Help!

I have this stubborn starting material that is quite reluctant to react the way I need it to, under typical Sonogashira conditions with propargyl alcohol (PdCl2(PPh3)2, CuI, pyrrolidine, heat).

Sonogashira

I am unfortunately not at liberty to disclose the exact structure, but what I can say is that the arylbromide is quite electron-rich (FGs = several e-donating groups, R = alkyl chain). The corresponding aryliodide does unfortunately not exist and would be pretty demanding to synthesize, so that is not really an option. The molecule also contains a silyl protection group, but that should not matter.

What conditions might get the desired reaction going? I now see a very slow conversion of the starting material over several days, and the isolated yield of the desired product is below 10 %. There is an annoying side-reaction too, which is not plain reduction, that consumes most of the arylbromide.

I am counting on your cross-coupling expertise here! Any obvious quick-fix? I should also say that this is on gram scale, so glove box-ish conditions are not acceptable. Do you think an NHC palladium catalyst would perform better? If so, which one? Conditions? The catalyst/ligand has to be commercial. Please include Sigma-Aldrich item numbers and/or DOIs :)

Thank you!

 

7 Responses to Help me nail this Sonogashira

  1. J.S. Boc says:

    Have you tried deoxygenating the mixture? Also, additives such as nBu4Br or KI are known to accelerate the coupling of unreactive partners (though I can’t imagine propargyl alcohol being that much of a problem).

  2. AtomicFire says:

    You may have seen this, and your conditions are somewhat similar, so propargyl alcohol seems to be a valid coupling partner:

    http://cssp.chemspider.com/Article.aspx?id=507

    If you want an effective general Pd catalyst, PEPPSI catalysts are very useful and highly active in many couplings, plus they are very stable to air/water – see the references in Sigma-Aldrich item 669032.

  3. drfreddy says:

    Awesome, guys! PEPPSI here we come.

  4. Rayn says:

    4 eq nBu4I, Diisopropylamine:dioxane=1:1, 80C and 20% PdCl2(PPh3)2, CuI was the condition I once used to make a very stubborn dibromide work.
    Hope this may help

  5. c_g_b says:

    Have you considered trying Buchwald’s copper catalyzed finkelstein reaction to convert your aryl bromide to the aryl iodide?

    http://dx.doi.org/10.1021/ja028865v

    Not sure how much of the aryl bromide you have at your disposal but repeating the reaction with a simple acetylene may allow you to rule out the acetylene. I know ArcticFire pointed you to reference where propargyl alcohol was successful but the catalyst system is slightly different and many of the cross-coupling reactions published are not as general as we would like them to be. So it be worth repeating the reaction with Et3N in place of pyrrolidine.

  6. SN says:

    If it’s super electron rich than PPh3 probably can’t get the job done. Try conditions that people have developed for aryl chlorides
    http://onlinelibrary.wiley.com/doi/10.1002/anie.200353015/abstract
    http://onlinelibrary.wiley.com/doi/10.1002/anie.200390273/abstract

    Alternatively, you can swap a bromide to an iodide: http://pubs.acs.org/doi/abs/10.1021/ja028865v
    It’s worked in my hands in slightly lower yields than in the paper, and the product is inseperable from starting material. However, a mixture of bromide and iodide could certainly be used. No particularly electron-rich examples in the paper though.

    PEPPSI is a great catalyst, but not for Sonogashira’s

  7. drfreddy says:

    Thanks a lot, all of you. I’ll keep you posted about how things progress.

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