Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C–C and C–N Cross-Coupling of Multiply Chlorinated Arenes through Substrate–Ligand Electrostatic Interactions

Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece “toolkit” comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki–Miyaura coupling and Buchwald–Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.