Palladium-Catalyzed Regioselective C-H Functionalization of Arenes Substituted by Two N-Heterocycles and Application in Late-Stage Functionalization.

Reported herein is a Pd-catalyzed regioselective C-H activation method that is used for C-H deuteration, carbonylation, halogenation, and oxidation of arene substrates substituted by two N-heterocycles. When conducted in acetic acid (AcOH), these reactions occur at the five-membered palladacycle sites, whereas they switch to the six-membered palladacycle sites in trifluoroacetic acid (TFA). This controllable regioselective C-H activation is applied for late-stage functionalization of bioactive molecules. A mechanism study indicated that the regioselectivity is achieved by Brönsted acid-Lewis base interactions and electronic effects (in TFA) and the different kinetic stabilities of palladacycle intermediates (in AcOH).