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 CāN 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 6ā30 h to complete.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andersen, B.M. et al. Process research and scale-up of the Īŗ-opioid receptor agonist CJ-15,161 drug candidate. Chimia 60, 554ā560 (2006).
Wrona, I.E., Garbarda, A.E., Evano, G. & Panek, J.S. Total synthesis of reblastatin. J. Am. Chem. Soc. 127, 15026ā15027 (2005).
Lindley, J. Copper assisted nucleophilic substitution of aryl halogen. Tetrahedron 40, 1433ā1456 (1984).
Beletskaya, I.P. & Cheprakov, A.V. Copper in cross-coupling reactions: the post-ullmann chemistry. Coord. Chem. Rev. 248, 2337ā2364 (2004).
Ley, S.V. & Thomas, A.W. Modern synthetic methods for copper-mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S bond formation. Angew. Chem. Int. Ed. Engl. 42, 5400ā5449 (2003).
Klapars, A., Huang, X. & Buchwald, S.L. A general and efficient copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc. 124, 7421ā7428 (2002).
Klapars, A., Antilla, J.C., Huang, X. & Buchwald, S.L. A general and efficient copper catalyst for the amidation of aryl halides and the N-arylation of nitrogen heterocycles. J. Am. Chem. Soc. 123, 7727ā7729 (2001).
Kwong, F.Y. & Buchwald, S.L. Mild and efficient copper-catalyzed amination of aryl bromides with primary alkylamines. Org. Lett. 5, 793ā796 (2003).
Shafir, A.S. & Buchwald, S.L. Highly selective room-temperature copper-catalyzed C-N coupling reactions. J. Am. Chem. Soc. 128, 8742ā8743 (2006).
Antilla, J.C., Klapars, A. & Buchwald, S.L. The copper-catalyzed N-arylation of indoles. J. Am. Chem. Soc. 124, 11684ā11688 (2002).
Antilla, J.C., Baskin, J.M., Barder, T.E. & Buchwald, S.L. Copper-diamine-catalyzed N-arylation of pyrroles, pyrazoles, indazoles, imidazoles and triazoles. J. Org. Chem. 69, 5578ā5587 (2004).
Altman, R.A. & Buchwald, S.L. 4,7-Dimethoxy-1,10-phenanthroline: an excellent ligand for the Cu-catalyzed N-arylation of imidazoles. Org. Lett. 8, 2779ā2782 (2006).
Jang, L., Job, G.E., Klapars, A. & Buchwald, S.L. Copper-catalyzed coupling of amides and carbamates with vinyl halides. Org. Lett. 5, 3667ā3669 (2003).
Marcoux, J.F., Doye, S. & Buchwald, S.L. A general copper-catalyzed synthesis of diaryl ethers. J. Am. Chem. Soc. 119, 10539ā10540 (1997).
Nordmann, G. & Buchwald, S.L. A domino copper-catalyzed C-O coupling-Claisen rearrangement process. J. Am. Chem. Soc. 125, 4978ā4979 (2003).
Kwong, F.Y. & Buchwald, S.L. A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides and thiols. Org. Lett. 4, 3517ā3520 (2002).
Gelman, D., Jiang, L. & Buchwald, S.L. Copper-catalyzed C-P bond construction via direct coupling of secondary phosphines and phosphites with aryl and vinyl halides. Org. Lett. 5, 2315ā2318 (2003).
Zanon, J., Klapars, A. & Buchwald, S.L. Copper-catalyzed domino halide exchange-cyanation of aryl bromides. J. Am. Chem. Soc. 125, 2890ā2891 (2003).
Hennessy, E.J. & Buchwald, S.L. A general and mild copper-catalyzed arylation of diethyl malonate. Org. Lett. 4, 269ā272 (2002).
Klapars, A. & Buchwald, S.L. Copper-catalyzed halogen exchange in aryl halides: an aromatic Finkelstein reaction. J. Am. Chem. Soc. 124, 14844ā14845 (2002).
Ghosh, A. et al. Cu-catalyzed N-arylation of oxazolidinones: an efficient synthesis of the kappa-opioid receptor agonist CJ-15161. J. Org. Chem. 71, 1258ā1261 (2006).
Still, W.C., Kahn, M. & Mitra, A. Rapid chromatographic technique for preparative separations with moderate resolution. J. Org. Chem. 43, 2923ā2925 (1978).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
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.
Rights and permissions
About this article
Cite this article
Altman, R., Buchwald, S. Cu-catalyzed Goldberg and Ullmann reactions of aryl halides using chelating N- and O-based ligands. Nat Protoc 2, 2474ā2479 (2007). https://doi.org/10.1038/nprot.2007.364
Published:
Issue Date:
DOI: https://doi.org/10.1038/nprot.2007.364
This article is cited by
-
Novel Synthesis of a New Surfactant 4ā((4āBromophenyl)(dodecyl)amino)ā4āOxobutanoic Acid Containing a Benzene Ring Using a Copper Catalyst CrossāCoupling Reaction and its Properties
Journal of Surfactants and Detergents (2013)
-
Synthesis of alkyl- and aryl-amino-substituted anthraquinone derivatives by microwave-assisted copper(0)-catalyzed Ullmann coupling reactions
Nature Protocols (2010)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
