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I have been working with suzuki couplings using substituted naphtalenes (typically 2-bromo-7-R-naphtalene) for a while now, and making the boronic specie is always a pain. I can't make the boronic acid because purification has shown to be complicated, and I need to obtain pure products of known mass (Can't use as is). Hence I have been making the Bpin species. I have tried using the Miyaura boronation or Hal exchange which resulted in poor yields.

I work under as strict conditions as possible. I flame dry my flasks, flush them with argon, use gas tight syringes which I flush with argon beforehand when adding liquids. I typically degass solvents using nitrogen and follow up with freeze pump thaw cycles.

For the miyaura coupling, I use potassium acetate that I flamedry under vacuum beforehand and PddppfCl2 as catalyst. I usually use dry dioxane as a solvent, but have also been using THF for solubility reasons of some compounds. My yields are lower than 50% and the major side product is the homocoupling product.

In nBuLi reactions, I add nBuLi dropwise in a dry solution of my compound (under Ar) in a few mL of THF (1 mmol scale) and leave the reaction stirring for 30 min at -78. I then check it by tlc to make sure all the starting material has been converted. I then quench it using 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as the boronic agent. My yield is 10%. The debrominated product is predominant and represents 30% of the reaction yield, while the homocoupling represents 15%. The compound seems to drag on column, so I may get some loss there, but I believe it to be minor based on ASPCI mass detection.

For the debrominated specie, I suspect the boronic agent to have gotten wet over time as the bottles we buy are not protected by a sure seal. I am still trying to figure out how to keep these bottles dry without totally transferring them to another bottle. Are molecular sieves enough?

I wanted to use Hal exchange to avoid the formation of the homocoupled product, so i was surprised to see it coupling without any Pd catalyst. Does anyone have experience with such reactions to avoid this side reaction ?

I am also totally opened to any advice or alternatives to the protocols I am following as I am really struggling.

Thank you!

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    $\begingroup$ Are you monitoring for any temperature rise when adding the BuLi for the Li-Hal exchange? Temperature control is crucial. Allowing the system to get above -60C will greatly increase side reactions. $\endgroup$
    – Waylander
    Commented Jun 24 at 6:47
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    $\begingroup$ Are you tied to using boronic acids/esters? Could you make the aryl tin and couple that? $\endgroup$
    – Waylander
    Commented Jun 24 at 6:52
  • $\begingroup$ I am not monitoring the temperature yet as the thermometers (ones that stand -78) are on their way (our lab didn't have any). I am not tied to boronic acids, I just have no experience with aryl tins and don't know anyone around me who has experience with them. Since tin is quite dangerous to work with I have been using the boronic esters. Would you recommend making the aryl tin? Or should I say, are aryl tins easy to purify/ make ? $\endgroup$
    – The Red Man Jolan Bonelli
    Commented Jun 24 at 7:32
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    $\begingroup$ Arylalkyls have measurable acidity, so you might get some products via deprotonation of alfa-position in the side chain. I would consider inverting the addition order and using excess of butillithium. Maybe use liquid nitrogen instead of dry ice (would require to move to DEE as solvent). But first of all, check the literature on similar compounds. Maybe benzene analogues, if you there is no similar reports on naphthalenes. $\endgroup$
    – permeakra
    Commented Jun 24 at 8:18
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    $\begingroup$ Aryltins are pretty easy to make and handle- they stand chromatography. I used tributylaryl tins made from aryllithium or Grignard and tributyl tin chloride. You have to dispose of residues in labelled waste but the tributyls are not as hazardous as the trimethyls. See for example pubs.acs.org/doi/10.1021/jo00072a028 thermofisher.in/content/dam/fishersci/chemicals/pdf/… $\endgroup$
    – Waylander
    Commented Jun 24 at 10:40

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