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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.

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