We report a Brønsted acid-catalyzed carbocyclization cascade, featuring condensation of an alcohol/sulfonamide with an aldehyde followed by an intramolecular three-component coupling involving an alkyne, an oxocarbenium/iminium ion, and an arene. A formal cycloaddition is embedded in the cationic cascade, which enables the synthesis of a wide range of fused heterotricycles. The diastereoselectivity of the cascade is studied using secondary alcohols/sulfonamides with different carbonyl partners. The described method results in the preparation of synthetically versatile scaffolds with ample opportunity for further derivatization at the resulting tetrasubstituted olefin, or by inclusion of other functionalizable motifs from the starting materials. It is worth noting that this chemistry also facilitates the synthesis of piperidines and 1,4-oxazepanes, as well as the inclusion of indoles and benzofurans, which are privileged motifs for medicinal chemistry. Herein we present the generality of this approach and some chemical transformations that can be achieved with our substrates.
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Design principles of the use of alkynes in radical cascades
One of the simplest organic functional groups, the alkyne, offers a broad canvas for the design of cascade transformations in which up to three new bonds can be added to each of the two sterically unencumbered, energy-rich carbon atoms. However, kinetic protection provided by strong π-orbital overlap makes the design of new alkyne transformations a stereoelectronic puzzle, especially on multifunctional substrates. This Review describes the electronic properties contributing to the unique utility of alkynes in radical cascades. We describe how to control the selectivity of alkyne activation by various methods, from dynamic covalent chemistry with kinetic self-sorting to disappearing directing groups. Additionally, we demonstrate how the selection of reactive intermediates directly influences the propagation and termination of the cascade. Diverging from a common departure point, a carefully planned reaction route can allow access to a variety of products.
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- Award ID(s):
- 2102579
- NSF-PAR ID:
- 10408059
- Editor(s):
- Stephanie Greed
- Date Published:
- Journal Name:
- Nature Reviews Chemistry
- ISSN:
- 2397-3358
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41570-023-00479-w
