The following protocol describes the selective cross-coupling of an amine with an aryl halide using a Pd-based catalyst to provide the corresponding N-arylated amine. This general procedure for C–N bond formation includes a detailed description of an appropriate reaction setup, two methods for assaying the crude reaction mixtures (thin layer chromatography (TLC) and gas chromatography (GC)) and procedures for the isolation, purification and characterization of the anticipated product. Reagents and catalyst precursors can be manipulated in the air; however, the cross-coupling reactions must be performed under an inert atmosphere. Two Pd-catalyzed C–N bond-forming reactions are included in the text as representative examples of these procedures. Although the reactions can proceed in <5 min, the protocols, including workup, generally take 6–30 h to complete.
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Funding for this work was provided by the National Institutes of Health (GM 58160). We thank BASF, Saltigo and Chemetall for the gifts of Pd(OAc)2, XPhos and Cs2CO3, respectively. R.A.A. thanks Pfizer for a graduate fellowship. We also acknowledge Merck, Amgen and Boehringer Ingelheim for additional unrestricted fiscal support.
The ligands and processes described in this protocol are the subjects of patents owned by MIT from which SLB receives royalties. These patents are licensed by Shasun Pharma Solutions (and their sublicensees), for whom SLB is a consultant and a member of the SAB, for the use of these ligands with this protocol.
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Altman, R., Fors, B. & Buchwald, S. Pd-catalyzed amination reactions of aryl halides using bulky biarylmonophosphine ligands. Nat Protoc 2, 2881–2887 (2007). https://doi.org/10.1038/nprot.2007.414