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Title: Palladium catalysed C(sp3)-H functionalisation of aldehydes and amines using transient imine directing groups
Author: St John-Campbell, Sahra
ISNI:       0000 0004 9356 7136
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Transition metal catalysed C–H functionalisation can enable more straightforward routes to small molecules by installing new C–C or C–X bonds in place of existing C–H bonds. C(sp3)⁠ H functionalisation is a particular challenge, and typically requires the presence of amide bound directing groups with distinct installation and removal steps, reducing efficiency. Transient directing groups bind to the substrate reversibly, facilitating directing group installation, C–H functionalisation and directing group removal, tracelessly and in one-pot. This thesis will describe the development of novel transient imine directing groups for the functionalisation of both aldehydes and amines. Section 3.1 describes the development of a direct β-C(sp3)–H arylation of tertiary aldehydes. Catalytic N-tosylethylenediamine was the optimal transient directing group for the arylation, however a large range of alternative amines were explored. Numerous aryl iodides and aldehydes could be used to form the products in good yields. The transient imine mechanism was supported through NMR studies and the isolation of an underivatised palladacycle. Section 3.2 explains methylene C–H arylation of secondary aliphatic aldehydes. Milder reaction conditions and β-aniline amide directing groups, which provided chelation through the carbonyl oxygen in a 6-membered palladacycle, provided the best results. The structures of the transient imino-amide directing groups were explored and compared with the parent acid. In Section 3.3, the first transient directing group promoted intramolecular C(sp3)–H annulation reaction was developed, using an amino-ether TDG. This is the only example of oxidative addition of a less reactive C–Br bond (vs C–I) using this approach. Section 3.4 describes applying ‘reverse’ transient imines for amine functionalisation. A simple aliphatic aldehyde was designed and developed, derived from an acetal precursor, that promotes selective γ-C(sp3)–H arylation of unprotected primary amines. Detailed mechanistic studies have been conducted to provide insight on the dual catalytic cycle.
Supervisor: Bull, James Sponsor: Engineering and Physical Sciences Research Council ; Royal Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral