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Couple Your Primary Amines


Here’s another neat carbon-carbon bond forming reaction (and no, we organic chemists just cannot get enough of these things). It’s from Mary Watson’s group at Delaware, and it formally takes a primary amine and turns it into a group that can couple with boronic acids. This goes through a Katritzky pyridinium salt, as shown at right, and a nickel-catalyzed coupling take that on to the product.

This is a nice connection between the various electrophiles that are known to do boronic acid couplings and the uses that these pyridiniums have been put to in the past. This appears to be the first protocol to take plain primary amino groups and use them to install their alkyl residues onto aryl rings in this way, and it appears to be compatible with a wide range of functionalities. Nitriles, alkynes, esters, amides, ketones, heterocycles, acetals, and tertiary amines all show up on both sides of the reaction, with no apparent problems. You do have to load on the BPhen ligand for the nickel, under current conditions, but (like all other metal-catalyzed couplings), this can no doubt be improved by people who are able to spend enough of their lives beating on the reaction variables.  I look forward to trying this one out!

14 comments on “Couple Your Primary Amines”

  1. PeptoidChemist says:

    A bit pedantic, I know, but the starting materials obviously aren’t proline or isoleucine for compounds 16 and 17 and it’s sloppy to label them as such. The SI even indicates the amine derivatives used that were purchased or synthesized, respectively. That out of the way, always nice to hear about new C-C bond forming chemistry.

    1. Cato says:

      I don’t understand your gripe.

      It’s FROM proline, they didn’t say it WAS proline… as in made starting from proline. If anything that’s more honest–obviously there are a couple steps to covert the carboxyl to amine.

      Chemists will complain about anything 😛

      1. PeptoidChemist says:

        But it isn’t made from proline, it’s made from commercial aminomethyl(boc)pyrrolidine. Even so, what two step process can convert the carboxylic acid of Boc-proline to that primary amine? Only thing I can think of is a Curtius rearrangement, and I doubt it would be all that efficient. I already caveated that it was a bit pedantic, but I want you to understand my gripe. I’ll hang up and listen.

        1. Hap says:

          Boc-proline coupling with ammonia and reduction with BH3 (or LAH/AlCl3)? (I think LAH would reduce the Boc to a Me group).

          1. PeptoidChemist says:

            I assumed if that was suitable they would have done that, since that’s the route employed from boc-isoleucine.

        2. Nick K says:

          I don’t think a Curtius rearrangement would work as a carbon atom is lost. Probably the best method would be conversion of the carboxylic acid to a primary amide followed by selective reduction with borane.

  2. Kirill says:

    Too bad that this method, as well as Baran’s recent RAE couplings, requires big excess of boronic acid (organoZn/Mg/etc in Baran’s case), making it a bit limited for medchem use. Lots of times we can make some precious boronic acid or organometallic derivative and we need as many diverse reagents to couple it with, as possible – would be great to add alkylpyridinium salts and RAE to this list.

  3. Creezus says:

    Delaware is becoming the new innovation hub isn’t it. I thought this was a cool paper when I came across it, although I considered that maybe this comes up a bit short with secondary alkyl groups. I expect many improvements will be made in the coming years.

  4. RBW says:

    It’s interesting chemistry if a bit esoteric.
    How often do you have the situation in medchem where you have an amine and say “Oh, actually I’d rather have an aryl group at the same position!”.
    I think it’s more common for us to want to introduce polar functionality into a molecule. Or to introduce aryl groups at a C-H bond or halide like leaving group rather than at the expense of an amine.

    1. Kirill says:

      To introduce HetAr instead of acylation/redAm/etc is a nice option, actually.

    2. HondaCivic says:

      I think that’s the wrong way to look at it, also. Think about an occasion where you’d want to make an aryl-alkyl C-C bond (probably all the time), now with the potential to do so from readily available boronic acids and an amine.

  5. Andy says:

    Isn’t there an easier way to make a nitrogen a good leaving group, by diazotisation? Quite a lot more atom economic, but possibly a bit frisky. Known to couple with boronic acids in the presence of palladium, but I’m probably missing something.

    1. Mister B. says:

      Diazotisation involve NaN3, isn’t it ? Maybe toxicity of this reagent is something to keep in mind. Including the need of strong acidic conditions.
      Diazo compounds are also unstable, they are rapidly converted into carbocations after loss of nitrogen. Plus, some are explosives, if I’m correct.

      These are the two mains reasons that comes to me when you talk about diazotisation.
      Having a good, bench-stable, easily-formed and reactive enough intermediate, is to me, still a good thing to keep in mind for a potential use in synthesis.

      I would add that academic research’s purpose is to explore new reactivity and new reagent. This paper is doing exactly this !
      Such as Kirill mentionned in his comment, improvment need to be done before an industrial use of this !

      1. kriggy says:

        No it does involve NaNO2 but the diazonium salts are only stable when they are aromatic.
        I actualy wonder, if you could use a another amine as a nucleophile? LIke amine-amine coupling

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