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The Chan-Lam Reaction, Tamed At Last

Many synthetic organic chemists will be familiar with the Chan-Lam reaction, where an organoboronic acid or ester is reacted with an amine in the presence of a copper salt. It’s an appealing way of making C-N bonds, because it’s complementary to Pd-catalyzed processes like the Buchwald-Hartwig reaction. The Chan-Lam transformation uses the “wrong” starting material from a palladium perspective, the organoboron compound instead of an organohalide, so you’re actually coupling two nucleophilic partners head-to-head, which always feels a little strange.

But if you’re familiar with this reaction, you’re also familiar with a lot of foul vocabulary to use while running it, because it’s always been a capricious beast. Chan-Lam aminations are flat-out notorious for suddenly performing poorly when you vary the starting materials in what seem to be trivial ways, and for stopping dead in their tracks at some point in the reaction, with no hope of revival. They’re also a lot harder to run with the (often easier to use) boronate esters than they are with the boronic acids themselves, for reasons that no one’s completely sure about, either.

Well, until now. This new paper from the Watson group Strathclyde University in partnership with GlaxoSmithKline (edit – corrected the credit)  seems to have given this reaction the sorting-out it’s long needed. Building on work by Shannon Stahl’s group at Wisconsin on the mechanism of the related copper-catalyzed ether formation, the GSK folks have done a thorough investigation of the reaction intermediates and catalytic cycles. It’s a mess – for example, potassium acetate was found, in the Stahl work, to inhibit the ether formation, but for the aminations it inhibits some of them and actually enhances some others. You can get a mess of byproducts, too, as aficionados of the reaction already know: starting from an arylboronic species, you can end up with your desired product, mixed in with the plain aryl-H from protodeboronation, the aryl-OH from oxidation, and the aryl-O-aryl from oxidative coupling, none of which you probably were in the mood for. If you really bear down and make sure that the acetonitrile solvent and reaction conditions are strictly anhydrous, you can shut down most of that phenol and diaryl ether crap, but your reward is an increase in aryl-aryl product through homocoupling.

Careful control experiments, spectroscopy, mass spec work, and even X-ray crystallography of intermediate species led to several insights. One is that the dissociation of the copper acetate paddlewheel dimer species (which is how that one starts off) is a key event in the reaction. It has to form a monocopper species that has an OH, an OAc, a molecule of the amine coupling partner, and an acetonitrile solvent molecule all coordinated to the copper atom, and the equilibria that produce this active species are key. Another thing to note is that the reason that boron pinacol esters are so temperamental is that the pinacol they produce is a vicious inhibitor of the reaction, likely through formation of pinacol/copper complexes that shut down the whole copper-catalyzed mechanism.

The mechanism goes through a redox cycle with copper, and another big factor in the success of the reaction is the re-oxidation of Cu(I) to Cu(II) species. That takes place with molecular oxygen (this is definitely not a reaction that you want to run under strict inert gas conditions). The copper-one species seem to be responsible for a lot of the side reactions, so coming up with conditions where it doesn’t hang around is a critical factor. As it happens, adding a tertiary amine (like triethylamine) to the reaction does two good things at once – it reacts with the acetic acid generated from the copper acetate starting reagent and prevents it from going back to the inactive paddlewheel species, and later on, the triethylammonium acetate provides some acid to help re-oxidize the copper (I).

The group then solved the pinacol problem mentioned above by adding plain old boric acid to the reaction, which complexes with it so that the valuable copper species doesn’t, so those two things are the key: add triethylamine and boric acid to your Chan-Lam reactions, and they will be much happier, and so will you. The same additives also make the related copper-catalyzed etherification and thioetherification reactions fly right, for the same reasons, and you can get the experimental conditions for all of these from the Supplementary Information file for free, if you need them. And if you ever run one of these reactions, believe me, you need them. Finally, this reaction is ready to move out of the foul-language category!

12 comments on “The Chan-Lam Reaction, Tamed At Last”

  1. anon says:

    I like mechanistic investigations! Much more interesting and useful than reporting a slightly different substrate scope each time. Thanks for sharing it.

  2. Andrew says:

    Workers at GSK and the University of Strathclyde, you mean.

  3. Dawn says:

    Yes definitely the folks at Strathclyde that did the clever work

  4. Ted says:

    I spent a few months developing a Chan-Lam coupling and found it quite interesting. Controlling the degradation of the boronic ester under the coupling conditions was the key variable for us. In order to scale up, however, we had to explore atypical solvent mixtures that would allow for coupling under atmospheric oxygen at sub flashpoint temperatures. That was a little tricky, but we figured it out. You can thread the needle by using doped/depleted oxygen atmospheres, but that can be a little expensive. A good transfer oxidant is what this reaction really needs!

    In our case, reaction efficiency was much greater on the plant scale, presumably due to improved oxygen delivery through the headspace sweep. It’s a pleasant surprise to find an 8 hour reaction in the hood or kilo lab becomes a 2 hour reaction in the pilot plant!

    -t

    1. Tena says:

      Hi Ted. I’m having the hidrolysis problem wih some substrates, I’m using the boric acid to avoid the formation of the pinacol in my reaction. However, it doesn’t work. Could you give me some tip?

      Thanks.
      VTP

  5. synthc says:

    Or…just run the analogous Ullman or Buchwald…..interesting work though. I have never come across a compound that required C-N coupling that I was only able to synthesize via the complicated Chan. Kudos for the determination.

    1. Hap says:

      I don’t know “can’t” but some of the aromatic Ir-catalyzed borylation products (which likely you can’t get from starting materials or electrophilic halogenation) would be better used directly rather than converted to halides. If you really couldn’t get them to couple, you could convert them to halides but it would be a whole lot easier not to.

  6. Dr CNS says:

    Looking at the paper, this seems an excellent contribution that shows that there is still chemistry that remains to be uncovered and understood.
    I wish funding agencies – public and private – took note before they grant another million bucks to explore totally unrealistic hypotheses…

  7. E says:

    For what it’s worth this really does work in an industrial setting (non-GSK).One of the students from Strathclyde presented at the August ACS and I was lucky enough to be in the room. Late last year I used the presented conditions to turn a sticky chan-lam situation into a spot-to-spot beauty. Glad to see the paper out now.
    Bravo team, bravo!

  8. one man CRO says:

    for what it is worth….. a customer needed 20g or more of a compound that required an O-phenyl tyrosine intermediate. I needed at least 30g of that intermediate to fill the order. I made several attempts to form the key aryl ether linkage on a protected iodotyrosine with phenol/CuI (Ullman) and sodium phenoxide/Pd2(dba)3/P(tBu)3 (Buchwald-Hartwig) conditions. those were all disastrous. not scalable at all. the first reaction i tried with Boc-Tyr-OMe (cheap) and phenylboronic acid (cheap) with Cu(OAc)2/pyridine worked well. i was able to scale to 50g with 95% isolated yield.

    anecdotal but may be interesting……to someone

  9. Patrick Lam says:

    As the co-discoverer of the reaction who knows the reaction well by having worked on the reaction over the past 20 years, I am quite impressed with Derek’s nice analysis of the paper. Vantourout and Watson’s mechanistic work is indeed very important. Solving the problem of using the useful pinacol boronate is a major accomplishment. This paper complements Stahl’s previous mechanistic work, which we collaborated with. Having talked to many dozens of chemists all over the world who had used this reaction, here is my summary of the reaction. The reaction in general works for many substrates and gives products in a big range of yields. However, if one put in the time to optimize the reaction, good yield can be obtained. There are hundreds of useful name reactions. However, only dozens of them are robust enough to be used in manufacturing. C-L coupling is being used in manufacturing. There is another perspective of the reaction. Currently, one can convert boron to twelve different elements using C-L coupling, making it, arguably the most diverse mild reaction known in organic chemistry. All these are described in the most updated review of C-L coupling in- “Synthetic Methods in Drug Discovery.” RSC, 2016, 1, 242-273.

  10. SP says:

    I can’t find where Boric acid is added as an additive in the journal article and the SI.

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