[Sach]

Hi guys,
I made an attempt to dibrominate protected thiophene as you can see in the attachment. The reaction did not give desired results. The H-nmr showed that mono- and dibrominated thiophene has been obtained (with some impurities) instead of pure dibrominated product. Because this mixture of mono- and disubstituted thiophene wouldn't be easy to separate using column chromatography (because of the little difference in polarity), I decided (with advice of my professor) to apply suzuki reaction to this mixture of mono- and dibrominated protected thiophene.
The Suzuki reaction didn't succeed but I have an explanation for that (a mistake made during setting up of suzuki reaction).
What I can't explain is why dibromination using NBS didn't give dibrominated product?
You can find the reaction using nbs (2eq of boronic acid and 1eq of protected thiophene), the H-nmr obtained after dibromination and the suzuki reaction in the attachments.
Thank you for your time guys

[rolnor]

I think you have drawn wrong, have you really used thiophene di-boronic acid? Should it not be mono-boronic acid?
As for the bromination, would it not be just to repeat it and use longer reaction time?

[Sach]

Yes you are right, I drew it wrong. I used 2-thienylboronic acid.
But my question is why dibromination using NBS did not work? Could it somehow be because of the presence benzyl carbamate (which I doubt)?
While performing dibromination reaction, the flask was not kept completely under nitrogen (there was a leak because of which solvent evaporated). This is a possible explanation I can think of.

[rolnor]

Did you monitor the bromination? I can think that the 1-position next to the amine in the thiophene is very activated because of the amine and bromination is quick but the 5-position is less reactive, maybe you just need longer reaction time?

[TheUnassuming]

That you are getting a mix of mono and di-brominated products suggests that it does work, you just need to push the reaction harder or go longer (or both) to get complete conversion. 

Good luck!

[OrganicDan96]

maybe use more NBS?

[kriggy]

Its hard to give you meaningful help if you dont tell us the experimental conditions you did try.
I would use more NBS or kick it with higher temperature. I did some bromination of indazoles with NBS and I did it in EtOH at RT and I had to use 3eq of NBS to get reasonable yield of the dibrominated compound (65%). Also, you might try it with elemental bromine as well or other bromination reagents (tetrabutylamonium or pyridinium tribromide?)

[Sach]

I added NBS to a stirred solution of protected thiophene in THF. I let the reaction mixture stir for 4h at 70°C. Like you guys suggested, I think it's better if I would have increased the temperature (to maybe 80°C or even keep the same temperature) and let the reaction mixture stir for a longer time and stop the reaction when there is only 1 spot visible on TLC.

[Sach]

While doing the Suzuki reaction with a mixture of mono- and dibrominated protected thiophene, shouldn't I get protected thiophene with 1 thiophene attached (reaction of monobrominated) and protected thiophene with 2 thiophenes attached ((reaction of dibrominated)?
Because I am not sure what would hinder the suzuki reaction.

[rolnor]

One important thing when working with Pd(0) is to exclude oxygen and also degassing solvent before adding Pd(0) to the reaction mixture. Otherwise I agree, you should get a mixture of mono- and di-thiophene substitution like you suggest if you use a mixture of mono- and di-bromo-startingmaterial.
I have made iodothiophenes by first making mercury-thiophene and react this with iodine, very simple reaction. Iodothiophene would be more reactive in the Suzuki-coupling.

[Sach]

Ok, and I remember after setting up the Suzuki reaction (under nitrogen), I saw that there was a leak and I think because of the leak, Pd(0) could have oxidized. And as a result, I didn't get the protected thiophene with 1 and 2 thiophenes attached.
And after the suzuki reaction, the strange thing was that the fractions obtained after the work up, could not be separated with column chromatography. And there was still some solvent (dried DMF) attached to those fractions.

[rolnor]

Small amounts of DMF can interfere with silicagel chromathopgraphy, you need to evaporate more thorough, maybe put the material on a freezedryer.

[Enthalpy]

Would it be conceivable that a fraction of NBS reacts with the amine?
(Sorry if I put nonsense)