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).


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:

    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?

    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

    Alternatively, you can swap a bromide to an iodide:
    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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