Development of a Novel, Highly Efficient Halide-Catalyzed Sulfenylation of Indoles

Abstract

[reaction: see text] The reaction of a variety of indoles with N-thioalkyl- and N-thioarylphthalimides to produce 3-thioindoles is reported. Catalytic quantities of halide-containing salts are crucial to the success of this reaction. This highly efficient reaction provides sulfenylated indoles from bench-stable, readily available starting materials in good to excellent yields.

An Efficient Catalytic Method for Regioselective Sulfenylation of Electron‐Rich Aza‐Aromatics at Room Temperature

“…Among these, CeCl 3 was found to be the most effective reagent, and gave the best results. The reactivity observed in all cases indicates that the reaction was being catalyzed by Lewis acidic cerium rather than the counter‐ion in CeCl 3 25. Thus, even though it would be premature to speculate on the exact nature of the mechanism, our findings can be rationalized by assuming that under these conditions,19c,22b an initial coordination of a cerium(III) Lewis acid species occurs at the oxygen of the imidic group (Scheme ).…”

“…It is difficult to rationalize how these reactions could fail if a very reactive sulfenyl iodide was formed as intermediate. Certainly, we cannot definitely rule out the possibility of the formation of a transient sulfenyl iodide as the actual sulfur‐transfer reagent, as in the mechanism described by Tudge 25. However, the high lability of sulfenyl iodides, compared to those of other halides,42 and their fast disproportionation to give disulfides, which were never isolated or observed as by‐products in our experiments, seem to suggest that the actual sulfur‐transfer species is a Lewis‐acid‐activated N ‐thiophthalimide, as shown in Scheme , and not a sulfenyl iodide.…”

“…Thus, a general electrophilic aromatic substitution reaction of indoles and pyrroles with this type of sulfur electrophile reagents under mild conditions of CeCl 3 · 7H 2 O/NaI catalysis seemed an attractive proposition. Indeed, our efforts have allowed us to develop a new general procedure that proceeds under mild catalytic reaction conditions, and unlike the method reported by Tudge et al,25 we have developed a sulfenylation protocol that proceeds at room temperature.…”

A Practical Regioselective Synthesis of Alkylthio- or Arylthioindoles without the Use of Smelly Compounds Such as Thiols

“…14) Many methods have been reported [15][16][17][18][19][20][21] for the synthesis of 3-alkyl-(or aryl-) thioindole derivatives, and some studies have utilized alkylsulfenyl chloride [15][16][17] alkyldisulfide, 18) or N-alkylthiophthalimide 20,21) as umpolung sulfonium cations. However, these reactions are directly substituted by the electron donating alkyl-or arylsulfanyl group.…”

Preparation of Sulfenyl Pyrroles

“…Furthermore, N-(phenylthio)phthalimide, [25][26][27] which has been used with enolates, enamines, and oximes, 28,29 has recently been utilized in the preparation of 3-sulfenyl indoles. 30 In this reaction, catalytic amounts of MgBr 2 (or alternative halide sources) activate the reagent to generate the corresponding sulfenyl bromide in situ, a process driven by concomitant loss of the phthalimide anion. Thus, N-(phenylthio)phthalimide is a stable and essentially odorless sulfenylating agent that is activated, only upon demand, through halide catalysis.…”