Pd-Catalyzed C–N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines

The ability to use
soluble organic amine bases in Pd-catalyzed
C–N cross-coupling reactions has provided a long-awaited solution
to the many issues associated with employing traditional, heterogeneous
reaction conditions. However, little is known about the precise function
of these bases in the catalytic cycle or about the effect of variations
in base structure on catalyst reactivity. We used 19F NMR
to analyze the kinetic behavior of C–N coupling reactions facilitated
by different organic bases. In the case of aniline coupling reactions
employing DBU, the resting state was a DBU-bound oxidative addition
complex, LPd­(DBU)­(Ar)­X, and the reaction was found to be inhibited
by base. Generally, however, depending on the binding properties of
the chosen organic base, increasing the concentration of the base
can have a positive or negative influence on the reaction rate. Furthermore,
the electronic nature of the aryl triflate employed in the reaction
directly affects the reaction rate. The fastest reaction rates were
observed with electronically neutral aryl triflates, while the slowest
were observed with highly electron-rich and electron-deficient substrates.
We propose a model in which the turnover-limiting step of the catalytic
cycle is dependent on the relative nucleophilicity of the base, compared
to that of the amine. This hypothesis guided the discovery of new
reaction conditions for the coupling of weakly binding amines, including
secondary aryl amines, which were unreactive nucleophiles in our original
protocol.