Buchwald Phosphine Ligands for Cross Coupling

The impact of cross-coupling methodologies to form C-C bonds is paramount in organic synthesis.¹ Of these, Suzuki-Miyaura coupling is among the most powerful transformations available as it has broad scope and wide functional group tolerance.² To this end, notable advances have been made in the laboratories of Prof. Stephen Buchwald at MIT.

We offer a series of Buchwald Ligands successfully used in processes, including Suzuki-Miyaura coupling, amination, amidation, enolate arylation, Sonogashira coupling and C-O bond formation (Table 1). While each ligand has documented utility, application of dimethoxy-substituted ligand 1, S-Phos, leads to a Pd-catalyst system with unprecedented scope, reactivity, and stability for Suzuki-Miyaura coupling processes.³ Selected examples (Table 2) illustrate the success of this system with respect to aryl chloride substrates, the generation of truly hindered biaryls, and heteroaryl cross-couplings.

Buchwald Phosphine Ligands (Table 1)

References: 1, 4-12
Product numbers: 638072, 638099, 638064, 638439, 638080, 638021

Table 2.

Triisopropyl-substituted ligand 2, X-Phos has key applications to Pd-catalyzed C-N bond formation.⁴ Table 3 gives examples that typify the expanded scope of this process utilizing X-Phos. X-Phos has also been successfully applied to Suzuki-Miyaura couplings with arene and vinyl sulfonates⁵ (Table 2), as well as Sonogashira coupling of alkynes⁶ (Table 4). 2-Di-t-butylphoshino-2’,4’,6’- triisopropyl ligand has been found to be a superior ligand for Pd-catalyzed coupling of phenols with aryl bromides and chlorides.⁷

Table 3.

Table 4.

References

1. Diedrich, F., Stang, , P. J. E, Weinhem, W. 1998. Metal-Catalyzed Cross-Coupling Reactions.

2. Miyaura N. 2002. Organoboron Compounds.11-59. https://doi.org/10.1007/3-540-45313-x_2

3. Hassan J, Sévignon M, Gozzi C, Schulz E, Lemaire M. 2002. Aryl?Aryl Bond Formation One Century after the Discovery of the Ullmann Reaction. Chem. Rev.. 102(5):1359-1470. https://doi.org/10.1021/cr000664r

4. Kotha S, Lahiri K, Kashinath D. 2002. Recent applications of the Suzuki?Miyaura cross-coupling reaction in organic synthesis. Tetrahedron. 58(48):9633-9695. https://doi.org/10.1016/s0040-4020(02)01188-2

5. Walker, S. R.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. . 2004. Chem. Intl. Ed., in press.  .

6. Huang X, Anderson KW, Zim D, Jiang L, Klapars A, Buchwald SL. 2003. 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(22):6653-6655. https://doi.org/10.1021/ja035483w

7. Muci AR, Buchwald SL. 2002. Practical Palladium Catalysts for C-N and C-O Bond Formation.131-209. https://doi.org/10.1007/3-540-45313-x_5

8. Nguyen HN, Huang X, Buchwald SL. 2003. The First General Palladium Catalyst for the Suzuki?Miyaura and Carbonyl Enolate Coupling of Aryl Arenesulfonates. J. Am. Chem. Soc.. 125(39):11818-11819. https://doi.org/10.1021/ja036947t

9. Gelman D, Buchwald SL. 2003. Efficient Palladium-Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction. Angew. Chem. Int. Ed.. 42(48):5993-5996. https://doi.org/10.1002/anie.200353015

10. Burgos C, Buchwald SL. manuscript in preparation. .

11. Harris MC, Huang X, Buchwald SL. 2002. Improved Functional Group Compatibility in the Palladium-Catalyzed Synthesis of Aryl Amines. Org. Lett.. 4(17):2885-2888. https://doi.org/10.1021/ol0262688

12. Wolfe JP, Tomori H, Sadighi JP, Yin J, Buchwald SL. 2000. Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates. J. Org. Chem.. 65(4):1158-1174. https://doi.org/10.1021/jo991699y