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UC Berkeley Electronic Theses and Dissertations (2018)

Making and Breaking C‒F Bonds via Palladium-Catalysis

By

Richard Thornbury

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor F. Dean Toste, Chair

Chapter 1 – A ligand controlled, palladium-catalyzed, enantioselective 1,3-arylfluorination of [2H]-chromenes was developed. The products were obtained in high enantioselectivity and with a syn- relationship of the introduced substituents. The pyranyl fluoride products were further derivatized to demonstrate the utility of the products. A ligand dependent divergent formation of 1,3- and 2,1- alkene difunctionalization products was also observed. This bifurcation in reactivity was investigated with a combination of experimental, computational, and statistical analysis tools. Ultimately, the site selectivity was found to be dependent on the ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.

Chapter 2 – A palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids was developed. Broad functional tolerance arises from a redox-neutral process in which a palladium(II) active species which is proposed to undergo a β-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases. As a demonstration of this method’s unique combination of reactivity and functional group tolerance, a Gleevec analogue, using a monofluorostilbene as an amide isostere, was synthesized in 4 steps from commercially available materials.

    Cover page: Making and Breaking C‒F Bonds via Palladium-Catalysis
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2016)
    The palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids is described. Broad functional-group tolerance arises from a redox-neutral process by a palladium(II) active species which is proposed to undergo a β-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional-group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.
      Cover page: Palladium‐Catalyzed Defluorinative Coupling of 1‐Aryl‐2,2‐Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2015)
      The development of an enantioselective palladium-catalyzed 1,1-fluoroarylation of unactivated aminoalkenes is described. The reaction uses arylboronic acids as the arene source and Selectfluor as the fluorine source to generate benzylic fluorides in good yields with excellent enantioselectivities. This transformation, likely proceeding through an oxidative Heck mechanism, affords 1,1-difunctionalized alkene products.
        Cover page: Palladium-Catalyzed Enantioselective 1,1-Fluoroarylation of Aminoalkenes
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2016)
        The gold-catalyzed enantioselective hydroazidation and hydroamination reactions of allenes are presented herein. ADC gold(I) catalysts derived from BINAM were critical for achieving high levels of enantioselectivity in both transformations. The sense of enantioinduction is reversed for the two different nucleophiles, allowing access to both enantiomers of the corresponding allylic amines using the same catalyst enantiomer.
          Cover page: Enantioselective, Stereodivergent Hydroazidation and Hydroamination of Allenes Catalyzed by Acyclic Diaminocarbene (ADC) Gold(I) Complexes
          • Article
          • Peer Reviewed
          UC Berkeley Previously Published Works (2017)
          A mild palladium-catalyzed ligand-controlled regioselective 1,3-arylfluorination of 2[H]-chromenes has been developed. The products with a syn-1,3 substitution pattern were obtained with high enantiomeric excess using a PyrOx ligand, wherein the utility of these pyranyl-fluorides was further demonstrated through their participation in a diastereoselective C-C bond forming reaction. Ligand dependent divergent formation of both the 1,3- and 1,2- alkene difunctionalization products was observed. The nature of this bifurcation was investigated through experimental studies in combination with computational and statistical analysis tools. Ultimately, the site selectivity was found to rely on ligand denticity and metal electrophilicity, the electronics of the boronic acid, and the donor ability of the directing group in the substrate.
            Cover page: The development and mechanistic investigation of a palladium-catalyzed 1,3-arylfluorination of chromenes
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