Issue 14, 2024

The “cesium effect” magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions

Abstract

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of β-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.

Graphical abstract: The “cesium effect” magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions

Supplementary files

Article information

Article type
Edge Article
Submitted
14 Jan 2024
Accepted
01 Mar 2024
First published
06 Mar 2024
This article is Open Access

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

Chem. Sci., 2024,15, 5277-5283

The “cesium effect” magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions

S. Biswas, W. B. Hughes, L. De Angelis, G. C. Haug, R. Trevino, S. O. Fremin, H. D. Arman, O. V. Larionov and M. P. Doyle, Chem. Sci., 2024, 15, 5277 DOI: 10.1039/D4SC00316K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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