Skip navigation
Please use this identifier to cite or link to this item:
Title: Palladium(0)-Catalyzed Aliphatic Carbon-Fluorine Bond Formation: Methods and Mechanism
Authors: Katcher, Matthew Herman
Advisors: Doyle, Abigail G.
Contributors: Chemistry Department
Keywords: allylic
Subjects: Organic chemistry
Inorganic chemistry
Issue Date: 2013
Publisher: Princeton, NJ : Princeton University
Abstract: Methods for carbon–fluorine (C–F) bond formation are widely practiced for the synthesis of materials, pharmaceuticals, agrochemicals, and radiotracers. However, the mild and selective introduction of fluorine into an organic molecule remains challenging. In particular, the formation of aliphatic C–F bonds presents significant difficulties related to chemo-, stereo-, and regioselectivity. This dissertation describes the application of palladium catalysis to new methods for aliphatic C–F bond formation. Notably, these methods rely on a nucleophilic source of fluorine, silver(I) fluoride, to achieve the desired reactivity and selectivity. The reactions described herein access allylic fluorides and monofluoromethylated heterocycles. These compounds, or derivatives thereof, are valuable in medicinal chemistry. We first illustrate the development of a catalytic method for the asymmetric synthesis of cyclic allylic fluorides. This transformation converts allylic chlorides to enantioenriched allylic fluorides using a Pd(0) catalyst and Trost bisphosphine ligand. Importantly, the reactions proceed with unprecedented ease of operation for Pd-mediated nucleophilic fluorination and allow access to organofluorine compounds that bear diverse functional groups. These conditions were then applied to the fluorination of acyclic allylic chlorides and bromides, yielding branched allylic fluorides in high selectivity. The regioselectivity obtained in this reaction is significantly higher than that observed in allylic substitutions with other nucleophiles. Many of the significant synthetic limitations previously associated with the preparation of branched allylic fluorides are overcome by this catalytic method. We then extended this reactivity to a Heck-fluorination cascade for tandem C–C and C–F bond formation. The intramolecular palladium-catalyzed carbofluorination of allenes provides monofluoromethylated heteroarenes. An intermolecular variant for the three-component coupling of allenes, aryl iodides, and silver(I) fluoride is also described. These reactions all proceed through an allylpalladium(II) intermediate, and the mechanism of C–F bond formation from this intermediate was investigated in detail. The data obtained from experimental and theoretical studies are most consistent with an outer-sphere mechanism in which a neutral allylpalladium fluoride attacks a cationic allypalladium electrophile. The observed reactivity and selectivity for C–F bond formation result from the unique characteristics of these intermediates. Late, product-like transition states are identified to rationalize regioselectivity.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

Files in This Item:
File Description SizeFormat 
Katcher_princeton_0181D_10636.pdf10.4 MBAdobe PDFView/Download

Items in Dataspace are protected by copyright, with all rights reserved, unless otherwise indicated.