New Catalytic Strategies for Metal-Free C–C Bond Formation

Abstract

This thesis describes investigations into new methods for metal-free C(sp³)-C(sp³) bond formation using ‘traceless’ activating groups, with a particular focus on saturated nitrogen heterocycles.

Chapter 1 provides an introduction to C(sp³)–C(sp³) bond formation, outlining the
state-of-the-art in alkyl–alkyl cross-coupling using both transition metal catalysis and radical chemistry, including visible-light photoredox catalysis.

Chapter 2 discusses attempts to utilise N-tosylhydrazones as ‘traceless’ activating groups for alkyl–alkyl cross-coupling via radical intermediates. Using photoredox catalysis with a variety of alkyl radical precursors (e.g. carboxylates, NHPI esters, silicates, trifluoroborates, C–H bonds), the reactivity of N-tosylhydrazones as radical acceptors is explored. The ultimate objective is to sequence alkyl radical addition to the C=N bond with concomitant generation of alkyl N-H diazene intermediates that extrude N₂, enabling a ‘traceless’ C(sp³)–C(sp³) coupling.

Chapter 3 details efforts to extend the ‘traceless’ alkyl–alkyl cross-coupling concept with N-tosylhydrazones to the synthesis of α-alkylated, saturated nitrogen heterocycles. Photoredox catalysis is used to access α-amino radicals from the α-C–H bonds of N-aryl or N-Boc amines, and trapping of these intermediates with N-tosylhydrazones is explored.

Chapter 4 describes the development of γ-amino phosphine oxide reagents (termed ‘amino phosphine oxide protocol’ or ‘A-POP’ reagents) for the modular, one-pot synthesis of α-aryl pyrrolidines from aromatic aldehydes. A simple imine formation and base-mediated 5-endo-trig cyclisation leads, under the same conditions, to an unusual elimination of a diphenylphosphinyl group, affording 1-pyrroline products. Again, this constitutes a ‘traceless’ C(sp³)–C(sp³) bond formation, and it opens up a realm of possibilities for (stereoselective) saturated azacycle synthesis.

Date of Award	8 Sept 2021
Original language	English
Awarding Institution	University of Bath
Supervisor	Alex Cresswell (Supervisor), Steven Bull (Supervisor) & Darren Stead (Supervisor)