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!