Copper-Mediated C–H Activation/C–S Cross-Coupling of Heterocycles with Thiols

TLDR

The study develops a copper‑mediated aerobic C–H activation strategy to synthesize aryl‑ or alkyl‑substituted 2‑mercaptobenzothiazoles from benzothiazoles and thiols, and demonstrates its applicability to thiazole, benzimidazole, and indole heterocycles. The reaction proceeds via CuI/bipyridine/Na₂CO₃‑promoted C–H activation, and detailed mechanistic work reveals the formation of a copper‑thiolate intermediate that drives the thiolation. Computational and experimental evidence shows that the [(L)Cu(SR)] complex is the first reactive intermediate and that a stepwise hydrogen‑atom‑abstraction pathway is energetically favored over alternative mechanisms.

Abstract

We report the synthesis of a series of aryl- or alkyl-substituted 2-mercaptobenzothiazoles by direct thiolation of benzothiazoles with aryl or alkyl thiols via copper-mediated aerobic C-H bond activation in the presence of stoichiometric CuI, 2,2'-bipyridine and Na(2)CO(3). We also show that the approach can be extended to thiazole, benzimidazole, and indole substrates. In addition, we present detailed mechanistic investigations on the Cu(I)-mediated direct thiolation reactions. Both computational studies and experimental results reveal that the copper-thiolate complex [(L)Cu(SR)] (L: nitrogen-based bidentate ligand such as 2,2'-bipyridine; R: aryl or alkyl group) is the first reactive intermediate responsible for the observed organic transformation. Furthermore, our computational studies suggest a stepwise reaction mechanism based on a hydrogen atom abstraction pathway, which is more energetically feasible than many other possible pathways including β-hydride elimination, single electron transfer, hydrogen atom transfer, oxidative addition/reductive elimination, and σ-bond metathesis.