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Author: Subject: Secondary amine Acylation
mnick12
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[*] posted on 4-5-2014 at 20:56
Secondary amine Acylation


So in the future when I get my lab set back up, I would like synthesize 2-chloro-N,N-dimethylacetamide for another reaction. My intended route is through the N-acylation of dimethylamine solution with chloroacetylchloride. Looking at some examples in literature they use two equivalents of amine for each equivalent of acyl halide, this results in the formation of the amide and the excess amine scavenges the formed hydrogen halide. This looks good to me however I would like to avoid using excess dimethylamine, and use some different base as a HX scavenger.

My question is could something like triethylamine work? I know diisopropylethylamine is usually used as a non nucleophilic base, but I don't have any and it is hard for me to purchase. Any ideas would be appreciated.

J. Am. Chem. Soc., 1947, 69 (3), pp 515–516
DOI: 10.1021/ja01195a012
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[*] posted on 5-5-2014 at 00:08


Triethylamine is typically used.
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Dr.Bob
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[*] posted on 5-5-2014 at 04:27


If you have another amine as a scavenger, you might get some of the dimethylamine then also reacting at the -CH2Cl via SN2, since the smines will be ableto transfer protons around. I would suggest that you use the eq of dimethylamine, and ten attempt to filter off the Me2NH2Cl as a solid if possible to recover it. That is the simplest way to not waste it, but will give the cleanest product.
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mnick12
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[*] posted on 7-5-2014 at 21:08


Dr. Bob: That is what I was afraid of, I guess using more dimethylamine is the best bet. To bad it smells so bad.

I was thinking of other ways to synthesize 2-chloro-N,N-dimethylacetamide. One of the ideas that came to mind was halogenation of dimethylacetamide. One example gives the synthesis of an alpha-bromo tertiary amide from the deprotonated amide and elemental bromine. The author used LiHMDS as the base, but I am sure there are alternatives. Additionally elemental bromine is used in the bromination, perhaps NBS or something similar could replace it. Does this seam feasible to anyone? Could the deprotonation of dimethylacetamide followed by halogenation give the desired halo-amide?

If this is possible I would be much more compelled to go through this route rather than use dimethylamine and chloracetyl chloride.

DOI: 10.1039/SP54 -Amide bromination
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mnick12
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[*] posted on 8-5-2014 at 14:40


Sorry for the double post,

This method looks viable to me, but not with out its own difficulties. Apparently the pKa of the alpha-hydrogen in dimethylacetamide is ~36, which means I would need a really freaking strong base for deprotonation. LDA would probably work, but I cant get it and preparation involves alkyllithium reagents which I do not feel comfortable working with outside a glove box. One alternative I was considering was grignards, is there a way to favor deprotonation over alkylation of the carbonyl? I understand most amides react fairly slowly with grignards, is there any way to encourage deprotonation with grignards?
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Dr.Bob
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[*] posted on 8-5-2014 at 18:07


The first method has been used to make 2-chloro-N,N-dimethylacetamide before, and works pretty well. As long as the reaction conditions are not too basic or too concentrated the acyl group should react first. I would add the amine slowly to the dichloride. Alternatively, if you want to react the -CH2Cl group at some point, the other solution is to use chloroacetic acid, and react it with an amine in the presense of base (Aq. NaOH sometimes works) to react at that spot first, then next couple the acid to your amine second. Look at the synthesis of lidocaine for examples.

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[*] posted on 14-5-2014 at 10:12


Generally when using acyl halides that have an alpha proton (so almost anything except benzoyl chloride, etc.) it's best to use a base like pyridine instead of triethylamine, otherwise you get elimination to the ketene as a side reaction, and that tends to lead to messy results.



I weep at the sight of flaming acetic anhydride.
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