Sustainable Thioetherification via Electron Donor-Acceptor Photoactivation Using Thianthrenium Salts

Abstract

The synthesis of sulfides has been widely studied because this functional subunit is prevalent in biomolecules and pharmaceuticals, as well as being a useful synthetic platform for further elaboration. Thus, various methods to build C-S bonds have been developed, but typically they require the use of precious metals or harsh conditions. Electron donor-acceptor (EDA) complex photoactivation strategies have emerged as versatile and sustainable ways to achieve C-S bond formation, avoiding challenges associated with previous methods. This work describes an open-to-air, photoinduced, site-selective C-H thioetherification from readily available reagents via EDA complex formation that tolerates a wide range of different functional groups. Moreover, C(sp² )-halogen bonds remain intact using this protocol, allowing late-stage installation of the sulfide motif in various bioactive scaffolds, while allowing yet further modification through more traditional C-X bond cleavage protocols. Additionally, various mechanistic investigations support the envisioned EDA complex scenario.

Keywords: C−S Coupling; Electron Donor-Acceptor Complex; Photochemistry; Thianthrenium Salts; Thioethers.

Figure 1.

Strategies to synthesize thioethers via EDA complex photoactivation.

Figure 2.

Mechanistic Studies: A. Visual appearance of individual reaction components and mixtures thereof. B. UV/Vis absorption spectra measured in DMSO (0.1 M) at 0.3 mmol scale. C. Job plot for a mixture of the thiolate anion of 2a and thianthrenium salt 1a in DMSO (0.1 M). D. Radical trapping experiment with TEMPO. E. Proposed mechanism to synthesize thioethers 3 via EDA complex photoactivation.

Scheme 1.

Optimization of Reaction Conditions: Optimization of reactions were performed using 1a (0.10 mmol), 2a (0.20 mmol), and base (0.20 mmol), in dry degassed solvent (1.0 mL, c = 0.1 M) under purple Kessil® irradiation (λ_max = 390 nm) for 2 h at rt. ^aCalculated using 1,3,5-trimethoxybenzene as internal standard (IS) from the crude mixture. ^bOpen-to air. ^cIsolated yield of 3a on 0.3 mmol scale. nr: no reaction.

Scheme 2.

Aryl Thiol Scope. Reaction conditions: 1a (0.30 mmol), 2a (0.45 mmol) and K₂CO₃ (0.45 mmol), in dry DMSO (3.0 mL, c = 0.1 M) under open-to-air blue Kessil® irradiation (λ_max = 427 nm) at rt. ^aK₂CO₃ (0.60 mmol).

Scheme 3.

Aryl Thianthrenium Salt Scope. Reaction conditions: 1a (0.30 mmol), 2a (0.45 mmol) and K₂CO₃ (0.45 mmol), in dry DMSO (3.0 mL, c = 0.1 M) under open-to-air blue Kessil® irradiation (λ_max = 427 nm) at rt. ^a2a (0.33 mmol) and K₂CO₃ (0.33 mmol). ^bK₂CO₃ (0.60 mmol). ^cGram scale reaction