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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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April 17, 2014

Gitcher SF5 Groups Right Here

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Posted by Derek

I think that several of us in medicinal chemistry have been keeping our eyes out for a chance to work in a pentafluorosulfanyl (SF5) group. I know I have - I actually have a good-sized folder on the things, and some of the intermediates as well, but I've never found the right opportunity. Yeah, I know, they're big and greasy, but since when that that ever stop anyone in this business?

Well, here are are some new routes to (pentafluorosulfanyl)difluoroacetic acid, a compound that had previously only existed in a few scattered literature reports (and those from nasty chemistry). So we all have even less of an excuse to start polluting enhancing our screening collections with these things. Who's first?

Comments (24) + TrackBacks (0) | Category: Chemical News | Life in the Drug Labs


COMMENTS

1. Deep Lurker on April 17, 2014 2:19 PM writes...

Well, the latest version of the "Rule of 5" is that a drug-like compound has to have 5 fluorine atoms...

I have to admit that my first thought when my boss wanted me to make an Ar-SF5 compound was "isn't that thing a powerful fluorinating reagent?" But my chemicists instincts were wrong about that.

And "Yeah, I know, they're big and greasy, but since when that that ever stop anyone in this business?" True. Didn't stop me. I've been responsible for a few t-butyl groups in my time.

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2. Anonymous on April 17, 2014 2:38 PM writes...

Being able to cross couple SF5 groups onto aryl halides or aryl boronic acids from precursors like SF5Cl or SF5Br or, ideally, SF6, will probably appear in literature someday, similar to how trifluoromethylation was developed. SF6 will be a challenge, but there are already some SF6 activation papers out there.

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3. Dr Octopus on April 17, 2014 2:57 PM writes...

How does the size of an SF5 group compare with say Br and I? And with t-butyl?

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4. MoMo on April 17, 2014 4:00 PM writes...

I'm getting NASH just looking at this substituent! Cant wait to see the metabolic profile on this beast.

Who wants to bet F- pops off readily after 1st liver pass, the way it does in bacteria and fungi?

Lemmings anyone?

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5. NaturalChemist on April 17, 2014 5:19 PM writes...

Can't get "One and Done" (4/16) comments to load

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6. ThirdWind on April 17, 2014 10:56 PM writes...

I think (no ref on hand at the moment) SF5 functional group already appeared ages ago in one of the earliest papers by Corwin Hansch; if memory serves it was an SF5-aniline just invented at DuPont. Most SF5 compounds ultimately used to derive from S2F10 which you can only make (at your own risk) from sulfur and F2. Which is why they remained few and far apart. A non-esoteric, large scale, recently invented synthesis of Ar-SF5 is in: Beilstein J. Org. Chem. 2012, 8, 461–471 by Umemoto and coworkers (open access).

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7. Fluorine Chemist on April 18, 2014 3:39 AM writes...

Aromatic SF5 is not too big challenge (ortho substitution is not really possible as SF5 is just too bulky) and 3-nitro and 4-nitro SF5 benzenes are available on process scale via fluorination of the disulfides with fluorine gas. In the last few years lots of interesting chemistries have been developed to transform these compounds into many other SF5 aromatics. I think Umemoto's approach (ref in @6) is a very promising complementary route to these.

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8. A Nonny Mouse on April 18, 2014 4:41 AM writes...

I seem to remember that Catylix was selling some of these intermediates.

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9. Rhenium on April 18, 2014 4:27 PM writes...

Is anyone trying to see the comments and then just getting a blank screen? This is the first time I've been able to comment all week.

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10. milkshake on April 18, 2014 4:44 PM writes...

Unlike the CF3 group on aryl, SF5 group is most likely incompatible with Grignard (there has been a powerful torpedo propulsion system fueled with Li metal and SF6 gas as oxidizer)

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11. weirdo on April 18, 2014 5:50 PM writes...

MoMo: No, in fact in our hands numerous SF5 derivatives are quite metabolically stable in vitro, have excellent PK in rodents and dogs, and show no untoward ADME issues.

And, milkshake, synthetically they have been very robust. I cannot say we've hit them with alkyllithium reagents, but lots of other stuff, including SnAr's under forcing conditions.

The thing is a rock. Like, literally. Just a big old lump of inert grease, if that is what you are looking for in your molecules.

Take that for what's it worth from an anonymous Internet contributor.

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12. Rhenium on April 18, 2014 6:09 PM writes...

Milkshake,

Thank you for that amazing piece of trivia regarding the Mark 50! I had never heard of such a thing.

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13. AVS-600 on April 19, 2014 12:28 AM writes...

@10 (Milkshake)

To be fair, you can also use elemental magnesium and fluorocarbons to cause a thermite-like reaction. The reducing power of the elemental metals is likely quite a bit higher than that of the Grignards and alkyllithiums.

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14. A Nonny Mouse on April 21, 2014 4:06 AM writes...

Actually, it's Spirochem that sells all of these. Huge catalogue of them.

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15. Spudnick on April 21, 2014 2:49 PM writes...

I have worked with these relatively recently and they are quite remarkable functional groups. There were a couple of questions about properties of ArSF5, and this is what I recall from prior reading:
- they are slightly smaller than t-Butyl
- they are about as lipophillic as C2F5
- their electron-withdrawing character is a little less than NO2 and CN
- They're octahedral! How. Cool. Is. That? For organic chemistry, anyway.
- under acidic conditions (conc. H2SO4), they are slightly more stable that CF3
- you can convert aryl bromides bearing SF5 to Grignard reagents with Mg and deprotonate them with t-BuLi, but they are unstable to BuLi
- they survive are sorts of electrophillic substitution chemistry (nitration, halogenation, etc.)

As for personal experience, I will concur with a prior comment that they are metabollically robust. I have yet to see an aromatic ring with an SF5 group so much as get touched by a liver enzyme. We also observed quite good PK & ADME properties with some compounds.

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16. Malaria on April 23, 2014 11:15 AM writes...

It's big and greasy, provides good binding to hydrophobic pockets and can enhance metabolic stability. It's actually a component of a compound called DSM265 in Phase I studies for malaria

J Med Chem. 2011 Aug 11;54(15):5540-61. doi: 10.1021/jm200592f. Epub 2011 Jul 14.

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17. Moissan on April 24, 2014 9:51 AM writes...

+1 for Spudnick's comments

Generally speaking, once you put an SF5 group in, it will survive most reaction conditions. Strong lewis acids (SbF5, AsF5) will also react with alkyl SF5 derivatives to form the monofluorinated alkyl group. I've listed a recent review of SF5 chemistry for interested parties.

J. Fluorine Chem. 2012, 143, 57-93.

In terms of medicinal use and effects of installing an SF5 group, the results seem to vary. The recent article coming out of Novartis listed below has a section devoted to SF5 and their comparison with CF3 analogues.

Current Topics in Medicinal Chemistry. 2014, 14, 855-864.

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18. Hap on April 24, 2014 2:18 PM writes...

This U Wisconsin PowerPoint presentation has a lot of information about SF5 compounds.

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19. LLoyd Garrick on June 18, 2014 1:46 AM writes...

I helped develop the first, and still the only, industrial scale-up, easy and economically practical method to produce these compounds. The potential is enormous! Then my research facility was shut down. And NOONE seems to be interested in pursuing this (except in China where i don't wanna go (yet().

"gitcher SF5" ? Gimme a lab and I'll make it for you!

Permalink to Comment

20. Walter on August 2, 2014 8:50 PM writes...

Interesting development with the SF5-group. I think that the slow acceptance of this substituent is rooted in a psychological phenomenon: It is new, looks exotic and, as Deep Lurker (top-most comment) writes, makes one think that it ought to be unstable.

There are worlds of differences between an SF3- (as in DAST & its derivatives) and an SF5-group. In the older writings CF3SF5 is occasionally used as a metathetic fluorinating agent at a few hundred degrees C.
The Umemoto procedure for these compounds is an amazing, principally similar to the Swartz process for making benzotrifluorides. It represents a revolution in the field of aromatic SF5-compounds, and it seems that there is no limit to make benzene (and hopefully naphthalene, etc.) derivatives. No more high-valency metal fluorides, interhalogen compounds or fluorine, as in the various older procedures, are needed. KF, chlorine and aromatic sulfides or thiols will do.
The aliphatic field is less developed, and there the building-block approach might be the solution. 1- and 2-SF5-butadiene are useful reagents, SF5-acetylene, SF5-ethanol, etc.
It was previously believed that the limited and difficult availability of precursors was the reason for the slow acceptance of the SF5-substituent. This reason is not valid anymore with Umemoto's procedure, or the new very easy methods for making SF5Cl, SF5Br or SF4.

Permalink to Comment

21. Walter on August 2, 2014 10:48 PM writes...

Interesting development with the SF5-group. I think that the slow acceptance of this substituent is rooted in a psychological phenomenon: It is new, looks exotic and, as Deep Lurker (top-most comment) writes, makes one think that it ought to be unstable.

There are worlds of differences between an SF3- (as in DAST & its derivatives) and an SF5-group. In the older writings CF3SF5 is occasionally used as a metathetic fluorinating agent at a few hundred degrees C.
The Umemoto procedure for these compounds is an amazing, principally similar to the Swartz process for making benzotrifluorides. It represents a revolution in the field of aromatic SF5-compounds, and it seems that there is no limit to make benzene (and hopefully naphthalene, etc.) derivatives. No more high-valency metal fluorides, interhalogen compounds or fluorine, as in the various older procedures, are needed. KF, chlorine and aromatic sulfides or thiols will do.

The aliphatic field is less developed, and there the building-block approach might be the solution. 1- and 2-SF5-butadiene are useful reagents, SF5-acetylene, SF5-ethanol, etc.
It was previously believed that the limited and difficult availability of precursors was the reason for the slow acceptance of the SF5-substituent. This reason is not valid anymore with Umemoto's procedure, or the new very easy methods for making SF5Cl, SF5Br or SF4.

Permalink to Comment

22. Walter on August 2, 2014 10:52 PM writes...

Now that's interesting:
My earlier post wasn't there when I checked, so I re-posted it and now it is there twice.
Sorry.

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23. David Rozzell on August 5, 2014 11:41 AM writes...

As an alternative to SF5 Catylix is offering building blocks that incorporate C2F5--pentafluoroethyl. This substituent offers all the benefits of SF5 (a little less electron withdrawing, not quite as lipophilic) with the additional benefits of broad synthetic access at reasonable cost. Here is link for more info: http://www.catylix.com/what-is-the-new-substituent-of-the-future.html

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24. LLoyd Garrick on August 21, 2014 9:23 PM writes...

Ar-SF5 is rock stable to Grignard. I have made a number of them, as well as the boronates from them.

A detailed summary of all things SF5 is here:

http://www.colorado-hiking.net/ArSF5.html

Check it out.

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