A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams

Carbonyl compounds are of central importance to organic chemistry and their reactions have been described as the ‘backbone of organic synthesis’. Over recent decades, palladium-catalysed C–H carbonylation reactions have emerged as a powerful means of introducing carbonyl motifs to organic molecules. This thesis describes the development of a general C–H carbonylation reaction of secondary aliphatic amines, which provides facile access to synthetically useful β-lactam products. The first part of the thesis explores the scope and limitations of this reaction. Whilst previous C(sp3)–H carbonylation methodologies were restricted to ‘Type F’ secondary aliphatic amines, the reaction described in this thesis was found to be broadly applicable all structural sub-classes of secondary aliphatic amine. Furthermore, the reaction was found to be remarkably tolerant of functional groups, even those that commonly cause issues in palladium-catalysed C–H activation reactions such as heteroaromatics and thioethers. The second part of this thesis investigates the mechanism of this C–H carbonylation reaction. Interestingly, the reaction was found not to proceed via a traditional C–H carbonylation mechanism comprising of C–H activation, 1,1-migratory carbon monoxide insertion and reductive elimination. Instead, a new mechanistic paradigm for palladium-catalysed C–H carbonylation is proposed, which invokes a putative ‘palladium anhydride’ intermediate. A series of DFT calculations and experiments were conducted in order to support this mechanistic proposal. The work described within this PhD thesis was published in Science.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2018

Author dc:creator

• Chappell, Benjamin Graham Neil

Advisor dc:contributor.advisor

• Gaunt, Matthew

• Palladium
• C–H activation
• Carbonylation
• Catalysis
• Organic Chemistry
• Beta lactams
• Aliphatic amines

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9a7a5f48-a216-4a4b-9a49-c6a1604e8f04/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

Author Identifier

0000-0001-8434-7818

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/274756