Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Sach on September 26, 2017, 04:33:22 AM
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Hi guys, I need to synthesize 3-aminothiophene since it is not commercially available at a good price and my professor doesn't want me to work with N-boc-3-aminothiophene.
The only method I have found on scifinder is the decarboxylation of 3-aminothiophene-2-carboxylate but a lot of steps are involved if I use decarboxylation for the preparation of 3-aminothiophene. Does anyone know a better (and easier) way to prepare 3-aminothiophene?
Thnx in advance
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I am going to use decarboxylation of 3-aminothiophene-2-carboxylate. I just need to find the exact reactants and conditions being used.
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An Easy Synthesis of 3-Amino- and 3-Nitrothiophene, Synthetic Communications, (1995), 25(23), 3729-3734
http://www.tandfonline.com/doi/abs/10.1080/00397919508011446
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I love the article name.
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Yes, that's the article I used. Thanks anyways
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I tried the method mentioned in the article above. I started with 5g of methyl-3-amino-2-thiophenecarboxylate and decarboxylated it like mentioned in the article. After the last step (evapôration of the solvent), I just got 0,2g of the product left and after the tlc analysis, I could see that the end product (which is supposed to be 3-aminothiophene) still contains methyl-3-amino-2-thiophenecarboxylate (starting material). Does anyone know a better method for decarboxylation of methyl-3-amino-2-thiophenecarboxylate to get 3-aminothiophene?
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How long did you leave before working it up compared to the paper? What was your (mini)-work-up like for TLC sampling during the reaction?
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In the US patent 2278762-(1942), is clearly stated that: “free amines of heterocyclic sulfur compounds are highly unstable toward oxidation and polymerization in themselves, as to make their manufacture and any industrial use impractical”.
Thus, it’s not a bad idea to repeat the procedure under slight nitrogen flow and adding 1-2% of an antioxidant, such as BHT or BHA.
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Good find pgk! OP, this also means the bench stability of this compound could be low. The decarboxylation also takes places at high temperature, which could mean that this procedure is poorly suited for what you are doing.
Perhaps the HCl salt is stable? For either during the reaction or storage of the product. Its very common to see that.
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I think you have to be careful when evaporating, the product is volatile.
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You can buy thiophene-3-carboxylic acid and do a Curtius-rearangement to the thiophene-3-isocyanate, then boil this in toluene with benzylalcohol, then you will get the Cbz-protected 3-aminothiophene without having to handle the sensitive free aminothiophene.
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If you do a Curtius rearrangement be careful! It can be exothermic to the point of explosiveness.
Why won't your prof let you use N-Boc-3-aminothiophene? Its a little pricey at $45 a gram, but once you fail a few times doing other ways you've blown right past that price point.
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If you have a solution in toluene its safe to do Curtius. I have suggested N-Boc-3-aminothiophene but Sachs professor dont want him to work with that.
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I am going to use 3-aminothiophene for direct arylation and my professor said that Boc protected aminothiophene won't be stable in the conditions we are going to use. Thank you everyone for the reply. Currently I am also watching videos and reading a book about laboratory techniques for organic chemistry because I am a student of applied engineering and I don't have a lot of lab experience for organic synthesis. on monday I will try the same procedure (for decarboxylation) under supervision of my professor to see whether or not I made a mistake during the lab session.
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Ah well you can at least buy the Boc-protected thiophene and use it to (very) easily make the aminothiophene instead of doing all this other difficult running around. I'm rather surprise that there will be conditions that can handle a free amine but not a Boc group
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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.
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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?
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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.
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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?
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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.
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Ok I will do that.
Thank you
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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?
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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.
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Ok thank you
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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?
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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.
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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.
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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.
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And what is according to you the role of ammonium hydroxide?
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It should somehow convert 3-amitnothiophene oxalate salt to 3-aminothiophene.
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Its just acid/base chemistry, that conversion should be self evident. Think about what happens when you basify aminothiophene oxalate salt.
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My guess is its the free aminothiophene carboxylic acid that decarboxylates, this is the case for malonic acids although this is another, cyclic mekanism. Try to monitor the reaction, TLC should be possible to use if you don not have LC-MS.
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So rolnor, you don't agree that decarboxylation is caused by NaOH followed by the heat?
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I am not sure about that, I can be wrong. You could monitor the reaction by TLC, maybe ethyl acetate/hexane 1:1. Then you can see where the decarboxylation step occurs
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Ok thank you