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1. Copper‐Catalyzed C(sp ³ )−H α‐Acetylation: Generation of Quaternary Centers

   https://doi.org/10.1002/anie.202418692  

   Okoromoba, Otome E; Chen, Ting‐An; Jang, Eun Sil; McMullin, Claire L; Cundari, Thomas R; Warren, Timothy H (January 2025, Angewandte Chemie International Edition)

   Abstract α‐substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in natural products and pharmaceuticals. We report the α‐acetylation of C(sp³)−H substrates R−H with arylmethyl ketones ArC(O)Me to provide α‐alkylated ketones ArC(O)CH₂R at RT with^tBuOO^tBu as oxidant via copper(I) ‐diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α‐substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu^II](CH₂C(O)Ar) that capture alkyl radicals R• to give R−CH₂C(O)Ar outcompeting dimerization of the copper(II) enolate to give the 1,4‐diketone ArC(O)CH₂CH₂C(O)Ar. 

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2. Copper( ii ) ketimides in sp ³ C–H amination

   https://doi.org/10.1039/D1SC01990B  

   Jayasooriya, Isuri U.; Bakhoda, Abolghasem; Palmer, Rachel; Ng, Kristi; Khachemoune, Nour L.; Bertke, Jeffery A.; Warren, Timothy H. (December 2021, Chemical Science)

   Commercially available benzophenone imine (HNCPh 2 ) reacts with β-diketiminato copper( ii ) tert -butoxide complexes [Cu II ]–O t Bu to form isolable copper( ii ) ketimides [Cu II ]–NCPh 2 . Structural characterization of the three coordinate copper( ii ) ketimide [Me 3 NN]Cu–NCPh 2 reveals a short Cu-N ketimide distance (1.700(2) Å) with a nearly linear Cu–N–C linkage (178.9(2)°). Copper( ii ) ketimides [Cu II ]–NCPh 2 readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R–NCPh 2 products in a process that competes with N–N coupling of copper( ii ) ketimides [Cu II ]–NCPh 2 to form the azine Ph 2 CN–NCPh 2 . Copper( ii ) ketimides [Cu II ]–NCAr 2 serve as intermediates in catalytic sp 3 C–H amination of substrates R–H with ketimines HNCAr 2 and t BuOO t Bu as oxidant to form N -alkyl ketimines R–NCAr 2 . This protocol enables the use of unactivated sp 3 C–H bonds to give R–NCAr 2 products easily converted to primary amines R–NH 2 via simple acidic deprotection. 

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3. Copper-Catalyzed C(sp3)–H Methylation via Radical Relay

   Figula, Bryan C.; Chen, Ting-An; Bertke, Jeffery A.; Warren, Timothy H. (September 2022, ACS catalysis)

   The methyl moiety is a key functional group that can result in major improvements in the potency and selectivity of pharmaceutical agents. We present a radical relay C–H methylation methodology that employs a β-diketiminate copper catalyst capable of methylating unactivated C(sp3)–H bonds. Taking advantage of the bench-stable DABAL-Me3, an amine-stabilized trimethylaluminum reagent, methylation of a range of substrates possessing both activated and unactivated C(sp3)–H bonds proceeds with a minimal amount of overmethylation. Mechanistic studies supported by both experiment and computation suggest the intermediacy of a copper(II) methyl intermediate reactive toward both the loss of the methyl radical as well capture of radicals R• to form R–Me bonds. 

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4. Divergent Concerted Proton–Electron Transfer (CPET) and Hydrogen Atom Transfer (HAT) Pathways of Amidyl Radical Reactivity Enable Chemoselective Functionalization

   https://doi.org/10.1021/acs.orglett.5c03705  

   Handlin, Alexandra D; Leibfarth, Frank A; Alexanian, Erik J (October 2025, Organic Letters)

   Amidyl radicals mediate a diverse array of intermolecular aliphatic C(sp3)–H and decarboxylative functionalizations. Interestingly, we have observed that decarboxylative processes proceed with excellent chemoselectivity even with substrates containing weak C(sp3)–H bonds. Herein, we report a mechanistic basis for understanding this high chemoselectivity of amidyl radicals through divergent reaction pathways. A computational assessment of the transition state SOMOs and intrinsic bonding orbitals for amidyl radical hydrogen atom transfer (HAT) and concerted proton-electron transfer (CPET) processes support a shift in mechanism between aliphatic C(sp3)–H or carboxylic acid O–H abstraction, which is supported by experimental studies. These findings provide a rationale for the chemoselectivity of decarboxylative reactions mediated by amidyl radicals. 

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5. Switching mesoionic carbene-organocatalysis from radical to ionic pathway through base-controlled formation of Breslow intermediates versus Breslow enolates

   https://doi.org/10.1039/D4SC08229J  

   Jiao, Jie; Zhang, Zengyu; Lu, Guangyin; Huang, Shiqing; Bian, Yajing; Gao, Fan; Bertrand, Guy; Yan, Xiaoyu (May 2025, Chemical Science)

   Base-controlled formation of Breslow intermediatesversusBreslow enolates has been achieved with mesoionic carbenes. Of particular interest is the coupling of aldehydes and alkyl halides to yield ketonesviaan ionic pathway. 

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