可见光诱导电子供体-受体复合物驱动的[1.1.1]螺桨烷与环状N-磺酰基醛亚胺和磺酰氯的1,3-磺酰化/杂芳基化反应

doi:10.6023/A26060191

摘要/Abstract

本工作开发了一种可见光诱导下、由电子供体-受体(EDA)复合物驱动的双官能团化策略, 实现了[1.1.1]螺桨烷与环状N-磺酰基醛亚胺及磺酰氯的1,3-磺酰化/杂芳基化反应. 在标准条件下, 该体系能以中等至优良的产率高效构建1-磺酰基-3-杂芳基双环[1.1.1]戊烷(BCPs). 该方法的合成价值体现在其对药物相关结构单元的兼容性、便捷的后续衍生化能力以及可放大的制备工艺. 反应历程依赖于EDA复合物在可见光激发下的独特活化途径, 无需外加过渡金属催化剂或外源性光敏剂. 此外, 该方案具有反应条件温和、操作简便及官能团兼容性高等显著优势.

关键词: 环状N-磺酰基醛亚胺, [1.1.1]螺桨烷, 磺酰化, 光诱导, 电子供体-受体复合物

Herein, we report a visible-light-induced difunctionalization of [1.1.1]propellane via an electron donor-acceptor (EDA) complex, enabling selective 1,3-sulfonylation/heteroarylation with cyclic N-sulfonyl aldimines and sulfonyl chlorides. This protocol provides an efficient route to 1-sulfonyl-3-heteroaryl bicyclo[1.1.1]pentanes (BCPs), rigid three-dimensional scaffolds valuable as bioisosteric substitutes for para-substituted arenes in drug discovery. Under standard conditions, the desired products were obtained in moderate to excellent yields. This transformation operates under visible light at room temperature without transition-metal catalysts or external photosensitizers. The EDA complex serves as the pivotal intermediate; upon photoexcitation, it triggers single-electron transfer to generate sulfonyl radicals and radical anions, initiating a cascade that constructs both C—S and C—C bonds at the bridgehead positions. This unique mechanism avoids precious metal usage and suppresses side reactions typical of UV or thermal conditions. Optimization studies identified triethylamine as the preferred base, 1,2-dichloroethane as the optimal solvent, 405 nm as the best light source, and 6 hours as the ideal reaction time. In a typical procedure, a nitrogen-purged Schlenk tube charged with cyclic N-sulfonyl aldimine (0.2 mmol), p-toluenesulfonyl chloride (0.3 mmol), [1.1.1]propellane (0.3 mmol), and triethylamine (0.4 mmol) in 1,2-dichloroethane (DCE, 2 mL) is irradiated at 405 nm for 6 hours. Purification by column chromatography affords the corresponding products. The substrate scope was systematically examined, covering various cyclic N-sulfonyl aldimines and sulfonyl chlorides bearing pharmaceutically relevant groups. Scale-up reactions delivered comparable results, and subsequent derivatizations converted BCP products into diverse architectures, illustrating synthetic utility. Mechanistic studies, including radical trapping and UV-vis spectroscopy, confirmed radical intermediates and EDA complex formation. Based on these findings, a plausible pathway is proposed: photoinduced electron transfer, sulfonyl radical generation, regioselective addition to [1.1.1]propellane, and radical trapping to forge the C-heteroaryl bond. Collectively, this work offers a mild, sustainable, and scalable approach to functionalized BCPs, enriching the medicinal chemistry toolbox with sp³-rich building blocks.

Key words: cyclic N-sulfonyl aldimines, [1.1.1]propellane, sulfonylation, visible-light-induced, electron donor-acceptor (EDA) complex

引用此文

王新嫦, 杜亚婷, 陈安, 张悦, 章鹏飞, 徐骏. 可见光诱导电子供体-受体复合物驱动的[1.1.1]螺桨烷与环状N-磺酰基醛亚胺和磺酰氯的1,3-磺酰化/杂芳基化反应[J]. 化学学报, 2026, 84(10): 1619-1625.

Xinchang Wang, Yating Du, An Chen, Yue Zhang, Pengfei Zhang, Jun Xu. Visible-Light-Induced Electron Donor-Acceptor Complex Driven 1,3-Sulfonylation/Heteroarylation of [1.1.1]Propellane with Cyclic N-Sulfonyl Aldimines and Sulfonyl Chlorides[J]. Acta Chimica Sinica, 2026, 84(10): 1619-1625.

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图/表 7

图式1. 先前及当前研究

Scheme 1. Summary of previous and current studies

Entry	Variants	Yield^b/%
1^a	none	70
2	365, 395, 420 nm LEDs instead of 405	32/45/50
3	DBU, DABCO, DIPEA instead of Et₃N	5/20/11
4	Ph₃N, DMAP, quinoline instead of Et₃N	0/14/47
5	DMC, DMF, MeCN instead of DCE	40/39/48
6	reaction proceeds for 3 h or 12 h	37/61

表1. 反应条件优化

Table 1. Optimization of the reaction conditionsa

图式2. 杂环底物适用范围

Scheme 2. Scope of heterocycle substratesa,b a Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (1.5 equiv.), 3a (1.5 equiv.), Et3N (2 equiv.), DCE (2 mL), 405 nm LEDs, r.t., 6 h, N2. b Isolated yields.

图式3. 磺酰氯底物适用范围

Scheme 3. Scope of sulfonyl chloride substratesa,b a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (1.5 equiv.), 3 (1.5 equiv.), Et3N (2 equiv.), DCE (2 mL), 405 nm LEDs, r.t., 6 h, N2. b Isolated yields.

图式4. 放大量和衍生化实验

Scheme 4. Large-scale reaction and synthetic transformation

图式5. 控制实验

Scheme 5. Control experiments

图式6. 反应机理

Scheme 6. Proposed mechanism

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