Gold(I)-Catalyzed Synthesis of 3-Sulfenyl Pyrroles and Indoles by a Regioselective Annulation of Alkynyl Thioethers

Abstract

The combination of nucleophilic nitrenoids and π-acid catalysis has emerged as a powerful tool in heterocycle synthesis. Accessing more varied heterocycle-substitution patterns by maintaining the same reaction pathways across different alkynes remains a challenge. Here we show that Au(I) catalysis of isoxazole-based nitrenoids with alkynyl thioethers provides controlled access to (3 + 2) annulation by a regioselective addition β to the sulfenyl group. The reaction with isoxazole-containing nitrenoids delivers sulfenylated pyrroles and indoles as single regioisomers bearing useful functional groups and structural variety.

Gold‐Catalyzed Annulations with Nucleophilic Nitrenoids Enabled by Heteroatom‐Substituted Alkynes

“…As shown in the reactions of alkynyl thioethers and isoxazoles, the use of gold catalysis delivers the annulation pathway that was not accessible under Zn(II) catalysis, so in that case at least the approaches complement each other. [50][51] In our experience, gold catalysis appears to offer a uniquely broad applicability, certainly as a tool for reaction discovery. The challenge of cost and sustainability could also be addressed through the development of more effective gold catalysts that can be used at much lower loadings.…”

“…[49] Sulfenylated pyrroles 77 were prepared as single regioisomers under Au(I) catalysis (Scheme 17). [50] The most effective catalyst was a N-heterocyclic carbene stabilized Au(I) complex. This observation contrasts with the inefficiency of such precatalyst systems with the N-substituted pyridinium N-aminide reactants, and highlights the importance of the type of nitrenoid in elucidating the most effective conditions.…”

“…[51] The reaction of alkynyl thioether 71 a with a trisubstituted isoxazoles 80 led to an annulation with rearrangement and desulfenylation to give pyrrole 82, alongside 81, raising the prospect of using a thioether as a traceless directing group in catalysis (Scheme 19). [50]…”

Transition Metal‐Mediated Functionalization of Isoxazoles: A Review

“…In the case of C4-substituted isoxazoles, in addition to the deacylative mechanisms, an unprecedented 1,5-acyl migration followed by desulfenylation could produce the all-carbon substituted pyrroles (Scheme 44). [65] Au-catalyzed annulation reactions of isoxazoles have been well developed while non-noble metal-catalyzed annulations (via the generation of an α-imino metal carbene intermediate) are scarce. In this regard, in 2018, Ye and co-workers reported a Zn-catalyzed formal [3 + 2] annulation of isoxazoles with ynol ethers leading to the synthesis of 2-alkoxyl 1H-pyrroles and 3H-pyrroles.…”

“…Recently, Davies and co‐workers reported an Au(I)‐catalyzed regioselective [3+2] annulation of alkynyl thioethers with isoxazoles and anthranils leading to the synthesis of 3‐sulfenyl pyrroles and indoles (Scheme 44). [65] In the final step, the desulfenylation led to an one‐step access to all‐carbon‐substituted pyrroles.…”