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Author Topic: Sille coupling  (Read 863 times)

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vikram

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Sille coupling
« on: December 04, 2018, 03:29:59 PM »

I have been trying to couple 2,4 dichloropyrimidine at one site (keeping other chloride intact).I took the tin reagent and aryl chloride in 1:1 ratio.Reaction temperature was set to 80°C as stated in the literature. However, I obtained more double coupled product when compared with mono coupled product.How could I increase the probability of having singly coupled product as major?

Should i decrease the temperature?
(also, the Rf value of the mono coupled product and starting material is same.Hence the taking aryl halide more would make me to difficult to monitor the reaction as well as separation)
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wildfyr

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Re: Sille coupling
« Reply #1 on: December 04, 2018, 03:40:00 PM »

The trick is to add things in the right order and and do them dilute and colder. I would have the 2,4 dichloropyrimidine tin adduct and the Pd already in solution, and slowly drip in the aryl chloride in a dilute solution. That way, at any given moment the amount of 2,4 dichloropyrimidine and tin is high compared to the amount of aryl chloride.

You're likely going to end up with some amount of double coupled product though, I don't feel like the monochloro pyrimidine material is that much less reactive than the dichloro.

Any way you could get an asymmetric pyrimidine? 2 bromo,4 chloropyrimidine? https://www.sigmaaldrich.com/catalog/product/aldrich/722413?lang=en&region=US Its not crazy expensive, then you could use the reactivity difference from the halides to pick and choose aryl coupling.

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vikram

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Re: Sille coupling
« Reply #2 on: December 04, 2018, 08:34:15 PM »

Thanks Wildfire for your feedback.Actually, I referred 2,4 dichloropyrimidine as aryl chloride.

Also,I am limited to 2,4 dichloropyrimidine as I want to keep my Cl at one position unaltered until my final product.

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kriggy

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Re: Sille coupling
« Reply #3 on: December 04, 2018, 09:34:06 PM »

@wildfir: I think you linked a bad compound, hes doing the coupling on pyrimidine not pyridine.

The 2-Cl-4Br-pyrimidine seems quite expensive >500£ /g however, it can be made from 2-bromopyrimidine which is reasonably cheap.

SYNTHESIS 2008, No. 22, pp 3697–3702

This paper might be interseting to OP as well, depending on what exactly is he trying to do it might be a way around the stille coupling.

wildfyr

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Re: Sille coupling
« Reply #4 on: December 05, 2018, 05:13:43 AM »

Sorry for the mistakes, I didn't double check my googling. I still think using a hetero-halide system is the best way to go about this. You need to get a reactivity difference between the two locations or else the bis-substituted material is going to be present in some amount. And if both run identically on a column, you are kinda screwed without some really clever recrystallization skills.

Aryl coupling reactivity is typically I>Br>Cl (and fluoride is its own monster). So finding or making a compound with Br/I at the spot you want would seem to be better than trying to play the statistics game for similarly reactive sites.

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rolnor

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Re: Sille coupling
« Reply #5 on: December 05, 2018, 08:00:08 AM »

Is it the 2-chloro atom you want to react?
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vikram

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Re: Sille coupling
« Reply #6 on: December 05, 2018, 06:30:34 PM »

Is it the 2-chloro atom you want to react?

Any Cl would be fine as the starting material is symmetrical and I want to retain one Cl for further steps.

That is why I am limited to use 2 Cl compound instead of Br or Iodo to have different reactivity @wildfyr
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sjb

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Re: Sille coupling
« Reply #7 on: December 05, 2018, 07:50:39 PM »

Any Cl would be fine as the starting material is symmetrical and I want to retain one Cl for further steps.

That is why I am limited to use 2 Cl compound instead of Br or Iodo to have different reactivity @wildfyr

2,4-dichloropyrimidine is not symmetrical in the way you describe. C1=CN=C(N=C1Cl)Cl
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vikram

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Re: Sille coupling
« Reply #8 on: December 05, 2018, 09:15:00 PM »

Oh I am sorry.I apologize you all.I was mistaken in naming the compound.It should be 4,6 dichloropyrimidine which is symmetrical.Thanks @sjb
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clarkstill

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Re: Sille coupling
« Reply #9 on: December 05, 2018, 09:20:47 PM »

I've observed exactly the same problem when doing Buchwald-Hartwig couplings on 4,6-dichloropyrimidine. In the end we just used 5 eq. of the pyrimidine, then recover the unreacted material and reuse (or not, the pyrimidine is pretty cheap).

The dichloropyrimidine also sublimes out of the reaction mixture on the buchi, so you can remove a fair amount of it before you even column it.
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