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1. Generalizing arene C−H alkylations by radical−radical cross-coupling

   https://doi.org/10.1038/s41586-025-08887-2  

   Großkopf, Johannes; Gopatta, Chawanansaya; Martin, Robert T; Haseloer, Alexander; MacMillan, David_W C (March 2025, Nature)

   The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a significant challenge in drug optimization campaigns. The late-stage introduction of alkyl fragments is especially desirable due to the high sp³-character and structural versatility of these motifs. Given their prevalence in molecular frameworks, C(sp²)−H bonds serve as attractive targets for diversification, though this process often requires difficult pre-functionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by employing Friedel–Crafts reaction conditions using strong Brønsted or Lewis acids. However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Herein, we report the application of a novel strategy for the selective coupling of differently hybridized radical species, which we term dynamic orbital selection. This mechanistic paradigm overcomes common limitations of Friedel-Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst based on their respective binding properties. As a result, we demonstrate herein a general and highly modular reaction for the direct alkylation of native arene C−H bonds using abundant and benign alcohols and carboxylic acids as the alkylating agents. Ultimately, this solution overcomes the synthetic challenges associated with the introduction of complex alkyl scaffolds into highly sophisticated drug scaffolds in a late-stage fashion, thereby granting access to vast new chemical space. Based on the generality of the underlying coupling mechanism, dynamic orbital selection is expected to be a broadly applicable coupling platform for further challenging transformations involving two distinct radical species. 

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2. Enantioselective Intermolecular Radical C–H Amination

   https://doi.org/10.1021/jacs.0c10415  

   Jin, Li-Mei; Xu, Pan; Xie, Jingjing; Zhang, X. Peter (December 2020, Journal of the American Chemical Society)

   null (Ed.)
3. Radical Benzylation of Quinones via C–H Abstraction

   https://doi.org/10.1021/acs.joc.9b01004  

   Galloway, Jordan D.; Mai, Duy N.; Baxter, Ryan D. (August 2019, The Journal of Organic Chemistry)
4. Photocontrolled Radical Polymerization from Hydridic C–H Bonds

   https://doi.org/10.1021/jacs.0c00287  

   Stache, Erin E.; Kottisch, Veronika; Fors, Brett P. (March 2020, Journal of the American Chemical Society)
5. Taming the Chlorine Radical: Enforcing Steric Control over Chlorine-Radical-Mediated C-H Activation

   https://doi.org/10.1021/jacs.1c13333  

   Gonzalez, Miguel; Gygi, David; Qin, Yangzhong; Zhu, Qilei; Johnson, Elizabeth J.; Chen, Yu-Sheng; Nocera, Daniel G. (January 2022, Journal of the American Chemical Society)

   Chlorine radicals readily activate C-H bonds, but the high reactivity of these intermediates precludes their use in regioselective C-H functionalization reactions. We demonstrate that the secondary coordination sphere of a metal complex can confine photoeliminated chlorine radicals and afford steric control over their reactivity. Specifically, a series of iron(III) chloride pyridinediimine complexes exhibit activity for photochemical C(sp(3))-H chlorination and bromination with selectivity for primary and secondary C-H bonds, overriding thermodynamic preference for weaker tertiary C-H bonds. Transient absorption spectroscopy reveals that Cl center dot remains confined through formation of a Cl center dot larene complex with aromatic groups on the pyridinediimine ligand. Furthermore, photocrystallography confirms that this selectivity arises from the generation of Cl center dot within the steric environment defined by the iron secondary coordination sphere. 

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