Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations

Abstract

The Suzuki–Miyaura reaction is the most practiced palladium-catalyzed, cross-coupling reaction because of its broad applicability, low toxicity of the metal (B), and the wide variety of commercially available boron substrates. A wide variety of boronic acids and esters, each with different properties, have been developed for this process. Despite the popularity of the Suzuki–Miyaura reaction, the precise manner in which the organic fragment is transferred from boron to palladium has remained elusive for these reagents. Herein, we report the observation and characterization of pretransmetalation intermediates generated from a variety of commonly employed boronic esters. The ability to confirm the intermediacy of pretransmetalation intermediates provided the opportunity to clarify mechanistic aspects of the transfer of the organic moiety from boron to palladium in the key transmetalation step. A series of structural, kinetic, and computational investigations revealed that boronic esters can transmetalate directly without prior hydrolysis. Furthermore, depending on the boronic ester employed, significant rate enhancements for the transfer of the B-aryl groups were observed. Overall, two critical features were identified that enable the transfer of the organic fragment from boron to palladium: (1) the ability to create an empty coordination site on the palladium atom and (2) the nucleophilic character of the ipso carbon bound to boron. Both of these features ultimately relate to the electron density of the oxygen atoms in the boronic ester.

Solvent effects in palladium catalysed cross-coupling reactions

“…192,193,194,195 It is now generally accepted that the latter is more representative of the reaction mechanism. 197,198,199 This does imply a closed transmetalation transition state would be favoured. 204 The solvent in this case was benzene, with water also present due to the hydroxide base having been added as an aqueous solution.…”

Hydrogenation of Borylated Arenes

“…The hydrogenation of free phenylboronic acid 2 ah provided access to the saturated cyclohexylboronic acid. Thus, our developed method provides access to alkyl boronic acid derivatives with various boron‐protecting groups, which can influence the rate of transmetalation in cross‐coupling reactions . Since saturated heterocycles are an important structural motif, we extended the scope of the hydrogenation to different heteroarenes ( 2 ai – 2 av ).…”

Hydrierung borylierter Aromaten

“…Hydrierung der freien Phenylboronsäure 2 ah ermöglichte den Zugang zur gesättigten Cyclohexylboronsäure. Somit bietet unsere entwickelte Methode Zugang zu Alkylboronsäurederivaten mit verschiedenen Borschutzgruppen, welche dafür bekannt sind die Transmetallierungsrate in Kreuzkupplungsreaktionen beeinflussen zu können . Da gesättigte Heterocyclen ein wichtiges Strukturmotiv darstellen, haben wir das Substratspektrum der Hydrierung auf verschiedene Heteroaromaten ( 2 ai – 2 av ) erweitert.…”