkylation if it was present?

I even found the method where CH3I is used with tetramethylguanidine in order to selectively alkylate only the thiol, but in that case the acid remains intact.

Could anyone give some suggestion? I'm considering using plain and simple CH3I with K2CO3 in MeOH or THF, but since I didn't find a single example, I'm really skeptical...

Would it be better to alkylate -COOH and -SH with previously Boc-protected Cys or do it on unprotected Cys instead?

Offline Urbanium

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Re: Double methylation in one shot?
« Reply #1 on: November 05, 2014, 10:14:36 PM »
Update: I found this one:

http://pubs.acs.org/doi/suppl/10.1021/jo701423w

where the authors use something similar, on the second page of supplement, but instead of Cys they use Met, which is Boc- protected and then converted (by Steglich esterification?) to tert-butyl ester.

In theory, could that one work if I switch t-butanol with methanol?

Offline salteen

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Re: Double methylation in one shot?
« Reply #2 on: November 06, 2014, 03:51:31 PM »
It seems unlikely to me that you'd be able to accomplish both these transformations in one shot, because they're not the same type of functional group.  You are not trying to "alkylate" the COOH group, you're trying to generate a methyl ester - mechanistically this is very different than methylating an thiol.  You'll need to use a different approach for each site.

You have numerous options to form your methyl ester, both of the ones you mentioned are possibilities.  Using SOCl2 is a quick and efficient route but it may not be successful with a free thiol present (I'm not sure if the SH group would be stable to SOCl2, you could give it a shot).  If not you may simply need to methylate the thiol group first and then form the ester.

Offline OrgXemProf

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Re: Double methylation in one shot?
« Reply #3 on: November 21, 2014, 05:37:55 PM »
You may be able to locate a suitable double-alkylation procedure in a review entitled "A Comparison of Several Modern Alkylating Agents" - see: Lamoureux, G.; Aguero, C. Arkivoc 2009, (i), 259-264.

This publication is available online and can be downloaded as a pdf file c/o http://www.arkat-usa.org/get-file/29478/

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