非活化烯烃的模块化三组分自由基氟烷基/硫双官能团化反应

doi:10.1016/S1872-2067(24)60190-7

催化学报 ›› 2025, Vol. 69: 249-258.DOI: 10.1016/S1872-2067(24)60190-7

非活化烯烃的模块化三组分自由基氟烷基/硫双官能团化反应

杨高峰^a, 刘志^a, 刘凯^a, 吴晓鹏^a, 朱成建^a^,^b^,^*(), 李伟鹏^a^,^*(), 谢劲^a^,^*()

^a南京大学化学化工学院, 配位化学国家重点实验室, 江苏省先进有机材料重点实验室, 化学和生物医药创新研究院, 江苏南京 210023
^b郑州大学化学与分子工程学院绿色催化中心, 河南郑州 450001

收稿日期:2024-09-24 接受日期:2024-11-05 出版日期:2025-02-18 发布日期:2025-02-10
通讯作者: *电子信箱: cjzhu@nju.edu.cn (朱成建), lwp1989@nju.edu.cn (李伟鹏), xie@nju.edu.cn (谢劲).
基金资助:
国家重点研发项目(2022YFA1503200);国家重点研发项目(2021YFC2101901);国家自然科学基金(22122103);国家自然科学基金(22101130);国家自然科学基金(22001117);国家自然科学基金(22271144);中央高校基本科研业务费(020514380304);中央高校基本科研业务费(020514380252);中央高校基本科研业务费(020514380272)

Modular three-component radical fluoroalkyl-sulfuration of unactivated alkenes

Gao-feng Yang^a, Zhi Liu^a, Kai Liu^a, Xiaopeng Wu^a, Chengjian Zhu^a^,^b^,^*(), Weipeng Li^a^,^*(), Jin Xie^a^,^*()

^aState Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, Jiangsu, China
^bGreen Catalysis Center, and College of Chemistry, Zhengzhou University, Zhengzhou 450001, Henan, China

Received:2024-09-24 Accepted:2024-11-05 Online:2025-02-18 Published:2025-02-10
Contact: *E-mail: cjzhu@nju.edu.cn (C. Zhu), lwp1989@nju.edu.cn (W. Li), xie@nju.edu.cn (J. Xie).
Supported by:
National Key Research and Development Program of China(2022YFA1503200);National Key Research and Development Program of China(2021YFC2101901);National Natural Science Foundation of China(22122103);National Natural Science Foundation of China(22101130);National Natural Science Foundation of China(22001117);National Natural Science Foundation of China(22271144);Fundamental Research Funds for the Central Universities(020514380304);Fundamental Research Funds for the Central Universities(020514380252);Fundamental Research Funds for the Central Universities(020514380272)

摘要/Abstract

摘要：

硫元素广泛存在于药物、天然产物、蛋白质及有机发光材料中, 是与生命化学和化学材料行业紧密相关的最重要元素之一. 另一方面, 将含氟官能团引入有机分子中可以显著提高其脂溶性、药效学和药代动力学性质. 鉴于硫元素与氟元素独特的化学性质, 在有机分子中同时引入含硫和含氟基团, 有望改变目标分子的药物及生物活性. 烯烃的自由基双官能化反应策略为复杂分子的构建提供了新型高效的合成平台. 然而, 通过三组分自由基氟烷基-硫化策略一步在烯烃分子中同时引入含氟烷基和含硫官能团极具挑战性, 主要的原因在于潜在的副反应较多, 尤其是两组分之间的偶联副反应很难被抑制. 尽管近年来在该研究领域取得了一些进展, 但是仍然面临着一些亟需解决的问题: 比如, 烯烃的适用范围非常有限, 特别是未活化的内烯烃反应活性低, 此外, 目前还缺乏一种模块化策略来实现一氟、二氟、三氟甲基以及多氟烷基硫化, 同时, 自由基氟烷基双硫化反应目前尚无报道.

本文采用可见光氧化还原催化策略, 在无过渡金属催化的条件下, 以市售的二硫化物和Langlois试剂为原料, 实现了未活化烯烃的自由基氟烷基单/双硫化反应(> 90个反应实例). 值得一提的是, 该反应对于烯烃底物具有良好的兼容性, 包括末端烯烃、双取代烯烃和三取代烯烃等未活化的烯烃, 均能有效地进行三组分偶联. 同时, 该反应使用不同种类的Langlois试剂, 可以合成得到各种氟烷基化产物. 此外, 不同种类的芳基或者烷基二硫试剂也能很好地参与反应, 商业易得的二硒化物对于该反应也能兼容. 值得一提的是, 以简单易得的芳基或者烷基四硫化物为原料时, 可以成功地得到非对称双硫产物, 并成功在药物分子中同时引入了含氟和含硫片段. 同时, 将该反应规模扩大至5.0 mmol时, 反应收率几乎不受影响, 实现了克级规模的制备. 还进行了深入的机理研究, 通过自由基钟实验、EPR实验、以及自由基捕获实验证明了硫自由基和氟烷基自由基的存在. 另一方面, 量子产率实验结果排除了自由基链式过程. 循环伏安法实验和Stern-Volmer猝灭实验验证了激发态的光催化剂通过与Langlois试剂的单电子氧化过程产生氟烷基自由基, 随后对烯烃进行自由基加成和自由基取代等过程得到非对称的硫醚产物.

综上, 本文利用无金属的光催化策略实现了一系列烯烃氟烷基/硫双官能团化反应, 表现出较好的底物适用范围和官能团耐受性, 是一种可以实现一氟、二氟、三氟甲基以及多氟烷基硫化的模块化合成方法, 为构建同时包含硫醚和氟烷基的小分子库提供了强有力的工具.

关键词: C(sp³)-S键, 非活化烯烃, 光氧化还原催化, 氟烷基化, 非对称硫醚

Abstract:

The accompanied forge of C(sp³)-S and C(sp³)-C(sp³) bonds across alkene frameworks serves as a potent strategy to construct biologically important compounds. Here, we report a metal-free, photochemically mediated fluoroalkyl-mono/disulfuration of unactivated alkenes with high efficiency and high selectivity. A wide range of terminal and internal alkenes are good coupling partners, affording the expected products in moderate to good yields (>90 examples). The exceedingly mild reaction conditions, exceptional functional group tolerance, broad substrate scope, and the potential for late-stage modifications of pharmaceutical molecules highlight the utility of this method in the preparation of privileged motifs from readily available disulfides, tetrasulfides, and diselenides. Mechanistic studies suggest that a secondary alkyl radical intermediate undergoes efficient homolytic substitution with disulfides, facilitating the modular synthesis of a diverse array of unsymmetrical thioethers.

Key words: C(sp³)-S bond, Unactivated alkenes, Photoredox catalysis, Fluoroalkylation, Unsymmetrical thioethers

杨高峰, 刘志, 刘凯, 吴晓鹏, 朱成建, 李伟鹏, 谢劲. 非活化烯烃的模块化三组分自由基氟烷基/硫双官能团化反应[J]. 催化学报, 2025, 69: 249-258.

Gao-feng Yang, Zhi Liu, Kai Liu, Xiaopeng Wu, Chengjian Zhu, Weipeng Li, Jin Xie. Modular three-component radical fluoroalkyl-sulfuration of unactivated alkenes[J]. Chinese Journal of Catalysis, 2025, 69: 249-258.

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链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(24)60190-7

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图/表 7

Fig. 1. Challenges and strategies in C(sp3)-S bond construction. (a) State of art methods for the C(sp3)-S bond preparation. (b) Common strategies used for the introduction of fluorine-containing groups in alkenes. (c) Containing of thioether motifs and fluoroalkyl groups in pharmaceuticals. (d) This work: Modular radical fluoroalkyl-sulfuration of unactivated alkenes. LG, leaving group; X, leaving group; FG, functional group; PC, photocatalyst.

Table 1 Optimization of the reaction conditions a.

Entry	Variation of standard conditions	Yield^b (%)
1	none	81(75) ^c
2	PC1 instead of 4CzIPN	78
3	PC2 instead of 4CzIPN	ND
4	TMG instead of BTMG	70
5	440 nm LEDs	72
6	390 nm LEDs	25
7	without BTMG	trace
8	without 4CzIPN	ND
9	without light	ND

Fig. 2. Scope of alkenes and fluoroalkylating reagents. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b TMG (1.0 equiv.) was used as base.

Fig. 3. Substrate scope of disulfides/diselenides/tetrasulfides. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b The base was DBU (0.8 equiv.). c 3.0 equiv. of BTMG was used.

Fig. 4. Modification of natural products or derivatives. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b The base was TMG (1.0 equiv.). c 3.0 equiv. of BTMG was used.

Fig. 5. Gram-scale reactions and diversification of products. a 3.0 equiv. of BTMG was used. b The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy.

Fig. 6. Mechanistic studies. a The E/Z configurations was determined by crude 1H NMR spectroscopy.

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非活化烯烃的模块化三组分自由基氟烷基/硫双官能团化反应

Modular three-component radical fluoroalkyl-sulfuration of unactivated alkenes

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