Overcoming Halide Inhibition of Suzuki–Miyaura Couplings with Biaryl Monophosphine-Based Catalysts

Abstract

The Suzuki−Miyaura reaction is one of the most widely employed transformations in synthetic chemistry. Despite extensive investigation, questions remain about the mechanistic nature of the transmetalation step when catalysts based on advanced ligands such as biaryl monophosphines are used, impeding the development of improved catalysts. Here we demonstrate that the often overlooked halide salt (KX) generated as a byproduct of cross-coupling renders the transmetalation step reversible with SPhos-based catalysts, leading to severe reaction inhibition with (hetero)aryl iodides. Stoichiometric and kinetic studies reveal that halide inhibition likely originates from disfavoring the formation of a highly reactive Pd−OH intermediate. We demonstrate that changing the organic solvent in the biphasic reaction mixture from tetrahydrofuran to toluene is sufficient to minimize this inhibition and enable the general Suzuki−Miyaura coupling of (hetero)aryl iodides. Our studies suggest that halide inhibition may be a more general problem in cross-coupling reactions, especially those involving reversible transmetalation processes.

The Suzuki–Miyaura Cross‐Coupling as the Key Step in the Synthesis of 2‐Aminobiphenyls and 2,2'‐Diaminobiphenyls: Application in the Synthesis of Schiff Base Complexes of Zn

“…Both 5‐chloro‐2‐iodoaniline and 2‐bromo‐5‐chloroaniline could be successfully employed as starting materials for the synthesis of biphenyl 1j (Scheme ). Interestingly, the bromoaniline was found to be more reactive than the iodoaniline, which may be attributed to the inhibiting effect of KI (generated during the reaction), on Suzuki–Miyaura reactions in aqueous THF as previously reported by Milner and co‐workers . Whereas 2‐bromo‐5‐chloroaniline reacted to give 1j with full consumption of the starting material, a significant amount of starting material could be recovered when 5‐chloro‐2‐iodoaniline was used, supporting the potential inhibiting effect of in situ generated KI.…”

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“…By changing the solvent in the biphasic reaction system from THF to toluene, this inhibition was effectively minimized. The study also revealed that inhibition by halide is likely a more general problem in metal-catalyzed cross-coupling reactions, in particular the ones that involve a reversible transmetalation step …”

Cellulose derived Pd nano-catalyst for efficient catalysis

“…4. [40][41][42] Firstly, aer the addition of aryl halides, the Pd complex (Ar-Pd-X) was formed over C-Pd catalyst via oxidative addition. The complex then formed an Ar-Pd-Ph complex with phenylboronic acid in the presence of K 2 CO 3 .…”