A reserach team led by Guangfan Zheng and Qian Zhang at Northeast Normal University reported a visible light-mediated photoredox catalytic radical-polar cross-coupling strategy to achieve bifunctionalization of ipso- and para-positions in substituted aromatics. By utilizing the rapid coupling between sulfur dioxide and the dearomatized radical-type Meisenheimer intermediate, the Smiles rearrangement process was successfully delayed. Following radical ipso-cyclization, the inert C–N bond and the para-C–H bond were activated stepwise. This in-situ and para-bifunctionalization mode is complementary to the Catellani reaction, providing a novel strategy for precise multi-site modification of substituted aromatics. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.
Background information:
Polysubstituted aromatic hydrocarbon skeletons are widely found in petrochemical products and biomass feedstocks, playing a crucial role in new drug development, natural product synthesis, and fine chemical preparation, and are closely related to human production and daily life. Statistics show that 85% of the top 200 best-selling small molecule drugs globally in 2023 contained aromatic ring skeletons. Therefore, developing efficient and precise methods for the construction and transformation of polysubstituted aromatic hydrocarbons is not only a core issue in the development of synthetic chemistry methodologies but also provides a key tool for the design of novel functional molecules. Compared to the well-established single functionalization strategies of C-H bonds or C-heterobonds, the synergistic transformation of substituted aromatic hydrocarbons at the in-situ (ipso-) site and CH bond can efficiently introduce two functional groups, achieving precise multi-site editing of the aromatic ring skeleton, demonstrating unique advantages in the synthesis of complex molecules. Existing bifunctionalization methods for substituted aromatic hydrocarbons (such as the Catellani reaction) are mainly limited to ipso- and ortho-site modifications and are only applicable to substrates such as activated aryl halides. However, due to the large spatial distance between the two sites, bifunctionalization at the ipso- and para-positions has long been a challenge in terms of relevant synthetic strategies (Figure 1) . Furthermore, important synthetic precursors such as anilines have consistently been difficult to activate effectively in multi-site transformations.
Highlights of this Article:
To address these challenges, thhe team proposed an innovative "delayed aryl migration" strategy. This strategy utilizes sulfur dioxide to rapidly capture the Meisenheimer intermediate generated during the Smiles rearrangement, effectively suppressing the classic free radical aryl migration pathway. For the first time, it achieved precise bifunctionalization of inert C–N bonds and para-C–H bonds in distal olefin-substituted aniline derivatives. This reaction system exhibits excellent compatibility with various substituents on the aromatic ring. Whether electron-donating or halogenated, it can achieve specific ipso/para-bifunctionalization with moderate to excellent yields and high selectivity, and this selectivity is unaffected by electronic effects or steric hindrance (Figure 2) . Furthermore, the N-protecting group has a wide range of applicability, including primary secondary alkyl, benzyl, cycloalkyl, and propargyl structures; the bifunctional reagent can also be extended to various perfluoroalkyl sulfinates; simultaneously, polyfluoroaromatic terminators not only cover common ester derivatives but are also compatible with substrates containing electron-withdrawing groups such as ketones, cyanos, and trifluoromethyl groups. This system has been successfully applied to the transformation of various natural products and bioactive molecular derivatives, achieving gram-scale synthesis and derivatization, demonstrating its practical potential in the late-stage modification of complex molecules. This work provides an efficient and green new route for drug development and fine chemical synthesis, showcasing significant synthetic application value.
Summary and Outlook:
This study developed a visible-light-mediated photoredox catalytic radical-polar cross-reaction, achieving for the first time the precise bifunctionalization of inert C–N bonds and para-C–H bonds in olefin-substituted aniline derivatives through a "delayed aryl migration" strategy. This strategy utilizes the reversible capture of Meisenheimer intermediates by sulfur dioxide to effectively suppress the classical radical aryl migration pathway, allowing the reaction to proceed along a tandem pathway of ipso-addition/para-functionalization/ionic C–N bond breaking. This method exhibits excellent site selectivity and broad substrate compatibility. Late-stage modification of natural products and bioactive molecules, gram-scale synthesis, and further derivatization of the products demonstrate the promising practical potential of this method in constructing complex molecules. In the future, this system is expected to be further extended to a wider range of aromatic compounds, providing strong support for the creation of novel drug molecules and functional materials, and offering new insights into the precise multi-site editing of substituted aromatic rings.
The findings were published as a Research Article in CCS Chemistry. Professors Guangfan Zheng and Qian Zhang from the College of Chemistry, Northeast Normal University, are the corresponding authors, and doctoral students Binghong Teng and Yunliang Guo are the co-first authors. This work was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
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About the journal: CCS Chemistry is the Chinese Chemical Society's flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem .
About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman's Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/ .
