Synthesis of 2-(3-methoxybenzyl)-1-methylpiperidine-3,5-dione

[hypervalent_iodine]

Thought I might make a most considering how quiet it's been around here lately.

 

Currently in my project I am looking at making a series of meta substituted phenolic ethers that contain nitrogen-tethered 1,3-dicarbonyls, which are precursors for later studies. I've made a few and designed some protocol for others, but there is one that I am yet to look at, so I thought I might post it here to see what strategies people could come up with.

 

This is the structure:

 

With similar products, I've taken a convergent approach and started with a 3-methoxybenzyl bromide and the dicarbonyl, deprotonated a position in the 1,-dicarbonyl ring with strong base (LDA or n-BuLi) and coupled at the benzylic position of the phenolic ether. This dicarbonyl on this is a little different though and I am not convinced I can take the same approach, so I thought maybe something more linear might work, starting from glycine and the benzyl bromide. Anyway, to be honest I've not looked at it to heavily since I am synthesising my other precursors first, but I thought I might table some ideas with the intelligent folk here for some inspiration

Edited June 12, 2011 by hypervalent_iodine

[solak]

This is an old post, but I found it interesting and invented the attached strategy...what do you think?

I'm wondering how you've done it.

 

 

[hypervalent_iodine]

I'm not sure I like using nitro groups so much. They are notoriously difficult to work with and very, very explosive. Methyl nitrate seems like it would be something I would have to make in situ or fresh by condensation with methanol and HNO₃. I feel like there would be an easier way to do that, maybe by using a cyano nucleophile or something I can later convert to an amine. I very much like the idea behind what you've done though, so I'll sit down and have a proper look at it later and make modifications where I see it needs them. At first glance, I might make the nitrogen nucleophile in the aminolysis pre-methylated. I have troubles with slightly similar reactions where I get methylation at essentially any position able to be deprotonated, so I try to avoid that by the N-alkyl groups pre-installed.

 

Thanks for reminding me about this compound, by the way. It's been on my to-do list for some time.

[John Cuthber]

Methyl nitrate

http://en.wikipedia.org/wiki/Methyl_nitrate

is horrid, but who cares?

The reactant here is nitromethane which is fairly well behaved.

http://en.wikipedia.org/wiki/Nitromethane

 

It has been ages since I did any synthetic chem so I won't comment on the rest of the proposed method except that it looks OK at first glance.

Edited October 29, 2011 by John Cuthber

[solak]

About the methylation thing...Have you tried Eschweiler Clarke before? It looks like a nice method for the last step.