Catalytic hydrosilylation in reductive ether synthesis and reductive Beckmann rearrangements

Wilson, James (2022) Catalytic hydrosilylation in reductive ether synthesis and reductive Beckmann rearrangements. PhD thesis, University of Nottingham.

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Abstract

This thesis explores some of the applications of hydrosilanes as reducing agents for the introduction of carbon-heteroatom bonds in contemporary organic synthesis. Two approaches are considered in detail: the synthesis of ethers through ester reduction and a reductive variation of the Beckmann rearrangement for the installation of a secondary amine.

Chapter 1 introduces the chemistry of organosilicon compounds and their role in synthesis. This chapter gives a theory-based overview of bonding at silicon which is used to explain the unique properties of organosilanes. This is supplemented by selected examples of practical synthesis methods where silicon plays an essential role in mediating reactivity. The chapter finishes on the main strategies to activate hydrosilanes and describes how this enables their widespread use as versatile reducing agents.

Chapter 2 explores methods for the formation of a carbon-oxygen bond, focussing on catalytic hydrosilylation as an emerging technique to synthesise ethers from esters. It describes the novel application of iron trichloride as an abundant and inexpensive catalyst for this transformation. Efforts to optimise this reaction are presented along with its implementation in a telescoped one-pot reductive etherification, using carboxylic acids as abundant electrophiles.

Chapter 3 broadly focusses on the merger of the hydrosilylation with the Beckmann rearrangement to reductively insert a nitrogen atom into a carbon-carbon bond. Two methods are described. The first uses triflic anhydride to facilitate an interrupted Beckmann rearrangement wherein the rich chemistry of nitrilium ions can be exploited (Figure 2A and 2B). The scope of this activation has been explored through the development of a mild, catalytic hydrosilylation to access structurally diverse amines, however further diversifications have also been demonstrated. The second-generation procedure (Figure 2C) initiates a Beckmann rearrangement using substoichiometric mesic anhydride, with the resulting sulfonic acid byproducts being used to activate phenylsilane towards a zinc-catalysed amide reduction. Finally, the reductive Beckmann reaction has been utilised in the first enantioselective synthesis of (-)-meptazinol, in which the active pharmaceutical ingredient is constructed over 6 steps in an 11% yield with an enantiomeric excess of 92%.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Denton, Ross
Keywords: Catalytic hydrosilylation, Reductive ether synthesis, Reductive Beckmann rearrangements
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 71521
Depositing User: Wilson, James
Date Deposited: 14 Dec 2022 04:40
Last Modified: 14 Dec 2022 04:40
URI: https://eprints.nottingham.ac.uk/id/eprint/71521

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