Structurally divergent reactivity of 2,2-disubstituted azetidines – mechanistic insights and stereochemical implications of amide coupling and ring expansion to 5,6-dihydro-4H-1,3-oxazines
File(s)
Published version
Author(s)
Sahay, Aditya K
Begg, Callum S
Zhang, Xiurong
Bull, James A
Spivey, Alan C
Type
Journal Article
Abstract
Azetidines have gained traction in drug discovery for their ability to introduce conformational constraint and modulate physiochemical properties. Strategies that enable their selective functionalization or controlled expansion into more complex scaffolds provide opportunities for molecular diversification to rapidly access new chemical space. Subjecting 2,2-disubstituted azetidines to amide coupling with carboxylic acids is found to effect either N-acylation or ring expansion to spiro and 6,6-disubstituted 5,6-dihydro-4H-1,3-oxazine, dependent on reaction conditions. A diverse range of topologically interesting heterocycles, which hold significant potential for pharmaceutical screening, have been prepared using this divergent reaction manifold. A mechanistic framework, supported by additive screening and trapping experiments, is presented to account for the ring expansion and racemization that accompanies these transformations when the substrate allows formation of a ring-opened azafulvenium intermediate.
Date Issued
2025-12-07
Date Acceptance
2025-08-26
Citation
Organic Chemistry Frontiers, 2025, 12 (23), pp.6556-6563
ISSN
2052-4129
Publisher
Royal Society of Chemistry
Start Page
6556
End Page
6563
Journal / Book Title
Organic Chemistry Frontiers
Volume
12
Issue
23
Copyright Statement
This journal is © the Partner Organisations 2025. This article is licensed under aCreative Commons Attribution-NonCommercial 3.0 Unported Licence (https://creativecommons.org/licenses/by-nc/3.0/)
License URL
Publication Status
Published
Date Publish Online
2025-08-28