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Meet the New Mitsunobu

Well, people have been searching for a reaction like this one for quite a while now: that link describes a catalytic Mitsunobu-like reaction, and the original has always been a transformation that synthetic organic chemists groan about but use anyway. It’s a way of substituting an OH group in one pot with what should be clean stereochemical inversion, and you can use a variety of nucleophiles. One common use is inverting a stereocenter by forming an ester product – hydrolyze it and you’ve got the alcohol back in the opposite stereochemistry. And it’s also used a lot to make ethers, particularly for intramolecular ring-forming ones or acyclic aryl ether formation. It’s been around for decades, it’s all over the literature, and you’d have to search for a bit to find a working synthetic chemist who’s never run one. So why all the grumbling?

Because it’s a mess. The classic Mitsunobu uses stoichiometric diethylazodicarboxylate and stoichiometric triphenylphophine, and the latter ends up as triphenylphosphine oxide. That last conversion is the thermodynamic “battery” that runs a number of organic chemistry transformations (such as the original Wittig reaction), but no one is happy about dealing with all the phosphine oxide when it’s purification time. Sometimes you can extract your product out or precipitate the TPPO out and get away clean, but other times it’s a slog. And you never feel like you’re doing elegant chemistry when you chew up so much reagent (both the DEAD and the TPP) to do something like flip a single OH group. If “atom efficiency” is your thing, you have to avert your eyes from the Mitsunobu.

I would not like to count the variations that have been proposed over the years, but most of these have involved alternatives to the azo reagent and still produce a phosphine oxide. Polymer-supported reagents, more water-soluble variants, all sorts of things have appeared. But getting both catalytic has been a tall order, because the DEAD gets reduced in the reaction while the TPP gets oxidized, so you’re going in two directions at once if you want to cycle those around. This new paper, though, has an ingenious solution shown at right. You start with the phosphorus already in the +5 oxidation state and go through a reactive cyclic intermediate that gets regenerated. So the reaction is catalytic in both directions (the oxidation and the reduction) and throws off only an equivalent of water as a byproduct. Pretty slick!

This also lets you do esterification on alcohols that are sensitive to the more common methods, and the pre-oxidized phosphine lets you get away with substrates that have groups (alkyl bromides/iodides, azides) that would reaction with triphenylphosphine itself. The authors (Univ. of Nottingham and GSK) do a thorough mechanistic investigation into the reaction, and they note that this system might also be applied to other phosphine/phosphine oxide driven reactions.

If this works as well as advertised – and I see no reason up front to think it doesn’t – then I would expect this to almost entirely replace the original Mitsunobu, which has had an over fifty-year run as a synthetic chemistry workhorse. It will also kill off the market for DEAD and similar reagents; if there were a good single-supplier play for azodicarboxylates I would have gone short their stock immediately on reading this paper. Congratulations to the authors!

19 comments on “Meet the New Mitsunobu”

  1. Anon says:

    It should be noted that the driving force for this reaction is driving off water via dean-stark. The reaction is typically done in xylenes @ reflux (~138C). A bit hot, but probably fine on large scale. I might stick with PPh3/DEAD on small scale though.

    1. Derek Lowe says:

      I’m figuring that you could toss in some sieves or even magnesium sulfate on a small scale? Although you might need the temperature of toluene/xylene reflux at the same time. . .

      1. ChemCam says:

        If you look in the SI, the addition of drying agents can affect the yield, ee and also the major enantiomer (inverted or non-inverted) seemingly in a generally undesirable way

      2. ErrHuman says:

        You can physically separate the molecular sieves:
        https://pubs.acs.org/doi/abs/10.1021/acs.joc.9b01541?ai=6677

    2. Scott says:

      You guys need to talk to steam-plant design engineers for designing your reaction vessels. Most steam plants run at a minimum of 300degC and 4MPa, and some are over 400degC at 22MPa.

      1. achemist says:

        The reaction vessels are not the problem for that one.

        Your chemicals becoming something else if heated too much is more of a problem often.

  2. Mad Chemist says:

    Dang, that is a slick reaction. Hopefully it’s very generalizable.

  3. A Nonny Mouse says:

    Best to use isopropyl on a small scale (or even large) as the P=O and reduced product co-crystallise. This removes about 90% or the rubbish.

    Nice reaction, though.

  4. A Nonny Mouse says:

    Fosinopril is made using a Mitsunobu, so it would be interesting to see if this could cut down production costs (3-OH N-benzoyl proline + methane sulfonic acid to invert and produce a leaving group for an F-C reaction with benzene).

  5. Andy says:

    A colleague of mine once suggested the acceptable/comfortable temperature window for chemists* has shifted over the years from something like 0 to 250°C down to -100 to +150, and I think I agree, so this temperature does look quite high to us modern chemists. However, things don’t fall to pieces or racemise necessarily at these kind of temperatures, there’s nothing to be afraid of.

    *To clarify, I’m talking about their reactions, not their bodies.

  6. Amazon says:

    The fact that the catalyst requires a highly acidic partner (dinitrobenzoic acid in this case) for activation really restricts the scope of the reaction and might prevent these conditions from replacing most of the ‘classical’ Mitsunobu’s out there…

    1. Woody says:

      I think this can be solved by tuning the electronics of your catalyst for your substrates. Yes it’s not as generally applicable as the Mitsunobu, but speaking as a process chemist fine tuning a system such as this to run on scale is much more palatable than trying to scale a Mitsunobu reaction.

      1. StillAReOrgChemist says:

        I agree Woody. It would be interesting to see if the catalyst becomes more efficient by e.g. having electron withdrawing groups on the phenol part. Modifications at the phenyl groups attached to the phosphine oxide may be equally interesting. Possibly, depending on the pKa of the HNu, different catalysts may be optimal.

  7. Dr Zoidberg says:

    I have never met a Mitsunobu condition I liked. I will try literally everything else before Mitsunobu because I’ve had more success/less headaches with them.

    While I agree that the temp is a bit on the high side I have had to work around all sorts of other nasty conditions (triflic anhydride, POBr3, etc) to do this transformation so I wouldn’t flinch looking at that.

  8. Mister B. says:

    I just want to mention that this project was initiated about 10 years ago. Valentin Magné (a close friend and co-author) mentionned it when we talked about his work !

    I wish I could have the full story here as they certainly have done a tremendous amount of work that remains unpublished !

  9. Anonymous says:

    Aaargh! Paywall! And nothing on Sci Hub yet! Derek’s summary looks very interesting. There have been some “alleged” catalytic Mitsunobu’s over the years, but, IMO, they fell far short of being truly catalytic. T. Y. S. But, P. H. Toy, J. Am. Chem. Soc., 2006, 128, 9636-9637 requires a stoichiometric chemical oxidant to regenerate the azo. This one looks real, in principle.

    Mitsunobu was a part of the Mukaiyama group at Tokyo. Mukaiyama did not invent but he formalized the “Oxidation – Reduction Condensation Reaction”: A + B + R-OH + R’-OH -> A=O + H-B-H + R-O-R’ .

    A is oxidized to A=O and B is reduced to H-B-H which lets them suck out a molecule of H2O (“condensation” of a “drop” of water) from the coupling of R and R’. The earliest synthetically useful examples of such reactions that I know of go back to the late 1940s – early 1950s. There are so many variations of A and B. “Mukaiyama Reagent” (N-methyl-2-chloropyridinium triflate) is another example of a pre-oxidized “Ox – Red Condensation” reagent.

    A STABLE pre-formed Mitsunobu reagent is the Castro Reagent https://onlinelibrary.wiley.com/doi/pdf/10.1002/047084289X.rn00125 . I think it was commercially available for a while. You can weigh it out on a balance in air but it is still reactive enough to facilitate a wide array of couplings.

    Other examples of systems that use a pre-oxidized P are the Bates – Hendrickson “POP”
    reagents: BF4(-) R3P(+)-O-P(+)R3 (-)BF4 and the (-)OTs and (-)OTf analogs. Bates reagent was commercially available for a while and it was included in a survey of “coupling reagents” where it did not fare well. FOR THE NON-CHEMIST READERS WHO LIKE HISTORICAL TIDBITS: I don’t think it was ever corrected in the literature, but I spoke with the author of that review / survey article and he mentioned that he had used an old bottle of commercial Bates reagent that was probably not very active. He probably should have prepared a fresh batch or bought a new bottle but he did not. That survey article kind of killed off interest in the Bates reagent for a long time, like almost forever.

    There are so many “Oxidation – Reduction Condensation” systems that have come and gone over the years. I hope I can get this article and follow along with its use and progress in the literature.

  10. Jalfrezi says:

    Syngenta (Jealott’s Hill) missing from the list of authors, although Steve is now gainfully employed elsewhere

  11. milkshake says:

    I find it interesting that phenol OH of the catalyst does not get alkylated in the process.

    Also, it should be possible to make a modification to make O=P(V) center to be less uphill into pentacoordinate adduct that dehydrates to phosphonium. One possible way to do this is to replace substituents on P with a 4-membered ring. Also, it would be interesting to replace phenol in the catalyst with N-hydroxybenztriazole moiety (which is more acidic), to see if you can lower the reaction temperature to something like boiling toluene, the most process-friendly solvent.

  12. The Aqueous Layer says:

    Prof. Rapoport used to consult at my pharma company back in the 90s. Whenever someone would put up a scheme with a Mitsunobu he’d say. “You know, there was plenty of good chemistry done before Mitsunobu was ever born…”

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