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Direct ⍺-C–H Functionalisation of Cyclic Alkylamines https://doi.org/10.17863/CAM.123720 Phillips, Rachel Gaunt, Matthew 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. University of Cambridge 2025-09-16 Thesis Doctoral Doctor of Philosophy (PhD) eng SynTech CDT https://www.repository.cam.ac.uk/handle/1810/393365 https://www.repository.cam.ac.uk/bitstreams/83f50852-de5b-40c4-9dcc-9bdb32c03a5a/download c585afbd1556d80e01a31508090e91d4 https://www.repository.cam.ac.uk/bitstreams/ea54a8c7-d210-4dd8-9726-fc75aaad9453/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved alkylamine iminium ion ⍺-C–H Functionalisation