——Green Pharmaceutical Team——
Starfish Review
【Background】The thioether group is widely present in functional materials, drug molecules (such as Montelukast and Diltiazem), and ligand design, but its chemical inertness limits its synthetic applications. Traditional activation of sulfides relies on direct oxidation of sulfur atoms (to form sulfoxides/sulfones), facing bottlenecks such as poor chemical selectivity (prone to over-oxidation), low functional group compatibility, and cumbersome multi-step operations (Scheme 1b). Especially in the late-stage modification of complex molecules, thioethers are difficult to act as “synthetic building blocks” for direct transformation. Developing a strategy that bypasses sulfur oxidation and directly activates the α-C–H bond is key to overcoming existing limitations.
【Strategy】The authors proposed and validated a photoexcited nitroarene-mediated, oxygen-free C(sp³)–H oxidation strategy to achieve direct functionalization of thioether α-positions, thus completing the formal cleavage and reconstruction of C–S bonds: 1. Design of bifunctional reagents: Nitroarenes absorb visible light and transition to triplet state (³ArNO₂*), selectively abstracting thioether α-C–H due to their strong hydrogen atom transfer (HAT) ability, generating carbon-centered radicals (1-rad) and nitrogen-oxygen radicals (ArNO₂H·); 2. Radical coupling and β-scission: 1-rad couples with oxygen radicals derived from nitroarene (C), releasing thiols through the cleavage of thioether intermediate D, generating aldehydes/ketones (2) in one step; 3. Cascade transformation: The in situ generated carbonyl compounds are combined with nucleophiles (such as amines, Wittig reagents, NaBH₄) to develop a one-pot synthesis of high-value products (Scheme 1d). Core breakthrough: By precisely controlling HAT selectivity (α-C–H BDE ≈82 kcal/mol) and anaerobic conditions, the differences in bond dissociation energies (BDE) between α-C–H and sulfur atoms are utilized to avoid competitive oxidation of sulfur atoms and over-oxidation of aldehydes.
【Innovation】This study achieved the first direct C(sp³)–H oxidation of thioethers that bypasses pre-oxidation of sulfur atoms, redefining thioethers as “latent carbonyl equivalents.” The authors proposed and validated a three-component synergistic mechanism of “photo-induced HAT–radical coupling–scission,” breaking through the traditional polar chemistry framework dependent on Pummerer or ylide pathways, efficiently converting inert thioethers into high-value scaffolds such as α-branched amines, secondary alcohols, and alkenes, significantly shortening the steps. Successfully applied to late-stage functionalization of non-benzyl primary and secondary alkyl thioethers, providing a mild and scalable tool for late-stage modification of complex drug molecules (such as fenofibrate and naproxen).
【Conclusion】This research pioneered a new paradigm of anaerobic oxidation of sulfides at α-C–H using photocatalysis: Efficient platform construction: Nitroarenes serve as bifunctional reagents to achieve direct conversion of thioethers to carbonyl compounds (aldehyde/ketone yields up to 74%), breaking through traditional multi-step oxidation limitations; Formal manipulation of C–S bonds: Through 12 types of cascade reactions, one-pot synthesis of α-tertiary amines, alkenes, secondary alcohols, and over 50 high-value products covering advantageous drug scaffolds; Redefining the role of thioethers: Transforming inert thioethers into “programmable synthetic building blocks,” providing new tools for late-stage modification of drugs. This strategy addresses the long-standing contradiction of selectivity and step economy in thioether activation, opening new pathways for precise synthesis of sulfur-containing molecules. Future expansions could include asymmetric α-functionalization of thioethers and efficient construction of bioactive molecules.
Article Information
Title: Direct Activation of Sulfides by C–H Oxidation with Photoexcited Nitroarenes:
Formal Manipulations of the C─S Bond
Journal: Angew. Chem. Int. Ed. 2025, e202509244
DOI: org/10.1002/anie.202509244
Organizer: Class of 2024 Pharmacy – Tang Zhicheng
Advisor: Liu Sensheng