Chemical Forums
Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Sach on September 19, 2017, 12:13:32 PM
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I am new to this forum and I hope I am not breaking any rules of this forum by posting this question. I am currently starting a project about metal organic frameworks. In order to start the project, I first need to find out that synthesis of which molucule (3-nitro thiophene or 3-amino thiophene) is more suited for direct arylation. Can anyone please help me out with this?
In the attachment, you can find the structure formulas of both molecules.
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Tell us what you know about direct arylation. What about an aryl ring makes it suitable for this reaction? What can cause side reactions?
This is not some tiny field you are asking about, but rather a concept that is richly described in the literature. Have you read a review paper or two on it yet? This review is what I found two entries on the first page of google results for "review direct arylation" has 2700 citations, perhaps it could be of use. http://pubs.acs.org/doi/abs/10.1021/cr0509760
I've never done the reaction, but these are basic steps any chemist would take before tackling a reaction.
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I am a masters student and I have never learnt about MOFs (or direct arylation) during my academic career. I recently started reading a book about MOFs and there was a chapter about direct arylation that I read, but to be honest I didn't understand the concept fully.
Thank you for your advice, I will start reviewing direct arylation on the internet.
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Maybe show the product of arylation you want to achieve - at least in general. Do you want to arylate the thiopnene or carbon or on the amino group?
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I want to arylate carbon (actually both carbons C2 and C5).
The following product should be the one I need to synthesize.
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I think you could do Suzuki reaction with 2,5-diiodo-3-acetamidothiophene and 4-ethoxycarbonylphenylboronic acid, then hydrolyze the acetamid and ethylester-groups in one step. I think synthesis of the startingmaterial can be find with Scifinder etc. Or maby the other way with the boronic acid-groups on the thiophene-ring and iodo on the phenyl-ring. I would try palladium as catalyst first.
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I like rolnor's approach, except that 2,5-diiodo-3-acetamidothiophene is not commercially available, and probably is a pain to make. 2,5-dibromo-3-nitro thiophene, however, is buyable, if expensive: http://carbosynth.com/carbosynth/website.nsf/(w-productdisplay)/4DE311093ED17E2E482580C5000D3FFC. Nitrating 2,5-dibromothiophene probably isn't hard and may be much cheaper if you want more than a few hundred mg.
You can reduce the nitro quite easily after the coupling reaction (or even probably do the hydrolysis and reduction in one step using something like a Bechamp reduction).
The boronic acid derivative he mentioned is fairly cheap and available however.
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Thank you for the reply guys. I really appreciate it.
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I have got one more question. Which of the following molecules would be easier to prepare in the lab? I thought 3 aminothiophene is easier to prepare but I am not sure. Thank you in advance.
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Do you have access to Scifinder? It will allow you to do some of the legwork yourself, and learn a lot more about organic chemistry in the process than you would get by us giving away the answer.
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My professor was going to give me access to scifinder but I haven't gotten it yet.
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Maybe ask again if its been a few days. Its a really worthwhile use of your time to learn how to use it, and go through the process of using it to examine reaction conditions. Many schools also have something called Reaxys which is similar.
"Easier to prepare" may also depend on what reagents and equipment you have already in lab.
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Yeah, check the review posted by wilfyr.
I did because it looks like an interesting synthesis. You probably want to see scheme 275 at page 230. ALthough my initial approach would be different:
(https://i.imgur.com/wRFfsn2.png)
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Thanks a lot guys! I have now gotten access to scifinder but only when I am on the campus, I can't use it at home. I guess I will be on the campus more often now to get used to scifinder. My professor also told me that one can learn a lot through scifinder.
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Kriggy,
Is it not risc that you get attack on the ketone-carbonyl in the first step rather than substitution of the bromide?
Also the amino-ketone looks difficult, you have a aminogroup as free base together with twoo ketone-carbonyls.
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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
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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
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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.
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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.
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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.
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But C2 and C5 being the most reactive carbons in 3 amino thiophene, would it still be necessary to block 3- and 4-positions?
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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.
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Thank you so much!!
I also had a proposal that you can find in the attachment. Any suggestions are welcome.
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And my target molecules is:
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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.
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Ok, thanks again for your help.
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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.
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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?
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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.
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Ok you really helped me a lot.
Thanks again.