Domino C−S/C−N Bond Formation Using Well‐Defined Copper‐Phosphine Complex Catalyst: Divergent Approach to 3‐Sulfenylated Indoles

Abstract

A protocol was developed for the synthesis of 3-thioindoles in good-to-excellent yields involving sulfenylation between 2-nitrocinnamaldehydes and various thiols using a well-defined copper(I)-phosphine complex catalyst. This unconventional divergent approach involves in situ generation of indoles via domino CÀ S/CÀ N bond formation initiated by sulfa-Michael addition followed by intramolecular N-heteroannulation. This protocol shows good chemoselectivity and broad substrate scope. To briefly demonstrate the value of this approach, 2-benzoyl-3-sulfenylated indoles were prepared from commercially available 2-nitrochalcones and thiols.

Copper–Catalyzed Construction of the Indole Core: Recent Advancements

“…In 2019, Lee et al carried out heteroannulation of 2-nitrocinnamaldehyde 56 with thiols 57 for direct construction of 3thioindoles 58 with the aid of Cu(I)-phosphene complex. [71] The reaction showed good tolerance towards 2-nitrocinnamaldehydes and a range of alkyl, aryl, heteroaryl substituted thiol systems (61-97 % yield). Under similar reaction conditions the use of o-nitrochalcones 59 instead of nitrocinnamaldehyde 56 delivered 2-benzoyl-3-sulfenylated indoles 60 in good yields.…”

“…In 2019, Lee et al carried out heteroannulation of 2‐nitrocinnamaldehyde 56 with thiols 57 for direct construction of 3‐thioindoles 58 with the aid of Cu(I)‐phosphene complex [71] . The reaction showed good tolerance towards 2‐nitrocinnamaldehydes and a range of alkyl, aryl, heteroaryl substituted thiol systems (61–97 % yield).…”

Annulation strategies for diverse heterocycles via the reductive transformation of 2-nitrostyrenes

“…In 2019, our group developed a new methodology for the direct construction of aryl-and heteroaryl-substituted indoles via C–N/C–S bond formation using a copper( i )-phosphine complex catalyst. 57 We found that the heteroannulation reaction of 2-nitrocinnamaldehydes 1a and thiols 85 in the presence of copper triphenylphosphine provided 3-sulfenylated indoles 86 via a sulfa-Michael addition followed by intramolecular reductive N-heteroannulation (Scheme 29). This reaction was highly tolerant to diversely substituted 2-nitrocinnamaldehydes 1a and thiols 85 bearing heterocyclic, alkyl, or aryl substituents with different electronic environments.…”