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Base-Metal-Catalyzed Borylation

Mechanism + Description

Use of base metal complexes to replace Pd – mechanism as for Pd-coupling/borylation via C-H activation.

General comments

There is currently a high degree of interest in replacing high life cycle impact metals like Pd in C-Halogen insertion, Ir in C-H activation borylation chemistry, and Pt group metals other borylation chemistries with readily available and less scarce metals like Ni, Zn, Co, Cu and Zn.

Key references

Coombs, J. R.; Green, R. A.; Roberts, F.; SImmons, E. M.; Stevens, J. M.; Wisniewski, S. R. Advances in Base-Metal Catalysis: Development of a Screening Platform for Nickel-CatalyzedBorylations of Aryl (Pseudo)halides with B2(OH)4. Organometallics 2019, 38, 157-166.

Bose, S. K.; Marder, T. B. Efficient Synthesis of Aryl Boronates via Zinc-Catalyzed Cross-Coupling of AlkoxyDiboron Reagents. Org. Lett. 2014, 16, 4562–4565.

Yao, W.; Fang, H.; Peng, S.; Wen, H.; Zhang, L. Hu, A.; Huang, Z. Cobalt-CatalyzedBorylation of Aryl Halides and Pseudohalides. Organometallics 2016, 35, 1559–1564.

Obligacion, J. V.; Semproni, S. P.; Chirik, P. J. Cobalt-Catalyzed C–H Borylation. J. Am. Chem. Soc. 2014, 136, 4133–4136.

Palmer, W. N.; Obligacion, J. V.; Pappas, I.; Chirik, P. J. Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and Functionalization of Remote, Unactivated C(sp3)–H Bonds. J. Am. Chem. Soc. 2016, 138, 766–769.

Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Copper-CatalyzedBorylative Transformations of Non-Polar Carbon–Carbon Unsaturated Compounds Employing Borylcopper as an Active Catalyst Species. Tetrahedron 2015, 71, 2183-2197.

Nelson, A. K.; Peck, C. L.; Rafferty, S. M.; Santos, W. L. Chemo-, Regio-, and Stereoselective Copper(II)-Catalyzed Boron Addition to Acetylenic Esters and Amides in Aqueous Media. J. Org.  Chem.  2016, 81, 4269-4279.

Stavber, G.; Ĉasar, Z. CuII and Cu0 Catalyzed Mono Borylation of Unsaturated Hydrocarbons with B2pin2: Entering into the Water. ChemCatChem 2014, 6, 2162-2174.

Peck, C. L.; Calderone, J. A.; Santos, L. W. Copper(II)-Catalyzedb-Borylation of Acetylenic Esters in Water. Synthesis 2015, 47, 2242-2248

Zhu, L.; Kitanosono, T.; Xu, P.; Kobayashi, S. Chiral Cu(II)-catalyzed enantioselective β-borylation of α,β -unsaturated nitriles in water. Beilstein J. Org. Chem. 2015, 11, 2007-2011.

Bose, S. K.; Deiβenberger, A.; Eichhorn, A.; Steel, P. G.; Lin, Z.; Marder, T. B. Zinc-Catalyzed Dual C–X and C–H Borylation of Aryl Halides. Angew. Chem. Int. Ed. 2015, 54, 11843–11847.

Molander, G. A.; Cavalcanti, L. N.; García-García, C. Nickel-CatalyzedBorylation of Halides and Pseudohalides with Tetrahydroxydiboron [B2(OH)4]. J. Org. Chem. 2013, 78, 6427–6439.

Cheng, Q.-Q.; Zhu, S.-F.; Zhang, Y.-Z.; Xie, X.-L.; Zhou, Q.-L. Copper-Catalyzed B–H Bond Insertion Reaction: A Highly Efficient and Enantioselective C–B Bond-Forming Reaction with Amine–Borane and Phosphine–Borane Adducts. J. Am. Chem. Soc. 2013, 135, 14094–14097.


Relevant Scale-up Example – Base-metal Catalyzed Borylation

Tian, Q.; Cheng, Z.; Yajima, H. M.; Savage, S. J.; Green, K. L.; Humphries, T.; Reynolds, M. E.; Babu, S.; Gosselin,  F. Askin, D.; et. al. Org. Process Res. Dev. 2013, 17, 97−107.

Green Review

  1. Atom efficiency (by-products Mwt)
    With optimized metal and ligand stoichiometry, catalytic metals and ligands have negligible contribution to the atom/mass intensity. By-products are inorganic salts and boric acid. In terms of leaving groups Cl < Br < Mesylate < I < Triflate < Tosylate. C-H activation is generally more atom efficient.
  2. Safety Concerns
    There are no major concerns around scaling Suzuki reactions. Lower mol wt alkyl phosphines if used as ligands can be highly flammable.
  3. Toxicity and environmental/aquatic impact
    The main concern is around 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. See next slide for more details. Some Ni salts are sensitizers and carcinogens and listed on the EU ECHA restricted list ( Hydrolysis of Boron-based reagents will lead to boric acid which is a suspected reprotoxic mutagen. A number of boron reagents are suspected to be Potential Genotoxic Impurities (PGI).

    Hansen, M. M.; Jolly, R. A.; Linder, R. Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity. J. Org. Process Res. Dev. 2015, 19, 1507-1516.

    There may be issues with discharging aqueous waste with high-boron content. Emerging data suggest boron compounds maybe more ecotoxic that 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 phosphines can be persistent and bio-accumulative 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 concentrations of phosphate that can be discharged as aqueous waste. Cs/Li bases should be substituted if possible.

  4. Cost, availability & sustainable feedstocks
    Due to it’s high catalytic efficiency, this methodology can be an economical way to access organoboron compounds.
  5. Sustainable implications
    All metals have a high LCA impact from mining and refining operations, so use should be catalytic with efficient recovery and recycle for precious Pt-group metals. No concern for abundant base metals like Ni and Fe.

Updated ICH Guidelines for Metals in API’s

ICH q3d guideline for elemental impurities 2018

When using catalytic or stoichiometric metals it is important to check that any wastes discharged to the environment have levels of precious/heavy metals less than levels permitted by local legislation.

There are also strict limits for metals in APIs and finished medicines to ensure patient safety.

For guidance see limits in µg gram-1 and permitted daily exposures