[DacBleda]

I'm trying to alkylate a secondary amide carbonyl with a primary grignard compound, but I have a problem. Grignard acts as a base instead of a nucleophile. Any idea to increase nucleophility of grignard and/or avoid the deprotonation in the alfa carbon of the amide?

[movies]

What are you hoping to accomplish?  After the reaction the nitrogen part is going to fall off anyway.

Are you familiar with the Weinreb amide?

http://www.organic-chemistry.org/frames.htm?http://www.organic-chemistry.org/namedreactions/weinreb-ketone-synthesis.shtm

[DacBleda]

The product its an N-alkylated pyperidone . I'm trying to introduce an alkyl chain (with a grignard reagent) into de carbonil position, generating the corresponding enamine (cause although the amino could act as a leaving group the resulting amino-ketone after the work-up could be cyclizated again with a Dean-Stark).
But in that case I just obtain an intermolecular by-product that could only be explained if the grignard has acted as a base in the alfa-carbon
As the pyperidone is N-alkylated I can't prepare a Weinreb-kind amide

[movies]

I'm having trouble figuring out exactly what molecule your dealing with.  Any chance you could provide a picture?

[cbee]

There are ways to increase the nucleophilicity of anion (transmetalation to Cerium come to mind) but I'm pretty sure that the amide proton is to acidic for that type of strategy to work (usually it is used to add to highly enolizable carbonyls such as tetralone). You will have to protect the amide (depending on your other functional groups a BOC , or Troc carbamate is pretty standard) and then add your nucleophile, and then deprotect.


Cisco

[movies]

There are ways to increase the nucleophilicity of anion (transmetalation to Cerium come to mind) but I'm pretty sure that the amide proton is to acidic for that type of strategy to work (usually it is used to add to highly enolizable carbonyls such as tetralone). You will have to protect the amide (depending on your other functional groups a BOC , or Troc carbamate is pretty standard) and then add your nucleophile, and then deprotect.

I'm inclined to agree with Cisco.  This is what I was thinking too, but there might be a simpler work around depending on the exact compound in question.

[DacBleda]

What?, As I told you the lactam is N-alkylated. There isn't any N-H !!!, BOC protection?, where? the acid proton is in the alfa-carbon. If it was an NH I'm not so stupid to know that grignard would act as a base for sure.

[movies]

In that case I wouldn't anticipate any problems unless you were using a very hindered Grignard reagent.  Sometimes alkyl lithium nucleophiles work better, or the cerium versions mentioned above.