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Chemistry Forums for Students => Organic Chemistry Forum => Organic Chemistry Forum for Graduate Students and Professionals => Topic started by: Sveinjk on February 05, 2009, 06:41:55 AM

Title: Vinylmagnesiumbromide and Weinreb amide
Post by: Sveinjk on February 05, 2009, 06:41:55 AM
Hello im working on problem involving weinreb amide and vinymagnesiumbromide. The problem is that I only get the michael product after workup (see attached picture ).
I have tried different workup procedure involving different acids to try to lower the nuchleophilicity of the N,O- dimethylhydroxylamine but I always end up with the michael product and not the grignard product:(
These are workup procedures I have tried:
NH4Cl
H2O:AcOH  5:1
H2O:AcOH  2:1
H2O:AcOH  1:1
AcOH 
MeOH:AcOH  1:1
HCl 1M
HCl 3M

This is a known problems with vinyl an weinreb amides and the only "solution" I have found is to use more acidic workup but that doesnt seem to work in my case, probably because of the pyridine ring.
If anybody has an suggestion on how to get this to work out I would be very grateful.

(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fimg5.imageshack.us%2Fimg5%2F8066%2Fweinrebjs6.th.jpg&hash=d7e6c9adf71069f6b75d3489fefae388939aeafa) (http://img5.imageshack.us/my.php?image=weinrebjs6.jpg)
Title: Re: Vinylmagnesiumbromide and Weinreb amide
Post by: azmanam on February 05, 2009, 07:48:30 AM
I've had the same problem.  It is a known problem and it's not very much fun.

2 suggestions.  1- add it to COLD strong acid.  That will swamp the system with acid and hopefully protonate some of the amine before it can add it.  The protonated amine is not nucleophilic.  2- add vinyl grignard into the corresponding aldehyde and oxidize the resultant alcohol in a 2-step procedure.  Sure, it adds a step, but if the 2-step yield is higher than the 1-step yield it seems worth it to me.  It's what I ended up doing.
Title: Re: Vinylmagnesiumbromide and Weinreb amide
Post by: kiwi on February 05, 2009, 07:57:47 AM
Quote from: azmanam on February 05, 2009, 07:48:30 AM
I've had the same problem.  It is a known problem and it's not very much fun.

2 suggestions.  1- add it to COLD strong acid.  That will swamp the system with acid and hopefully protonate some of the amine before it can add it.  The protonated amine is not nucleophilic.  2- add vinyl grignard into the corresponding aldehyde and oxidize the resultant alcohol in a 2-step procedure.  Sure, it adds a step, but if the 2-step yield is higher than the 1-step yield it seems worth it to me.  It's what I ended up doing.

thinking outside the box; have you considered doing the reaction on the corresponding pyridine N-oxide? that should kill the electron-deficiency of your pyridine ring, which in my mind is probably is at the root of the problem
Title: Re: Vinylmagnesiumbromide and Weinreb amide
Post by: azmanam on February 05, 2009, 08:07:48 AM
Eh, I think the root of the problem is protonation of the enone when you add acid to the system during workup.  The system I was working on was a simple TES-protected b-hydroxy Weinreb amide.  Nothing special pulling electron density out of that system. 
Title: Re: Vinylmagnesiumbromide and Weinreb amide
Post by: kiwi on February 05, 2009, 10:12:02 PM
Quote from: azmanam on February 05, 2009, 08:07:48 AM
Eh, I think the root of the problem is protonation of the enone when you add acid to the system during workup.  The system I was working on was a simple TES-protected b-hydroxy Weinreb amide.  Nothing special pulling electron density out of that system. 

fair enough, i understand the mechanism of what is occurring. i've seen simple a simple alkyl version of this system go just fine - i presumed the electron deficiency of the pyridine was encouraging the micheal addition. but if you've seen this in alkyl systems then i guess some systems are just luckier than others
Title: Re: Vinylmagnesiumbromide and Weinreb amide
Post by: Dynamic on February 10, 2009, 04:35:52 PM
Maybe you should quench the reaction in acrylic acid?