The palladium-catalyzed Miyaura borylation reaction is a convenient way to prepare aryl boronic esters which can be used for Suzuki reactions. The method is particularly important for the preparation of pharmaceuticals where use of the simpler Grignard-based protocol is often impossible because of the presence of sensitive functional groups. In general this reaction is performed at 80 °C or above with an excess of base. Such conditions could cause problems in the preparation of pharma compounds, especially if functional groups containing chiral centers are present in the molecule. In order to run this reaction under mild conditions a base screen was performed, which found that sterically hindered bases such as potassium 2-ethyl-hexanoate performed best. To get a better understanding of the effect of the base in this reaction, we have performed detailed kinetic studies. Unexpectedly, it was revealed that the reaction is inhibited by potassium acetate, but not by the more hindered bases. A likely explanation is the formation of anionic palladium complexes under the influence of excess potassium acetate. These complexes apparently are no longer active in the Miyaura borylation reaction. Using potassium ethyl hexanoate, the borylation reactions could be performed under mild conditions (35 °C) in a short reaction time (as short as 1 hour for some examples) with a fairly low catalyst loading (0.5 mol% of Pd).

Mechanistic studies of Pd-catalyzed Miyaura borylation reaction

ACS Spring Meeting 2021

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