The Pd-catalyzed cross-coupling reactions have grown into a central technology in drug discovery and manufacture. Last centuries’ development of specialized phosphine ligands has enabled the C-C coupling of highly diversified (hetero)aromatics bearing a wide range of coordinating substituents. Such functional groups (amines, nitriles, amides, sulfoxides, etc.) are indispensable in potent medicinal compounds to interact with their drug target. However, coordinating functionalities often hinder the activity of metal-based catalysts. While the direct C-H activation of (hetero)aromatics without preinstalled functional or directing groups is inherently more efficient, the use of current C-H activation catalysts remains challenging in convergent, late-stage cross-coupling for pharmaceutical compounds. In this work, we report on a dual ligand approach that enables regiospecific C-H coupling of purine-like N-heterocycles with aryl halides. A basic 5-methyl-2-hydroxypyridine ligand modulates the reactivity of traditional Pd-phosphine catalysts towards highly active and robust C-H activation, with turnovers over 10 000. Computational modelling and an in situ XAS study of the Pd K-edge elucidate the speciation of the active catalyst and its reaction mechanism throughout the catalytic cycle. Based on these combined insights, a kinetic model was devised that matches the observed time profiles. Comparison of the experimental kinetic parameters across a range of coupling partners and ligand combinations revealed QSARs between the reactant and catalyst (i.e. Hammett equation). These results highlight the predictable tunability of the catalytic system: electron-donating phosphine ligands promote oxidative addition of the aryl halide, whereas higher basicity of the 2-hydroxypyridine ligand enables a fast C-H deprotonation. Moreover, the effect of common coordinating groups of pharmaceutical relevance was assessed. In contrast to the state-of-the-art electrophilic C-H activation catalysts, catalyst inhibition was overcome due to the excellent compatibility with phosphine ligands. While using minimal loadings of Pd-catalyst, its wide scope was demonstrated in the synthesis of 50 examples including potent protein kinase inhibitors in preclinical development.

C-H coupling of pharmaceutically relevant N-heterocycles via rational catalyst design

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