[rolnor]

Here is a scheme, you can choose any alcohol in the last step. You can run the scheme without isolating the intermediates, one-pot. You can buy thiophene-3-carboxylic acid.

[Sach]

Actually my professor wasn't convinced about the fact that free amine would be stable in the conditions we can going to use for direct arylation but I came with the proposal of decarboxylation and my professor thought it's worth a shot. I will propose to buy Boc-protected amine and deprotect it to get 3-aminothiophene. My guess is also that free amine won't be stable. Do you think it's a good idea if we buy Boc-protected amine, deprotect it and then use Cbz protection before doing the direct arylation?

[wildfyr]

Yes I do think it's a good idea. And easy synthesis too most  importantly. If you try rolnors idea I highly suggests you DO NOT isolate the acyl azide. This is a pretty energetic material.

[Sach]

I really appreciate the help of you guys. I think that my professor would like to use methyl-3-amino-2thiophenecarboxylate before purchasing something new because last week we bought 25grams of methyl-3-amino-2thiophenecarboxylate. Is there another way of decarboxylation of methyl-3-amino-2thiophenecarboxylate to get 3-aminothiophene?

[wildfyr]

I think you need to do the google and scifinder grunt work on this one. People have decarboxylated thiophene many times. A google search gave 3 me obvious ways on the first page, one of which you've tried. I am sure there at at least 10 ways people have done it in the past 50 years.

[Sach]

Ok I will do that.
Thank you

[Sach]

I am trying get a better understanding of the mechanism of decarboxylation of a thiophene (with the ester attached on position 2). I read some articles including the two you can find in the attachment. In one article, they use oxalic acid and in the other one DBU. I still couldn't figure the exact mechanism that takes place for the decarboxylation. Can someone explain me a bit?

[wildfyr]

I like the oxalic acid method, it seems really simple. Its also your precise molecule.

In my head the mechanism is driven by the fact that once you deprotonate an aryl carboxylic acid and heat it up, its just quite entropically favorable for it to become carbon dioxide. This leaves behind a thiolene anion, which of course quickly grabs a proton from whatever is around (such as water), to give the thiolene.

Both these procedures basically just involve exposing the molecule with a carboxylic acid to base then cooking it. Entropy does the rest.

[Sach]

Ok thank you

[Sach]

I am following the procedure described in the article (p 7729, 5.1.17 and 5.1.18) to get 3-aminothiophene. You can find the article in the attachment. First time when I did this procedure, I didn't get the yield as described. I am now trying the procedure but I will reflux for 2h with NaOH (for hydrolysis) instead of 30min as described in the article and I will also stir for 2h with oxalic acid (for decarboxylation) instead of 1h as described. I am not entirely sure if this will help because I don't exactly know what exactly causes the decarboxylation. I assume it takes place because of the oxalic acid but I don't know how it actually happens and whether or not more refluxing and more stirring will give me a better result. Does anyone have an idea about whether or not more reflux and more stirring will give better results?

[wildfyr]

The NaOH followed by the heat is what causes decarboxylation. The oxalic acid is added to give you a stable amine salt that easy to isolate from the crude mixture. If you want to check my explanation, take NMR of the filtrate that is collected after the first step before the material is resuspended and oxalic acid is added.

I think you didn't understand my last explanation of the mechanism. I freely admit I am guessing here, but I don't see how stirring in room temp oxalic acid causes decarboxylation, and if it did why you would need to cook the molecule in hot NaOH beforehand.


Here is what I think happens in that prep:
The NaOH deprotonates the thiophenecarboxylic acid to give the carboxylate sodium salt, which will thermally degrade to CO2+aminothiophene anion. Thiophene anion gets a proton from water. HCl is added to precipitate the impure aminothiophene HCl salt. Impurity is probably starting material and whatever aminothiophene degrades into, which is also an HCl salt now. The crude aminothiophene HCl salt is dissolved in acetone, then oxalic acid is added. The 2-aminothiophene oxalate salt is not soluble in ether, while the methyl-3-amino-2-thiophene carboxylate oxalate salt and whatever other garbage is around is soluble. Collect the pure starting product by filtration.

As for refluxing for more than 30 min, I think you need to be careful. Aminothiophene is apparently not that stable. It is possible that longer reflux will degrade it. You may just be losing yield during your workup steps just during glassware transfer and such. That NMR of the crude I suggested should show conversion, which will give you the yield you're "supposed" to get.

[Sach]

Thank you so much for the elaboration.

By looking at scheme 2 on page 7725 of the article you can find in attachment (you can also find a screenshot of the scheme in attachment), I thought that refluxing with NaOH removes the methyl group from methyl 3-amino-2-thiophenecarboxylate and oxalic acid decarboxylates and eventually converts it to a 3-aminothiophene oxalate salt. ammonium hydroxide then turns the oxalate salt into 3-aminothiophene. This is what I kind of understood from the article.

[wildfyr]

I think they both happen in the NaOH solution reflux step, and its just broken up in the scheme for clarity. I'd be happy to hear the opinion of another organic chemist however.

[Sach]

And what is according to you the role of ammonium hydroxide?

[Sach]

It should somehow convert 3-amitnothiophene oxalate salt to 3-aminothiophene.