Use of Soluble Pd Complexes and Soluble Pd-Ligand Combinations

Mechanism + Description

The aryl halide (or other leaving group – OTf, N₂+) and boronic acid are reacted with a Pd catalyst (with or without additional ligands) in the presence of a base. The initial step is the oxidative addition of the aryl halide to a Pd (O) species. If Pd is charged as Pd²⁺, then a prior reduction to the active form for oxidative insertion is required. Transmetallation of the boron coupling partner then occurs, usually via an activated boronate anion. Reductive elimination produces the product and the active catalyst. The active Pd^(O) catalyst is ligated if it is a monomeric species, but in some cases a Pd nanoparticle species could be involved as the active catalyst or reservoir for the active Pd.

General comments

Typically, the reagents are mixed with a Pd complex or a mixture of a simple Pd salt/complex and added ligands to generate the active catalyst in situ. The Pd can be added as Pd²⁺ or Pd^O. Pd(OAc)₂ is the most common Pd²⁺ salt and Pd(Ph₃)₄ and Pdx(DBA)y are the most common Pd⁰ catalysts. Traditional ligands for the Suzuki reaction are Ph3P and (o-Tolyl)₃P, although in the past 20 years, a wide range of other ligands – principally phospines and stabilized carbenes – have been developed to fine-tune catalytic activity and allow for reactions with traditionally difficult or unreactive coupling partners, like aryl chlorides and very electron-rich aryl/hetreo-aryl bromides. Depending on the catalyst system and reactivity of the coupling partners, added ligands are not always required. Bases are typically amines like Et3N or Hunig's base, or inorganics like NaOH, Na/K₂CO₃, Na/KHCO₃ and K_XH_YPO₄.

Common side reactions that can reduce yield are proto-deboronation and the homocoupling of the boronic acid. If using arylphospine ligands and electron-rich aryl halides, an exchange of aryl groups between the phosphine and palladium center can occur, lowering the yield and introducing extra by-products.

O'Keefe, D. F.; Dannock, M. C.; Marcuccio, S. M. Palladium Catalyzed Coupling of Halobenzenes with Arylboronic Acids: Rôle of the Triphenylphosphine Ligand. Tetrahedron Lett. 1992, 33 (44), 6679-6680.

 

Key references

Billingsley, K.; Buchwald, S. L. Highly Efficient Monophosphine-Based Catalyst for the Palladium-Catalyzed Suzuki−Miyaura Reaction of Heteroaryl Halides and HeteroarylBoronic Acids and Esters. J. Am. Chem. Soc. 2007, 129 (11), 3358-3366.

Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Practical Aspects of Carbon−Carbon Cross-Coupling Reactions Using Heteroarenes. Org. Process Res. Dev. 2010, 14 (1), 30-47.

Szilvási, T.; Veszprémi, T. Internal Catalytic Effect of Bulky NHC Ligands in Suzuki–Miyaura Cross-Coupling Reaction. ACS Catal. 2013, 3 (9), 1984–1991.

Selective reaction of iodo over the bromo group in Suzuki reaction:  Fray, M. J.; Dickinson, R. P.; Huggins, J. P.; Occleston, N. L. A Potent, Selective Inhibitor of Matrix Metalloproteinase-3 for the Topical Treatment of Chronic Dermal Ulcers. J. Med. Chem. 2003, 46 (16), 3514-3525.

Glasspoole, B. W.; Keske, E. C.; Crudden, C. M. Stereospecific and Stereoselective Suzuki-​Miyaura Cross-​Coupling Reactions. New Trends in Cross-Coupling: Theory and Applications; Catalysis Series; Royal Society of Chemistry: Cambridge, U.K., 2014; 521-550.

Manjunatha, S. G.; Rangappa, P.; Sythana, S.; Babu, S. M.; Tadiparthi, K.; Gundala, C. A Simple Way of Recycling of Homogeneous Catalyst in Suzuki Reaction. Green Chemistry Letters and Reviews. 2013, 6(1), 77-87.

Denmark, S. E.; Ambrosi, A. Why You Really Should Consider Using Palladium-Catalyzed Cross-Coupling of Silanols and Silanolates. Org. Process Res. Dev. 2015, 19 (8), 982-994.

Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Palladium Complexes of N-Heterocyclic Carbenes as Catalysts for Cross-Coupling Reactions—A Synthetic Chemist's Perspective. Angew. Chem., Int. Ed. 2007, 46 (16), 2768-2813.

Dreher, S. D.; Lim, S.; Sandrock, D. L.; Molander, G. A. Suzuki-Miyaura Cross-Coupling Reactions of Primary Alkyltrifluoroborates with Aryl Chlorides. J. Org. Chem. 2009, 74 (10), 3626-3631.

Slagt, V. F.; de Vries, A. H. M.; de Vries, J. G.; Kellogg, R. M. Practical Aspects of Carbon−Carbon Cross-Coupling Reactions Using Heteroarenes. Org. Process Res. Dev.  2010, 14 (1) , 30–47.

Kondolff, I.; Doucet, H.; Santelli, M. Tetraphosphine/Palladium Catalysed Suzuki Cross-Coupling Reactions of Aryl Halides with Alkylboronic Acids. Tetrahedron. 2004, 60 (17), 3813-3818.

Peh, G.; Kantchev, E. A. B.; Er, J.; Ying, J. Y. Rational Exploration of N-Heterocyclic Carbene (NHC) Palladacycle Diversity: A Highly Active and Versatile Precatalyst for Suzuki-Miyaura Coupling Reactions of Deactivated Aryl and Alkyl Substrates. Chem. Eur. J. 2010, 14 (13), 4010-4017.

Hoshi, T.; Honma, T.; Mori, A.; Konishi, M.; Sato, T.; Hagiwara, H.; Suzuki, T. An Active, General, and Long-Lived Palladium Catalyst for Cross-Couplings of Deactivated (Hetero)aryl Chlorides and Bromides with ArylboronicAcids. J. Org. Chem. 2013, 78 (22), 11513-11524.

Molander, G. A.; Trice, S. L. J.; Kennedy, S. M. Scope of the Two-Step, One-Pot Palladium-CatalyzedBorylation/Suzuki Cross-Coupling Reaction Utilizing Bis-BoronicAcid. J. Org. Chem. 2012, 77 (19), 8678-8688.

Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. A Highly Active Catalyst for Suzuki-Miyaura Cross-Coupling Reactions of HeteroarylCompounds. Angew. Chem., Int. Ed. 2006, 45 (21), 3484-3488.

Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. A General Palladium Catalyst System for Suzuki-Miyaura Coupling of Potassium Aryltrifluoroborates and Aryl Mesylates. J. Org. Chem. 2010, 75 (15), 5109-5112.

Ikawa, T.; Saito, K.; Akai, S. Palladium-Catalyzed One-Pot Cross-Coupling of Phenols Using  Nonafluorobutanesulfonyl Fluoride. Synlett. 2012, 23 (15), 2241-2246.

 

Relevant Scale-Up Examples with Scheme

Org. Process Res. Dev. 2009, 13 (4), 751–759.
Experimental
15 kg scale

Org. Process Res. Dev. 2014, 18 (9), 1128−1136.
Experimental
500 g scale

Org. Process Res. Dev. 2014, 18 (1), 228−238.
Experimental
65 g scale

Org. Process Res. Dev. 2011, 15 (1), 148–157.
Experimental
3 kg scale

Org. Process Res. Dev. 2014, 18 (1), 228−238.
Experimental
4.5 kg scale

Org. Process Res. Dev. 2014, 18 (1), 228−238.
Experimental
3 kg scale

Org. Process Res. Dev. 2015, 19 (7), 721−734.
Experimental
7 kg scale

Org. Process Res. Dev. 2015, 19 (7), 721-734
Experimental
2.5 kg scale

Org. Process Res. Dev. 2006, 10 (3), 512-517.
Experimental
4 kg scale

Org. Process Res. Dev. 2011, 15 (5), 1138–1148.
Experimental
2.4 kg scale

Org. Process Res. Dev. 2011, 15 (5), 1138–1148.
Experimental
1.5 kg scale

Org. Process Res. Dev. 2010, 14 (4), 849–858.
Experimental
3 kg scale