Stepwise oxidative addition of copper(I) complexes to form copper(III) species via single electron transfer (SET) events has been widely proposed in copper catalysis. However, direct observation and detailed investigation of these fundamental steps remain elusive owing largely to the typically slow oxidative addition rate of copper(I) complexes and the instability of the copper(III) species. We report herein a novel aryl-radical-enabled stepwise oxidative addition pathway that allows for the formation of well-defined alkyl-Cu-III species from Cu-I complexes. The process is enabled by the SET from a Cu-I species to an aryl diazonium salt to form a Cu-II species and an aryl radical. Subsequent iodine abstraction from an alkyl iodide by the aryl radical affords an alkyl radical, which then reacts with the Cu-II species to form the alkyl-Cu-III complex. The structure of resultant [(bpy)Cu-III(CF3)(2)(alkyl)] complexes has been characterized by NMR spectroscopy and X-ray crystallography. Competition experiments have revealed that the rate at which different alkyl iodides undergo oxidative addition is consistent with the rate of iodine abstraction by carbon-centered radicals. The Cu-II intermediate formed during the SET process has been identified as a four-coordinate complex, [Cu-II(CH3CN)(2)(CF3)(2)], through electronic paramagnetic resonance (EPR) studies. The catalytic relevance of the high-valent organo-Cu-III has been demonstrated by the C-C bond-forming reductive elimination reactivity. Finally, localized orbital bonding analysis of these formal Cu-III complexes indicates inverted ligand fields in sigma(Cu-CH2) bonds. These results demonstrate the stepwise oxidative addition in copper catalysis and provide a general strategy to investigate the elusive formal Cu-III complexes.

Despite the recent advancements of Cu catalysis for the cross-coupling of alkyl electrophiles and the frequently proposed involvement of alkyl-Cu(III) complexes in such reactions, little is known about the reactivity of these high-valent complexes. Specifically, although the reversible interconversion between an alkyl-CuIII complex and an alkyl radical/CuII pair has been frequently proposed in Cu catalysis, direct observation of such steps in well-defined CuIII complexes remains elusive. In this study, we report the synthesis and investigation of alkyl-CuIII complexes, which exclusively undergo a Cu-C homolysis pathway to generate alkyl radicals and CuII species. Kinetic studies suggest a bond dissociation energy of 28.6 kcal/mol for the CuIII-C bonds. Moreover, these four-coordinate complexes could be converted to a solvated alkyl-CuIII-(CF3)2, which undergoes highly efficient C-CF3 bond-forming reductive elimination even at low temperatures (-4 °C). These results provide strong support for the reversible recombination of alkyl radicals with CuII to form alkyl-CuIII species, an elusive step that has been proposed in Cu-catalyzed mechanisms. Furthermore, our work has demonstrated that the reactivity of CuIII complexes could be significantly influenced by subtle changes in the coordination environment. Lastly, the observation of the highly reactive neutral alkyl-CuIII-(CF3)2 species (or with weakly bound solvent molecules) suggests they might be the true intermediates in many Cu-catalyzed trifluoromethylation reactions.

Despite the success of Sonogashira coupling for the synthesis of arylalkynes and conjugated enynes, the engagement of unactivated alkyl halides in such reactions remains historically challenging. We report herein a strategy that merges Cu-catalyzed alkyne transfer with the aryl radical activation of carbon-halide bonds to enable a general approach for the coupling of alkyl iodides with terminal alkynes. This unprecedented Sonogashira-type cross -coupling reaction tolerates a broad range of functional groups and has been applied to the late-stage cross-coupling of densely functionalized pharmaceutical agents as well as the synthesis of positron emission tomography tracers.

Organic molecules that contain alkyl-difluoromethyl moieties have received increased attention in medicinal chemistry, but their synthesis in a modular and late-stage fashion remains challenging. We report herein an efficient copper-catalyzed radical relay approach for the carbo-difluoromethylation of alkenes. This approach simultaneously introduces CF 2 H groups along with complex alkyl or aryl groups into alkenes with regioselectivity opposite to traditional CF 2 H radical addition. We demonstrate a broad substrate scope and a wide functional group compatibility. This scalable protocol is applied to the late-stage functionalization of complex molecules and the synthesis of CF 2 H analogues of bioactive molecules. Mechanistic studies and density functional theory calculations suggest a unique ligand effect on the reactivity of the Cu-CF 2 H species.

Given their ubiquity in natural products and pharmaceuticals, alcohols represent one of the most attractive starting materials for the construction of C-C bonds. We report herein the first catalytic strategy to harness the reactivity of aryl radicals for the activation of C-O bonds in alcohol-derived xanthate esters, allowing for the discovery of the first catalytic deoxygenative difluoromethylation reaction. Under copper-catalyzed conditions, a wide variety of alkyl xanthate esters, readily synthesized from alcohol feedstocks, were activated by catalytically generated aryl radicals and were converted to the alkyl-difluoromethane products via alkyl radical intermediates. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage modification of complex pharmaceutical agents. A one-pot protocol has been developed that allows for the direct use of free alcohols without purification of the xanthate esters. Mechanistic studies are consistent with the hypothesis of aryl radicals being formed and initiating the cleavage of the C-O bonds of xanthate esters, to generate alkyl radicals as the key intermediates. This aryl radical activation approach represents a new strategy for the activation of alcohols as cross-coupling partners.

The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi–type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi–type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.

Difluoromethyl groups are of great importance to synthetic and pharmaceutical chemistry because of their unique properties that regulate molecular bioactivity. In this article, approaches towards difluoromethylation are discussed and the development of the first aliphatic decarboxylative difluoromethylation reaction is detailed. With a broad scope, the real-world utility of the protocol is demonstrated.