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.