[cpncoop]

Hi,

I've been struggling with a Buchwald reaction for weeks.  I'm trying to couple an aminopyrazole to a 2-chloropyrimidine using Pd(dbba) with BINAP.  For most of the substrates I've been making, the conditions work fine using t-BuOK in toluene so long as everything is thoroughly degassed.  However, one coupling has proven surprisingly difficult, and I was wondering if you could suggest an alternate ligand that you've had better success with (I was thinking of Xantphos or S-phos).  I could also switch the palladium source, but assuming the catalyst hasn't gone off, it shouldn't really matter what I use.  Thanks,

[cundi]

X-Phos

[g-bones]

Are your other coupling partners chloroarenes too?  Maybe you need to force oxidative addition into the the C-Cl bond.  I agree with cundi that trying an electron-rich, hindered phosphine like X-Phos should do the trick (there are many other ligands in this "Buchwald ligand" class to also try).  If you still find it stubborn you can move to extreme cases with tri-alkylphosphines (although these can be much more tricky to work with) like tri-nButylphosphine or tri-tertbutyl phosphine (glove box only!) good luck and let is know how it works out for you!

[OC pro]

The best standard conditions are 0.06equiv. Pd(OAc)2, 0.06equiv. BINAP and Cs2CO3 as base in refluxing toluene (in cases where product/starting material decompose under the reaction conditions we ran the reactions at 80-90 °C). S-Phos and X-Phos often give dramatically better yields in cases BINAP fails.
I just checked our database, most surprisingly we have done >500 different B-H reactions so far  .   

[cpncoop]

Just an update.  Using X-Phos as opposed to BINAP gives about 30% conversion vs 15%.  Switching solvents to xylene (vs. toluene), increases conversion to about 50%.  I'm going to try xantphos today, hoping that the larger bite angle may force reductive elimination.  I also may change the synthesis to remove the buchwald coupling, since it's difficult.  I think doing metathesis to switch from chloro to iodo may increase the likely hood of being able to run an SnAr directly.

[lavoisier]

We often use 1,4-dioxane as the solvent, xantphos + Pd2dba3, Cs2CO3, 100.C.

But sometimes these reactions just won't work, in which case we try reversing the polarity of the reactants.

[g-bones]

Just an update.  Using X-Phos as opposed to BINAP gives about 30% conversion vs 15%.  Switching solvents to xylene (vs. toluene), increases conversion to about 50%.  I'm going to try xantphos today, hoping that the larger bite angle may force reductive elimination.  I also may change the synthesis to remove the buchwald coupling, since it's difficult.  I think doing metathesis to switch from chloro to iodo may increase the likely hood of being able to run an SnAr directly.

At least things are improving    careful note, from what it sounds like, you are planning to use an aryl iodide for an SnAr reaction.  If you are planning on making an aryl iodide it would be much better to try the coupling reaction on that since OI is easier into iodides.  If you are looking to use SnAr stick with the aryl chloride, or if possible, use the aryl fluoride as these are MUCH MUCH more reactive in SnAr reaction due to their electron-withdrawing nature.

[cpncoop]

In general, you're completely correct that increased electronegativity increases likelihood of SnAr (due to Meisenheimer transition state, etc...), but for this specific pyrimidine, yields (in the literature) are improved going to iodides and displacing (so maybe SnAr is the incorrect assignment for the reaction). Thanks for all of the advice though, and I will try the coupling with the iodide as well,