[kriggy]

I suppose you could play with the reaction a bit. The bromoketone should be way more reactive than the ester. The amino group could be problematic but you can reduce the azide later or just do the bromination and substitute later after the thiophene is formed. The direct arylation seems easier if you can find the conditons

[Sach]

I was asked to use palladium catalyzed direct arylation. What I have understood from reading some articles on (palladium catalyzed) direct arylation is that it follows an electrophilic mechanism (after the oxidative addition of palladium). So this mechanism prefers electrophiles which in my case is 3-amino thiophene instead of 3-nitro thiophene.
Can someone please confirm this?
Thnx in advance

[rolnor]

You can have both electronwithdrawing and -donating groups present when doing Suzuki reaction. I have never seen 3-aminothiophene and I wonder if it is very reactive. If you do the reaction with 3-nitrothiophene you can always reduce it later if you want the amino. If you want to make 2,5-diiodo-3-nitrothiophene its very easy.
You treat thiophene in THF with 1eqv. LDA, then add 1 eqv. of iodine, then repeat to get the second iodo in place. Then you can nitrate to get the 2,5-diiodo-3-nitrothiophene.

[Sach]

I am actually only supposed to use direct arylation (no suzuki or kamada). After reading the following article (see attachment), I was pretty convinced that the electron rich 3 amino-thiophene is well suited for direct arylation. I couldn't find any proper mechanisms for direct arylation of 3-nitro thiophene.

[rolnor]

In the paper they have 3- and 4-positions ocupied by substituents, maby you need to block the 4-position with a trimethylsilyl-group, this is no problem, you can remove it with TBAF after the coupling. I think its better to have for example a acylated amino-group like Boc-NH that you can easily de-protect after coupling.

[Sach]

But C2 and C5 being the most reactive carbons in 3 amino thiophene, would it still be necessary to block 3- and 4-positions?

[rolnor]

That I do not know, maby you can ask the author of the paper. I think they have this position blocked for a reason.
Here is a suggestion, its may seem like a lot of steps but its not easy if you want to protect the 4-position. I am struggling with the software so its a bit messy, sorry.

[Sach]

Thank you so much!!
I also had a proposal that you can find in the attachment. Any suggestions are welcome.

[Sach]

And my target molecules is:

[rolnor]

If you can do the reaction without protecting the 4-position and have the amino-group free it will be much easier, as in your scheme. I do think it will be better to work with the bromobenzoic acid as a ester, not free acid. The product will be a amino acid and its difficult to isolate and purify it. If you have  ester you can purify on silica gel before hydrolysis to the final product.

[Sach]

Ok, thanks again for your help.

[rolnor]

I checked and you can not buy 3-aminthiophene from Aldrich, but you can buy it
Boc-protected. This would indicate that 3-aminothiophene is hard to work with.

[Sach]

Ooh ok. So the scheme I proposed would be difficult to execute in the lab.
As starting molecules, I was given the choice between amino thiophene and nitro thiophene for direct arylation. I thought amino thiophene is better suited for direct arylation because it's electron rich. Do you think I could apply the same or a similar scheme if I replaced amino thiophene with nitro thiophene?

[rolnor]

I think perhaps 3-nitrothiophene is too unreactive, in the paper they work with a 3-aminothiophene with a
electron-withdrawing carboxyl-group also, and that gives a medium-reactive molecule. That is why I suggest the
3-Boc-aminothiophene, also being moderately active.

[Sach]

Ok you really helped me a lot.
Thanks again.