November 29, 2020, 03:00:34 PM
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Topic: Kumada-coupling of thienothiophene with alkyl chain  (Read 200 times)

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Offline columbo123

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Kumada-coupling of thienothiophene with alkyl chain
« on: November 22, 2020, 01:11:49 PM »
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.

Offline Guitarmaniac86

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #1 on: November 22, 2020, 01:28:52 PM »
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.
Don't believe atoms, they make up everything!

Offline columbo123

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #2 on: November 22, 2020, 02:29:19 PM »
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.

Offline Guitarmaniac86

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #3 on: November 22, 2020, 02:33:24 PM »
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.







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Offline columbo123

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #4 on: November 22, 2020, 03:16:23 PM »
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.

Offline Guitarmaniac86

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #5 on: November 22, 2020, 04:01:49 PM »
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.

Don't believe atoms, they make up everything!

Offline rolnor

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Re: Kumada-coupling of thienothiophene with alkyl chain
« Reply #6 on: November 24, 2020, 10:01:41 AM »
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?

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