Preparation of Potassium Acyltrifluoroborates (KATs) from Carboxylic Acids by Copper-Catalyzed Borylation of Mixed Anhydrides

Summary

Potassium acyltrifluoroborates (KATs) are the acylboron partners in KAT ligation, but before this work the only route from a carboxylic acid used a hard-to-handle borylzinc reagent. Here carboxylic acids are activated as isobutyl mixed anhydrides with isobutyl chloroformate and N-methylmorpholine, then borylated with bis(pinacolato)diboron under a commercial N-heterocyclic-carbene copper catalyst (IMesCuCl) with sodium methoxide as base, and finally converted to the KAT with aqueous potassium bifluoride (KHF2).

Key findings

• Carboxylic acids are converted to KATs in one pot via isobutyl mixed anhydrides, copper-catalyzed borylation with B2(pin)2, and aqueous KHF2 workup.
• The optimized conditions use 15 mol% of the commercial catalyst IMesCuCl with sodium methoxide; primary aliphatic acids gave up to 72% yield by 19F NMR.
• Primary, secondary, and tertiary aliphatic acids and aromatic acids were converted, and alkenes, esters, halides, nitriles, and protected amines were tolerated.
• Fmoc-, Boc-, and Cbz-protected amino acids were converted directly to amino-acid KATs (43 to 68% isolated), though some substrates underwent partial racemization from the basic conditions.
• N-heteroaromatic, alkenyl, and alkynyl acids were unreactive and the starting acid was recovered.

Questions this paper answers

How can potassium acyltrifluoroborates (KATs) be made from carboxylic acids?

Tung, Schuhmacher, Schilling, Bode, and Mankad (Angew. Chem. Int. Ed. 2022, 61, e202114513) activate the carboxylic acid as an isobutyl mixed anhydride, borylate it with bis(pinacolato)diboron under IMesCuCl copper catalysis with sodium methoxide, and convert the product to the KAT with aqueous KHF2.

Read the paper

• Publisher version (doi:10.1002/anie.202114513)
• PubMed 34913236
• Accepted manuscript (OSTI, green open access)
• Preprint (ChemRxiv, 2021)

How to cite

Tung, P.; Schuhmacher, A.; Schilling, P. E.; Bode, J. W.; Mankad, N. P. Preparation of Potassium Acyltrifluoroborates (KATs) from Carboxylic Acids by Copper-Catalyzed Borylation of Mixed Anhydrides. Angew. Chem. Int. Ed. 2021, 61, e202114513. https://doi.org/10.1002/anie.202114513

@article{Tung2021Preparation,
  author = {Tung, Pinku and Schuhmacher, Anne and Schilling, Philipp E. and Bode, Jeffrey W. and Mankad, Neal P.},
  title = {{Preparation of Potassium Acyltrifluoroborates (KATs) from Carboxylic Acids by Copper-Catalyzed Borylation of Mixed Anhydrides}},
  journal = {Angewandte Chemie International Edition},
  volume = {61},
  number = {7},
  pages = {e202114513},
  year = {2021},
  doi = {10.1002/anie.202114513},
  url = {https://doi.org/10.1002/anie.202114513}
}