Conformation-driven C3-C(sp3)–H arylation of saturated azacycles using Pd catalyst
- 1Department of Chemistry, The Scripps Research Institute, La Jolla, CA USA
Abstract
Directed Pd-catalysed site-selective C(sp3)–H activation offers an effective route to functionalized amines that are highly valued yet synthetically challenging in drug discovery. Despite the central importance of diverse saturated azacycles in biologically active molecules, a general strategy harnessing native endocyclic nitrogen that only works for specific types of conformation as the directing element for C–H activation of these scaffolds has remained unsolved due to conformational constraints imposed by transannular transition states. Here we report a Pd-catalysed, site- and diastereo-selective C3-C(sp3)–H arylation of saturated azacycles, enabled by temporarily converting the endocyclic nitrogen into an N-oxide directing group and a bifunctional ligand. This one-bond extension strategy enables favourable five-membered cyclopalladation, with axial N-oxide orientation being crucial for overcoming transannular ring strain as to reach the syn-axial C3-C(sp3)–H bond. The C–H activation of secondary and tertiary amines under directed Pd(II) catalysis remains challenging. Now the authors report a Pd-catalysed, site- and diastereoselective C3-C(sp3)–H arylation of saturated azacycles, enabled by conversion of the endocyclic nitrogen as N-oxide directing group and a bifunctional ligand.
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BibTeX
@article{chen2026conformationdriven,
title = {{Conformation-driven C3-C(sp3)–H arylation of saturated azacycles using Pd catalyst}},
author = {Chia-Yu Chen and Zhoulong Fan and Daniel A. Strassfeld and Hau Sun Sam Chan and Miguel Cohen Suarez and Md Emdadul Hoque and Jin‐Quan Yu},
journal = {Nature Catalysis},
year = {2026},
month = jun,
doi = {10.1038/s41929-026-01548-1},
url = {https://doi.org/10.1038/s41929-026-01548-1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Conformation-driven C3-C(sp3)–H arylation of saturated azacycles using Pd catalyst
AU - Chia-Yu Chen
AU - Zhoulong Fan
AU - Daniel A. Strassfeld
AU - Hau Sun Sam Chan
AU - Miguel Cohen Suarez
AU - Md Emdadul Hoque
AU - Jin‐Quan Yu
PY - 2026
DA - 2026/06/02
JO - Nature Catalysis
DO - 10.1038/s41929-026-01548-1
UR - https://doi.org/10.1038/s41929-026-01548-1
AB - Directed Pd-catalysed site-selective C(sp3)–H activation offers an effective route to functionalized amines that are highly valued yet synthetically challenging in drug discovery. Despite the central importance of diverse saturated azacycles in biologically active molecules, a general strategy harnessing native endocyclic nitrogen that only works for specific types of conformation as the directing element for C–H activation of these scaffolds has remained unsolved due to conformational constraints imposed by transannular transition states. Here we report a Pd-catalysed, site- and diastereo-selective C3-C(sp3)–H arylation of saturated azacycles, enabled by temporarily converting the endocyclic nitrogen into an N-oxide directing group and a bifunctional ligand. This one-bond extension strategy enables favourable five-membered cyclopalladation, with axial N-oxide orientation being crucial for overcoming transannular ring strain as to reach the syn-axial C3-C(sp3)–H bond. The C–H activation of secondary and tertiary amines under directed Pd(II) catalysis remains challenging. Now the authors report a Pd-catalysed, site- and diastereoselective C3-C(sp3)–H arylation of saturated azacycles, enabled by conversion of the endocyclic nitrogen as N-oxide directing group and a bifunctional ligand.
SN - 2520-1158
ER -