C(sp³)H/N(sp²) Cross-Coupling Reaction for the Synthesis of Tertiary Arylamines via Fluxional SOX·Pd(II) Catalysis

N-alkyl arylamines are important structural motifs in pharmaceuticals, yet traditional alkylating methods rely on the nucleophilicity of the amine and make access to such compounds with valuable bioproperties challenging. While metal-mediated reactions may alleviate these limitations, they often encounter amine-metal interactions that can hinder catalysis or lead to deleterious pathways. Herein, we report a palladium(II) [Pd(II)]/sulfoxide-oxazoline(SOX)/phosphoric acid-mediated C(sp3)H/N(sp2) cross-coupling of 53 arylamine nucleophiles and 39 terminal olefins to furnish >80 diverse tertiary (3°) arylamines in excellent yields (average 82%) and selectivities (>20:1 E/Z, >20:1 linear/branched). The reaction furnishes electron-deficient and sterically bulky arylamines as well as those housing alkyl/aryl halides, epoxides, carbonyls, epimerizable centers, carboxylic acids, and N-triflyl/tosyl alkylamines, showcasing orthogonal scope to existing aminations. The generality of this reaction enables facile synthesis of six pharmaceuticals and derivatives (e.g., zafirlukast) and five late-stage drug fragment couplings (e.g., flutamide-duloxetine). Whereas spectroscopic studies identify a catalytically inactive bis(arylamine)·Pd(II) complex 4 as the resting state, the reaction proceeds with high efficiencies (short reaction times, low catalyst loadings). Mechanistic studies reveal that the SOX ligand L1 [(±)-MeO-SOX = MaSOX)] establishes a dynamic equilibrium with 4 to generate the active catalyst. Phosphoric acids promote the reaction by affording a significant increase in the functionalization rate, rendering a lower energy allylic C–H cleavage as the rate-determining step. We anticipate that this reaction will find broad use in the discovery of complex and medicinally relevant N-alkyl arylamines and that the mechanistic insights will be leveraged to improve efficiencies of other metal-catalyzed aminations.