Sweet, another use for saccharin, as a trifluoromethylthiolating agent.

It seems quite a few of my readers were interested with Palau’chlor.  I still find readers go to this post and why not.  Chlorine is an important substituent to introduce into a molecule, no question there.  Although somewhat unrelated, it was in the news a short while ago, that artificial sweeteners wreak havoc with gut bacteria causing glucose intolerance. It was published in Nature 514, 181–186 (09 October 2014) doi:10.1038/nature13793 by Eran Elinav et al.  You can check it out if this is news to you.

Well, what can I do with saccharin ?   Make a trifluoromethylthiolating agent with it.   A shelf-stable reagent like Palau’chlor.   Consider the following paper in Angewandte Chemie, “N-Trifluoromethylthiosaccharin: An Easily Accessible, Shelf-Stable, Broadly Applicable Trifluoromethylthiolating Reagent” by Chunfa Xu, Bingqing Ma, and Qilong Shen, Angew. Chem. Int. Ed. 2014, 53, 9316 –9320. doi: 10.1002/anie.201403983.  I haven’t ever needed to add a trifluoromethylthiol to a molecule, but I am sure, with popularity amongst discovery chemists, we may need to find out how to add such a group to an API.   This is the set of reactions to generate this trifluoromethylthiolating agent.  But really how good is it ?

trifluoromethylsaccharin-11092014

These following reagents had been used in the past to electrophilically add a trifluoromethylthiol group.  I could elaborate here, but I think it is important to note that this newly discovered saccharin analogue was found to be quite effective at introducing a trifluoromethylthiol in the model reaction.

trifluoro11102014trifluoromodel-111012014

 

The N-Trifluoromethylthiosaccharin could be used to add to this ketoester.

ketoneester_20141125

Then to this indole.

indole_20141125

And to this alcohol.

alcohol_20141125

I picked some of the higher yielding reactions.  This seems to have broad applicability.  It is interesting that a common molecule, (a sweetener) was converted into a useful reagent with good stability.  Hopefully, my custom synthesis folks and pharmaceutical colleagues will be able to make use of this.

I found this on the web, with some applications for trifluoromethylthiolation.

http://www2.chemistry.msu.edu/courses/cem958/FS13_SS14%5CZeren_Zhang.pdf

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2 thoughts on “Sweet, another use for saccharin, as a trifluoromethylthiolating agent.

    • Ahhhhh, you got me there. I was wondering what they were going to do with all the artificial sweeteners if they do, indeed, mess with your
      gut bacteria. I think I did see the silver salt there, but was intrigued with the idea of using a well-known starting material and converting
      it to a reagent. I wonder if there is a workaround. I still believe this might have some merit. If saccharin can be made on kilo-scale, could a
      synthesis be made to make this trifluoromethylating agent because it seems to be more effective than the other agents. Not saying it is easy,
      but if the reaction conversions are good, maybe this reagent can be made another way.

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