PTCs in Biphasic Suzuki-Miyaura Cross-Couplings

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Nat. Commun. 2014, 15, 5436. DOI: 10.1038/s41467-024-49681-4 ◆ Intimate understanding of the rate-limiting step of a metal catalyzed cross-coupling is required to drive down the metal loading to a level suitable for use long-term. ◆ The Hein group studied the rate-limiting transmetalation step of the biphasic coupling of boronic esters with benzylic electrophiles. ◆ A significant driver of the rate was found to be lowering the amount of the water-immiscible solvent relative to the amount of water. The use of a phase-transfer additive switched the predominant transmetalation pathway from oxopalladium-based to boronate-based, giving an up to 12- fold increase in the rate, and allowing the use of a homeopathic level of catalyst for a gram-scale demonstration. ◆ The validity of the conclusions was underpinned by high-quality data generated by an automated sampling platform coupled to online HPLC analysis. ………………………………