Copper mediated oxidative C-H sulfonylation of aldehydes and amines: a study of reactivity and mechanism
File(s)
Author(s)
Higham, Joe Ivan
Type
Thesis
Abstract
Oxidative couplings have emerged as a powerful means of coupling two nucleophilic components ‘head on’. An oxidant is required to sequester electrons formed as part of the reaction. When coupling substrates possessing oxidatively sensitive moieties, the properties of the oxidant must be carefully controlled to prevent degradation. This thesis describes work achieved using an oxidative coupling approach to achieve C–H functionalisation of aldehydes and amines with high site selectivity. Chapter 1 introduces the concepts of C–H activation and oxidative couplings, and chapter 2 details the aims of this thesis to achieve selective -, - and -functionalisation.
As described in chapter 3, highly selective -sulfonylation of branched aldehydes using sulfinate salts is achieved through the in situ generation of copper enolates. Subsequent aldehyde derivatisation enables access to a wide range of functionally diverse sulfone compounds, in only two steps from commercial starting materials. The acid tuneable oxidation potential of MnO2 is used to achieve an efficient coupling without degradation of the aldehyde moiety.
More challenging -sulfonylation of benzaldehydes is described in chapter 4, in which a catalytic transient directing group strategy is employed to successfully direct copper and generate a cupracycle intermediate to couple with sulfinate salts. -Sulfonylation of 2-napthaldehydes is efficiently achieved by a proposed [6,6] cupracyclic intermediate. In addition to demonstrating product derivatisation, mechanistic understanding is achieved by deuteration, kinetics and DFT studies highlighting a turnover limiting Wheland-type mode of C–H activation.
The development of an improved dual catalytic system for the -sulfonylation of benzylamines is described in chapter 5, whereby co-catalytic copper and 2-hydroxynicotinaldehyde are employed to achieve C–H sulfonylation using MnO2 as a cheap stoichiometric oxidant. Deuteration and DFT studies indicate a similar mechanism to the methodology described in chapter 4, however with a fundamentally reversable but turnover–limiting C–H activation step.
As described in chapter 3, highly selective -sulfonylation of branched aldehydes using sulfinate salts is achieved through the in situ generation of copper enolates. Subsequent aldehyde derivatisation enables access to a wide range of functionally diverse sulfone compounds, in only two steps from commercial starting materials. The acid tuneable oxidation potential of MnO2 is used to achieve an efficient coupling without degradation of the aldehyde moiety.
More challenging -sulfonylation of benzaldehydes is described in chapter 4, in which a catalytic transient directing group strategy is employed to successfully direct copper and generate a cupracycle intermediate to couple with sulfinate salts. -Sulfonylation of 2-napthaldehydes is efficiently achieved by a proposed [6,6] cupracyclic intermediate. In addition to demonstrating product derivatisation, mechanistic understanding is achieved by deuteration, kinetics and DFT studies highlighting a turnover limiting Wheland-type mode of C–H activation.
The development of an improved dual catalytic system for the -sulfonylation of benzylamines is described in chapter 5, whereby co-catalytic copper and 2-hydroxynicotinaldehyde are employed to achieve C–H sulfonylation using MnO2 as a cheap stoichiometric oxidant. Deuteration and DFT studies indicate a similar mechanism to the methodology described in chapter 4, however with a fundamentally reversable but turnover–limiting C–H activation step.
Version
Open Access
Date Issued
2022-10-10
Date Awarded
01/12/2022
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Bull, James
Sponsor
Royal Society
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)