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Understanding the nature of the intermediate species operating within a palladium catalytic cycle is crucial for developing efficient cross‐coupling reactions. Even though the XPhos/Pd(OAc)2 catalytic system has found numerous applications, the nature of the active catalytic species remains elusive. A Pd0 complex ligated to XPhos has been detected and characterized in situ for the first time using cyclic voltammetry and NMR techniques. In the presence of XPhos, Pd(OAc)2 initially associates with the ligand to form a complex in solution, which has been characterized as PdII(OAc)2(XPhos). This PdII center is then reduced to the Pd0(XPhos)2 species by an intramolecular process. This study also sheds light on the formation of PdI–PdI dimers. Finally, a kinetic study probes a dissociative mechanism for the oxidative addition with aryl halides involving Pd0(XPhos) as the reactive species in equilibrium with the unreactive Pd0(XPhos)2. Remarkably, the reportedly poorly reactive PhCl reacts at room temperature in the oxidative addition, which confirms the crucial role of the XPhos ligand in the activation of aryl chlorides.

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

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Furans may be ring opened via pallado-catalyzed reactions leading to α,β-unsaturated aldehydes and ketones tethered to indole and isoquinoline moieties. Besides their synthetic interest, these fragmentations bring interesting elements into the discussion around the reaction mechanisms involved in palladium C-H activations of electron-rich heterocycles.