α-Alkylation of Cyclic Ketones via β-Alkoxyazoalkenes and β- Hydroxyazoalkenes

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2017-05

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Abstract

The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. The first chapter of this thesis provides an overview of this method as well as other ketone α-alkylation methods including α-alkylation of ketones using unactivated alkenes as electrophiles and α-alkylation of ketones via azoalkene species. Chapter 2 describes an α-alkylation method via β-alkoxyazoalkene intermediates. The transformation involves the addition of Grignard reagents to α-epoxy N-sulfonylhydrazones—directed by the alkoxide of the 1-azo-3-alkoxy propene intermediate formed in situ via base-induced ring opening of the epoxide—and leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonylhydrazones with α-quaternary centers. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl as well as alkenyl, aryl, allenyl and alkynyl groups. Some mechanistic studies involving the coordination of magnesium with the alkoxide of β-alkoxide azoalkene intermediate are described. As an extension of the ketone α-alkylation study, the final chapter demonstrates the use of 3-hydroxy-1-azopropenes—stable and isolable intermediates—as 1,3-dipoles for the formation of C-Nu and O-E bonds. This species possess multiple nucleophilic and electrophilic sites and may well inspire the development of a wide range of new synthetic methods and/or find application in the development of new drugs and materials. By taking advantage of the 1,3-dipolar nature of these functional groups, a new annulation strategy leading to syn-β,γ-fused γ-lactones, including those having quaternary centers, is described.

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Keywords

Ketone alpha alkylation, Alkoxyazoalkene, Hydroxyazoalkene

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