Synthesis

Metal-free, Organocatalytic Intramolecular C-H Amination

“Organocatalytic, Oxidative, Intramolecular C-H Bond Amination and Metal-free Cross-Amination of Unactivated Arenes at Ambient Temperature” Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem. Int. Ed. 2011, 50, 8605-8608. DOI: 10.1002/anie.201102984

For constructing aryl C-N bonds, the traditional synthetic sequence (i.e., what we teach undergrads) involves nitration followed by reduction, the nitration requiring harsh conditions and the reduction generating a stoichiometric amount of Sn waste.

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More recently, Buchwald and Hartwig have improved on this through the use of catalytic Pd. This reaction, however, requires a pre-oxidized aryl halide, which must be prepared prior to coupling.

C-H bond amination has been highlighted recently as a method to streamline the synthesis of aryl C-N bonds (see the work of White or Dubois for examples of allylic and aliphatic C-H amination reactions, respectively). Fewer synthetic steps means less waste and an overall greener reaction. Most catalytic C-H aminations, however, require the use of Rh, an expensive heavy metal. The Antonchick group recently reported the metal-free, organocatalytic synthesis of carbazoles by aryl C-H amination. This chemistry is novel and complements the work others are doing to use earth-abundant metal complexes as C-H amination catalysts (esp. Fe and Cu).

The Antonchick group starts by optimizing the conditions for the synthesis of N-protected carbazole 2a from the precursor 2-aminobiphenyl 1a in 81 % isolated yield from a 12 hr reaction in hexafluoro-2-propanol (HFIP) at room temperature.

They then improve their conditions by using catalytic amounts of iodoarene in the presence of peracetic acid as their oxidant avoiding the generation of a stoichiometric amount of iodobenzene waste from their initial conditions. Note that their optimized conditions require a mixed solvent system consisting of HFIP and methylene chloride.

In addition to providing an impressive scope of intramolecular, organocatalytic C-H aminations, the Antonchick group also reports the intermolecular cross-amination of unactivated arenes, though this reaction requires a stoichiometric amount of a hypervalent iodine oxidant. Though the scope in this initial communication is limited, the reaction tolerates both electron-withdrawing and electron-donating groups on the N-acetylated aniline.

This is a great advance in selective C-H amination, especially since this transformation usually requires the use of transition metal complexes (and usually Rh or Pd). In the future, I hope to see a catalytic version of the intermolecular C-H amination and a version avoiding the use of halogenated solvents.

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5 thoughts on “Metal-free, Organocatalytic Intramolecular C-H Amination

  1. I’m interested in the switch from hypervalent iodine to peracetic acid as the oxidant. In the lab, where recycling of byproducts isn’t typically practiced peracetic acid seems like the hands-down greener oxidant. However, I found this reference:
    http://dx.doi.org/10.3390/10010217
    In it, they made their hypervalent iodine reagent FROM peracetic acid. I had always been turned off by this iodine oxidant because of the stoichiometric iodobenzene waste produced. However, perhaps on the industrial scale with recycling of the waste product that concern wouldn’t be relevant.

    1. Good point! That’s basically what they propose here: the peracetic acid oxidizes the catalytic iodoarene to form a hypervalent iodine reagent that then mediates the C-H amination to regenerate the iodoarene, thereby allowing the reaction to recycle the iodoarene during the catalytic cycle.

  2. Hexafluoro-2-propanol seems like a pretty exotic solvent choice. I am wondering if the authors wrote mentioned why this particular solvent was used? Did they screen others? This seems particularly important since it is both corrosive and potentially toxic according to the MSDS. I would almost say that diluting it with DMC is an improvement!

    1. They appear to have used HFIP because it gave the highest yield of the carbazole in their initial optimization (they get roughly a third less carbazole with trifluoroethanol and no carbazole in methanol). They also only achieved low yields of the carbazole (ca 10 %) in MeCN, DCM and nitromethane. They didn’t report yields in ethanol or isopropanol.
      Since their yield is highest in their most acidic solvent choice (the pKa of HFIP is 9.3), I’m interested in the yield using a different acid of similar acidity: ammonium chloride and boric acid both have a pKa of 9.2. Maybe the reaction could be run in water with the right acid?

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