Tuesday, August 19, 2008

How to make a primary amide - The Ley Way

Steven Ley's Group really produces some cracking results. This time they have developed a really simple method for preparing primary amides from carboxylic esters. This is very good news because this seemingly simple transformation is in fact not as simpel as one could have hoped for. In the past I have used ammonia in methanol to achieve this. The commercially available NH3 in MeOH is rather variable in quality so making it fresh by saturating methanol with ammonia using a gas cylinder is preferable. It's an annoying exercise making the solution and the actual reaction CO2R to CONH2 doesn't really work that well.So when Steven Ley comes up with a method that involves scooping solid magnesium nitride into a flask with your ester and some methanol, heating it to 80 oC for 24 hr, work up, filter, done! then that is really exciting good news to the synthetic organic chemist.
Magnesium nitride is reasonably priced, e.g. Aldrich (#415111) 10 g for less than 40 Euros. D!


Milo said...

It's an annoying exercise making the solution and the actual reaction CO2R to CONH2 doesn't really work that well.

This is why we have Parr Bombs. If a sealed tube does not work, then 200 C and 600 psi most likely will.

Daniel Sejer said...

Hmmmm yes. I think I prefer the method that doesn't involve bombs. D!

pmgb said...

Nice method. I tried to make amides from ethyl esters using 7N ammonia in methanol in a sealed tube. Works fine but sometimes takes longer time to complete.

milkshake said...

There is another method for mild aminolysis that uses NH4Cl + Me3Al 1:1 in anhydrous conditions and RT to 40C and Ar. I think the method comes from Weinreb. It works very nicely with primary and secondary aliphaic amines too (preferably used as free base, not a hydrochloride)

Mg-nitride is a better workup of course and the reagent got to be cheap, it is made readily from the elements - but one has to use a pressure flask. There is analogous Li3N nitride, thats what makes the dark coating on chunks of Li metal. Maybe the workup wuld be easier still.

Anonymous said...

This reaction actually has a significant exotherm early on and can be extemely dangerous to run an any type of scale if you don't control this first exotherm associated with the formation of NH3. I recently was a witness to the damage a 800mg scale reaction can make. I would never run this reaction on anything bigger than 50mg.