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 and 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. In general, however, depending on the binding properties of the chosen organic base, increased 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 -deficient substrates. We propose a model in which the turnover-limiting step of the catalytic cycle depends 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.