[Kysi]

Hello there,

I pursued a few Buchwald-Hartwig coupling reactions of chosen heteroarylbromid with different amines. The reactions didn't work and I isolated the dehalogenated heteroarene in relatively high yields (more than 70%). I thought that beta-hydride elimination was the cause. However, I isolated the dehalogenated heteroarene even when aniline was used as an amine, but it don't have any beta-hydrogen.. So where's that hydrogen from? Any ideas?

[Dan]

Can you show your conditions? Sounds like it's protodemetallation, so:

Ar-PdBr + XH ArH + XPdBr

I assume you have some base to mop up the HBr? Is your solvent dry?

[Kysi]

I tried different bases, for the reaction with aniline t-BuONa, Cs₂CO₃ and K₃PO₄ were employed.
I used dry DMF as a solvent and the reactions were carried out under Ar, so moisture shouldn't be the problem. Could the solvent itself be the source of hydrogen in this case?

[Dan]

Hmmm. Not sure about that. I'm not actually sure you need a dry solvent, seeing as you generate weak acids in the reaction anyway. I'm not an expert in B-H coupling, but isn't toluene normally the solvent of choice in the lit? Any reason you're using DMF, is it a lit prep?

[Kysi]

You’re right - toluene is mostly the solvent of choice, but other solvents such as THF or DMF can be employed, too. My reaction is not a lit prep.. I’ve chosen DMF because of practical insolubility of the starting heteroarylbromide in toluene.

[djt]

but isn't toluene normally the solvent of choice in the lit?

Yes, I have done a number of BW couplings in my time and the only solvent I have ever used is toluene, not that others can't be used, but toluene is usually the one to start with.

Can you provide additional details about your prep.

I usually carry such reactions out in anhydrous toluene. My prep go's something like this. In a glove box, weigh base (t-BuONa), catalyst (Pd2(dba)3) and haloarene (if solid) into a schlenck tube. I then remove from glove box with schlock tube stoppered with suba seal. I then add my aniline dissolved in anhydrous toluene (which has been degassed), place schlenk tube in oil bath (preheated, 100ºC) and finally add my ligand (P(t-Bu)3). Reactions are usually complete within minutes to an hour.

If you are using Pd2(dba)3, that could well be your problem, we have had a number of problems with this particular catalyst, depending on the source. Now, we (or at least I) try to buy from the same supplier and where possible request a particular batch that I know works well.

Hopefully that will get you started, if not post some more details and we'll see if we can help.

djt

[Kysi]

My prep goes like this:
I put starting heteroarylbromide (solid), catalyst (Pd2(dba)3) and ligand (mostly BINAP, but I tried dppf and XPhos, too) into a dry, tree necked flask, which was repeatedly evacuated and flushed with Ar earlier. Then I add dry DMF, aniline and finally a base. I place the flask into an oil bath and heat it (80°C). I weight both catalyst and ligand under Ar.

What was the problem with Pd2(dba)3? Though I don’t suspect it to be the cause of failure in my case, since I did a lit prep of an aminopyridine via Buchwald-Hartwig reaction with the same source of Pd (Pd2(dba)3 from Alfa Aesar) and it worked perfectly.

I know you haven’t work with it yourself, but do you think DMF could be unsuitable solvent in this case? I’ve chosen it over toluene because of solubility issues.

[discodermolide]

My prep goes like this:
I put starting heteroarylbromide (solid), catalyst (Pd2(dba)3) and ligand (mostly BINAP, but I tried dppf and XPhos, too) into a dry, tree necked flask, which was repeatedly evacuated and flushed with Ar earlier. Then I add dry DMF, aniline and finally a base. I place the flask into an oil bath and heat it (80°C). I weight both catalyst and ligand under Ar.

What was the problem with Pd2(dba)3? Though I don’t suspect it to be the cause of failure in my case, since I did a lit prep of an aminopyridine via Buchwald-Hartwig reaction with the same source of Pd (Pd2(dba)3 from Alfa Aesar) and it worked perfectly.

I know you haven’t work with it yourself, but do you think DMF could be unsuitable solvent in this case? I’ve chosen it over toluene because of solubility issues.

It may have been the same source but was it the same batch of Pd2(dba)3. I have had problems with suppliers with this compound. One had to repeat the synthesis 3 times before he got it right. I only needed 3 Kg.

[Kysi]

Wow, 3kg of catalyst? You work on much larger scale than I!

It surely was the same batch of Pd2(dba)3, it was taken from the very same 5g bottle.

[djt]

Kysi,

Sorry I was in a bit of rush, didn't read the thread properly and just posted a quick reply.

I use BH coupling for polymerisations, problems I've had with Pd2(dab)3 relate to the catalytic activity from batch to batch. For my work it's crucial to control the molecular weight and my reactions with a good quality catalyst take as little as 20 s. A poor quality catalyst can be anything up to an hour.

I'm not sure of the source of your dehalogenation. I suspect it is just a consequence of the coupling not occurring. Whenever I have problems with a reaction, the first thing I look at is solvent and catalyst. You are obviously using DMF due to solubility issues. However, whilst your arene is insoluble in cold toluene, have you checked it's solubility in hot (80 ºC, if thats the temp you run the reaction at). I would also check solubility in xylene.

I've never been a fan of using DMF for any type of coupling reaction. Others to check could be ethylene glycol dimethyl ether. 

Not being a literature prep, I understand you might not want to post the structure of your prep, but can you list any functional groups on the arene and aniline derivatives? There might be something in there that completely deactivates the catalyst.

Have you thought about about other catalytic systems?

discodermolide, how much catalyst are you using in each reaction? That must cost a small fortune for 3 Kg.

[discodermolide]

Kysi,

discodermolide, how much catalyst are you using in each reaction? That must cost a small fortune for 3 Kg.

We were developing a compound and it's normal scale up. I think the 3Kgs cost around 5000 Swiss francs per kilo, which is not a lot compared to the clinical development (>500 million $). I can't give any more detail than that, sorry.

[Nosterius]

In another reaction (not HB), I have had problems with DMF, because of the small amount of dimethylamine in it. Also, DMF degrades faster in a basic media. With dimethylamine, beta-hydride elimination could be a cause of your dehalogenation reaction, but I am not sure it could explain your high yield of dehalogenated compound.

Try to go with djt's suggestion of hot toluene. Even if your starting materials are but only sparingly soluble, it might be enough.

I've personally had trouble with a HB reaction recently. We were using PdCl2dppf, and depending on the source, the reaction gave the undesired dehalogenated product in 50% to 1-2% yield by GCMS.