Methyl amine w/ a sulfonyl chloride

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SUMMARY

The discussion focuses on the challenges of synthesizing sulfonamides using methyl amine and sulfonyl chlorides. Users report difficulties with the reaction, particularly when using methyl amine in a 2.0 M THF solution, leading to the formation of unidentified byproducts. Suggestions include using triethylamine as a base, performing inverse addition of sulfonyl chloride, and testing with tosyl chloride to troubleshoot the reaction. Successful results were achieved by utilizing the hydrochloride salt of methyl amine with DIEA.

PREREQUISITES
  • Understanding of sulfonamide synthesis
  • Familiarity with LC/MS analysis
  • Knowledge of reaction mechanisms involving amines and sulfonyl chlorides
  • Experience with organic solvents like THF and ethyl acetate
NEXT STEPS
  • Research the use of triethylamine in sulfonamide synthesis
  • Learn about inverse addition techniques in organic reactions
  • Investigate the reactivity of tosyl chloride with primary amines
  • Explore the effects of using hydrochloride salts of amines in reactions
USEFUL FOR

Chemists, particularly those in organic synthesis, researchers working with amine reactions, and anyone involved in developing methodologies for sulfonamide production.

gravenewworld
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Does anyone have any secret tricks to get this rxn to go? Usually a secondary amine with a sulfonyl chloride gives the sulfonamide really easily, but I am now trying it w/ methyl amine, which is obviously primary, and it does not want to go at all. I tried dissolving the sulfonyl chloride in ethyl acetate and adding the amine which LC/MS said didn't work. I also tried dissolving the sulfonyl chloride in ethyl acetate, adding 15 eq. of methyl amine, and some DMAP, still without success according to LC/MS. Anyone have any bright ideas on how to get this one to go?
 
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Maybe add a little base? That's really weird. That reaction should go like a shot. Are you using neat MeNH2 or the aqueous solution? What about heating it up for a while?
 
I am using methyl amine in THF 2.0 M solution. When I add the amine to the solution a white precipitate forms, but its not my product. It is some mystery compound w/ a mass I don't recognize in the LC/MS. Can that extra proton on the amine moiety fall off and react w/ something else in the reaction? The UV trace on the LC/MS didn't show a peak for my desired compound at all. Would heating still help it then? I wish I could be more descriptive w/ the material I am working with, but its confidential.
 
Heh, I understand the confidentiality thing. Is it a heterocycle by any chance?

I would start by trying to add 2 equiv of triethylamine. The solid might be methylamine-HCl, but you should get at least some of your desired produce.

Does the LCMS hit for MeNH2 reacting with 2 equivalents of sulfonyl chloride? If that is the case then try an inverse addition (add a solution of the sulfonyl chloride dropwise to the MeNH2 solution).

Any other reactive functionalities in the sulfonyl chloride part?

You might also just try a test reaction with MeNH2 and tosyl chloride just to make sure that it isn't a problem with your technique or something. There ought to be a procedure for that exact reaction out there somewhere.
 
Last edited:
Hmm for some reason I got the reaction to go using the hydrochloride salt of methyl amine w/ some DIEA. Thanks for the suggestions though.
 
Hey, whatever works!
 

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