Mechanistic studies of the Cu-catalyzed C−N coupling of sterically hindered aryl iodides with sterically hindered anilines are carried out to shed light on how a recently reported pyrrol-ol ligand affects the reaction. Kinetic, spectroscopic, and computational tools help to probe the nature of the active catalyst species and the rate-determining step in the cycle. In contrast to most known Cu systems, oxidative addition is found to precede coordination of the amine. These studies help to design an efficient process under mild conditions using a fully homogeneous system as well as protocols that enable high yields by temperature scanning and controlled addition of the base. The insights obtained for the XX-type ligand may lead to a general approach for challenging substrate classes in Cu-catalyzed coupling reactions.

The advent of benchtop nuclear magnetic resonance (NMR) instrumentation has paved the way for the use of this technology away from traditional NMR facility settings. Still, a wider adoption of benchtop NMR systems for routine identification testing has been hampered by inherent instrumental limitations (including low sensitivity and reduced signal dispersion) and workflow automation challenges. The present study summarizes the results of a cross-company collaboration aiming at the development of rapid, automated identification tests for incoming materials in liquid form intended for pharmaceutical manufacturing. Potential scenarios that analysts may encounter during the development of identification tests using benchtop NMR instrumentation are described, and suitable strategies for data collection and analysis are discussed. Challenges and opportunities for benchtop NMR implementation are illustrated using common organic solvents and laboratory reagents in a neat form, for which reference NMR data are provided.

Thioethers represent prevalent motifs in highly sought after biologically active small molecules such as active pharma-ceutical ingredients (APIs) and natural products. While nucleophilic aromatic substitution (SNAr) has traditionally been used to synthesize aryl thioethers, modern approaches leverage transition metals to catalyze thermal or photochemical cross-coupling. During platform technology development for photochemical transformations, we uncovered an exceedingly mild thioetherification that does not require light, transition metal or exogenous base. An array of thiols and halogenated heterocycles were coupled to produce 40 diverse products including the penultimate precursor to the immunosuppressant azathioprine (1-step). Reaction progress kinetic analysis (RPKA) and computational studies support a unique mechanism, here termed proton transfer dual ionization (PTDI) SNAr. Rate-limiting proton transfer (RLPT) pre-equilibrium results in dual nucleophile and electrophile ionization prior to an asynchronous concerted SNAr. This transformation complements modern approaches to thioethers and motivates additional research evaluating PTDI as a general activation mode between coupling partners.