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

Abstract

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 (S_NAr) 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) S_NAr. 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.

Scheme 1.

(A) Sulfur-Containing Active Pharmaceutical Ingredients. (B) Synthetic Approaches to Aryl Thioethers. (C) Photocatalyst-Free C–S Coupling Reported by Miyake and Co-Workers. (D) Work Accomplished in this Study

Scheme 2.

Proposed Reaction Mechanism Supported by RPKA and Computational Studies

Scheme 3.. Nucleophile and Electrophile Substrate Scope^d

^aGeneral conditions: N (1.1 equiv), E (1.0 equiv), MeCN (0.5M), 18h. ^bDimerization: thioacetic acid (2.0 equiv), MeCN (0.5M). ^cThiolation: thioacetic acid (0.5M); Left column: Nucleophile scope; Right column: Electrophile scope; Inset: Competition experiments between E8 and E5. ^dPPTS = Pyridinium p-Toluene Sulfonate.

Scheme 4.. General Data-Driven Workflow for Modeling in This Work^a

^aThe data set of nucleophiles and electrophiles integrates both initial data and HTE data. Quantum chemical calculations are performed to parametrize the molecules included in the data set. Subsequently, a decision tree classification model is trained based on these parameters. The final decision tree, along with its accuracy and the parameters defining the decision nodes, is visualized. For validation, known targets (target-oriented synthesis) are predicted and tested experimentally.

Scheme 5.. Fourteen Targets Used to Validate the Classification Model^a

^aPTDI: PTDI S_NAr conditions used to prepare target; Lit: conditions from literature used to prepare target; Blue square: disconnection prediction in azathioprine. Gray inset: legend for classification model; B = both nucleophile and electrophile out of model; E = electrophile out of model; N = nucleophile out of model; Green inset: PTDI S_NAr heterodimerization formal synthesis of TNO-155.