Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

Chaodong Wang, Zhi Chen, Jie Sun, Luwei Tong, Wenjian Wang, Shengjie Song and Jianjun Li ()
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Chaodong Wang: Zhejiang University of Technology
Zhi Chen: Zhejiang University of Technology
Jie Sun: Zhejiang University of Technology
Luwei Tong: Zhejiang University of Technology
Wenjian Wang: Zhejiang University of Technology
Shengjie Song: Zhejiang University of Technology
Jianjun Li: Zhejiang University of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.

Date: 2024
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DOI: 10.1038/s41467-024-49337-3

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