Late-Stage Photoredox C-H Amidation of N-Unprotected Indole Derivatives: Access to N-(Indol-2-yl)amides

The late-stage functionalization of N-unprotected indoles can be useful for modifying low-molecular-weight drugs and bioactive peptides. Whereas indole carboxamides are valuable in pharmaceutical applications, the preparation N-(indol-2-yl)amides with similar structures continues to be challenging. Herein we report on visible-light-induced late-stage photoredox C-H amidation with N-unprotected indoles and tryptophan-containing peptides, leading to the formation of N-(indol-2-yl)amide derivatives. N-Unprotected indoles and aryloxyamides that contain an electron-withdrawing group could be coupled directly to eosin Y as the photocatalyst by irradiation with a green light-emitting diode at room temperature. Mechanistic studies and density functional theory calculations indicate that the transformation might proceed through the oxidative C-H functionalization of indole with a PS* to PS center dot- cycle. This protocol provides a new toolkit for the late-stage modification labeling and peptide-drug conjugation of N-unprotected indole derivatives.

Automated summary

This study presents a novel visible-light-induced late-stage photoredox C-H amidation method for the modification of N-unprotected indoles and tryptophan-containing peptides, leading to the formation of N-(indol-2-yl)amide derivatives. The mechanism involves the oxidative C-H functionalization of indole with a PS* to PS center dot- cycle, providing a new toolkit for the late-stage modification labeling and peptide-drug conjugation of N-unprotected indole derivatives.