Mild, Additive-Free Thioetherification via Proton Transfer Dual Ionization Mechanism

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.