Sciencemadness Discussion Board

Eschweiler-Clarke reaction with protected amines

idk - 6-9-2018 at 14:52

Does the reaction proceeds with N-acyl protected amines, or the hydrolysis is inevitable? If acyl-protecting is not sufficient then are there any protecting groups that coud make it?

Sigmatropic - 6-9-2018 at 21:16

The Eschweiler-Clarke proceeds through an iminium ion. N-acyl compounds can't form an iminium ion. Benzyl protection comes to mind. Are you trying to protect one amine while reacting the other or getting mono methylation on one amine?

Loptr - 7-9-2018 at 06:20

You could make the tosylate and then alkylate with an alkyl halide. I have a reference I will dig up for you shortly.

Couldn't you just alkylate with an alkyl halide? The nitrogen of the amide is less nucleophilic due to the resonance stabilization of the nitrogen lone pair provided by the amide carbonyl group. This means there is less chance of over alkylation. It might require more forcing conditions.



[Edited on 7-9-2018 by Loptr]

n-methyl-2-phenyl-3-aminobutane.png - 276kB

CuReUS - 7-9-2018 at 08:58

Quote: Originally posted by idk  
Does the reaction proceeds with N-acyl protected amines
It does,but you need a stronger reducing agent then HCOOH-https://www.tandfonline.com/doi/abs/10.1080/0039791770940927...
Quote:
If acyl-protecting is not sufficient then are there any protecting groups that coud make it?
You might not even need a PG,if you tell what you are aiming for :)
Quote: Originally posted by Sigmatropic  
getting mono methylation on one amine?
means ?
Quote: Originally posted by Loptr  
Couldn't you just alkylate with an alkyl halide? It might require more forcing conditions.
https://pubs.acs.org/doi/abs/10.1021/ja01125a053

btw,this looks interesting -https://pubs.acs.org/doi/10.1021/ol401362k

[Edited on 7-9-2018 by CuReUS]