[columbo123]

Hey there,
it's my first post so please forgive possible redundant questions or not up to quenstion-standard phrasings.
I have a question about a reaction I've been struggling with the last two weeks.
I am trying to alkylate a 3-bromothienothiophene with either a n-C11 chain or oligo ethyleneglycol chain, by means of a first conversion of the chain to a Grignard reagent (successful) and subsequent Kumada coupling with the mentioned aryl bromide.
The problem I experienced is that either no reaction at all occurs (even after reflux in THF for 30 hours I only isolated the unreacted aryl-bromide). In case of C11 chain, I got a little of the desired product, however in very low yields (below 10 %). However, the Grignard chain seems to be consumed, probably by homocoupling with itself.
My question is if you have pro-tips for Kumada coupling reactions, or also if maybe the thienothiophene is too electronrich for this reaction type. In this case, can you suggest alternative reaction pathways?

Kind regards.

[Guitarmaniac86]

Before following the suggestions below, may I ask if you are sure your reaction is water free and done under inert atmosphere? It could be a case of you not oven drying your glassware before hand.

I have had trouble with the Kumada using that Ni catalyst.

Try using 10% Pd(OAc)2 with either 20% XPhos, CPhos or SPhos. You might see a better conversion.

I trialled a lot of Pd catalysts and you could also try Pd(dba)2 with either of the ligands I have suggested.

I would advise doing a catalyst and ligand screen to see what gives you the best conversion.

[columbo123]

Thank  you for the swift suggestion.

I was suspicious of water traces too, so I flame-dried all glassware multiple times on full vacuum. Also I dried the solvents and all reagents including the catalyst. Also I suspected a maybe too low reaction temperature with diethyl ether, so I switched to THF, but this also led to very poor conversion.
Trying a Pd catalyst is a great suggestion, thank you.

[Guitarmaniac86]

Out of interest, what temperature do you do your Kumada at?

Room temperature is often enough as from personal experience, heating can kill the Grignard.

[columbo123]

I charged the Schlenk flask with ether, aryl bromide and catalyst and then dropwise added the Grignard reagent at RT. Since reaction control by TLC showed no reaction I then started heating to reflux (ether, 35 °C). When then still nothing seemed to happen I evaporated the ether and added THF as solvent and heated to 50 °C.

[Guitarmaniac86]

Did you let air get to the reaction when you removed the ether? I assume you removed the ether using a buchi or similar or did you boil it off?

Either way that can destroy your Grignard reagent.

Try different catalysts as I suggested in my first post, you might have better luck.

What I do is I oven or flame dry my glassware, add my catalyst, ligand and aryl halide to the flask and slowly take it to vacuum and very slowly let nitrogen in making sure I do not let all my solids get blown about the flask. I then inject my Grignard into the flask. I don't normally have solvent in there, I just use the Grignard solution as my solvent.

I use two equivalents of Grignard normally.

Do you titrate your Grignard to see what concentration it is? Your Grignard might not be at an acceptable concentration. I tend to get my Grignard to about 0.2M when I make it. Below 0.15M and my Kumada's do not work.

[rolnor]

I think you can make a grignard from your thiophene and alkylate this with you bromide, maybe with catalytic Cu(i).
When making your grignard, do you not get beta-elimination?

[opsomath]

I agree that titration is worth doing any time you have a Grignard that requires any precision - that is, where the separation of products isn't trivial, or where the unconverted halide might cause a side reaction. I generally do Kumadas of thiophenes while cooling with an ice bath, too, although I've never tried a PEG coupling. You may also consider starting in THF to begin with. A lot of reactions simply don't work in ether that do work in THF. I have never seen a Ni Kumada that required reflux, so that is probably not helping.