C7‐Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

Abstract

C7−H‐functionalized indoles are ubiquitous structural units of biological and pharmaceutical compounds for numerous antiviral agents against SARS‐CoV or HIV‐1. Thus, achieving site‐selective functionalizations of the C7−H position of indoles, while discriminating among other bonds, is in high demand. Herein, we disclose site‐selective C7−H activations of indoles by ruthenium(II) biscarboxylate catalysis under mild conditions. Base‐assisted internal electrophilic‐type substitution C−H ruthenation by weak O‐coordination enabled the C7−H functionalization of indoles and offered a broad scope, including C−N and C−C bond formation. The versatile ruthenium‐catalyzed C7−H activations were characterized by gram‐scale syntheses and the traceless removal of the directing group, thus providing easy access to pharmaceutically relevant scaffolds. Detailed mechanistic studies through spectroscopic and spectrometric analyses shed light on the unique nature of the robust ruthenium catalysis for the functionalization of the C7−H position of indoles.

Recent Advances in Metal‐Catalyzed Functionalization of Indoles

“…In 2020, Ackermann and co‐workers reported a novel carboxylate‐assisted Ru(II)‐catalyzed C7−selective C−H amidation and olefination of indoles using N‐pivaloyl as a key directing group (Scheme 31). [56] Notably, only the combination of N‐pivaloyl directing group and the biscarboxylate Ru(II) catalyst, [Ru(OAc) 2 ( p ‐cym)], [11] facilitated the C7−H amidation, while other directing groups and catalysts did not afford the desired product. For amidation, indole and sulfonyl azide were reacted in TFE at 40 °C in the presence of a [Ru(OAc) 2 ( p ‐cym)] (10 mol%) and AgSbF 6 (20 mol%).…”

“… Ruthenium‐catalyzed C7−H selective amination and olefination of indoles by Ackermann [56] …”

Recent Advances in Metal‐catalyzed Alkylation, Alkenylation and Alkynylation of Indole/indoline Benzenoid Nucleus

“…Later, Ackermann and co‐workers developed a Ru‐catalyzed C7‐alkenylation of indoles via C7−H bond activation using acrylates at ambient temperature (Scheme 44). [45] The scale‐up and easy‐removal of the DG are the important features.…”

External oxidant-compatible phosphorus(III)-directed site-selective C–H carbonylation

“…1B, bottom). Because of the inherent reactivity of these two positions in indoles, the C7selectivity faces substantial challenges (37)(38)(39)(40)(41)(42).…”