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New Looks At Two Classic Reactions

It’s hard to imagine a functional group that’s been more heavily studied than amides. They are, of course, the literal backbone of protein chemistry, and they’re hugely important in all sorts of organic synthesis. The number of drug candidates with an amide bond formation in their synthesis could not be counted. So you’d think that we know pretty much what there is to know about them by now.

One of those things that we do know is that much of an amide group’s character is due to resonance. The double-bond oxygen is more properly thought of as less than a double bond, and the single bond to the nitrogen group is actually more than a single bond. That’s a big factor in the slow rotation around that bond, which can often be observed in NMR spectra through separate peaks for the two rotamers. You only see the two because that bond resonance tends to keep the whole group planar, so it’s sort of a click-stop from one to the other (the cis-amide to the trans and back).

But what if it’s not? It’s been known for some time now that many cyclic amides (lactams) and bicyclic systems don’t have the classic planar geometry, and this definitely affects their reactivity. In recent years, people have started taking deliberate advantage of this, and this new paper (from the Szostak group at Rutgers and collaborators at Yangzhou) is a good example of that. If you functionalize the NH of a secondary amide via a Boc or tosyl group (and this can be done transiently as part of a one-pot reaction), you get a nonplanar “non-amide” that’s suddenly much more reactive. You can, as the paper shows, react this with another different amine and do a transamidation at room temperature, which is something that you’d be waiting around for years to happen otherwise. There are other ways to do this, but it’s hard to come up with something else this mild.

Amide formation from an acid and an amine, via some sort of dehydrating reagent, is of course one of the most classic organic chemistry reactions of all. It’s long been a standing joke among medicinal chemists that if you can make amides and run palladium-catalyzed couplings, then you’ve pretty much got the whole toolkit to make a success of yourself in the lab. It’s funny because it’s sometimes uncomfortably close to the truth – few indeed are the medicinal chemists who have not set up arrays of either reaction to crank out a list of new analogs off a given scaffold.

Now, if you can’t get amides to form, there’s either a big problem with your compound or a big problem with you, because most of the time that’s a slam-dunk. Metal-catalyzed couplings are another story. You can usually get something to happen with standard conditions, but it may be ugly, and every substrate in a series can act a bit differently. On the flip side, it’s a truism that every single Pd-catalyzed coupling can be optimized to high yield if you’re just willing to spend enough of your life messing around with the conditions (process chemists will be nodding their heads wearily).

Here’s another new paper that illustrates the point. The authors (from Eli Lilly and collaborators at University College London and Penn) are looking at conditions for the C-N Buchwald-Hartwig coupling, which is very widely used, and whose yields are very widely known to be subject to a lot of different factors. Taking a cue from the “robustness test” proposals for new reactions, they take a model coupling reaction and try running it in the presence of a whole list of other small molecules containing different functional groups, to see how these might interfere. Screening these across a set of standard-ish coupling conditions gave over three thousand reactions, which were evaluated in 96-well plates under high-throughput conditions (which is really the only way to get through something like this).

Many of the functional additives had no real effect on the reaction, but there were several classes that did knock the yields down. (It should go without saying that none of them raised any of the yields; organic chemists know that that just doesn’t happen!) The team then went back and tried optimizing these problematic ones, varying the solvents, temperature, catalysts, etc. in order to find new conditions that would bring things back up. These could indeed be found, but high-throughput techniques came in very useful there, too, because the variations are many and subtle. To give you the idea, the model reaction (2-bromonapthalene coupling with morpholine), when run in the presence of benzenesulfonamide, was very sensitive to the base and solvent conditions. Potassium t-butoxide in dimethoxyethane gave 5% yield, but the same reaction in dioxane (which is merely the cyclized form of dimethoxyethane, when you get down to it) was quantitative. That’s just the sort of thing that makes you hold your head with this kind of chemistry.

Plowing through these variables was easier when some sort of mechanistic insight pointed the way, but that’s not always the case (and some of those mechanistic insights turn out to be wrong, anyway). The idea is to do this sort of mechanized gruntwork up front so that libraries set up with valuable intermediates will go on to have a higher success rate, which is a worthy cause. What’s good here is that the authors have shared the fruits of their labors with the rest of the community, because there are a lot of Buchwald-Hartwig reactions run out there, and a lot of them could use an improvement.

25 comments on “New Looks At Two Classic Reactions”

  1. A Nonny Mouse says:

    Sorry to say that I don’t really see what is so novel in the first paper; it is well documented that making N-Boc amides activates them significantly. Cyclic Boc-amides can be hydrolysed easily with hydroxide or methoxide (Grieco).

    Similarly, hydrazine has been used to deprotect an N-benzoyl after activation with Boc (paclitaxel synthesis).

    1. Ir(DTF)bpy says:

      Bro it’s in org let. That’s a career killer, no one said it was a major advance

      1. anon says:

        The IF is ~6. Better than JOC.

      2. What's in a name? says:

        The real sad thing is that if the same reaction had blue LED’s and a certain famous corresponding author it probably would be in Science

      3. Anon says:

        Well this is awkward… Guess someone was too busy riding the nickel catalysis high to do a control study.

        1. Skeptik says:

          That paper actually has a control without the Ni catalyst and ligand in the supporting info. Transamidation still does not occur according to the author. However, there is no guarantee there is not a background reaction in all the other examples.

          1. Anon says:

            I’m wondering if the ligand may be basic enough to promote the reaction?

            Given the paper Derek presented above it seems like their control experiment may be badly designed. The control should have had a base. As mentioned above the reaction is known to occur with base.

            I’m surprised morphline isn’t a good enough base by itself. What was that above about only high impact journals being good science? Strangly the opposite is more often true.

          2. anon says:

            Nature Communications has a high impact, but the science there is not that high quality. Just read a few articles and you will arrive to the same conclusion.

      4. Dr. ZAL says:

        As someone who routinely publishes work in journals with IF ranging from 3 to 7, I am glad to learn that my career is now officially dead.

        1. kriggy says:

          Well damn, so are almost all publication from my departmen, seems I ended in a hole 😀

          nvm, this piece is however pretty interesting to me because I did run into problems with lactone opening so thanks. Also the Boc opening mentioned by Nonny Mouse is something useful for me (did not realy delved deep into the literature becaues its more like side project) THanks guys

    2. Anchor says:

      @ Nonny house: I share your sentiments. I myself has utilized Grieco’s observation to open up bridged lactam after activating the “amide” to BOC amide. Works like charm after activation!

  2. anon the II says:

    I found the paper from the Lilly scientists to be particularly interesting. Fifteen years ago, Lilly had the technology and people in-house to do those experiments really easily without using a glove box. They tossed it all out with extreme prejudice in an attempt to distance themselves from “Combinatorial Chemistry.”

    1. Barry says:

      If Lilly just published this, it’s probably because it is work that they did fifteen years ago.
      I took a physical organic course as an undergrad from Bill Doering who explained that after a week in Europe discussing solvent effects with Lars Onsager, he came back to the U.S. to spend the rest of his career studying chemistry in the vapor phase, which we can hope to understand, rather than just document.

      1. anon the II says:

        Nope, it’s new. One of the authors was in high school fifteen years ago.

    2. Hap says:

      Leaving stuff around because it might be useful fifteen years in the future sounds like a hoarder talking. The equipment probably would probably require significant updates, if not new stuff, to use now, and so keeping it when you weren’t using it (at least for fifteen years) doesn’t make so much sense.

      Trudging through the valley of despair after climbing and descending the mountain of hype is hard.

  3. Magrinho says:

    Agreed with above. Flynn/Grieco was the first time this sort of reactivity was reported.

    Maybe more interesting is the reaction that puts Boc groups on amides: it only works with Boc2O/DMAP. DMAP catalyzes decomposition of Boc2O to a very hot “boc-ylating agent”, CO2 and tert-butoxide. In other words, same conditions do not add a Cbz group or related.

  4. John Wayne says:

    This post made me realize that I am old enough to be grumpy about people repackaging old discoveries.

  5. Anonymous says:

    I had a friend who protected a lot of amides using “Boc-ON” = 2-(tert-Butoxycarbonyloxyimino)-2-phenyl­acetonitrile.

    He deprotected them with something from a lecture bottle he labeled “Boc-OFF” (anhydrous HCl). 🙂

    It was almost as easy as “Clap ON! Clap OFF! Clap on, clap off, THE CLAPPER!”

    1. Hap says:

      ….unless you manage to isolate the ON and not your Boc-amine. 🙁

  6. Nerd v geek says:

    Sorry Derek, but I think you mean bromonaphthalene

  7. GevatterDurg says:

    But if you attach a BOC group to an amide, it is not a amide any more… it`s more an imide. In my opinion the headline is just wrong and incorrect, but as long as it is catchy…

  8. JUPACsRevenge says:

    But if you have a BOC group on an amide it is not an amide anymore… It`s like calling an ester a carboxylic acid. Even in the headline, this is just incorrect and concerning, that

  9. tangent says:

    “Potassium t-butoxide in dimethoxyethane gave 5% yield, but the same reaction in dioxane (which is merely the cyclized form of dimethoxyethane, when you get down to it) was quantitative.”

    It’s amazing to me that this type of relatively minor change in conditions can have such an effect, and chemical work would benefit so hugely if we could understand and predict these, and nobody knows how.

    Oh, we know general tendencies like what polarity does, sure, but what fraction of the total information about specific reactants/solvents would you say we’ve captured in those?

    Tell me, if somebody had years and resources to dive in to this specific dioxane/diMeOEt solvent pairing for these specific reactants, how much could they likely understand about the mechanics?

    1. Anonymous says:

      And THF is just the cyclized form of diethyl ether. And there are many other close relatives, depending on how you choose to define “close” and “relative”. Considerable effort has been put into understanding solvents, especially if you want to include scientific work done by the pioneers in the 1800s. (You can go back to the alchemists and before, too.) There are several computational models of solvents and solvent mixtures. Yes, it would be nice to understand this stuff. Got any ideas on how to speed things along?

      1. tangent says:

        Computational chemistry seems like it ought to be a good way to get control over all this unpredictability. You might even say in the end computation has to be the way, since it seems clear by this point that there’s not a “handwaving and electron-pushing” mechanistic explanation that’s enough, and computational methods in general keep advancing. Obviously hard though. (It makes me smile when I hear people say “why do we have to try things on animals and people, why not simulate a human on a computer.”)

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