Visible-Light-Promoted C-S Cross-Coupling via Intermolecular Charge Transfer

Abstract

Disclosed is a mild, scalable, visible-light-promoted cross-coupling reaction between thiols and aryl halides for the construction of C-S bonds in the absence of both transition metal and photoredox catalysts. The scope of aryl halides and thiol partners includes over 60 examples and therefore provides an entry point into various aryl thioether building blocks of pharmaceutical interest. Furthermore, to demonstrate its utility, this C-S coupling protocol was applied in drug synthesis and late-stage modifications of active pharmaceutical ingredients. UV-vis spectroscopy and time-dependent density functional theory calculations suggest that visible-light-promoted intermolecular charge transfer within the thiolate-aryl halide electron donor-acceptor complex permits the reactivity in the absence of catalyst.

Figure 1

(a, b) UV–vis absorption spectra of mixtures of 1a, 2a, and Cs₂CO₃ in DMSO (path length = 1 cm) at concentrations of (a) 6 × 10⁻⁴ M and (b) 0.1 M for each species. The inset of (b) shows the formation of a yellow compound (proposed EDA complex) upon mixing of 1a, 2a, and Cs₂CO₃. (c) Time-dependent DFT calculations to predict UV–vis absorptions of the EDA complex. (d) Proposed mechanism for visible-light induced C–S cross-coupling.

Scheme 1

Importance of C–S Bonds and Approaches for Their Formation

Scheme 2. Scope of Thiols^a

^aGeneral conditions: 1a (0.2 mmol), 2 (1.5 equiv), Cs₂CO₃ (1.5 equiv), DMSO (1.5 mL). Isolated yields are provided. ^b50 mmol scale. ^c2.0 equiv of Cs2CO3.

Scheme 3. Scope of Aryl Chlorides/Bromides/Iodides^a

^aGeneral conditions: 1 (0.2 mmol), 2 (1.5 equiv), Cs₂CO₃ (1.5 equiv), DMSO (1.5 mL). Isolated yields are provided. ^b2.0 equiv of Cs₂CO₃.

Scheme 4. Scope of (Hetero)arene Coupling Partners^a

^aGeneral conditions: 1 (0.2 mmol), 2 (1.5 equiv), Cs₂CO₃ (1.5 equiv), DMSO (1.5 mL). Isolated yields are provided. ^b2.0 equiv of Cs₂CO₃.

Scheme 5

Synthetic Applications of the Visible-Light-Promoted C–S Bond Formation