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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Parabon's DNA Structures: What The Hey? | Main | More on the Parabon NSF Press Release »

December 18, 2012

Know How to Make 3,4 Difluorothiophene?

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Posted by Derek

34-difluorothiophene.pngHere's an interesting challenge: over at Synthetic Remarks, there's a need for a couple of grams of 3,4-difluorothiophene. But you can't buy that much, and the literature has very little useful to say about how one would make it. So is there a practical route to the stuff (at least on paper) that's worth trying? Note that Dr. Freddy stipulates "No Sandmeyer crap, for heaven's sake", so no Balz-Schiemann chemistry, folks.

The prize? Any chemistry book worth up to $150 from Amazon, sent to your door. (Just think of the possibilities) So if any of you have any bright fluorination ideas, have a crack at it, and good luck!

Comments (33) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. PI on December 18, 2012 4:00 PM writes...

Just heat the crap out of thiophene and pyridinium fluoride in toluene. Layer on pentane and it'll make crystals. Done. ;)

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2. PI on December 18, 2012 4:06 PM writes...

by pyridinium fluoride i was thinking something like n-fluoropyridinium triflate or selectfluor

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3. Sili on December 18, 2012 4:11 PM writes...

I hate that I've been out of the 'business' so long that I had to look at that Sandmeyer link.

(Not that I've ever tried it, but it was standard on the written exams.)

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4. Anonymous on December 18, 2012 5:06 PM writes...

2,3-dibromothiophene is even annoying to make. I seem to recall that we fully brominated thiophene and then selectively reduced it at those super-active 1,4-positions.

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5. Justin Peukon on December 18, 2012 5:15 PM writes...

Maybe something like the 2-step procedure reported in Miller et al. JACS (2006) 128, 17057 (see Scheme 2, and Ref. 6). Just need butene-1,4-dithiol as starting material and the suitable oxidant for the 2nd step.

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6. dave w on December 18, 2012 7:40 PM writes...

I'm just wondering what the stuff would be good for if one -did- come up with a good way make it...

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7. Anonymous on December 18, 2012 8:44 PM writes...

I would take a 1,5 diester that is 2, 3 - fluorinated and treat that with Lawesson's reagent.

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8. thomas fallon on December 18, 2012 8:59 PM writes...

Maybe buy some 3,4-dibromothiophene - treat it with 1eq of BuLi, which will give mono selective lithium/halogen exchange, and then quench it with one the electrophilic fluorination reagents. This should give you 3-bromo-4-fluoro-thiophene. Repeating the procedure should give the 3,4-difluoro.

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9. N on December 18, 2012 10:33 PM writes...

I have a related question:

How would one synthesize 2-methoxyimidazole? The closest reported synthesis is of 2-ethoxyimidazole, that synthesis is contested and it involves both a forward and reverse DA reaction. I tried several strategies (except for that one) and none of them got me there.

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10. anon on December 19, 2012 1:16 AM writes...

@9:

Standard synthesis of 2-alkoxybenzimidazoles is to treat the dianiline with tetra-alkoxymethane. The DA/retro-DA approach probably allows you to apply this approach, and that is probably what I would go with. I haven't looked it up, of course.

Can you react ethylenediamine with tetramethoxymethane, then oxidize the imidazoline somehow? Maybe NBS to give the N-Br species, then DBU or other base?

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11. PotStirrer on December 19, 2012 3:01 AM writes...

@5:
Ah yes, diiodofuran (DIF). I had the pleasure of working on this project and fortunately never had to make DIF. The grad student who filled up the freezer with many grams of it before I joined bitched repeatedly about what a horrible procedure it was though. That same batch of DIF (I believe) continued its usefulness in another project in the Trauner group [Kienzler et al. JACS (2008) 130, 8604.]

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12. dhertsen on December 19, 2012 4:50 AM writes...

As a computational chemist I have to ask: what is this crap in the Sandmeyer reaction?

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13. N on December 19, 2012 8:24 AM writes...

@10

I tried exactly that, ethylene diamine reacts well with tetramethoxymethane but the oxidation didn't work under a couple different reported conditions. I'm not sure what you mean with the NBS but 2-bromoimidazole would not undergo nucleophillic aromatic substitution even with NaH as the base.

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14. Harry on December 19, 2012 8:34 AM writes...

Just off the top of my head, take the dichloro or dibromo analog and heat with patassium or cesium fluoride)in acetamide or sulfolane (or even neat in an autoclave).

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15. RB Woodweird on December 19, 2012 9:16 AM writes...

For some reason this request reminds me of how someone can in five minutes give you suggested experiments that will take you six months to run. It's why in graduate school you learned to dodge your advisor as much as possible. He could drop a dozen ideas on you passing in the hallway - and of course you better have tried them all, plausible and downright stupid, by the next time he saw you.

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16. BOB on December 19, 2012 10:25 AM writes...

Problem with this compound is it is going to have a boiling point considerably less than thiophene (which is 84 C).

So the conditions had better be distillation friendly. I personally love distilling electrophilic fluorination reactions :)

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17. Old Lab Rat on December 19, 2012 10:25 AM writes...

Hey, didn't any one read the previous post? Just send the specifications to Parabon and they'll print out as much as you want!

Or you might try making the appropriate 2,3-difluoro-1-aldehyde-4-ethyl-butanoate and heat with elemental S in a neutral solvent.

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18. myma on December 19, 2012 10:29 AM writes...

Back in the day (way, way back), I had to make thiophene derivatives for my thesis. iirc there was this ancient reference book in the library, part of a series of heterocyclic chemistry, circa 1950's, 2 inches thick, with every possible thiophene substitution pattern and how to make it. It was an extraordinary reference. No I don't remeber the book's name, but I suggest that you look way back for ideas.

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19. Greg Strand on December 19, 2012 11:20 AM writes...

If a person is smart enough to offer a solution to this rather tricky problem, then that person certainly won't do it for a "$150 chem book to your door."

Post a fair price and a working solution will be offered.

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20. MoMo on December 19, 2012 1:23 PM writes...

What a trade off! You give us a synthesis that works and you get a Free Oven Mitt!

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21. Sisyphus on December 19, 2012 1:34 PM writes...

I agree with Myma. Need to go back and rediscover what was already discovered and forgotten. A book on heterocycles? What is a book? I can't find any of these ancient texts at my company since everything was thrown in the dumpster and our eLibrary budget gets cut every year because it is a cost center, not a profit center. My best hope is to find a fragment of the texts in the public domain on googleBooks or similar. Sometimes I think I am an archeologist searching for pieces of ancient biblical texts. We spend so much time screening reaction conditions when a little literature searching could give the same answer.

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22. Triflate on December 19, 2012 2:50 PM writes...

@18 - Yes, I've seen these reference books as well. The author is Salo Gronowitz. It's a multi-volume collection which covers all aspects of thiophene synthesis including substituent patterns & synthesis.

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23. matt on December 19, 2012 7:32 PM writes...

@18,21,22:
is this the book?
http://books.google.com/books/about/Thiophenes.html?id=7SaAnTX-TFYC

$340 eBook ^^

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24. matt on December 20, 2012 12:15 AM writes...

or this one:

http://books.google.com/books?id=eMNKAAAAMAAJ&source=gbs_similarbooks

from 1952, Howard Dale Hartough author.

@15: this made me laugh...yes, exactly!

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25. Hurin on December 20, 2012 12:59 AM writes...

As a computational chemist I have to ask: what is this crap in the Sandmeyer reaction?

It involves generating a diazonium intermediate which can be explosive in some cases (5-aminotetrazole is a very dangerous compound to diazotize for obvious reasons) and prone to side reactions in all cases.

The other reason might be that making this compound with Sandmeyer wound require having, 3,4- diaminothiophene, and that might not be easy to make either.

I'm neither a heterocycle chemist or very experienced with Sandmeyer chemistry, so there might be other more specific reasons, this guy doesn't want to go that route. These are just guesses.

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26. Craig on December 20, 2012 7:12 AM writes...

There's already some very interesting suggestions.

My immediate thoughts were to take the 2,5-dibromothiophene and try electrophilic substitution with Selectfluor / strong hindered base ie. LDA and carry out a deprotometallation and trap out the dianion with NFSI followed by debromination at the 2,5 positions. When you glance at the literature, you see 3,4-difluorothiophene with substituion at 2,5-Br / TMS / SnR3, therefore, it seems as though a bromine blocking strategy has been used. There is also a reference on C-3-fluorination on 2,5-dibromothiophene using fluorine as the fluorinating agent if you have the equipement to handle fluorine.

Another approach, if the toxicity of raw materials doesn't pose any issues and the direct approach doesn't work, is to try and make an intermediate "metal" ie., 3,4-trimethyltin analogue. Aromatic stannanes can be converted directly to their fluorides using std fluorinating agents under mild conditions. Conditions have greatly improved in recent years.

Permalink to Comment

27. Craig on December 20, 2012 7:12 AM writes...

There's already some very interesting suggestions.

My immediate thoughts were to take the 2,5-dibromothiophene and try electrophilic substitution with Selectfluor / strong hindered base ie. LDA and carry out a deprotometallation and trap out the dianion with NFSI followed by debromination at the 2,5 positions. When you glance at the literature, you see 3,4-difluorothiophene with substituion at 2,5-Br / TMS / SnR3, therefore, it seems as though a bromine blocking strategy has been used. There is also a reference on C-3-fluorination on 2,5-dibromothiophene using fluorine as the fluorinating agent if you have the equipement to handle fluorine.

Another approach, if the toxicity of raw materials doesn't pose any issues and the direct approach doesn't work, is to try and make an intermediate "metal" ie., 3,4-trimethyltin analogue. Aromatic stannanes can be converted directly to their fluorides using std fluorinating agents under mild conditions. Conditions have greatly improved in recent years.

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28. Keith on December 20, 2012 2:45 PM writes...

Very nice piece! Many of these small heterocycles are hard to make and require many steps to obtain the regioisomer that is required. Some of them are small little devils!

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29. Design Monkey on December 21, 2012 5:02 PM writes...

I probably would think about taking Thiophene-2,5-dicarboxylic acid (or ester), fluorinating it with electrolytically generated fluorine and decarboxylating after. (should check with databases)

Somebody here should uphold classical traditions of synthesis in spite of various fancy-schmancy tinorganics and Selectafluors. :)

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30. jj on January 11, 2013 12:44 PM writes...

The Chemistry of Heterocyclic Compounds, Thiophene and Its Derivatives (Chemistry of Heterocyclic Compounds: a Series of Monographs) (Part 3, Volume 44)

Salo Gronowitz, Ed

18 euro

http://www.alibris.co.uk/booksearch.detail?invId=11108707816&pwork=10563735&pisbn=9780471838333&_ptid=%205Nv03vHgBCI&cm_mmc=scrapers-_-bookfinder-_-na-_-na

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31. Anonymous on February 11, 2013 11:40 PM writes...

Would the 2,5-TMS-3,4DF variant suffice? http://www.tcichemicals.com/eshop/en/us/commodity/D3701/.html

Of course there's only 3 grams of the stuff in the entire United States...

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32. www.localleadsminer.com on October 18, 2013 3:34 PM writes...

I do accept as true with all the ideas you've presented to your post.
They are very convincing and will definitely work. Nonetheless, the
posts are very quick for novices. May you please prolong them a bit from next
time? Thanks for the post.

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33. Yo on December 8, 2013 7:03 PM writes...

A year late, but your target made it into a JOC ASAP paper.

http://pubs.acs.org/doi/pdf/10.1021/jo402373x

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