Direct ⍺-C–H Functionalisation of Cyclic Alkylamines

Saturated N-alkyl heterocycles are among the most important structural motifs in natural products, small-molecule biological probes and pharmaceutical agents. Substituted derivatives of these cyclic tertiary alkylamine scaffolds often exhibit markedly different physicochemical and biological properties compared to their unsubstituted counterparts. Consequently, methods for the selective functionalisation of these scaffolds would greatly facilitate the optimisation of biological activity, physicochemical properties and the systematic evaluation of structure-activity relationships. This thesis describes efforts towards the development of a novel transformation for the direct ⍺-functionalisation of N-alkyl piperidines through the design of a sequential process involving iminium ion formation followed by the 1,2-addition of carbon-based nucleophiles. Key to this strategy was the selective formation of endo-iminium ions from six-membered N-heterocycles, achieved via α-C–H elimination from the corresponding cyclic tertiary alkylamine N-oxides. The subsequent in situ addition of diverse carbon-based nucleophiles to the iminium intermediates enabled the α-alkylation and α-trifluoromethylation across a range of piperidine-based systems. Furthermore, the formal C–H functionalisation sequence was successfully applied to the late-stage modification of complex bioactive molecules, underscoring the potential of this methodology to expand drug-like chemical space.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Phillips, Rachel

Advisor dc:contributor.advisor

• Gaunt, Matthew

• alkylamine
• iminium ion
• ⍺-C–H Functionalisation

Licence

• https://www.repository.cam.ac.uk/bitstreams/ea54a8c7-d210-4dd8-9726-fc75aaad9453/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.123720

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/393365