kamal
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Alkylation with Ph-Et-Br
I'm doing one alkylation reaction involving N-Ethoxycarbonylmethyl-L-Valine & 2-Phenylethyl Bromide as under :
EtOOC-CH2-NHCH-CH(CH3)2-COOH + 2-PhCH2CH2Br -------> EtOOC-CH(CH2CH2Ph)-NHCH-CH(CH3)2-COOH
I tried using K2CO3 in diff. solvents, Na-EtOH, but could not get the conversion at all. 
May I get some suggetions for this Alkylation ? 
Thanks,
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Nicodem
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How do you suppose to get a C alkylation of such weakly acidic hydrogen in the presence of an unprotected amine and carboxylic group? And furthermore
with K2CO3!
PS: Besides your rational formulas are irrational. Count the hydrogens and bonds on carbon.
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unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
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ziqquratu
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The amine is protected with a carbamate, so it should be ok (although I've only ever alkylated fully substituted amides, never one with any free
protons, so I cant be sure). My first impression was that the acid was protected as the methyl ester, but on second glance I'm not certain. If it is
the ester, fine. If not, it needs to be protected!
In any case, when I've alkylated amides, I used sodium bis(trimethylsilyl)amide, also known as sodium hexamethyldisilazide, in sodium-dried THF. Nice
strong, non-nucleophilic base. Another popular option, and one that may be more accessable, is lithium diisopropylamide (made by treating
diisopropylamine with 1eq of n-BuLi). My working procedure was to pretreat the molecule to be alkylated (the amino acid in this case) with 1.1eq of
the base in THF at -78*C, stir for 30min, then add the alkylating agent either as a liquid or as a solution in THF and stir for another hour (still at
-78*C, if I remember). Quench carefully with saturated NH4Cl solution and extract and purify as desired!
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Nicodem
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| Quote: | Originally posted by ziqquratu
The amine is protected with a carbamate, so it should be ok |
Check again. It is a ethyl carboxymethylene group (EtOOC-CH2-) and he wants to C-alkylate the alpha position of the ester. Even the chemical name
implies that. That is, if he wrote it correctly since he wrote wrongly the rest of the molecule.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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ziqquratu
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Hey nicodem, you could very well be right. I originally took it to be an ethoxycarbonyl-protected amine and a methyl ester, but the semi-structural
representation then threw me. I'm no longer sure which (if either) of my interpretations is correct. I originally read
"N-Ethoxycarbonylmethyl-L-Valine" as:
CH3COONHCH(CH(CH3)2)COO-Me
Kamal, perhaps you could provide a picture of the molecule to eliminate ambiguity?
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kamal
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Sorry if I've mistaken in structure writing in my original posting, as I'm not a perfect chemistry guy.
Here is the image for this reaction attached.
[Edited on 25-11-2006 by kamal]
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ziqquratu
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Nope, you were basically right. I, however, managed to badly confuse myself.
Anyway, as Nicodem said, you need to protect both the amine and the carboxylic acid before alkylation where you desire is even a remote possibility.
For the amine, I believe a carbonate (eg BOC) should do the trick. And since you'll need a non-aqueous, non-nucleophilic base for the alkylation, I
think an ester should be stable. Certainly hope so, else your starting material has problems! Of course, selective removal of the appropriate ester at
the end may be a problem. In any case, check out the book "protecting groups in organic synthesis" (cant remember the authors offhand). It'll give you
a more certain idea of what protecting groups are suitable.
The other problem I envisage is regioselectivity of the reaction. The more stable of the two possible enolates should be the one formed by
deprotonation of the CH(iPr) (ie, from the carbonyl on the right in your image). This means the PhCH2CH2- would preferentially attach to the carbon on
the right of the amine, rather than to the carbon you intend. I have no idea of how to deal with this issue!
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