amide: N- vs O-alkylation
Frederik
I'm trying to alkylate the nitrogen atom of an amide . First I tried to use
NaH and the alkyl bromide. This led almost exclusivly to O-alkylation. As
the N-anion is the softer of the two resonating anions, I figured Cs2CO3
should do the trick. A common solvent for these alkyations is 1,4-dioxane.
This reaction indeed led exclusively to the desired N-alkylated product. The
downside of this reaction, however, is the long reaction time. Therefore, I
tried to carry out the reaction in acetone, hoping the salts would dissolve
better in the reaction mixture. This surprisingly leads to a mixture of N-
and O-alkylated product. Can this be accounted to the cation- vs.
anion-solvating nature of the solvents? Which solvent/conditions would you
suggest to enhance the alkylation (THF?).
many thanks,
Frederik
--
Paul J. Franklin (moderator - sci.chem.organic.synthesis)
http://chemistry.gsu.edu/post_docs/koen/wnewshp.html
Georgia State University <che...@panther.gsu.edu>
Atlanta, GA
Uncle Al
Frederik wrote:
>
> Hello everyone,
> I'm trying to alkylate the nitrogen atom of an amide . First I tried to use
> NaH and the alkyl bromide. This led almost exclusivly to O-alkylation. As
> the N-anion is the softer of the two resonating anions, I figured Cs2CO3
> should do the trick. A common solvent for these alkyations is 1,4-dioxane.
> This reaction indeed led exclusively to the desired N-alkylated product. The
> downside of this reaction, however, is the long reaction time. Therefore, I
> tried to carry out the reaction in acetone, hoping the salts would dissolve
> better in the reaction mixture. This surprisingly leads to a mixture of N-
> and O-alkylated product. Can this be accounted to the cation- vs.
> anion-solvating nature of the solvents? Which solvent/conditions would you
> suggest to enhance the alkylation (THF?).
How 'bout O-silylating, then going after the nitrogen? Cesium
carbonate is expensive.
--
Uncle Al
http://www.mazepath.com/uncleal/
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http://www.guyy.demon.co.uk/uncleal/
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Bill Smith
oxygen with lithium. Also, allyl iodide is a soft electrophile favoring
N-alkylation and would also increase reaction rates. Another idea would be
look at some chemistry of KF/Al2O3. There is alot of references for
N-alkylation, -arylation etc.... Fluoride mediated hydrogen bonding is thought
to attenuate reactivity. If interested I can e-mail some leading references or
reviews. Hope this helps. Bill
Frederik wrote:
> Hello everyone,
>
> I'm trying to alkylate the nitrogen atom of an amide . First I tried to use
> NaH and the alkyl bromide. This led almost exclusivly to O-alkylation. As
> the N-anion is the softer of the two resonating anions, I figured Cs2CO3
> should do the trick. A common solvent for these alkyations is 1,4-dioxane.
> This reaction indeed led exclusively to the desired N-alkylated product. The
> downside of this reaction, however, is the long reaction time. Therefore, I
> tried to carry out the reaction in acetone, hoping the salts would dissolve
> better in the reaction mixture. This surprisingly leads to a mixture of N-
> and O-alkylated product. Can this be accounted to the cation- vs.
> anion-solvating nature of the solvents? Which solvent/conditions would you
> suggest to enhance the alkylation (THF?).
--
Bill Smith: wjs...@umich.edu
University of Michigan
Dept. of Chemistry
930 N. University Ave.
Ann Arbor, MI 48109-1001
(734) 647-8337
Frank Werner
"Frederik" <romb...@hartree.chem.kuleuven.ac.be> schrieb im Newsbeitrag
news:8ivpnb$c...@panther.Gsu.EDU...
> .....the N-anion is the softer of the two resonating anions, I figured
Cs2CO3
> should do the trick. ..
> ....is the long reaction time. ..
>...Which solvent/conditions would you suggest to enhance the alkylation
(THF?).
> ...
Hello Frederik
In 1971 A. Luettringhaus and G.L. Isele published in Synthesis p 267 ( in
german, sorry ) a procedure using powdered KOH in DMSO taking from 1-7 hours
at RT to 80°C, depending on substrate.
A colleague of mine used it with excellent results for (di-)benzylation.
Hope it helps....
Frank