Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pd-catalyzed amination reactions of aryl halides using bulky biarylmonophosphine ligands

Abstract

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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2: Pd-catalyzed amination reactions of aryl halides.
Figure 3: Biarylmonophosphine ligands for Pd-catalyzed C–N bond-forming reactions.
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12

References

  1. Fang, Y.Q., Karisch, R. & Lautens, M. Efficient syntheses of KDR kinase inhibitors using a Pd-catalyzed tandem C-N/Suzuki coupling as the key step. J. Org. Chem. 72, 1341–1346 (2007).

    CAS  Article  Google Scholar 

  2. Damon, D.B., Dugger, R.W., Hubbs, S.E., Scott, J.M. & Scott, R.W. Asymmetric synthesis of the cholesteryl ester transfer protein inhibitor torcetrapib. Org. Process Res. Dev. 10, 472–480 (2006).

    CAS  Article  Google Scholar 

  3. Yandulov, D.V. & Schrock, R.R. Catalytic reduction of dinitrogen to ammonia at a single molybdenum center. Science 301, 76–78 (2003).

    CAS  Article  Google Scholar 

  4. Heaney, H. The benzyne and related intermediates. Chem. Rev. 62, 81–97 (1962).

    CAS  Article  Google Scholar 

  5. Smith, M.B. & March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure 5th edn. (John Wiley & Sons. Inc., New York, 2001).

  6. Belfield, A.J., Brown, G.R. & Foubister, A.J. Recent synthetic advances in the nucleophilic amination of benzenes. Tetrahedron 55, 11399–11428 (1999).

    CAS  Article  Google Scholar 

  7. Lindley, J. Copper assisted nucleophilic substitution of aryl halogen. Tetrahedron 40, 1433–1456 (1984).

    CAS  Article  Google Scholar 

  8. Beletskaya, I.P. & Cheprakov, A.V. Copper in cross-coupling reactions: the Post-Ullmann chemistry. Coord. Chem. Rev. 248, 2337–2364 (2004).

    CAS  Article  Google Scholar 

  9. 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, 5400–5449 (2003).

    CAS  Article  Google Scholar 

  10. Jiang, L. & Buchwald, S.L. Palladium-catalyzed aromatic carbon-nitrogen bond formation. In Metal-Catalyzed Cross-coupling Reactions 2nd edn. (eds. de Meijere, A. & Diederich, F.) 699–760 (Wiley-VCH, New York, 2004).

    Chapter  Google Scholar 

  11. Old, D.W., Wolfe, J.P. & Buchwald, S.L. A highly active catalyst for palladium-catalyzed cross-coupling reactions: room-temperature Suzuki couplings and amination of unactivated aryl chlorides. J. Am. Chem. Soc. 120, 9722–9723 (1998).

    CAS  Article  Google Scholar 

  12. Huang, X. et al. Expanding Pd-catalyzed C-N bond-forming processes: the first amidation of aryl sulfonates, aqueous amination, and complementarity with Cu-catalyzed reactions. J. Am. Chem. Soc. 125, 6653–6655 (2003).

    CAS  Article  Google Scholar 

  13. Wolfe, J.P. & Buchwald, S.L. A highly active catalyst for the room-temperature amination and Suzuki coupling of aryl chlorides. Angew. Chem. Int. Ed. Engl. 38, 2413–2416 (1999).

    CAS  Article  Google Scholar 

  14. Anderson, K.W., Tundel, R.E., Ikawa, T., Altman, R.A. & Buchwald, S.L. Monodentate phosphines provide highly active catalysts for Pd-catalyzed C-N bond-forming reactions of heteroaromatic halides/amines and (H)N-heterocycles. Angew. Chem. Int. Ed. Engl. 45, 6523–6527 (2006).

    CAS  Article  Google Scholar 

  15. Old, D.W., Harris, M.C. & Buchwald, S.L. Efficient palladium-catalyzed N-arylation of indoles. Org. Lett. 2, 1403–1406 (2000).

    CAS  Article  Google Scholar 

  16. Klapars, A., Huang, X. & Buchwald, S.L. A general and efficient copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc. 124, 7421–7428 (2002).

    CAS  Article  Google Scholar 

  17. 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, 7727–7729 (2001).

    CAS  Article  Google Scholar 

  18. Kwong, F.Y. & Buchwald, S.L. Mild and efficient copper-catalyzed amination of aryl bromides with primary alkylamines. Org. Lett. 5, 793–796 (2003).

    CAS  Article  Google Scholar 

  19. Shafir, A.S. & Buchwald, S.L. Highly selective room-temperature copper-catalyzed C-N coupling reactions. J. Am. Chem. Soc. 128, 8742–8743 (2006).

    CAS  Article  Google Scholar 

  20. Antilla, J.C., Klapars, A. & Buchwald, S.L. The copper-catalyzed N-arylation of indoles. J. Am. Chem. Soc. 124, 11684–11688 (2002).

    CAS  Article  Google Scholar 

  21. 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, 5578–5587 (2004).

    CAS  Article  Google Scholar 

  22. 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, 2779–2782 (2006).

    CAS  Article  Google Scholar 

  23. Buchwald, S.L., Mauger, C., Mignani, G. & Scholz, U. Industrial-scale palladium-catalyzed coupling of aryl halides and amines—a personal account. Adv. Synth. Catal. 348, 23–39 (2006).

    CAS  Article  Google Scholar 

  24. Anderson, K.W., Ikawa, T., Tundel, R.E. & Buchwald, S.L. The selective reaction of aryl halides with KOH: synthesis of phenols, aromatic ethers, and benzofurans. J. Am. Chem. Soc. 128, 10694–10695 (2006).

    CAS  Article  Google Scholar 

  25. Burgos, C.H., Barder, T.E., Huang, X. & Buchwald, S.L. Significantly improved method for the Pd-Catalyzed coupling of phenols with aryl halides: understanding ligand effects. Angew. Chem. Int. Ed. Engl. 45, 4321–4326 (2006).

    CAS  Article  Google Scholar 

  26. Vorogushin, A.V., Huang, X. & Buchwald, S.L. Use of tunable ligands allows for intermolecular Pd-catalyzed C-O bond formation. J. Am. Chem. Soc. 127, 8146–8149 (2005).

    CAS  Article  Google Scholar 

  27. Murata, M. & Buchwald, S.L. A general and efficient method for the palladium-catalyzed cross-coupling of thiols and secondary phosphines. Tetrahedron 60, 7397–7403 (2004).

    CAS  Article  Google Scholar 

  28. Meyers, C. et al. Study of a new rate increasing 'base effect' in the Palladium-catalyzed amination of aryl iodides. J. Org. Chem. 69, 6010–6017 (2004).

    CAS  Article  Google Scholar 

  29. Still, W.C., Kahn, M. & Mitra, A. A rapid chromatographic method. J. Org. Chem. 43, 2923–2925 (1978).

    CAS  Article  Google Scholar 

  30. MacNeil, S.L., Wilson, B.J. & Snieckus, V. Anionic N-fries rearrangement of N-carbamoyl diarylamines to anthranilamides. Methodology and application to acridone and pyranoacridone alkaloids. Org. Lett. 8, 1133–1136 (2006).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen L Buchwald.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2007.414

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing