Isohypsic Pd(II)-Catalyzed Cross-Coupling Enables C2-Selective Amination of 2,4-Dihalopyrimidines

4-Substituted-2-(arylamino)pyrimidines are a privileged motif found in protein kinase inhibitors, but synthetic routes to these compounds are limited by the reactivity of 2,4-dihalopyrimidine precursors. 2,4-Dihalopyrimidines typically react preferentially at C4 during cross-couplings and nucleophilic aromatic substitutions, which is problematic when late-stage installation of the 4-substituent is desirable. In Pd(0)-catalyzed cross-couplings, selectivity usually arises during oxidative addition, which is heavily biased toward the C4-halide site. We report a Pd(II)-catalyzed cross-coupling that enables the first C2-selective amination of 2,4-dichloropyrimidine. The unusual selectivity arises from a novel isohypsic mechanism in which there is no oxidative addition step. Diverse 4-chloro-2-(arylamino)pyrimidines can be synthesized by this method. The work reveals that redox steps do not have to be a part of cross-coupling catalytic cycles using Pd.