Due to the low intrinsic acidity of amines, palladium-catalyzed C-N cross-coupling has been plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C-N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base-sensitive functional groups. Additionally, insightful heteronuclear NMR studies using N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center.

Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues associated with heterogeneous reaction conditions. Still, homogeneous C–N cross-coupling approaches cannot yet employ bases as weak and economical as trialkyl­amines. Furthermore, organic base-mediated methods have not been developed for Ni­(0/II) catalysis, despite some advantages of such systems over those employing Pd-based catalysts. We designed a new air-stable and easily prepared Ni­(II) precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines using triethyl­amine (TEA) as base. The method is tolerant of sterically congested coupling partners, as well as those bearing base- and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the electron-deficient auxiliary ligands decrease both the pK a of the Ni-bound amine and the barrier to reductive elimination from the resultant Ni­(II)–amido complex. Moreover, we determined that the preclusion of Lewis acid–base complexation between the Ni catalyst and the base, due to steric factors, is important for avoiding catalyst inhibition.

Recent advances in Pd-catalyzed carbon–nitrogen cross-coupling have enabled the use of soluble organic bases instead of insoluble or strong inorganic bases that are traditionally employed. The single-phase nature of these reaction conditions facilitates their implementation in continuous flow systems, high-throughput optimization platforms, and large-scale applications. In this work, we utilized an automated microfluidic optimization platform to determine optimal reaction conditions for the couplings of an aryl triflate with four types of commonly employed amine nucleophiles: anilines, amides, primary aliphatic amines, and secondary aliphatic amines. By analyzing trends in catalyst reactivity across different reaction temperatures, base strengths, and base concentrations, we have developed a set of general recommendations for Pd-catalyzed cross-coupling reactions involving organic bases. The optimization algorithm determined that the catalyst supported by the dialkyltriarylmonophosphine ligand AlPhos was the most active in the coupling of each amine nucleophile. Furthermore, our automated optimization revealed that the phosphazene base BTTP can be used to facilitate the coupling of secondary alkylamines and aryl triflates.

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 19 F 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.

A rhodium-catalyzed cross-coupling of aryl and aliphatic quinolinyl ketones with boronic acids has been developed. Proceeding via quinoline-directed carbon-carbon σ bond activation, the transformation demonstrates tolerance of a range of functional groups on both the ketone and aryl boronic acid substrates, providing good to excellent yields of the new ketones, particularly those containing electron-withdrawing substituents. Catalyst reactivity is dependent on quinolinyl ketone substrates, with alkyl ketones requiring Rh(PPh3)3Cl instead of the more reactive [Rh(C2H4)2Cl]2. With the use of K2CO3 as an additive, methyl boronic acid is also a competent substrate, giving rise to an unprecedented methylation technique.