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The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

Simple ligand = Ph3P, o-Toly3P
Complex ligand = one requiring multi-step (3 -8 RXN) synthesis
Exact positioning on grid will depend on catalytic efficacy for any individual reaction

General Overview

The Suzuki reaction is a catalytic reaction widely used for the construction of sp2-sp2 carbon bonds from aryl boron compounds and aryl halides. The reaction is usually employed to construct aryl-aryl, aryl-heteroaryl and heteroaryl-heteroaryl compounds, but can be extended to non-aromatic, appropriately functionalizing coupling partners like alkenes. Typically, coupling partners are halides (e.g., I, Br, Cl), sulphonates, triflates, and boron compounds, such as boronic acids, esters, cyclic esters, and fluoroborates that are reacted together with a metal catalyst and a base. Recent developments have delivered catalytic reactions that result in the same products as in Suzuki couplings, but that are not classic Suzuki reactions, e.g., decarboxylative coupling and C-H activation.

From an environmental perspective, the Suzuki reaction has a number of challenges. Historically, it has used palladium, which is a precious metal with a high carbon footprint and high environmental impact due to its extraction and purification requirements. The reaction also often requires complex ligands with high carbon footprints and undesirable solvents, such as DMF, NMP, DMAC and 1,4-dioxane.

A number of greener variants to the traditional Suzuki reaction have been developed with the use of heterogeneous catalysts, such as palladium/carbon, for example. The advantage of using Pd/C is that the Pd can be efficiently recovered and the product resulting from the reaction is unlikely to be contaminated with palladium residues that require purification to meet the tight Pd limits for APIs. A lot of Suzuki reactions have been reported in water or mixed aqueous systems, and increasingly greener solvents like 2-MeTHF and CPME are being employed.

As an alternative to the use of Pd, a growing number of publications are using base metal catalysis for the Suzuki couplings. This is a rapidly growing area that has great potential. With nickel’s carbon footprint being 935 times smaller than palladium’s, the potential advantages of its use are clear, though the toxicity issues of Ni do need to be considered as well.

Green Criteria for Suzuki Coupling

  1. Large molar excesses of reagents should be avoided if possible.
  2. Base metals should be used as catalysts in preference to Pd or other precious metals if possible.
  3. If Pd needs to be used, Pd/C (or other heterogeneous catalyst form) is preferred.
  4. Ligand-less reactions are preferred if possible.
  5. If ligands are used, simple, low molecular weight ligands are preferable.
  6. Metal and ligand loadings should be optimized.
  7. Simple, inorganic bases are preferred to organic amine bases.
  8. Solvents like DMF, NMP, DMAC and 1,4-dioxan should be avoided if possible.
  9. Work-up/DSP should ensure metal levels are reduced to relevant specifications in the product and any waste streams. If a Pd catalyst or other precious metal is used, it should also ensure that the recovery and recycle of the metal is optimized.
  10. Due to the number of variables involved, the design of experiments can be a useful tool to optimize Suzuki reactions and ligand selection.

Murray, P. Case Study: Ligand Selection for a Suzuki Reaction. (accessed Sept. 2017).

Ekebergh, A.; Lingblom, C.; Sandin, P.; Wennerås, C.; Mårtensson, J. Exploring a Cascade Heck–Suzuki Reaction Based Route to Kinase Inhibitors Using Design of Experiments. Org. Biomol. Chem. 2015,13, 3382-3392.

Example of DOE in Suzuki optimization: Filipponi, P.; Ostacolo, C.; Novellino, E.; Pellicciari, R.; Gioiello, A. Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors. Org. Process Res. Dev. 2014, 18 (11), 1345−1353.

Moseley, J. D.; Murray, P.M. Ligand and Solvent Selection in Challenging Catalytic Reactions. J. Chem. Technol. Biotechnol. 2014, 89 (5), 623-632.

Apodeca, R. Optimizing Organic Reactions with Design of Experiments and Principal Component Analysis. (accessed Sept. 2017).

General Reviews

Moseley, J. D.; Murray, P. M.; Turp, E. R.; Tyler, S. N. G.; Burn, R. T. A Mild Robust Generic Protocol for the Suzuki Reaction Using an Air Stable Catalyst. Tetrahedron. 2012, 68 (30), 6010-6017.

Magano, J.; Dunetz, J. R. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111 (3), 2177–2250.

Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. Catalysts for Suzuki−Miyaura Coupling Processes:  Scope and Studies of the Effect of Ligand Structure. J. Am. Chem. Soc. 2005, 127 (13), 4685–4696.

Lennox, A. J. J.; Lloyd-Jones, G. C. Selection of Boron Reagents for Suzuki–MiyauraCoupling. Chem. Soc. Rev. 2014, 43, 412 -443.

Maluenda, I.; Navarro, O. Recent Developments in the Suzuki-Miyaura Reaction: 2010–2014. Molecules. 2015, 20 (5), 7528-7557.

Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of OrganoboronCompounds. Chem. Rev. 1995, 95 (7), 2457–2483.

Schaub, T. A.; Kivala, M. Cross-Coupling Reactions to sp Carbon Atoms. Metal-Catalyzed Cross-Coupling Reactions and More; Wiley: Weinheim, Germany, 2014.

Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies From the Pharmaceutical Industry; Magano, J.; Dunetz, J. R. , Eds.; Wiley, 2013.

Suzuki Coupling. Organic Chemistry Portal [Online]. (accessed Sept. 2017).

Suzuki Reaction. Wikipedia [Online]; Posted July 30, 2015. (accessed Sept. 2017).

Green Review

  1. Atom Efficiency (by-products Mwt)
    With optimized metal and ligand stoichiometry, catalytic metals and ligands make negligible contributions to the atom/mass intensity. By-broducts are inorganic salts and boric acid. In terms of leaving groups: Cl
  2. Safety Concerns
    There are no major concerns around the scaling of Suzuki reactions. Lower mol wt alkylphosphines can be highly flammable.
  3. Toxicity and Environmental/Aquatic Impact
    The main concern is around the loss of precious metal/heavy metal catalysts into waste streams. Most precious and heavy metal levels are tightly regulated. The same applies to potential carry-through into the API. Some Ni salts are sensitizers and carcinogens listed on the EU SVAH list; this is of less concern for metallic hydrogenation catalysts. Hydrolysis of boron-based reagents will lead to boric acid, which is a suspected reprotoxic mutagen. There may be issues with discharging aqueous waste with high B content. Emerging data suggests Boron compounds may be more ecotoxic than previously thought.

    Schoderboeck, L.; Mühlegger, S.; Losert, A.; Gausterer, C.; Hornek, R. Effects Assessment: Boron Compounds in the Aquatic Environment. Chemosphere. 2011, 82 (3), 483-487.

    Hydrophobic, high mol wt phospines can be persistent and bioaccumulative, and should not be discharged into aqueous waste streams.

    Simple bases like Na/K hydroxide, carbonate, bicarbonate and phosphates are preferred over organic amines. Local regulations may limit the concentrations of phosphate that can be discharged in aqueous waste. Cs2CO3 is widely used in Suzuki reactions. This should be substituted if possible.