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Baran Strikes Again (Decarboxylative Coupling)

Phil Baran’s group has (yet another) good synthetic methods paper out, this one on metal-catalyzed cross-coupling. Now, there are an awful lot of metal-catalyzed cross coupling reactions out there, so if you’re going to propose a new one, it has to have some advantages over the back catalog. The group’s Open Flask blog has some back story on this one, and you can tell that they were thinking along these lines.

What this one does is create a bond between an aryl carbon and an aliphatic carbon. The aryl group comes in as an arylzinc reagent – you can buy quite a few of these, since they’re quite stable, and (thanks to Paul Knochel‘s group, among others) methods for making them are well optimized. That side of the reaction is not particularly surprising; there have been plenty of organozinc couplings, and the number of aryl organometallics used in such reactions is beyond counting. That’s not to discount the amount of work that went into this part – as the blog post mentions, the reaction was first realized using a preformed arylnickel reagent, which is a much less attractive beast.

But it’s the aliphatic partner that’s really unusual: your R group comes in from an R-carboxylic acid derivative. The blog post goes into some of the details behind this. Originally, they were using Barton esters, but those (although interesting compounds) can be rather painful to work with, because they’re light-sensitive. The team went on a search for more practical esters, and N-hydroxyphthalimide turned out to work well. Pushing things along even further, it turns out that you can do the condensation to make this intermediate from the carboxylic acid, followed by the Ni-catalyzed arylzinc coupling in the same pot. You can make and keep a solution of your favorite arylzinc around, which makes the rest of the reactions (as the blog puts it) basically dump-and-stir jobs, room temperature, done overnight. You don’t have to be wildly anhydrous, either – the nickel source is nickel chloride hydrate, which has the advantages of being cheaper than some kinds of dirt, as well as having one of the most intense green colors in all of chemistry. Jacob Edwards, who wrote the Open Flask post, specifically mentions enjoying the way that the reactions go from green to orange on completion, and I assume that he’s also the reason that there’s a St. Louis Cardinals logo at the bottom of the page (I approve!)

The only place to object to these reactions is in atom efficiency – you’re tossing quite a bit of stuff off your R group to couple it to the aryl ring. But for high-value products, which is what I’m used to while working on drug optimization, that’s not as big a concern. There are an awful lot of carboxylic acids out there in the world, and being able to one-pot-couple them to a variety of aryl and heteroaryl systems is a good ability to have!

29 comments on “Baran Strikes Again (Decarboxylative Coupling)”

  1. Isidore says:

    Thank you for these updates! Although I have been a mass spectrometrist throughout my professional career, I do consider myself an organic chemist (this is what my PhD diploma says) and I can certainly appreciate the elegance of well-designed organic syntheses.

  2. anon says:

    I’m honestly trying to understand the attractiveness here. You activate both coupling partners stoichiometrically… Wouldn’t an actual catalytic activation be more useful?

    Also there are some problems with the statement in Table 1: unactivated (non-heteroatom stabilized) acids. This seems like a direct dig @ MacMillan/Doyle, right? Especially when the “unactivated acids” Baran uses are, quite literally, stoichiometrically activated.

    I just don’t see how this represents a “good synthetic methods paper” when it pretty much is the opposite of an idealized coupling of acids and aryl groups.

    1. Doc Oc says:

      You feel an awful lot of butthurt for Dave MacMillan for no reason, his work has been highlighted on this blog several times. There’s plenty of room for improvement in this reaction, sure. If you’re so hellbent on catalytic couplings why don’t you invent some yourself and publish them? Better yet, propose how to achieve this same transformation using only catalytic activation and similarly easy-to-obtain coupling partners.

    2. JFlaviusT says:

      Have to agree here. I honestly don’t see a ton of novelty either (and I’m usually very enthusiastic about the chemistry of Baran’s group). Okada established N-acyloxyphthalimides as surrogates for alkyl halides in single electron reductions 25 years ago (JACS 1991, 113, 9401). And it’s not like this idea vanished into obscurity afterward, since Overman has been doing the same thing in the past few years. From here it’s simple application of the Ni chemistry developed by Negishi, Kochi, Kumada, Fu and others to come to this coupling. I understand that the acids may be more readily available, cheaper, and more stable than the corresponding alkyl halides, so it’s an advance in this sense, but certainly at the expense of atom economy. I think this may be a somewhat attractive new method from the perspective of a medicinal chemist, but decidedly less than exciting when view from the perspective of someone well-versed in the history of nickel catalysis…

      1. Mr. obvious says:

        Flavius thats what makes this so interesting. Since Okada everyone including Overman thought that these esters could only be converted to radicals using photochemistry and by merging two different catalytic cycles to get coupling.

        This work skips the photons and lets Nickel do both jobs. That part is unprecedented. Get it?

        1. Rhenium says:

          Calm down . Your arguments have been ad hominem or appeal to authority so far Baran boy.

          1. Plutonium says:

            Looks like you’re the one in the excited state Rhenium 🙂

            kind regards, plutonium

        2. JFlaviusT says:

          No reduction that can be done by a photocatalyst cannot be done by a tradition chemical reductant (and (diamine)Ni(I)Ar complexes have long been known to be single electron reductants). It’s simple a matter of half cell potentials and thermodynamics. The two reactions are fundamentally identical. The idea that the photocatalyst was “required” for the reduction of these esters is misconceived and I don’t think anyone knowledgeable in the field held this belief. I apologize and am aware that I am sounding argumentative here, but I don’t think what you said is correct.

          1. Scrtyer says:

            “I don’t think anyone knowledgeable in the field held this belief.”

            Hmmmm. Then why didn’t someone report this reaction? Please provide the reference that shows Nickel can do what Okada’s photochemical reaction did. And the use of HOAt esters, did someone report that too?

  3. protchin says:

    @Anon – The activating group appears to be the same (HOAt or NHPI) that peptide chemists use for making amides. They could use 1000 equivalents of the activator and the nickel catalyst and still be less expensive than iridium or the exotic ligands. Not to mention that the much hyped photochemistry doesnt work unless your system is stabilized (meaning the radical you make is stable such as next to a nitrogen atom).

    This is the first decarboxylative coupling that people might actually use in real life.

    1. a. nonymaus says:

      Kolbe would like a word about that.

    2. DrDdot says:

      This comment. This is why the chemistry is worthwhile. In cases on discovery, atom economy is not necessary. Ease of use, availability of reagents, and utility are paramount. If you can take stock solutions of activator and setup a matrix and send it off to purification, then this is a step forward in opening “new” routes.

  4. DRP says:

    It’s OK, hardly blown away, but I take issue with the closing sentence of the abstract:

    “The simple procedure and extremely inexpensive nature of both the substrates and pre-catalyst (NiCl2·6H2O, ca. $9.5/mol) bode well for the immediate widespread adoption of this method.”

    Sounds pretty up his own arse there. How about you tell us what you’ve done and let us decide if it’s that good.

  5. Bagger Vance says:

    I don’t know what’s better, the war of pro- vs anti-Baran fanatics or the need to publicize papers before minimal formatting. Click over–here we go again–ouch, my eyes–shrug, it’s not like I’ll need this in the next two weeks, I’ll look at it then.

  6. Lyle Langley says:

    What is the point of the picture in Figure 2? What does this add? It’s some sort of showmanship, but is more idiotic than anything? Are we impressed that someone put some clear liquid/oil in a vial and wrote the structure in Sharpie? Yes, show us the Supplemental Material to prove you have the compound you say – in this instance the picture (NMR spectra, etc.) are worth more than a 1,000 pics of a 1 dram vial.

    1. JFlaviusT says:

      The point of the picture is for you to look at the background, see Torrey Pines overlooking the Pacific Ocean, and wish you could also be in beautiful La Jolla.

      1. Lyle Langley says:

        Then it was a success!

  7. milkshake says:

    my only small is the limitation to secondary radicals, and the need to use 3 equivs of aryl zinc. (If the aryl is big or hard to make/expensive, destroying 2 equivs of Ar to get one in would be a drawback). Otherwise, excellent methodology.

    1. Design Monkey says:

      Exactly. If carboxylic acid component is presented as the cheap and easily accessible one, then the expensive and rare component is supposed to be the zinc-organic? And it has to be shoveled in in 3 equivalents?

      But yes, may be an useful method. Someday, when stars and molecules of projects fall in an appropriate configuration.

      1. milkshake says:

        give them some time, this is just the first report on this system, and the info that you could generate radicals in this way is pretty useful on its own -another nice reductive method. They will figure out what is consuming their ArZnX, and maybe find some additive or technique to limit the problem. Also, if you check their blog, they mention in the comment section that the reaction seems workable for primary radials also, they just did not optimize it to useful yields yet. So maybe they will develop some more robust/more active catalyst that will let them to expand the substrate scope

  8. Bagnar says:

    Baran’s paper have proven many times to be fair, highly reproductible and innovative too.
    This one is a good step in the right direction. I can imagine they are already working on a catalytic version of this reaction, possibly already established.
    It’s both the opportunity of a second excellent paper and possibly a patent on this type of reaction (I must be corrected if I’m wrong here).

    Rome wasn’t built in a day. So, wait for it.

  9. Albert says:

    This paper is chemically interesting, but from my perspective not very practical when looking for synthesis usable on kilogram scale (or beyond). Baran is touting cheapness of nickel, but the high cost here comes from low atom economy and stoichiometric activating agents.

    1. Roger says:

      Albert are you kidding? The cost of the activating agent is a few dollars per mole.

      They manufacture peptides with more expensive reagents than this work.

      1. Albert says:

        Depends what exactly you want to manufacture, on what scale and what price you can afford… Having said that I also agree with other comments here that for standard medchem that is irrelevant since the key is convenience not cost.

  10. Squib says:

    As someone in industry, this is very useful for library synthesis ie hit to lead chemistry. Whether you’re expanding on the zinc or acid side, it looks like it would be pretty easy to set up 50 of these in a day then come back the next day and send them to purification. On mg scale atom economy is meaningless.

  11. Roger says:

    who are the followers? Photo stuff was known to make radicals already 30 years ago from acids.

    Baran showed you don’t need the photo to get the same reactivity. Nickel alone will do the job. That’s not following unless someone can produce a reference where this is known??

  12. MoMe says:

    James all these people are followers by your definition. Nickel known for decades to do radical coupling. Ruthenium photo catalysts known for decades to make radicals from acid derivatives.

    Take a microscope and nothing is conceptually new.

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