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New Chemistry, Making New Things

In a perverse way, I’m enjoying how modern organic synthesis is upsetting the classic undergraduate sort of test-question syntheses. You know – Grignards, ester condensations, oxidation and reduction of carbonyls, Wittigs, Sandmeyer reactions, Friedel-Crafts, good ol’ hammer-and-tongs bond formation. I had sophomore organic back in the early 1980s, so we didn’t even have palladium couplings in there (I didn’t even run my first Pd aryl-aryl ring coupling reaction until about 1992 or so; it felt like performing a magic trick).

But there are a lot more ways to form bonds than there used to be. Those early Suzuki-style Pd-tetrakis couplings opened the gates to a massive pile of transition metal chemistry, and photochemistry (particularly the photoredox varieties) is providing even more. Many of these transformations would look downright odd if you hopped into the time machine and showed them to a bunch of people doing total synthesis in (say) 1972 or so. “OK, then we’ll go from here to here and -” “You’ll what now? How?”

This new paper from Tobias Ritter’s group at the Max Planck Institute is a good example of that. Direct C-H functionalization was not a strength of classic organic synthesis, outside of things like radical bromination or the occasional brute-force oxidation reaction. But it would, of course, be a wonderful thing to be able to step in and do selectively, especially if you had your choice of functional groups coming out the other end of the reaction. But that’s sort of what we’re looking at there. This new chemistry goes through S-substituted thianthrene derivatives, which form with a great deal of para selectivity right on the C-H of aryl rings. If there’s no carbon answering to that description, they seem to like the ortho position next to electron-donating groups.

Once you have those, you can do a wide variety of metal-catalyzed coupling, photochemical reactions, Minisci couplings, all sorts of stuff. And the chemistry seems to be compatible with a range of functional groups (ketones, esters, sulfonamides, tertiary amines, heterocycles). The thianthreniums react more quickly than aryl triflates or bromides in metal-catalyzed chemistry, and will do photochemical reactions in the presence of things like aryl iodides, which is a nice touch as well.

So yeah, this is not the sort of thing that you learned in second-year organic, for sure. The closest thing I can think of in classical organic chemistry is in fact the Sandmeyer reaction (diazotization of an aryl amine, followed by conversion to several different possible functional groups). But that one starts out from an amine, whereas this sort of chemistry is grown on the bare rock of an aryl C-H group (and doesn’t involve any diazonium intermediates, either). Friedel-Crafts reactions are the classic method for C-H aryl chemistry, but they (1) generally provide just alkyl or acyl substitution and (2) are often run under pretty savage acidic conditions, since they depend on cation formation.

Seeing chemistry like this done on a complex core (functionalization of strychnine is used as an example in the paper) demonstrates that these newer methods are a lot less severe than the older ones as well, opening the door to a lot more late-stage derivative formation off of what would normally be considered final products, rather than relegating these transformations to the brutal stuff that you figure you can get away with on more robust intermediates. You don’t see too many people doing late-stage Sandmeyer chemistry if they can possibly avoid it, for example, and if anyone’s just taken strychnine itself and tried running a Friedel-Crafts on it, I’ve missed it.

(OK, I just ran the Ritter paper’s strychnine ethyl ester product through Reaxys – there’s one hit, from a 1931 paper where some real buckaroos in Berlin oxidized the natural product and its derivatives with chromic acid and other such things to see what would happen. No Friedel-Crafts, though, and naturally the 1931 paper doesn’t have a great deal in the way of structures in it, since the overall assignment of strychnine was one of the toughest efforts in all of early natural product chemistry. So the NMR characterization of that compound in this new paper marks its first real appearance in the world, as far as I’m concerned).

One wonders what other sorts of molecules would undergo these reactions – if you took a short (or not-so-short) peptide that had a phenylalanine in it, could you functionalize the para C-H of that Phe residue? Does anything happen on the nucleoside bases? And so on – that’s what I like about completely new reactions; they open up possibilities for transformations and for products that previously you wouldn’t have even let yourself think of. . .


31 comments on “New Chemistry, Making New Things”

  1. myma says:

    I also have experience finding century-old references from German chemist buckaroos who performed something remarkably similar to what I was trying to do, with far more extreme conditions.

    Its been a long time since I learned or performed any synthesis – 90’s era myself here. I think I would fail orgo this time around. Ok maybe get a B or B-, which is my mind is close to. Is modern orgo still relevant for pre-meds? Or is it still used as a weed out course due to difficulty?

    1. Dan Berger says:

      Modern orgo tends to point up biological applications of classical organic reactions.
      Synthetic organic chemists may not be doing a lot of classical organic chemistry any more. But biological systems never stopped.

  2. Georg says:

    Cool chemistry, but am I the only one thinking of Seveso and TCDD when looking at the Tetrafluorothiantren used here?

    1. PhotoDeTox says:

      Good point. I’m not sure about the tox mechanisms of TCDD but I could imagine the large flat structure may be one of the factors. Thianthrenes are not planar so maybe this helps?

      The regioselectivity of this new method seems outstanding. We’ve done Ir-catalyzed C-H borylations which do work but selectivity was often an issue and separations of the regioisomers difficult. Also, this new method seems to be easier to set-up with no need of an inert atmosphere.

      Is it easy to get rid of the thianthrene after the follow-up reactions or will this be the next triphenylphosphineoxide?

      1. Mitsunobu says:

        It’s used in a catalytic amount. I don’t think you should compare it to TPPO.

        1. PhotoDeTox says:

          The sulfoxide is used equimolar and this thing ends up in the product. So, after the next step, e.g. Suzuki, you have one equivalent of thianthrene waste. Most likely as the thianthrene, no?

          1. mfernflower says:

            I’d be concerned about the fully reduced tetrafluorothiantrene thing being toxic as it seems that TCDD toxicity is dependent on the planar structure as it’s a potent agonist of the arylhydrocarbon receptor

  3. A Nonny Mouse says:

    Do you mean Minisci coupling? One of my favourites.

  4. Jason Martin says:

    I guess this could easily become a part of the chemistry toolbox if the TFT and TFT-oxide reagents become commercially available!

  5. luysii says:

    To someone from the Woodward era, the new stuff is definitely fabulous. What all this type of work appears (to me) to be doing is using the large transition metal atom as a reaction vessel but with the reactants on the outside of the vessel rather than inside.

    So synthesis isn’t dead despite some quibbling about whether total synthesis is worth it.

  6. An Old Chemist says:

    Derek, I wish I could blow up the diagram in your post, but it seems there is no way. Quite often, you post such diagrams and often they are not large enough to be viewed clearly. Thanks.

    1. Chris Phoenix says:

      Right click, and select “Open image in new tab.”

      1. tlp says:

        It’s a bit weird. If I do that on this page it still opens 300×202 preview
        If I do that from the rss reader it can access full-resolution picture

          1. An Old Chemist says:

            tlp: THANKS! Now, is there a way that I can blow up all the images in Derek’s many blog, dating back and dating forward both?.

          2. SSG says:

            You should be able to get it directly from this page too. I just tried and it was fine. Sure you’re not zoomed out? (Sounds silly, but just in case!)

          3. tlp says:

            @ SGS
            it gets even weirder: on my mac i can only open yet another, mid-size, preview picture

            looks like system/browser/wp specific thing

    2. me says:

      It’s not generally the images that blow up as much as the reactants that they represent. (At least in “Things I won’t work with”)

    3. RTW says:

      As a work around I often save the images to the desktop from my browser and open them up in Paint of something where I can zoom in. If they are high enough resolution images I can read them fine that way.

    4. Mike Turner says:

      In Internet Explorer, ctrl+ expands the page, and after about 5 of these I can understand the diagrams. I don’t know if it works in other browsers though.

    5. cynical1 says:

      Also using a MacOS (Mojave) and Safari and can only view an unreadable image unlike the one you linked. I tried opening in new window, saving and expanding the view all to no avail. I also tried my old PC with Windows 7 and Explorer and same image problem…….

      Thanks for the links though so we can read the image!

  7. Stephen says:

    I could see this being useful occasionally – though in many cases they showed you could just as well electrophilically brominate, and use Grignard or Palladium chemistry to get the same products. It seems most useful when you want to activate an unhindered ring, rather than the most electrophilic ring. Not very atom efficient either.

  8. Nick K says:

    One drawback i can see is poor atom efficiency. The thianthrene moiety is huge!

  9. Hatorade says:

    Broke: Electrophilic aromatic substitution
    Woke: C-H functionalization

    Well played Prof Ritter

    1. Nick K says:

      I doubt my former colleagues in Process Research would agree. Electrophilic substitution is going to remain important on a kilo scale and above.

      1. Derek Lowe says:

        Yeah – the paper demonstrates this on a 25g scale, but that’s not process scale by any means. This will be a discovery chemistry technique, and a good one, but not for the kilo lab and above (!)

      2. Hatorade says:

        You misunderstood my perhaps poor attempt at sarcasm. I actually agree with your points about atom economy. My point was that this “C-H functionalization” is very similar to age-old, reliable SEAr chemistry, and the regioselectivity and reactivity pattern is clearly driven by the same principles in the Ritter paper. I was rather criticizing the use of buzzwords.

    2. Hap says:

      As noted above, that’s a lot of weight to throw around on scale, even if you can find a way to recycle it. It’s good for diversification, and if someone has to make their drug this way on scale, they’ll do it, but it doesn’t seem like a replacement for Friedel-Crafts on scale. (I don’t think flavor or perfume people are going to give up F-C soon, for example).

      1. Hap says:

        Sorry. I misunderstood.

  10. Chris Dockendorff says:

    This appears to be extremely useful for med. chem. diversification of complex structures. Congrats to the Ritter lab for this discovery!

  11. eChem was cool tho says:

    Well, I wouldn’t exactly call multiple eq of HBF4Et2O and TFAA mild either… I’m sure a BOC group would have trouble hanging on!

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