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.