Browsing by Author "Kao, Shih-Chieh"

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    Photochemical diazidation of alkenes enabled by ligand-to-metal charge transfer and radical ligand transfer
    (Springer Nature, 2022) Bian, Kang-Jie; Kao, Shih-Chieh; Nemoto, David; Chen, Xiao-Wei; West, Julian G.
    Vicinal diamines are privileged synthetic motifs in chemistry due to their prevalence and powerful applications in bioactive molecules, pharmaceuticals, and ligand design for transition metals. With organic diazides being regarded as modular precursors to vicinal diamines, enormous efforts have been devoted to developing efficient strategies to access organic diazide generated from olefins, themselves common feedstock chemicals. However, state-of-the-art methods for alkene diazidation rely on the usage of corrosive and expensive oxidants or complicated electrochemical setups, significantly limiting the substrate tolerance and practicality of these methods on large scale. Toward overcoming these limitations, here we show a photochemical diazidation of alkenes via iron-mediated ligand-to-metal charge transfer (LMCT) and radical ligand transfer (RLT). Leveraging the merger of these two reaction manifolds, we utilize a stable, earth abundant, and inexpensive iron salt to function as both radical initiator and terminator. Mild conditions, broad alkene scope and amenability to continuous-flow chemistry rendering the transformation photocatalytic were demonstrated. Preliminary mechanistic studies support the radical nature of the cooperative process in the photochemical diazidation, revealing this approach to be a powerful means of olefin difunctionalization.
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    Radical ligand transfer: a general strategy for radical functionalization
    (Beilstein-Institut, 2023) Jr, David T. Nemoto; Bian, Kang-Jie; Kao, Shih-Chieh; West, Julian G.
    The place of alkyl radicals in organic chemistry has changed markedly over the last several decades, evolving from challenging-to-generate “uncontrollable” species prone to side reactions to versatile reactive intermediates enabling construction of myriad C–C and C–X bonds. This maturation of free radical chemistry has been enabled by several advances, including the proliferation of efficient radical generation methods, such as hydrogen atom transfer (HAT), alkene addition, and decarboxylation. At least as important has been innovation in radical functionalization methods, including radical–polar crossover (RPC), enabling these intermediates to be engaged in productive and efficient bond-forming steps. However, direct engagement of alkyl radicals remains challenging. Among these functionalization approaches, a bio-inspired mechanistic paradigm known as radical ligand transfer (RLT) has emerged as a particularly promising and versatile means of forming new bonds catalytically to alkyl radicals. This development has been driven by several key features of RLT catalysis, including the ability to form diverse bonds (including C–X, C–N, and C–S), the use of simple earth abundant element catalysts, and the intrinsic compatibility of this approach with varied radical generation methods, including HAT, radical addition, and decarboxylation. Here, we provide an overview of the evolution of RLT catalysis from initial studies to recent advances and provide a conceptual framework we hope will inspire and enable future work using this versatile elementary step.
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    The Development of Iron Photoredox Strategies in Organic Transformations for the Construction of C–N and C–C Bonds
    (2024-08-09) Kao, Shih-Chieh; West, Julian G.
    Organic transformations via photoredox strategies have emerged as a powerful tool for the synthesis of valuable chemical products; however, prevailing strategies heavily relied on the use of precious transition-metal catalysts such as iridium, ruthenium or silver, impeding their general applications. The motivation of this work was to develop new catalytic systems using cheap and sustainable earth-abundant element metals that allow efficient synthesis of otherwise challenging molecules via photoredox mechanisms. Vicinal diamines are prevalent in bioactive molecules, pharmaceuticals, and molecular catalysts, underscoring their significance. Olefin diazidation emerges as a promising strategy for synthesizing these motifs due to the ability to reduce azides to amines and the availability of structurally diverse olefins. Traditional diazidation methods often involve harsh conditions and have limited substrate scopes. Recent advancements using azidobenziodoxolone (ABX, Zhdankin reagent) or electrochemical methods, overcome some of these challenges; however, they introduce different limitations such as high costs and procedural complexity. In chapter 1, we introduce an innovative photochemical diazidation approach utilizing cheap iron salts, which leverages visible light-induced homolysis (VLIH) and radical ligand transfer (RLT). This methodology, which eschews the need for additional oxidants or complex reaction apparatus, offers sustainability and economic benefits while demonstrating compatibility with continuous flow chemistry, providing an efficient and practical route for the synthesis of organic diazides. Preliminary mechanistic studies support the radical nature of the cooperative process in photochemical diazidation, demonstrating this approach as a highly effective method for olefin difunctionalization. Decarboxylative functionalization is a potent strategy for synthesizing diverse products, with ligand-to-metal charge transfer (LMCT) involving earth-abundant 3d metals emerging as a prominent method for reaction design. While recent advancements in coppermediated decarboxylative C–N bond formation via a LMCT/radical polar crossover (RPC) mechanism have been demonstrated, they face limitations in catalytic function and substrate scope with unactivated alkyl carboxylic acids, challenging their general applicability. In chapter 2, we present a novel photochemical, nucleophilic decarboxylative azidation using iron-catalyzed visible light-induced homolysis (VLIH) and radical ligand transfer (RLT). Our proposed iron-catalyzed approach leverages inexpensive iron nitrate and simple azide sources to convert a variety of carboxylic acids into organic azides under mild conditions. This method avoids the need for external oxidants, complex ligands, or pre-activation of carboxylic acids. Mechanistic studies suggest a radical pathway with nitrate acting as an internal oxidant, offering a “redox-neutral” transformation. This new methodology provides a straightforward and efficient route for synthesizing aliphatic azides, expanding the toolkit for C-N bond formation in pharmaceutical and organic synthesis. Hydroalkylation, the addition of a carbon fragment and hydrogen across an alkene, is an optimal method for forming C(sp3)–C(sp3) bonds from readily available starting materials. Despite notable advancements in branch-selective hydroalkylation via transition metal catalysis, a general strategy for linear-selective hydroalkylation remains underdeveloped, with certain reactions, such as hydroethylation, remaining largely elusive. In chapter 3, we demonstrate that these challenging reactions can be achieved catalytically through traceless radical polarity reversal (TRPR), which employs a removable electron-withdrawing group to facilitate radical alkene addition, followed by in situ removal under reaction conditions. This approach facilitates a variety of previously unattainable hydroalkylation reactions, such as hydromethylation, hydroethylation, and hydrocyclobutylation, all with high linear selectivity using simple malonic acids as alkyl donors. Additionally, it allows for the rapid and efficient synthesis of bioactive molecules, exemplified by a GPR119 agonist, which was produced in good yield and efficiency. To further showcase the practical utility of our approach, we demonstrated that mono- or difluoromalonic acids can act as novel mono- or difuoromethylene linchpins for accessing gem-mono- or gem-difuoroalkyl skeletons from abundant feedstock chemicals. Importantly, our unified iron/thiol dual catalytic system manages both the alkene addition and the removal of the polarity reversal group, offering a sustainable and straightforward method for these transformations. Preliminary mechanistic studies suggest a dual-catalytic radical mechanism involving decarboxylation via ironmediated visible light-induced homolysis (VLIH) and hydrogen atom transfer steps. Overall, traceless radical polarity reversal provides a versatile solution for alkene hydroalkylation in both simple and complex settings. In general, these new iron photoredox strategies have shown great advantages and improved sustainability compared to the previous work using noble and expensive transition metals and/or harsh conditions. In addition, these strategies allowed us to study the unprecedent catalytic properties of earth-abundant elements and synthesize a wide variety of valuable and traditionally inaccessible molecules, advancing fundamental knowledge in the fields of homogeneous catalysis and synthesis.