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. . .