Mechanistic Studies Of A Pd-Catalyzed Direct Arylation En Route To Beclabuvir: Dual Role Of A Tetramethylammonium Cation And An Unusual Turnover-Limiting Step

Mechanistic investigations on the intramolecular direct arylation of an indole-containing aryl bromide en route to the HCV NS5B inhibitor beclabuvir are reported. A combination of stoichiometric, kinetic, and computational studies revealed the origin of the unique effectiveness of the tetramethylammonium acetate (TMAOAc) base and uncovered an unexpected dual role of the tetramethylammonium cation, as well as an unusual turnover-limiting step for this intramolecular direct arylation reaction. The arylpalladium bromide oxidative addition complex is in equilibrium with the key arylpalladium acetate complex that undergoes C-H bond cleavage, and this equilibrium favors the former species. As a consequence, the Br/OAc exchange process becomes increasingly disfavored as the catalytic reaction progresses because of the liberation of bromide ions, but with TMAOAc as the base, the reaction can be efficiently driven forward by sequestration of bromide as the poorly soluble tetramethylammonium salt. A reversible C-H bond cleavage event that proceeds via a concerted metalation-deprotonation process is followed by a turnover-limiting reductive elimination to release the cyclized product. The knowledge gained from these studies enabled the successful execution of this chemistry on a 50 kg scale, and more broadly, this work underscores the impact that stoichiometric halide byproducts can have on the efficiency of transition metal-catalyzed transformations.