Direct Bis-Alkyl Thiolation for Indoles with Sulfinothioates under Pummerer-Type Conditions

Abstract

A base-free bis-alkyl thiolation reaction of indoles with sulfinothioates under Pummerer-type conditions is described. Sulfinothioates, activated with 2,2,2-trifluoroacetic anhydride, are demonstrated to be an efficient thiolation reagent for wide applications. This approach enabled double C–H thiolation at the C2 and C3 of the indole in one pot. The mechanism studies suggested the thiolation was realized through the sulfoxonium salt rather than sulfenyl carboxylate.

Recent advances in selective mono-/dichalcogenation and exclusive dichalcogenation of C(sp2)–H and C(sp3)–H bonds

“…Organic & Biomolecular Chemistry (Scheme 22). 158 It was interesting to find that the model reaction between N-acetyl indole and S-ethylethanesulfinothioate produced only the dithiolated product even with 0.4 equiv. of sulfur source.…”

“…In the same year, Du and coworkers reported a base-free 2,3-dialkylthiolation of N -protected indoles 76 using sulfinothioates 80 as novel thiolation reagents and 2,2,2-trifluoroacetic anhydride (TFAA) as an activator under Pummerer-type conditions via electrophilic aromatic substitution pathways (Scheme 22). 158 It was interesting to find that the model reaction between N -acetyl indole and S -ethylethanesulfinothioate produced only the dithiolated product even with 0.4 equiv. of sulfur source.…”

S-Protected Cysteine Sulfoxide-Enabled Tryptophan-Selective Modification with Application to Peptide Lipidation

“…This cation then electro-philically attacks Trp at 37 °C to give the desired 3f. 36 Alternatively, the sulfonium cation is thought to participate in forming 3f′ at the low reaction temperature. The reactions of Ac-Nle-Cys(MBzl)(O)-NH 2 with Bz-Met-OMe in the presence or absence of Ac-Trp-OMe contributed to the identification of 3f′ (Figure S18).…”

“…We hypothesized that the dramatic change that was observed could be attributed to the S -chlorocysteine species reacting preferentially with Met rather than Trp to afford the S -sulfenylated Met sulfonium cation. This cation then electrophilically attacks Trp at 37 °C to give the desired 3f . Alternatively, the sulfonium cation is thought to participate in forming 3f′ at the low reaction temperature.…”