As coupling partners in Suzuki type reactions, plain arylboronic acids and esters belong in the past, together with a few other things (Figure 1).

Phenylboronic acid
Figure 1. Outdated occurrences: Dinosaurs, mullets, SCART cables, wasp waists and phenylboronic acids; requiescat in pace

So much progress in the field of transition metal catalyzed cross-couplings has been made lately that I say it is about time we abandon boronic acids and the usual esters (pinacol, neopentyl and so forth) for good. I am thinking of the contributions by two people, primarily, namely the young gun Martin Burke and the old fox Gary Molander. I have had the pleasure of attending lectures held by both, respectively, and they are in my opinion highly gifted and entertaining speakers and cutting-edge scientists.

The most common problems with “plain” Suzuki couplings using dusty, old boronic acids – if these can be prepared in the first place and are stable enough for purification and storage – such as protodeboronation, homo-coupling and polymerization leading to by-product formation, if there indeed is any reaction at all (without employing ridiculous catalyst loadings), can be avoided. Burke and Molander have chosen slightly different strategies to address these issues, and both have demonstrated a number of brilliant solutions, of which I will merely touch upon a few to get your taste buds tingling.

Burke
Figure 2. Burke’s variation.

Burke has gained fame for his so called MIDA boronates (Figure 2), many of which are now commercially available. Pay close attention: MIDA boronates are much less reactive than the corresponding acids under cross-coupling conditions. Let me tell you why this is good. Firstly, since they are so robust, purification becomes much easier. Column chromatography and/or recrystallization under standard conditions are possible, which is often not the case for boronic acids. Secondly, “indefinite” storage in air at room temperature appears perfectly OK, whereas auto-protodeboronation can be a serious problem for boronic acids and esters. The true nature of the N-B bond can be debated, and is beyond the scope of this write-up.

Burke has gone to great lengths to show how unreactive these little bastards are. For instance, MIDA boronates are inert under oxidative (Jones, Swern, DDQ), reductive (sodium borohydride), strongly acidic (triflic acid, hydrofluoric acid), halogenating (iodine, triphenylphosphine) and silylative (TBSCl, imidazole) conditions. Please, name any other useful functional group that survives all that! Remarkably, upon treatment with relatively weak bases (1 M sodium hydroxide), the boronic acid is slowly released in situ, optionally under rate-control. This opens up a world of possibilities, such as site-selective and iterative couplings. In addition it should be noted that in order to obtain MIDA boronates, you do not have to go via the boronic acid, which would render all of the above pretty useless. One example is you can take a vinylic TMS group, treat it with boron tribromide and MIDA(2-)Na(2+) (also commercial) to directly give the MIDA boronate. Further reading:

ChemFiles 2009, 9(1) – available here; and references cited therein.
J. Am. Chem. Soc. 2009, 131, 6961–6963. (DOI: 10.1021/ja901416p)

(Somewhat off-topic: Martin Burke is not only a PhD, associate professor in organic chemistry. While studying, he decided to spice up his resume with a MD degree as well. In fact, during one of his talks he said that he had synthesized candidate drugs as a chemist, and later used his very own compounds in clinical trials on patients as the treating physician. Respect, yo!)

Molander
Figure 3. Molander’s variation.

Back to Molander now. He likes organotrifluoroborates (Figure 3). Even though these are structurally dissimilar to Burke’s MIDA boronates, Molander’s strategy shares several key features: Coupled with good shelf-lives, swift preparation and purification, organotrifluoroborates are stable sp3-hybridized intermediates that can be converted to more reactive species in situ. Think of these as protected boronic acids. Typically, a base is needed to generate the reactive species, since organotrifluoroborates are intrinsically too electron-deficient to react under Suzuki conditions.

Likewise, Molander has millions of papers out in which he (of course backed up by many independent groups) describes the awesomeness of these. Air- and water-stable, of course. And there are many ways to prepare them without going via the boronic acid; I am personally a big fan C-H activation methods, for obvious reasons. A random selection of recent publications:

J. Org. Chem., Article ASAP. (DOI: 10.1021/jo201313a)
Chem. Rev. 2008, 108, 288–325. (DOI: 10.1021/cr0509758)
Org. Lett. 2008, 10, 1795–1798. (DOI: 10.1021/ol800357c)

So in conclusion – which one is the winner then? I like both. A lot. If you absolutely must compare apples and oranges, check this out for a competitive study between MIDA boronates and organotrifluoroborates under certain conditions:

J. Org. Chem. 2010, 75, 3147–3150. (DOI: 10.1021/jo100318s)

And finally, it would be inappropriate to post something about boron, the unhappiest element in the periodic table, these days without a link to the coolest thing in decades: Boron derivatives as Lewis BASES – the doors to a new world of discoveries.

 

5 Responses to Plain boronic is plain moronic

  1. It’s a topic close to my heart.
    Molander has reported the direct conversion of Ar-Cl substrates into the corresponding boronic acids, MIDA boronates or trifluoroborates using B2(OH)4 and showed it’s possible even to convert them directly to the Suzuki coupled product IN SITU by adding another Ar’-Cl substrate because the catalyst for the first part is Pd.

    Here is the original work:
    G. A. Molander, S. L. J. Trice, S. D. Dreher, J. Am. Chem. Soc. 2010, 132, 17701–17703. (DOI: 10.1021/ja1089759)

    Here is a ACIE highlight about this and other uses of B2(OH)4 (ahem!)
    L. T. Pilarski, K. J. Szabó, Angew. Chem. Int. Ed. 2011, Article ASAP. (DOI: 10.1002/anie.201102384)

  2. drfreddy says:

    Thanks for the additional lit refs! I took the liberty to update your post with working DOI-links. Hope you don’t mind.

    Note to other people who would like to post links as comments. Do not post more than two links at once, or your post will be trapped in the spam filter. (And I don’t have the time to go through hundreds manually every day.)

  3. drfreddy says:

    I should also say that @DavidMLindsay on Twitter sent me this:

    Angew. Chem. Int. Ed. 2010, 49, 5156-5160. (DOI: 10.1002/anie.201001522)

    Another masterpiece for those interested in learning more about the exact mechanisms for Molander’s Suzuki variation.

  4. Theodore R. Hedral says:

    Whoah, whoah, whooooaahhh!!

    Before you start burning all your copies of Liebig’s Annalen and throwing away your Billy Ray Cyrus albums I’d like to send some props out to old school staples like mullets and boronic acids. I’ve had a ton of success using boronic acids in Suzuki-Miyaura couplings, especially since Buchwald’s innovation with XPhos precatalyst systems which significantly improve the use of unstable boronic acid coupling partners with aryl bromides. Boronic acids are ridiculously easy to isolate and purify through crystallization and when care is taken to store them properly their shelf life can be of considerable length.

    Respect for all God’s creations! The more tools in the toolbox the better :)

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