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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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August 17, 2011

New Ways to Fluorinate

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Posted by Derek

There have been some neat ways to make fluorinated molecules reported recently, which I wanted to mention. We med-chemists just love our fluorines - as long as we don't have to use, like, fluorine itself to make them - because they armor-plate parts of our molecules against being metabolized and can change the binding profiles of the parent structures like nothing else can.

Over at New Reactions, there's a nice writeup on a new way to generate difluorocarbene, which (as it should) immediately adds to alkenes to give you difluorocyclopropanes. (It'll add to alkynes to give you the somewhat more exotic difluorocyclopropenes, too). This is from G. K. Surya Prakash and George Olah, and from the looks of it, it's simplicity itself: take your alkene and some TMS-CF3 in THF, and either run it hot with sodium iodide or in the cold with the anhydrous TBAF substitute TBAT. So there's what looks like a perfectly useful med-chem structural motif, suddenly made widely available.

The second paper is from the Baran and Blackmond labs at Scripps, and is a completely new way to introduce trifluoromethyl groups onto heterocyclic rings. This one generates trifluoromethyl radicals under very mild conditions, using the hitherto-obscure (but stable and relatively cheap) Langlois reagent as a source. You don't need any special group on the substrate to make this work - it charges right in and attacks the more active C-H bonds of the parent heterocycle. A wide variety of useful ring systems are shown to work, and it looks like you can change the regiochemistry by varying the solvent. I'm sure that people will think of other uses for the CF3 radical, now that it's much easier to get ahold of, but this one just by itself is going to be adopted very quickly.

These, I have to say, are just the kinds of new reactions that working chemists like to see: they make useful compounds that have been hard to access, they use commercial reagents, the conditions are not hideous and require no special equipment, and the authors have taken the time to demonstrate them on a very wide range of structures. The more things like this that get discovered, the better off we are.

Comments (29) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. Anonymous on August 17, 2011 1:35 PM writes...

Interesting to see these papers garnering so much attention while MacMillan's trifluoromethylation of aldehydes and ketones has gone virtually unnoticed.

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2. Morten G on August 17, 2011 2:31 PM writes...

This post would be so much nicer to read with pretty pictures.

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3. Brent Michael Krupp on August 17, 2011 2:40 PM writes...

It's pretty darn neat that even in 2011 people can come up with new organic chemistry reactions.

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4. eugene on August 17, 2011 2:49 PM writes...

Interesting... I was expecting to see the Ritter paper, but I'm really impressed by the Baran and Blackmond labs' work. In fact, I'm going to order that reagent and for something completely different than putting a CF3 group onto a heterocycle. For the other paper, you forgot to mention the Chinese corresponding author, Jinbo Hu from a Key laboratory.

Oh, here is the Ritter paper on deoxyfluorination

http://pubs.acs.org/doi/abs/10.1021/ja2048072?source=chemport

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5. cynical1 on August 17, 2011 3:02 PM writes...

Personally, I'm not a fan of sticking trifluoromethyl groups in drugs at all. Want to increase your protein binding, increase distribution into fat, and increase your volume of distribution? Then add a couple trifluoromethyl groups. See dutasteride - 5 week half life. No thanks...........

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6. CR on August 17, 2011 3:22 PM writes...

Okay, I'll say it...Baran's paper...PNAS? Really?

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7. Anonymous on August 17, 2011 3:59 PM writes...

I'd like to know more about the safety / toxicity of this electrophilic reagent! Given the toxicity of TMS-diazomethane and methyl fluorosulfonate (magic methyl), I'd be wearing thick gloves when using this baby ...at least until someone takes a bath in it and survives LOL (just kidding). Given the origin of this reagent (Olah et al.) I'd be careful with it in the near term.

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8. Anonymous on August 17, 2011 4:21 PM writes...

TMS-CF3 (Ruppert's reagent) is easily handled, as is sodium trifluoromethanesulfinate.

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9. SteveM on August 17, 2011 7:45 PM writes...

Re: Anonymous "TMS-CF3 (Ruppert's reagent) is easily handled, as is sodium trifluoromethanesulfinate.

But not after a couple of drinks.

While one could Grignard away totally smashed. (Wearing safety goggles and with sufficient insurance of course.)

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10. Anonymous on August 17, 2011 7:49 PM writes...

@8 & 9 How about the soup created after treatment with TBAF...what if the rb flask fell and broke in the hood and the mix got on the skin?

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11. Anonymous on August 17, 2011 9:34 PM writes...

As far as fluorination reagents go, these are indeed both quite mild.

It's probably worth plugging George Whitesides' recent JACS paper on perfluoroalkyl groups binding hydrophobic regions of proteins while we're discussing organofluorine chemistry (http://pubs.acs.org/doi/full/10.1021/ja2045293)

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12. dumb biologist on August 17, 2011 10:04 PM writes...

Adding a trifluoromethyl would make your compound less soluble, right? A colleague told me the opposite.

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13. blah on August 17, 2011 10:34 PM writes...

Nice work! If someone can solve the problems associated with the regioselectivity in the Baran work.. then this method may become useful!

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14. Pharma employee on August 17, 2011 10:53 PM writes...

We started using the baran reaction a month ago after he presented it in our company. If your in med chem mixtures are great. So #13 is not entirely correct.

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15. Anonymous on August 18, 2011 6:36 AM writes...

On a related note, here's Ritter's paper on silver-mediated trifluoromethoxylation of aryl stannanes & boronic acids.


http://pubs.acs.org/doi/pdf/10.1021/ja204861a

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16. Vader on August 18, 2011 9:07 AM writes...

Go with the fluo.

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17. Anonymous on August 18, 2011 9:40 AM writes...

MacMillan has work similar to Baran's. We tried both sets of conditions in the lab on an electron-deficient heterocycle: MacMillan's worked, Baran's did not. I'm not implying that one is superior, just recognizing the a complementary approach to CF3-ylation.

Angew. Chem. Int. Ed., 50, 6119-6122 (2011)

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18. MoMo on August 18, 2011 10:44 AM writes...

What the hell is wrong with some of you chemists? Deriding this work in chemical evolution! You should be ashamed to be Americans, if you are, as these reactions show the spirit of entrepreneurship that sets us apart from other countries.

And to complain that the reactants are "too toxic". Boo-Hoo you crybabies. If you cant work with the most toxic molecules safely and effectively you need to get out of the business and make room for those pioneers and others that publish such progressive chemistry and reactions.

I salute the scientists above that reported those reactions and you should too!The Spirit of America in the form of new reactions lives on!

Keep up the good work and cant wait to try them on my own scaffolds!

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19. huh? on August 18, 2011 11:57 AM writes...

To #17 - I don't get it - that paper is for carbonyl fluorination, why would you try that for a heterocycle? Seems macmillan conditions are quite complex, I bet #17 is a macmillan group member...

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20. Anonymous on August 18, 2011 12:21 PM writes...

To #6: This would make a really good Org. Lett. paper

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21. Anonymous 2 on August 18, 2011 1:05 PM writes...

To #20: Yup, just like #17

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22. Ckellz on August 18, 2011 10:25 PM writes...

Thanks for the reference! And my personal passion in org chem right now is introducing fluorine into organic molecules. Its just such a different sort of chemistry than the standard chemistry you were taught or read about.

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23. Guppy on August 19, 2011 11:43 AM writes...

"Adding a trifluoromethyl would make your compound less soluble, right? A colleague told me the opposite."

Since he didn't say soluble-in-what, he would not be incorrect, and neither would you!

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24. confused on August 19, 2011 3:58 PM writes...

To #19: I'm confused by the comments from #17 as well. Without mentioning a specific heterocycle the critique seems missplaced/unfair. Moreover, if given the choice between condensing 10 equivalents of CF3I versus adding a simple solid, I know which protocol I would attempt first. The beauty of industrial chemistry is that really facile and effective procedures will always rise to the top when they work well, so that will be the true proving ground.

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25. dumb biologist on August 19, 2011 4:31 PM writes...

@23, in water

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26. Anonymous on August 19, 2011 9:04 PM writes...

@#18...I'm detecting some arrogance typical in the pharma industry....

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27. Jack D. Ripper on August 22, 2011 9:39 AM writes...

New Ways to Fluorinate

Still trying to poison our precious bodily fluids, I see...

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28. MoMo on August 22, 2011 2:14 PM writes...

Arrogance? You have have it all wrong Anonymous! Chemicals and their industry determine the wealth of nations, and if chemists keep innovating we can help pull this country out of the Funk that it is in.

Then are the legions of wimpy-scientists that complain all the time about their lot in life, bashing chemists here on this blog.

To you Naysayers again I say-You either Lead, Follow or Get out of the Way!

But our Industry is filled with Cry-Babies who expect to be adored with their Ph.D.s. Instead the reality is to getback in the lab, change some pump oil, set up dangerous and interesting reactions and get back to innovating!

We Leave the Arrogance for the MBAs!

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29. Anonymous on August 23, 2011 4:15 PM writes...

@28

"But our Industry is filled with Cry-Babies who expect to be adored with their Ph.D.s. Instead the reality is to getback in the lab, change some pump oil, set up dangerous and interesting reactions and get back to innovating!"

Now that sounds like arrogance to me!!! Who do you think you are E.J. Corey. What have you accomplished????

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