Efficient C-2 arylation of azoles via [κ2N] Pd(ii)-triazolyl-pyridine complexes enabled by silver in HFIP

Abstract

Two Pd(II) complexes (3a and 3b), with N-bound triazolyl-pyridine ligand structures, were designed and prepared for the C-2 arylation of azoles using aryl iodides and bromides. These Pd(II) complexes feature bidentate N-bound triazolyl-pyridine ligands, as confirmed via single-crystal X-ray diffraction analysis. Among them, the novel [κ²N] (bpmtmp)PdCl₂ complex (3a) demonstrated high catalytic efficiency in the C-2 arylation of substituted benzothiazole and benzoxazoles with various aryl iodides and bromides, using Ag₂CO₃ as a co-catalyst and HFIP as the solvent under ambient conditions. Relatively, the higher (ca. 6%) %V_bur of complex 3a compared to 3b supports its superior catalytic performance in the described reaction. This developed methodology was effectively utilized for the synthesis of the PMX-610 antitumor agent (6m) and demonstrated high catalytic reactivity in C-arylation of 2,2′-bipyridine. We have performed several experiments for the establishment of a plausible reaction pathway. The H/D exchange experiment and the parallel kinetic isotope experiment support that the C–H bond activation of azoles is not the rate-determining step. X-ray photoelectron spectroscopy (XPS) analysis of the intermittent reaction mixture further supports the functioning of a Pd(0) to Pd(II) catalytic cycle.