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Cu-catalyzed Goldberg and Ullmann reactions of aryl halides using chelating N- and O-based ligands

Abstract

The following protocol can be applied in the selective cross-coupling reaction of an amine with an aryl iodide or bromide using a copper (Cu)-based catalyst to provide the corresponding N-aryl amine. The general procedure described in this text includes a detailed description of an appropriate reaction setup, two methods for assaying the crude reaction mixture (gas chromatography and thin layer chromatography) and a procedure for the isolation, purification and characterization of the anticipated product. Manipulation of the reagents can be done in the air, without the use of a glovebox; however, the cross-coupling reactions must be performed in a sealed reactor under an inert atmosphere. Three C–N bond-forming reactions are included in the protocol as representative examples of this procedure. Although the reactions can proceed in <1 h, the protocols, including workup, generally take 6–30 h to complete.

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Acknowledgements

Funding for this work was provided by the National Institutes of Health (GM 58160). We also acknowledge Merck, Amgen and Boehringer-Ingelheim for additional unrestricted fiscal support. We are grateful to Chemetall for providing the Cs2CO3 for this work. R.A.A. thanks Pfizer for a graduate fellowship.

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Correspondence to Stephen L Buchwald.

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This work is covered by patents owned by MIT from which SLB receives royalties.

These patents are licensed by Shasun Pharma Solutions for whom SLB is a consultant and member of the SAB.

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Altman, R., Buchwald, S. Cu-catalyzed Goldberg and Ullmann reactions of aryl halides using chelating N- and O-based ligands. Nat Protoc 2, 2474–2479 (2007). https://doi.org/10.1038/nprot.2007.364

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