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   Yu, Kaili; Li, Minyan; Deng, Guogang; Liu, Chunxiang; Wang, Jing; Liu, Zhengfen; Zhang, Hongbin; Yang, Xiaodong; Walsh, Patrick J. (July 2019, Advanced Synthesis & Catalysis)

   Abstract Isochromenes are important pharmacophores present in biologically active molecules and natural products. Their synthesis is generally limited to cyclization of phenyl propargyl ether precursors under transition metal catalyzed conditions. Herein, we present a novel disconnection that rapidly constructs isochromene derivatives through a cascade radical cyclization strategy. Generation of aryl radicals by SET reduction of 2‐iodo benzyl allenyl ethers is followed by radical cyclization to construct the isochromene core with formation of an allylic radical. The allylic radical then undergoes coupling with the azaallyl radical to give products in good to excellent yields. The elaborated 2‐iodo phenyl propargyl ether precursors can be used to construct isochromenes bearing various functional groups. magnified image 

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2. Radical Polarity

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   Garwood, Jacob_J A; Chen, Andrew D; Nagib, David A (October 2024, Journal of the American Chemical Society)
3. Impact of Catalyzed Radical Termination (CRT) and Reductive Radical Termination (RRT) in Metal-Mediated Radical Polymerization Processes: Impact of Catalyzed Radical Termination (CRT) and Reductive Radical Termination (RRT) in Metal-Mediated Radical Polymerization Processes

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4. 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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