The regiospecificity of conventional cross-coupling reactions, though advantageous
for its predictability and retrosynthetic simplicity, constrains chemical-space exploration.
Discovery efforts have become biased toward examining substitution patterns for which
coupling partners are readily obtainable. To address this problem, we have developed
a migratory (‘ring-walking’) cross-coupling approach that integrates the isomerization
of arylpalladium(II) intermediates into catalytic cycles. A reversible isomerization
was achieved through ligand design and the use of cesium fluoride as the base, and
this process was then combined with a dynamic kinetic resolution of the regioisomeric
aryl halides with a broad range of oxygen- and nitrogen-centered nucleophiles. The
method permits rapid access to meta-substituted arenes from para-substituted electrophiles. This account summarizes the key mechanistic principles
established during the development of these reactions.
Key Words
cross-coupling - Curtin–Hammett - isomerization - ring-walking - transition-metal
catalysis
