Development of a Thioetherification of Heteroarene Electrophiles with Broad Scope via a Proton Transfer Dual Ionization Mechanism

Sulfur-derived
functional groups represent prevalent motifs in
highly sought-after small molecules, such as active pharmaceutical
ingredients (APIs). Thioethers are one such example, being commonly
encountered in APIs, prodrugs, and as valuable synthetic “linchpins”
to access an array of sulfur-derived functional groups. 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. While
studying photochemical thioetherification reactions, we uncovered
a remarkably mild condition that does not require light, transition
metals, or exogenous bases. An array of thiols and halogenated heterocycles
were coupled to produce >70 diverse products. Reaction progress
kinetic
analysis (RPKA) and computational studies support a unique mechanism
termed proton transfer dual ionization (PTDI) SNAr. Finally,
a predictive statistical model was constructed aided by high-throughput
experimentation (HTE) to understand when the PTDI processes are successful,
resulting in the completion of ten target-oriented syntheses. This
transformation complements modern approaches to thioether synthesis
and motivates additional research evaluating PTDI as a general activation
mode between reaction partners.