Purdue University Graduate School
Browse

Radical Functionalization Reactions of gem-Difluoroalkenes and Palladium-Catalyzed C-H Functionalization of (Hetero)Arenes

thesis
posted on 2025-01-29, 19:38 authored by Andrew John IntelliAndrew John Intelli

The installation of fluorine and fluorinated moieties into molecules can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds relevant to the development of therapeutics, agrichemicals and biological probes. However, some fluorinated functional groups lie outside of current synthetic methodologies. To address the gap in synthetic methodology, our group exploits reactions of gem-difluoroalkenes as synthons for gem-difluoro-containing molecules. Although functionalization reactions of gem-difluoroalkenes are well known, these reactions typically result in a net C-F functionalization to deliver mono-fluorovinyl products. Thus, the work in the Altman lab is to develop hydro or difunctionalization reactions of gem-difluoroalkenes that avoid kinetically facile β-F elimination events from unstable anionic intermediates. One way to circumvent the β-F elimination pathway is through radical addition reactions, which avoid unstable anionic intermediates. Thus, this dissertation discusses two such processes: a peroxide initiated hydrophosphinylation of gem-difluoroalkenes (Chapter 2) and a palladium and copper co-catalyzed chloro-arylation reaction of gem-difluorostyrenes (Chapter 3).

C-H functionalization strategies enable rapid diversification of a wide array of substrates which are important in drug discovery, agrichemicals, and the pharmaceutical industry. In particular, the practical advantages of aryl C-H functionalization depends on the chemoselective activation of a single C-H bond over many others in a substrate (i.e. benzylic vs aryl o/m/p), which is challenging to control. Many attempts using pre-functionalized substrates have been reported, however, a method that delivers C-H functionalized products without bulky directing groups is scarce. Thus, this dissertation discusses two C-H functionalization reactions: a dearomatization and C-H functionalization of a substituted benzothiophene and a palladium-catalyzed para-selective C-H functionalization of arenes.

History

Degree Type

  • Doctor of Philosophy

Department

  • Medicinal Chemistry and Molecular Pharmacology

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Ryan Altman

Additional Committee Member 2

V. Jo Davisson

Additional Committee Member 3

Dan Flaherty

Additional Committee Member 4

David Thompson

Usage metrics

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC