May 20, 2019, 04:55:24 PM
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Topic: N di- Methylation of a secondary Amide  (Read 177 times)

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Offline jaylovesproteins

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N di- Methylation of a secondary Amide
« on: May 05, 2019, 11:29:02 PM »
So I'm trying to develop a synthesis going from a primary amide (RNH-COCH3) --> a tertiary amine (RNMe2) (Where R=R) Ideally, I would be able to do this relatively green-ly and/or without specific catalysts.

I'm thinking of something like this:

                                               +     
R-NH-COCH3 + 2 MeI ------> R-N(Me2)-COCH3  ----NaOH---->  RNMe2   (+  H3CCO2-)


I'm just not sure whether methyl iodide is a strong enough methylating agent to methylate a weak neucleophile like an amide (let alone dimethylate it!!). But if I hydrolyze the amide --> amine first, then it'll be too reactive, and it'll methylate 3 times! (and/or mix of pdts).

Anyway, I would love to know a) whether this plan would work at all, and b) if not, does anyone have a good idea for either increasing the neucleophilicty of the amide and/or a better methylating agent? (Preferably a way that doesn't break the bank /  require rly specific equipment etc)

Thanks!

Offline kriggy

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Re: N di- Methylation of a secondary Amide
« Reply #1 on: May 06, 2019, 05:00:25 AM »
Hydrolyze first and then use formic acid/formaldehyde to get dimethylation. Probably even methylation with MeI could work fine if you carefully control the conditions

Offline OrganicDan96

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Re: N di- Methylation of a secondary Amide
« Reply #2 on: May 06, 2019, 08:23:02 AM »
how about deptotonate amide with strong base then treat with MeI, then hydrolyse and methylate again

Offline wildfyr

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Re: N di- Methylation of a secondary Amide
« Reply #3 on: May 06, 2019, 08:37:52 AM »
Don't you need a base like nBuLi or LDA to deprotonate an amide?

I've always been under the impression that reductive amination is the "easy" way to get secondary amines. You can do it twice from ammonia with acetaldehyde to get diethylamine for instance. Doesn't get much greener than that (aside from the NaBH4). I think that's what kriggy was getting at.

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