Issue 45, 2024

Dearomative spirocyclization of ynamides

Abstract

Spiro N-heterocycles, particularly aza-spiro piperidines, have shown significant promise in pharmaceutical applications due to their ability to enhance physicochemical properties. Despite their potential, the preparation of these complex structures poses significant challenges. To address this, we propose a one-pot dearomative spirocyclization reaction of ynamides. This method involves a copper-catalyzed carbomagnesiation reaction, achieving chemo-, regio-, and stereoselective formation of vinyl metal intermediates. Upon the addition of a Lewis acid, these intermediates undergo a regioselective nucleophilic dearomatization event, facilitating the synthesis of diverse aza-spiro dihydropyridine scaffolds with multiple functional handles. Various Grignard reagents, diverse ynamides, and acylating reagents have been explored. A subsequent hydrogenation reaction provides access to both partially and fully reduced spirocyclic frameworks, broadening the scope of spirocyclic structures with potential medicinal applications.

Graphical abstract: Dearomative spirocyclization of ynamides

Supplementary files

Article information

Article type
Edge Article
Submitted
18 Aug 2024
Accepted
21 Oct 2024
First published
22 Oct 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-NC license

Chem. Sci., 2024,15, 19136-19141

Dearomative spirocyclization of ynamides

M. Agbaria, N. Egbaria and Z. Nairoukh, Chem. Sci., 2024, 15, 19136 DOI: 10.1039/D4SC05541A

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