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Trifluoromethyl Amides, Now Available

Early-stage medicinal chemists are going to be all over this paper that’s just come out in Nature. That’s because it opens up a whole interesting class of molecules that we’ve never really had access to: N-trifluoromethyl amides. That phrase won’t do much for you unless you’re a synthetic organic chemist, and especially one doing drug discovery work, but here’s why it’s a big deal.

Amides are everywhere, for starters. Amide bonds are what stitch amino acids into proteins, and the number of other biomolecules with amide functional groups is probably beyond counting, too. As you’d imagine, it’s a widely used motif in synthetic drug molecules as well, not least because forming garden-variety amides is one of the easiest and most reliable reactions known to science. If you have an amine group that you’d like to functionalize in this way, the number of carboxylic acids available to you is huge, and if you have a carboxylic acid, the same goes for the number of commercial amines. Amide formation is such an obvious way to crank out huge numbers of compounds that it’s long since become a cliché in the business, as in “I don’t want to just see five hundred amides coming out of this series”.

Going from a secondary amide (where there’s still an NH) to a tertiary one (where there are two carbons on the nitrogen) is a big switch. You can see that from the protein world; the only one of the canonical amino acids that has two substituents on its amine is proline. A simple methyl group on the nitrogen changes things – the polarity of the group, its hydrogen-bonding character, the rotation around the relevant bonds, and its stability against the (very wide) variety of enzymes that can break amides back down again. So N-methylation is one of the classic ways to modify a known peptide and turn it into something that might be unnatural enough to hang around longer in the gut or the bloodstream; it’s really one of the first things you do.

The medicinal chemists in the crowd know all this well, and they also know how important fluorinated compounds are in the business. I’ve gone on about them several times here, too, of course: fluorine is nearly the size of a plain hydrogen substituent, but is wildly different electronically. It pulls electron density out of whatever it’s attached to (which can change the character of things very much), its polarity gives it odd and useful interaction properties with all sorts of other functional groups, and the strength of the carbon-fluorine bond is legendary. If you see a C-H on your drug structure that’s being oxidatively metabolized and clearing out your drug candidate too quickly, the first thing you think of is whether that spot can be fluorinated, because the C-F analog will stop that in its tracks.

Now the big reveal: there has never been a good way to make N-trifluoromethyl amides. A few examples are known, but they’re been mostly one-offs. Those streams (N-methyl amides and fluorinated functional groups) have rarely crossed, because the N-CF3 group just ruins all those slick and easy ways to prepare amides. For starters, you can’t really get compounds containing the H-N-CF3 combination; they tend to be unstable, and if they can they’ll rip themselves apart through an elimination reaction and spit out HF, and nobody wants that. You wouldn’t expect that behavior so much from an N-trifluoromethyl amide, but it’s been hard to know, since they’re so hard to get to in the first place. Until now.

The paper linked above, from Franziska Schoenebeck and co-workers Thomas Scattolin and Samir Bouayad-Gervais at Aachen, provides an ingenious solution to the problem. As shown in the scheme, they start from an isothiocyanate (smelly, but widely available) and react that with silver fluoride. The group had already shown that this combination fluorinated the central carbon of such compounds, and in this case it goes all the way the a trifluoromethyl while stripping off the sulfur entirely. You’re left with that odd-looking trifluoromethylamine silver salt, which has the advantage of being stable enough to react cleanly with more silver fluoride and the phosgene equivalent bis(trichloromethyl) carbonate to give the acyl fluoride intermediate. Those, they found, are actually stable enough to store, which is good, because the final step gives you the diversity on the carbonyl end – reacting the acyl fluoride species with a Grignard (or probably several other sorts of organometallic reagents, I’d guess) gives you the desired N-trifluoromethyl amide, which you have been able to sneak up on without it realizing what you’re up to. Usefully, that final Grignard addition is fast enough that a bromoaryl group in your molecule will survive without doing metalation reactions of its own.

That acyl fluoride intermediate had also been known in a few examples in the literature, but the preps for such things tended to involve stoichiometric amounts of mercury salts and plenty of fluorophosgene gas, an extremely unappealing prospect. Silver fluoride and BTC is a lot easier system to deal with. Now, as the Nature “News and Views” piece on this paper notes, this whole procedure does go through five equivalents of silver fluoride on the way, which is not something that can be scaled up to drug-production levels. We early-stage research types can (and will!) use this system to explore this new world of functionality, but the world is going to need another way to make these things if we’re going to turn them into wonder drugs. (If someone has an idea for directly N-trifluoromethylating secondary amides, now’s the time to break it out. But that’s not going to be easy, since no one’s accomplished it already).

The paper shows a number of amino acid derivatives (chirality is retained, no problem) and many other structures containing aryls, heteroaryls, esters, sulfones, triflates, nitriles and so on. You can take the fluoroacyl intermediate and turn it into ureas and carbamates as well, which opens up still more possibilities. It turns out the the trifluoromethyl amides themselves are stable, can be taken through standard sorts of chemistry (such as Pd couplings) without reacting or falling apart, and show notably reduced barriers to bond rotation compared to the plain N-methyl analogs.

This work has application beyond medicinal chemistry, of course, materials science and polymer work being the first things that come to mind. But it’s for sure that no drug binding sites have ever laid eyes on a trifluoromethyl amide before. A lot of new compounds with unusual properties are going to get prepared pretty quickly, and it will be quite interesting to see what comes out!

38 comments on “Trifluoromethyl Amides, Now Available”

  1. Jake O says:

    There’s a selenocarbamate buried in that substrate scope. Those poor people had to deal with selenophenol!

    1. anoneemous says:

      I once made methaneselenol (MeSeH) as a side-product in grad school. It smelled like death and rotten onions and wet dog all at once. I get nervous sweats just thinking about it.

      1. ScientistSailor says:

        You’re probably luck to be alive…

  2. Red Agent says:

    Hmmm. Help me out here. What’s the problem with consuming 5 equivalents of AgF for each of these beauties?

    1. The Hunt Brothers says:

      Nothing, nothing at all.

      1. Derek Lowe says:

        Hah! You’ve just revealed your age with that joke. . .but yeah, the problem is both the (large) consumption of an expensive silver reagent, but the recovery/waste stream that would be generated on the back end.

        1. Joshua Rose says:

          Great, now I need someone to explain the joke as well.

          1. Derek Lowe says:

            The Hunt Brothers tried to actually corner the silver market in 1980, the sort of thing that one had previously only read about. It worked part of the way, and then failed – the NY Merchantile Exchange (COMEX) changed the rules about buying on margin, and the Hunts were unable to hold on to their position as the silver market collapsed around them. Quite a tale: https://en.wikipedia.org/wiki/Silver_Thursday

        2. Scott says:

          Not a chemist, but it looks like that waste stream (at the AgF reaction) would be mostly pure silver?

          While it would be a pain in the butt to deal with in a mass-production sense (solid silver clogging up the pipes), I don’t think it’d be that big a deal once you got it out of the reactor.

          What am I missing?

          1. Al says:

            The scale-up drawback for such methods is only partially related waste streams, or to the relatively high price for a superstoichiometric reagent. The biggest concern would probably be that residual metals are not so easy to control downstream – the ICH limit for oral drug products is 15 ug/g (or ppm), and a fraction of that (<1ppm) for other modes of administration for silver.
            So you both need to make sure that you removed all the metal by appropriate process controls, and to develop (validated) methods suitable for testing for those trace metals, and procedures for cleaning equipment and testing the cleanliness after each batch/production campaign. If you can avoid these steps, it's better. If you can avoid a lot of waste that's great too 🙂

      2. Anonymous says:

        (If In The Pipeline was, software-wise, a forum rather than a blog, I could just click the “like” or “thumbs up” button on the clever post by The Hunt Brothers. Instead, I have to type out this post … on a Silver Thursday, I note.)

  3. A Nonny Mouse says:

    Agree with the fluorophosgene comment; I accidentally made it once when I was trying to displace an activated aromatic chloride with fluoride from an isomer mixture.

    It did that but it also displaced an OCF3 on the isomer (which was in the activated position) which converted to fluorophosgene. The nitrogen balloon wasn’t to well afterwards.

    1. milkshake says:

      one of the problem with low-reactivity fluorines in groups like CF3, CHF2 etc is that they may not be completely unreactive in vivo. For example if there is a metabolite with phenol o, p next to CF3, F(-) eliminates from it quite readily. Likewise, we had a pyridine piece substituted with CHF2 group that decomposed already with a mild base like K2CO3, probably due to acidity of that CH. One has to be on watch out especially if the compound is to be given orally, high dose, over extended period that the metabolically inert F is really inert.

      1. Nick K says:

        The same problem exists with anilines substituted with difluoromethyl or trifluoromethyl in ortho or para. Very recently, we made 4-difluoromethylnitrobenzene, which was perfectly stable, as one might expect. Catalytic reduction of the nitro group gave the aniline which decomposed in minutes. We tried adding HCl to trap it as the salt, but that merely accelerated the decomposition.

      2. Metabolic pathways says:

        Right. Seems obvious that once that amide bond is metabolically cleaved, the resulting secondary anime will rapidly eliminate fluoride. It seems that the electron withdrawing nature of the CF3 group might make it easier to hydrolyze (enzymatically or otherwise) these amides and therefore promote this pathway.

        1. Derek Lowe says:

          This is definitely something to check out – I’m curious if the compounds will bind well enough in the hydrolase active sites, but if they do, they may well break down more quickly.

  4. John Campbell says:

    I wonder if [18-crown-6] potassium fluoride (I.e., one equivalent of18-crown-6 for each K) would do the trick? I think it is soluble in acetonitrile ( I have found higher yields using 1 equiv of the crown ether than 5-10%).

    1. milkshake says:

      you need a thiophilic plus halophilic metal metal like silver (or mercury or thallium), to push this exchange through. Another route to this type of compounds is based on oxidative defluorination of C=S, the typical reagent is N-iodosuccinimide + NEt3.3HF combo, although things like ArIF2 would also work. Not a very nice chemistry too, and it needs large excess of some form of anhydrous HF which makes process people unenthusiastic

      1. John Csmpbell says:

        True, id forgotten about silver suprise precipitation.

        1. John Campbell says:

          # I’d and sulfide although silver surprise sounds nice.

  5. BernYeeFluorines says:

    Great. More Teflon-based molecules to bury themselves in everything that moves and breathes.

    I was just getting used to the subtherapeutic amounts of Prozac I get from my water.

    Stop making fluorine based molecules- All of You!. They don’t degrade and you all are poisoning the environment.

  6. Dmpk says:

    I don’t prefer to block metabolism with halogens since they have a tendency to slow metabolism at the expense of increasing inhibition potency of CYPs

    1. anon says:

      What are some alternatives?

      1. Stanislav Radl says:

        Deuteration does not block but decrease extend of metabolic reactions.

  7. Will says:

    I have to be a persnickety person (blame my organofluorine research in grad school). Fluorine is much larger than hydrogen is (Bondi’s original values have it as 147 pm for fluorine and 120 for hydrogen). Fluorine is only 5 pm smaller than oxygen (152 pm) and 27 pm larger than hydrogen. The claim that fluorine is the same size as hydrogen is pervasive but misguided. Several papers (the only one I could find off hand: https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.200800321) have placed a trifluoromethyl group as equivalent in size to an ethyl group (or larger and somewhere between an ethyl and isopropyl).

    This is all to say that you state that a fluorine and hydrogen substituent are nearly the same size but this is misleading (especially to someone who made such a statement during an early group meeting and then got torn apart by their peers, for example…. *ahem*).

  8. Thomas says:

    Hi guys, I am one author from the paper discussed here. Many thanks Derek for the great overview of our work, highly appreciated!

    As said above by Derek and by Jonathan Clayden in the “News and Views” article, the main drawback of our approach is the use of 5 equivalents of silver(I) fluoride (you actually need at least 4, but we used 5 to be sure).
    However I would like to note that the reaction is rather clean and only generates inorganic silver salts byproducts [1 equivalent of silver(I) sulfide Ag2S and 2 equivalents of silver(I) chloride AgCl] and as shown in the picture here https://ibb.co/6rVJwtx, those salts can readily be collected from the filter aid (here Celite, probably could be done with sand?). Meaning no other inorganic or organic material would come to contaminate the silver salts.

    Please correct me if I am wrong (I am not an expert in metal recycling) but I read that silver is one of the precious metal with the highest recycling rate. So if the people using this methodology would collect those silver salt byproducts, send them off for recycling, the whole process seems more likely to be feasible at larger scale (again no other byproduct during the transformation than silver salts).

    I would be more than happy to hear from colleagues dealing with the recycling of metal salts, and more specifically silver to have a better idea on this. Thanks again for the highlight!

    1. AlloG says:

      Yo! Whats with the Hi Guys? You forget the other sexes. So can I put dat group where a diethylamide exists normally?

      And what about Bernie Sanders Yee’s words? Dey going to end up in me belly cells?

      1. oliver James says:

        Other sexes? How many makes ‘other’?

  9. Wheels17 says:

    I used to work at Kodak and my office looked out over the section of the plant where all the silver nitrate was produced. Armored tractor trailer loads of silver bars would be unloaded, dissolved in nitric acid, and the resulting silver nitrate shipped out for further processing into light sensitive salts for film. Unfortunately, I don’t recall the actual amounts at the peak, but even in the year Kodak went bankrupt, they used 8.5 million troy ounces of silver. In 1998, near the peak of silver halide photography, the worldwide consumption was 257 million troy ounces for photographic purposes.

    Search for “kodak silver recovery” and you’ll find a lot of information on the services provided for end user (processors) recovery of the silver used in film.

    1. Thoryke says:

      I believe the silver jewelry material known as “precious metal clay” originated with silver particles recycled from filmstock. When sintered in the correct type of kiln, the objects made with that clay are solid silver. I’m not sure how the particles are obtained now, given the state of photography film production. There are also gold and bronze versions of the ‘clay’.

    2. Olandese Volante says:

      Legend has it that at one time the sludge on the bottom of the Hudson’s lower reaches could have been profitably mined for silver…

  10. Confused Biologist says:

    >Going from a secondary amide (where there’s still an NH) to a tertiary one (where there are two carbons on the nitrogen)

    Wait, am I missing something obvious or should it be “three carbons on the nitrogen” here?

    1. Peptide Robot says:

      Technically yes, but the carbonyl carbon is implied as it is an amide group.

  11. loupgarous says:

    NIOSH’s exposure limits for phosgene are much less than those for fluorophosgene.

    The US Navy sold off a large part of its phosgene stockpile to what is now BASF’s chemical plant near Geismar, LA. I watched it being shipped up that way from the front porch of my family’s home 30 miles west of New Orleans. Fortunately, I was a teenage boy, so all the huge placards on the sides of the tank cars telling everyone to RUN, not WALK away in the event of a derailment, writing your last will as you do so, provoked the “kewl” response that is responsible for all the other stupid crap teenage boys do.

    Supposedly, the phosgene was an intermediate for something the plant at Geismar made. This surprised me not at all, considering the Union Carbide (now Dow Chemical) plant in Taft, 8 miles across the swamp from our house used a LOT of acrolein as an intermediate for various acrylic monomers.

    The 12-14 petrochemical plants in my home parish could have adapted the Air Force Tactical Air Command’s unofficial motto from “Peace is our Profession, War is Just a Hobby” to “Chemistry is our Profession, Explosions are Just a Hobby”.

    The one BIG detonation back home that rattled the shingles on our side of the swamp, though, wasn’t acrolein letting go, but boring old light alkanes which hadn’t been properly vented from a barge before three guys were sent over to chip the rust off it with chisels. The identifiable remains of that work detail amounted to a boot or two.

    Moral of this story? Once you guys discover a wonder drug using silver fluoride, write it up and some chemical engineers back where I grew up will develop a large-scale production process using fluorophsogene and mercuric salts. The grandkids of the guys who worked with phosgene as a feedstock at Geismar will make your medicine in railcar lots.

    BASF Geismar still teaches a safety course on working safely with phosgene. If they can do that, they can handle fluorophosgene.

  12. AC says:

    Tweeted this but figure I might as well post it here too:

    Now I’m curious, what other functional groups/structural motifs have you thought of that you wish you could introduce but there just wasn’t any literature precedent for making them?

    1. milkshake says:

      Convenient easy to use procedure that introduces cubane and SF5 group. Cubane building blocks are available but very dear, and cubane moiety does not play well with many transition metal catalysts used in medchem couplings. SF5 is pretty stable, chunkier analog of CF3 group, some building blocks with SF5 are available but not too many, chemistry is limited to radical reaction of (.)SF5 generated from precursors like BrSF5

  13. Niek says:

    Sounds like some exciting chemistry, although I am happy that someone else figured out how to make this conversion work. If the oxidation state of the silver is not changed, then I surely expect to see future work from this group or another where the silver can be substituted mostly, or even used catalytically, with the remainder of the fluorine coming form other sources (NaF, KF, maybe Quaternary ammonium salts?).
    Although maybe, before we get a new generation of PhD’s breaking there head over this problem it would be good to see the general affect that this group has in drug molecules. More variety in novel compounds is always interesting, but not always the most useful.

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