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Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2012)

This study describes a facile nickel-catalyzed method to achieve the synthetically useful amination of aryl sulfamates and carbamates. This approach uses an air-stable Ni(II) precatalyst, which, when employed with a mild reducing agent, efficiently delivers aminated products in good yields. The scope of the method is broad with respect to both coupling partners. For instance, substrates with electron-donating and electron-withdrawing groups are tolerated, as well as those that possess ortho and para substituents. Furthermore, heteroaryl substrates may also be employed as coupling partners.

    Cover page: Nickel-Catalyzed Amination of Aryl Carbamates and Sulfamates Using an Air-Stable Precatalyst
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2016)

    Transition metal-catalyzed cross-couplings provide a powerful means to assemble carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds. Although Pd catalysis is most commonly used in these transformations, Ni catalysis offers a valuable alternative due to the low cost and high reactivity of Ni. More importantly, Ni catalysis has proven effective for the activation of traditionally inert carbon–heteroatom bonds and therefore provides exciting opportunities with regard to chemical reactivity and synthetic applications.

    Chapter one, two, and three describe the development of practical cross-coupling methodologies. Chapter one explains the amination of aryl sulfamates and carbamates that relies on an air-stable Ni(II) precatalyst. Chapter two introduces the development of green cross-couplings of phenolic derivatives and aryl halides to form biaryls. Subsequently, the couplings of heterocycles, which are commonly encountered in natural product synthesis and in the pharmaceutical sector, are described. Chapter three describes the development of green cross-couplings of aryl sulfamates and chlorides to form aryl amines.

    Chapter four and seven concern the utility of amides as electrophilic cross-coupling partners. These traditionally unreactive moieties are activated by nickel and coupled to alcohols to form acyl C–O bonds. This study suggests that amides may serve as useful building blocks to construct carbon–carbon and carbon–heteroatom bonds. Chapter four describes the development of nickel-catalyzed activation of benzamides and chapter seven introduces the development of nickel-catalyzed activation of aliphatic amide derivatives.

    Chapter five describes the nickel-catalyzed activation of the acyl carbon–oxygen bonds of methyl esters through an oxidative addition process. The oxidative addition adducts, formed using nickel catalysis, undergo in situ trapping to provide anilide products. DFT calculations are used to support the proposed reaction mechanism, understand why decarbonylation does not occur competitively, and to elucidate the beneficial role of the substrate structure and Al(OtBu)3 additive on the kinetics and thermodynamics of the reaction.

    Chapter six focus on the nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in bioactive molecules.

      Cover page: Development of Nickel-Catalyzed Cross-Coupling Reactions
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2015)
      A modern undergraduate organic chemistry laboratory experiment involving the Suzuki-Miyaura coupling is reported. Although Suzuki-Miyaura couplings typically employ palladium catalysts in environmentally harmful solvents, this experiment features the use of inexpensive nickel catalysis, in addition to a "green" alcohol solvent. The experiment employs heterocyclic substrates, which are important pharmaceutical building blocks. Thus, this laboratory procedure exposes students to a variety of contemporary topics in organic chemistry, including transition metal-catalyzed cross-couplings, green chemistry, and the importance of heterocycles in drug discovery, none of which are well represented in typical undergraduate organic chemistry curricula. The experimental protocol uses commercially available reagents and is useful in both organic and inorganic instructional laboratories.
        Cover page: Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling in a Green Alcohol Solvent for an Undergraduate Organic Chemistry Laboratory
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2018)
        Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH)2, proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O-glycosylated peptides in water.
          Cover page: Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2014)
          The nickel-catalyzed amination of aryl O-sulfamates and chlorides using the green solvent 2-methyl-THF is reported. This methodology employs the commercially available and air-stable precatalyst NiCl2(DME), is broad in scope, and provides access to aryl amines in synthetically useful yields. The utility of this methodology is underscored by examples of gram-scale couplings conducted with catalyst loadings as low as 1 mol % nickel. Moreover, the nickel-catalyzed amination described is tolerant of heterocycles and should prove useful in the synthesis of pharmaceutical candidates and other heteroatom-containing compounds.
            Cover page: Nickel-Catalyzed Amination of Aryl Chlorides and Sulfamates in 2‑Methyl-THF
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2016)
            Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C-N bond, with formation of a C-C or C-heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel-catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni-catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C-N bond cleavage processes.
              Cover page: Nickel‐Catalyzed Esterification of Aliphatic Amides
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2016)
              We report the first catalytic method for activating the acyl C-O bonds of methyl esters through an oxidative-addition process. The oxidative-addition adducts, formed using nickel catalysis, undergo in situ trapping to provide anilide products. DFT calculations are used to support the proposed reaction mechanism, to understand why decarbonylation does not occur competitively, and to elucidate the beneficial role of the substrate structure and the Al(OtBu)3 additive on the kinetics and thermodynamics of the reaction.
                Cover page: Nickel-Catalyzed Activation of Acyl C-O Bonds of Methyl Esters.
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2015)
                Amides are common functional groups that have been studied for more than a century. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond. Although amides can readily be cleaved by enzymes such as proteases, it is difficult to selectively break the carbon-nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon-nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon-heteroatom or carbon-carbon bonds using non-precious-metal catalysis.
                  Cover page: Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds
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