Isohypsic Pd(II)-Catalyzed Cross-Coupling Enables C2-Selective Amination of 2,4-Dihalopyrimidines
Year: 2026
Type: preprint
Abstract: 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.
Source: ChemRxiv
Institution: Montana State University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G1310521215, G2523737452, G3434531728, G3749790172, G3902111948, Ultra Performance Liquid Chromatography Tandem Mass Spectrometer for Metabolomics, MRI: Acquisition of a cryoprobe- and autosampler-equipped AVANCE III 500 MHz solution NMR, G6401591588, G6551576117, MRI: Acquisition of a Small Molecule Single Crystal X-ray Diffractometer for Research and Education Across Montana, MRI: Acquisition of a 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer, MT INBRE: A Multidisciplinary Research Network, Biomolecular Structure and Dynamics
OpenAlex ID: W7133362872