Copper is one of the most abundant and less toxic transition metals. Nature takes advantage of the bioavailability and rich redox chemistry of Cu to carry out oxygenase and oxidase organic transformations using O2 (or H2O2) as oxidant. Inspired by the reactivity of these Cu-dependent metalloenzymes, chemists have developed synthetic protocols to functionalize organic molecules under enviormentally benign conditions. Copper also promotes other transformations usually catalyzed by 4d and 5d transition metals (Pd, Pt, Rh, etc.) such as nitrene insertions or C–C and C–heteroatom coupling reactions. In this review, we summarized the most relevant research in which copper promotes or catalyzes the functionalization of organic molecules, including biological catalysis, bioinspired model systems, and organometallic reactivity. The reaction mechanisms by which these processes take place are discussed in detail.
The use of copper in directed C−H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc.
2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O−O cleavage to generate reactive RO• species, which are responsible for key C−H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.
The use of copper for C-H bond functionalization, compared to other metals, is relatively unexplored. Herein, we report a synthetic protocol for the regioselective hydroxylation of sp 2 and sp 3 C-H bonds using a directing group, stoichiometric amounts of Cu and H 2 O 2. A wide array of aromatic ketones and aldehydes are oxidized in the carbonyl γ-position with remarkable yields. We also expanded this methodology to hydroxylate the β-position of alkylic ketones. Spectroscopic characterization, kinetics, and density functional theory calculations point toward the involvement of a mononuclear LCu II (OOH) species, which oxidizes the aromatic sp 2 C-H bonds via a concerted heterolytic O-O bond cleavage with concomitant electrophilic attack on the arene system.
In this article, we describe simple one‐pot syntheses of 2H‐1,3‐benzoxazines from ketones utilizing an imino‐pyridine directing group (R1R2‐C=N−CH2‐Pyr), which promotes a Cu‐directed sp2 hydroxylation using H2O2 as oxidant and followed by an oxidative intramolecular C−O bond formation upon addition of NEt3. This synthetic protocol is utilized in the gram scale synthesis of the 2H‐1,3‐benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2‐azallyl anion intermediate, which is oxidized to the corresponding 2‐azaallyl radical before the C−O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.
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