The introduction of a trifluoromethyl (CF
) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general ...methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp
)-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp
)-CF
products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF
' species is formed during this process and the critical C(sp
)-CF
bond-forming step involves the copper catalyst.
The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient ...generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.
The direct α‐arylation of cyclic and acyclic ethers with heteroarenes has been accomplished through the design of a photoredox‐mediated CH functionalization pathway. Transiently generated α‐oxyalkyl ...radicals, produced from a variety of widely available ethers through hydrogen atom transfer (HAT), were coupled with a range of electron‐deficient heteroarenes in a Minisci‐type mechanism. This mild, visible‐light‐driven protocol allows direct access to medicinal pharmacophores of broad utility using feedstock substrates and a commercial photocatalyst.
Use visible light! The direct α‐arylation of cyclic and acyclic ethers with heteroarenes can be achieved at room temperature through a photoredox‐mediated CH functionalization pathway. This mild, visible‐light‐driven protocol allows direct access to medicinal pharmacophores of broad utility using feedstock substrates and a commercial photocatalyst. SET=single‐electron transfer.
The direct conversion of aliphatic carboxylic acids to the corresponding alkyl fluorides has been achieved via visible light-promoted photoredox catalysis. This operationally simple, redox-neutral ...fluorination method is amenable to a wide variety of carboxylic acids. Photon-induced oxidation of carboxylates leads to the formation of carboxyl radicals, which upon rapid CO2-extrusion and F(•) transfer from a fluorinating reagent yield the desired fluoroalkanes with high efficiency. Experimental evidence indicates that an oxidative quenching pathway is operable in this broadly applicable fluorination protocol.
Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product ...isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.
The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox ...catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.
Alkyl chlorides are bench-stable chemical feedstocks that remain among the most underutilized electrophile classes in transition metal catalysis. Overcoming intrinsic limitations of C(sp
)-Cl bond ...activation, we report the development of a novel organosilane reagent that can participate in chlorine atom abstraction under mild photocatalytic conditions. In particular, we describe the application of this mechanism to a dual nickel/photoredox catalytic protocol that enables the first cross-electrophile coupling of unactivated alkyl chlorides and aryl chlorides. Employing these low-toxicity, abundant, and commercially available organochloride building blocks, this methodology allows access to a broad array of highly functionalized C(sp
)-C(sp
) coupled adducts, including numerous drug analogues.
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