Constructions of Biaryl‐Bridged Macrocycles Through Phosphine‐Ligand‐Controlled Switch of Selectivity Between Intra‐ and Intermolecular Cyclizations

Abstract The rigid biaryl‐bridged macrocycles serve as core scaffolds in numerous bioactive molecules. However, constructing biaryl‐bridged macrocycles smaller than 14‐membered ring remains challenging, partially due to the strain present in the cyclic intermediates formed during their synthesis. Here, we report that a Pd catalyst supported by P( t Bu) 3 effectively promotes the intramolecular ortho C─H arylation of phenols with aryl bromides, leading to the efficient synthesis of both strained 2‐hydroxybiaryl‐bridged macrocycles and strain‐free bimolecular counterparts. The success of this Pd‐catalyzed intramolecular cyclization in generating strained macrocycles originates from the dissociation of the P( t Bu) 3 ligand from the Pd center, which facilitates dual chelation of functional groups of substrates to the Pd center of palladacycle intermediate for alleviating its strain. Additionally, Pd catalysts supported by PPh 3 promote intermolecular cyclization of the same substrates, enabling formation of larger macrocycles bridged by two 2‐hydroxybiaryl motifs. These two distinct cyclization modes illustrate how phosphine ligands control the switch of chemoselectivity in Pd‐catalyzed cyclizations.