[nair168]

Hi!

I am fairly new to Pd-catalyzed coupling reactions. Thus far, I've managed to pull off a couple of Suzuki couplings, but now I need to carry out a Miyaura borylation on a terpyridine. At the moment I'm following a procedure for the same substrate in Eur. J. Inorg. Chem 2007, p1752-1769. However, I had to replace Pd(dppf)₂Cl₂ with Pd(PPh₃)₂Cl₂ and KOAc with NaOAc. I'm also concerned about my technique. In our lab, I never see anyone using Schlenk techniques. I normally set up these reactions by combining reagents and solvent in a flask, degassing it for about 15 min with N₂ and then fitting a condenser w/ N₂ inlet before heating.
I would really appreciate inputs from people who routinely carry out borylations. Please tell me the most important details/caveats to bear in mind when carrying out this type of reaction.

[opsomath]

Hmm...I have done tons of cross coupling but this reaction only a couple of times. IIRC I made 4-iodoaniline into the corresponding boronic acid pinacol ester. I thought we used toluene distilled from ketyl as solvent, but it's been years.

- Definitely degas, use argon instead of N2 if you can.

- Schlenk lines are best for this sort of thing, but you can make it work with just a tube and nitrogen bubbler like you describe.

- I'm afraid I can't recall what the phosphine ligand I was. It might not matter, because you have a terpyridine, and that is going to be a ligand itself.

Anyway, from what I recall the reaction was a simple matter of mix up the ingredients except for BPin2, degas, then add the borane. Heat for a few hours, then you get product. I didn't have to column mine, and you may not either. I don't have Wiley journals here so I can't look at the exact procedure you're working.

[nair168]

In the reference they use the Pd(dppf)₂Cl₂ and KOAc in dioxane. As I mentioned earlier, I used a different catalyst and NaOAc keeping everything else the same. It doesn't seem to work, and the biggest problem is I have no idea what I'm doing wrong. Could it be the catalyst or base? Please advise.

[Dan]

In that case, I would repeat the literature reaction exactly to check whether the problem is you or the reagents.

[opsomath]

I agree with Dan, particularly since the use of the potassium bases was the result of a screen of quite a few reagents. Solubility matters a lot in organic solvents.

[g-bones]

I can only speak from my experience with these types of borylations, but it doesnt mean its extendable to your system.  I would agree following the procedure for a substrate closest to yours is the best.  In my experience, I didn't need crazy, rigorously dry and air free conditions.  I flame dried my schlenk flask containing the potassium acetate and cooled it under a flow of nitrogen, used DMF from a sure seal and tossed in all of the other solids.  If my product was a liquid, I would add it as a solution in DMF.   evacuate/backfilled about 3 times and heated it up (mine was about 80 C).  The toughest thing is purification from B2Pin2.  If you arent having trouble with that, than thats good but it does tend to streak on the column.  Either use a kugelrohr or treat your mixture (preferably after column that leaves just product and b2pin2) with IBX in refluxing ethyl acetate then flash it.  Worked for me.  Hope this Helps!

[nair168]

I noticed that as soon as I added solvent (dioxane) the reactants formed a brown blob at the bottom of my flask. I'd seen this happen before and I assume it's a bad sign. I'm not sure if it's air or moisture causing the problem, or if I need to follow a particular sequence while combining the reactants. I dried the solvent over activated 3A molecular sieves for several days and degassed initially and also after adding it to my flask. I noticed that most reports describe using a Schlenk tube. Here we have a couple of those which have a ground glass joint rather than screw-neck, so I just used a regular RB flask. We do use pressure tubes, but I'm not sure if those are suitable for this reaction. If anyone has faced the sort of issue I described and has an idea of what may be causing it, please let me know.

[BobfromNC]

The  Pd(dppf)2Cl2 catalyst is critical.  There are other catalysts that may work, but the normal Suzuki ones will not work (tetrakis, etc).   I find that excess diborane (2-5 eq) helps a lot, but be aware that it is invisible in the UV, so it is very hard to separate from the product, you need a large column and to check your fractions by UV and other methods.  Also, you must use the KOAc.   I have heard of several solvents working, so that is about the only place you can make minor changes.   Dry/oxygen free is good, but I never used special apparatus, just dry glassware and solvents, N2 and careful purging of the flasks.   

[nair168]

Thanks everyone! I managed to get the reaction to work in DMSO. Although the same reaction had been reported to work in dioxane, I discovered that there was a solubility problem there (KOAc). Apparently, DMSO is one of the best solvents for both borylations and Suzuki coupling reactions