大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用★

doi:10.6023/cjoc202506005

有机化学 ›› 2025, Vol. 45 ›› Issue (9): 3351-3360.DOI: 10.6023/cjoc202506005 上一篇下一篇

研究论文

大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用^★

王楠^a, 汤文军^a^,^b^,^c^,^*()

^a 上海科技大学物质科学与技术学院上海 201210
^b 中国科学院上海有机化学研究所生命过程小分子调控全国重点实验室上海 200032
^c 国科大杭州高等研究院化学和材料科学学院杭州 310024

收稿日期:2025-06-03 修回日期:2025-06-29 发布日期:2025-07-11
基金资助:
国家重点研发计划(2022YFA1503702); 国家重点研发计划(2021YFF0701601); 国家自然科学基金(82188101)

A Sterically Hindered Phosphorus Ligand for Palladium-Catalyzed Sterically Hindered Aryl-Alkyl Coupling Reaction^★

Nan Wang^a, Wenjun Tang^a^,^b^,^c^,^*()

^a School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210
^b State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
^c School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024

Received:2025-06-03 Revised:2025-06-29 Published:2025-07-11
Contact: *E-mail: tangwenjun@sioc.ac.cn
About author:
^★ Academic Papers of the 27^th Annual Meeting of the China Association for Science and Technology.
Supported by:
National Key R&D Program of China(2022YFA1503702); National Key R&D Program of China(2021YFF0701601); National Natural Science Foundation of China(82188101)

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摘要/Abstract

发展大位阻芳基烷基偶联反应对于促进有机合成和电子材料的发展具有重要意义. 设计和合成了构象确定的、大位阻、富电子单膦配体^PAd-AntPhos及其作为配体在钯催化大位阻芳基卤化物和环状烷基硼酸间Suzuki-Miyaura偶联反应中的应用. 为发展高效的大位阻芳基烷基偶联反应, 作者在现有高效偶联配体AntPhos的结构基础上, 设计和合成更大位阻的^PAd-AntPhos. 在2,4,6-三异丙基溴苯和环己基硼酸间的偶联反应中, 通过对配体、温度和碱等反应条件的筛选, ^PAd-AntPhos表现出优秀的反应活性, 以87%的收率得到目标产物. 一系列大位阻芳基烷基偶联产物均以前所未有的的反应收率顺利得到. 与AntPhos配体相比较, ^PAd-AntPhos更能容忍更大位阻的交叉偶联.

关键词: 钯, 膦配体, 偶联反应

The development of sterically hindered aryl-alkyl coupling reactions is of great significance in promoting the advancement of organic synthesis and electronic materials. A conformationally well-defined, sterically hindered, electron-rich monophosphorus ligand ^PAd-AntPhos was designed and synthesized, and its application as a ligand in the palladium-catalyzed Suzuki-Miyaura coupling reaction between sterically hindered aryl halides and cyclic alkylboronic acids were studied. To develop an efficient sterically hindered aryl-alkyl coupling reaction, a more sterically hindered ^PAd-AntPhos based on the structure of AntPhos was designed and synthesized. In the coupling reaction between 2,4,6-triisopropyl bromobenzene and cyclohexylboronic acid, ^PAd-AntPhos has shown excellent reactivity, yielding the target product in 80% yield by screening various reaction conditions including ligands, temperature, and bases. A series of sterically hindered aryl-alkyl coupling products have been obtained in unprecedentedly high yields. Compared to AntPhos, ^PAd-AntPhos has shown good tolerance of steric hindrance.

Key words: palladium, phosphorus ligands, cross-coupling

引用此文

王楠, 汤文军. 大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用^★[J]. 有机化学, 2025, 45(9): 3351-3360.

Nan Wang, Wenjun Tang. A Sterically Hindered Phosphorus Ligand for Palladium-Catalyzed Sterically Hindered Aryl-Alkyl Coupling Reaction^★[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3351-3360.

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图/表 6

图式1. 芳基-烷基交叉偶联反应及PAd-AntPhos的设计

Scheme 1. Aryl-alkyl cross-couplings and design of PAd-AntPhos

图式2. PAd-AntPhos的合成

Scheme 2. Synthesis of PAd-AntPhos

Entry^a	Ligands	Base	Conv.^b/%	Yield/% of 7a
1	SPhos	K₃PO₄	0	0	0
2	CPhos	K₃PO₄	100	0	100
3	RuPhos	K₃PO₄	88	0	88
4	BrettPhos	K₃PO₄	100	0	100
5	L1	K₃PO₄	100	65	35
6	L2	K₃PO₄	88	80	8
7^c	L2	K₃PO₄	100	87	13
8^d	L2	K₃PO₄	72	53	19
9	L2	KOH	100	0	100
10	L2	TMSOK	0	0	0
11	L2	^tBuOK	92	64	28

表1. 大位阻芳基-烷基偶联反应条件筛选

Table 1. Screening of reaction conditions for steric hindrance aryl-alkyl coupling

表2. 底物范围

Table 2. Substrate scope

图式3. 偶联反应过程跟踪

Scheme 3. Monitoring of the cross-coupling process

图式4. 伊曲莫德中间体11的合成

Scheme 4. Synthesis of etrasimod intermediate 11

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大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用^★

A Sterically Hindered Phosphorus Ligand for Palladium-Catalyzed Sterically Hindered Aryl-Alkyl Coupling Reaction^★

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大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用★

A Sterically Hindered Phosphorus Ligand for Palladium-Catalyzed Sterically Hindered Aryl-Alkyl Coupling Reaction★

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大位阻膦配体在钯催化芳基烷基交叉偶联反应中的应用^★

A Sterically Hindered Phosphorus Ligand for Palladium-Catalyzed Sterically Hindered Aryl-Alkyl Coupling Reaction^★