Issue 11, 2025

Site- and stereoselective silver-catalyzed intramolecular amination of electron-deficient heterobenzylic C–H bonds

Abstract

We report a method for the site- and stereoselective intramolecular amination of electron-deficient heterobenzylic C–H bonds via silver-catalyzed nitrene transfer (NT). A silver complex supported by a tripodal piperidine-based ligand afforded excellent reactivity under mild conditions (up to 96% yield), site-selectivity (up to >20 : 1), and diastereoselectivity (up to >20 : 1 dr) for the amination of heterobenzylic C–H bonds that reacted poorly with other metal-based catalysts for NT. Our catalyst proved highly amenable to substrates bearing diverse competing sites for functionalization, including complex molecules derived from pharmaceuticals and natural products. Ligand screening revealed the importance of scaffold rigidity, leading to the discovery of an analogous quinuclidine-based ligand that further improved the site-selectivity against tertiary C–H bonds in a handful of challenging substrates. The cyclic sulfamate products were readily converted into highly functionalized motifs containing nitrogen-based heterocycles and diverse functional groups. Mechanistic studies suggested a radical-based pathway displaying relatively low sensitivity towards the electronic profiles of the heterobenzylic C–H bond, which contributes to the excellent substrate tolerance of this method.

Graphical abstract: Site- and stereoselective silver-catalyzed intramolecular amination of electron-deficient heterobenzylic C–H bonds

Associated articles

Supplementary files

Article information

Article type
Edge Article
Submitted
27 Dec 2024
Accepted
07 Feb 2025
First published
07 Feb 2025
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2025,16, 4796-4805

Site- and stereoselective silver-catalyzed intramolecular amination of electron-deficient heterobenzylic C–H bonds

T. A. Trinh, S. Cherempei, D. S. Rampon and J. M. Schomaker, Chem. Sci., 2025, 16, 4796 DOI: 10.1039/D4SC08757G

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