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Lookup NU author(s): Jack Wootton, Natalie Roper, Dr Paul Waddell, Dr Roly ArmstrongORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
C–N atropisomeric amides are important compounds in medicinal chemistry and agrochemistry. Atropselective methods for their synthesis are therefore important. In this study, a novel strategy to make C–N atropisomeric amides based on intramolecular acyl transfer via a tethered Lewis basic pyridine or tertiary amine group is reported. The reactions operate under kinetic control and in most cases are highly atropselective, with the products isolable as pure, single atropisomers following chromatography. The kinetically favored atropisomer can also be isomerised into the alternative thermodynamically favored atropisomer upon heating. The kinetic and thermodynamic outcomes are supported by computational studies, while additional mechanistic studies support operation via initial fast acylation of the Lewis basic group, followed by rate-determining acyl transfer, which also enables control over the atropisomer formed.
Author(s): Wootton J, Roper NJ, Morris CE, Maguire VE, Duff L, Waddell PG, Whitwood AC, Gammons R, Miah AH, Lynam JM, Armstrong RJ, Unsworth WP
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2025
Volume: 16
Issue: 9
Pages: 3938-3945
Online publication date: 23/01/2025
Acceptance date: 19/01/2025
Date deposited: 23/01/2025
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D4SC05760K
DOI: 10.1039/D4SC05760K
Data Access Statement: The data that support the findings of this study are available in the supplementary material of this article, including detailed experimental procedures, characterization data for new compounds, and details of computational methods. Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre: CCDC 2363258 (6b), 2363259 (6e) 2363260 (6w) 2362628 (6zf), 2362629 (6zi) and 2363322 (9a).
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