镍催化吲哚酮的选择性异戊烯化和反异戊烯基化反应

doi:10.1016/S1872-2067(24)60218-4

催化学报 ›› 2025, Vol. 70: 444-454.DOI: 10.1016/S1872-2067(24)60218-4

• 论文 • 上一篇

镍催化吲哚酮的选择性异戊烯化和反异戊烯基化反应

刘盈盈^a^,^b, 李莹^a^,^b, 李雪婷^a^,^b, 徐溯阳^a^,^b, 季定纬^a^,^*(), 胡向平^a^,^b^,^*(), 陈庆安^a^,^b^,^*()

^a中国科学院大连化学物理研究所, 辽宁大连 116023
^b中国科学院大学, 北京 100049

收稿日期:2024-12-03 接受日期:2024-12-30 出版日期:2025-03-18 发布日期:2025-03-20
通讯作者: * 电子信箱: dingweiji@dicp.ac.cn (季定纬),xiangping@dicp.ac.cn (胡向平),qachen@dicp.ac.cn (陈庆安).
基金资助:
国家自然科学基金(22201281);国家自然科学基金(22071239);国家自然科学基金(22371275)

Unified construction of prenylated and reverse-prenylated oxindoles from isoprene launched by Ni catalysis

Ying-Ying Liu^a^,^b, Ying Li^a^,^b, Xue-Ting Li^a^,^b, Su-Yang Xu^a^,^b, Ding-Wei Ji^a^,^*(), Xiang-Ping Hu^a^,^b^,^*(), Qing-An Chen^a^,^b^,^*()

^aDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
^bUniversity of Chinese Academy of Sciences, Beijing 100049, China

Received:2024-12-03 Accepted:2024-12-30 Online:2025-03-18 Published:2025-03-20
Contact: * E-mail: dingweiji@dicp.ac.cn (D.-W. Ji),xiangping@dicp.ac.cn (X.-P. Hu),qachen@dicp.ac.cn (Q.-A. Chen).
Supported by:
National Natural Science Foundation of China(22201281);National Natural Science Foundation of China(22071239);National Natural Science Foundation of China(22371275)

摘要/Abstract

摘要：

C3戊烯基或反异戊烯基取代的吲哚酮是许多具有重要生物活性的天然产物和药物分子的骨架结构, 因此开发吲哚酮的高效异戊烯基或反异戊烯基化方法吸引了有机和药物化学家的广泛关注.

传统上, 在过量碱的存在下通过吲哚酮与异戊烯基卤代物的亲核取代反应, 可以实现吲哚酮的C3异戊烯基化反应. 但这类反应往往缺乏原子经济性且反应的选择性主要依赖于底物结构性质. 利用过渡金属催化体系, 则可以实现对反应选择性的有效调控. 但文献中已报道的反应方法均需要在吲哚酮的C3位置预先引入一个取代基,这限制了产物后续的转化利用. 目前为止, 对于C3未取代吲哚酮的选择性异戊烯基或反异戊烯基化反应依然是一项挑战性的工作.

基于前期关于异戊二烯氢官能团化反应的研究, 本文使用丰产金属镍与单齿膦配体的催化体系, 以较好的化学和区域选择性实现了C3未取代吲哚酮与异戊二烯的反异戊烯基化反应. 机理上反应首先经历零价镍与吲哚酮C-H键的氧化加成, 生成二价镍-氢金属物种, 随后该物种再与异戊二烯配位以及迁移插入, 最后通过还原消除获得目标产物. 该反应过程中没有当量副产物生成, 具有原子经济性. 利用吲哚酮产物在C3位还有一个活泼反应位点的优势, 可以通过一系列亲核取代反应快速构建结构多样性的3,3-二取代吲哚酮. 此外, 利用对反应添加剂(碱, 三苯基膦)的调控, 在空气氛围中实现了反异戊烯基取代吲哚酮产物的C-H选择性羟基化反应, 发散性地得到反异戊烯基和戊烯基取代的α-羟基-吲哚酮. 机理研究表明, 在碳酸铯/三苯基膦反应体系中, 反异戊烯基取代吲哚酮C3位点的C-H键被碱活化, 并被空气中的氧气氧化生成过氧化物, 最后在三苯基膦的还原作用下生成C3-羟基化的动力学产物. 而在过量的氢化钠强碱体系中, C3位点上的反戊烯基先后进行的逆-[2,3]-Witting重排和[1,2]-Witting-重排, 最后生成热力学稳定的戊烯基取代的羟基化产物. 将该羟基化产物原位酯化后, 可以通过傅-克反应与吲哚酮C5位点偶联, 高效地构建二聚吲哚酮骨架; 或与苯酚反应得到结构新颖的螺环化合物. 最后, 基于吲哚酮骨架结构对产物进行了多样性转化, 并实现了天然产物debromoflustramine A和B前体的合成.

综上, 本文在金属镍催化条件下实现了C3未取代吲哚酮的选择性反异戊烯基化反应. 利用产物C3位的活泼C-H键, 可以通过亲核取代、C-H键选择性氧化羟基化, 以及随后的亲电取代或环化反应, 实现结构丰富的异戊烯基和反戊烯基取代吲哚酮产物的快速构建, 为相关生物碱天然产物和药物分子的合成与制备提供了新思路.

关键词: 镍催化, 一体化合成, 异戊二烯, (反)异戊烯基化, 吲哚酮

Abstract:

As important natural and pharmaceutical motifs, the catalytic construction of structurally diverse 3,3-disubstituted oxindoles often requires elaborate synthetic efforts on optimizations. Herein, we developed a simple and divergent approach for constructing reverse-prenylated and prenylated oxindoles launched by Ni catalysis with bulk chemical isoprene. Using C3-unsubstituted oxindoles as starting materials, mono reverse-prenylation was demonstrated in high chemo- and regioselectivities facilitated by the combination of Ni(0) and monodentate phosphine ligand. Using the obtained reverse-prenylated oxindoles as versatile synthon, substitutions at the pseudobenzylic position with various electrophiles created vicinal quaternary centers in a concise way. With the help of additives (PPh₃ and NaH), air could be directly used as green oxidant to construct prenylated and reverse-prenylated α-hydroxy-oxindoles divergently from the same substrates. In situ esterification of prenylated α-hydroxy-oxindoles allowed subsequent Friedel-Crafts substitutions with diverse nucleophiles to deliver prenyl substituted dimeric or spiro-oxindoles. This protocol provides a divergent synthetic approach for the construction of highly functionalized 3,3-disubstituted oxindoles, which have been otherwise difficult to access in a unified approach.

Key words: Nickel catalysis, Unified construction, Isoprene, (Reverse-)prenylation, Oxindole

刘盈盈, 李莹, 李雪婷, 徐溯阳, 季定纬, 胡向平, 陈庆安. 镍催化吲哚酮的选择性异戊烯化和反异戊烯基化反应[J]. 催化学报, 2025, 70: 444-454.

Ying-Ying Liu, Ying Li, Xue-Ting Li, Su-Yang Xu, Ding-Wei Ji, Xiang-Ping Hu, Qing-An Chen. Unified construction of prenylated and reverse-prenylated oxindoles from isoprene launched by Ni catalysis[J]. Chinese Journal of Catalysis, 2025, 70: 444-454.

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链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(24)60218-4

https://www.cjcatal.com/CN/Y2025/V70/I3/444

图/表 6

Fig. 1. Unified construction of prenylated and reverse-prenylated oxindoles from isoprene launched by Ni catalysis.

Table 1 Optimization for nickel catalyzed reverse-prenylation of oxindole with isoprene.

Entry	Ligand	Yield (%)					Entry	Ligand	Yield (%)
Entry	Ligand	3a	4a	5a	6a	(7a + 8a + 9a) ^c	Entry	Ligand	3a	4a	5a	6a	(7a + 8a + 9a) ^c
1	dcpm	39	2	1	12	42	8	PPh₂Cy	55	—	—	4	—
2	dcpe	1	1	2	9	85	9	PPhCy₂	77	—	—	5	—
3	dcpp	3	—	3	19	74	10	PCy₃	84	—	—	4	—
4	dcpb	14	—	19	30	28	11 ^b	PCy₃	96	—	—	2	—
5 ^a	IPr·HCl	77	—	—	10	—	12	CyJohnPhos	16	—	—	—	—
6 ^a	SIPr·HCl	56	—	—	20	—	13	SPhos	20	—	—	—	—
7	PPh₃	35	—	—	2	—	14	P^tBu₃	—	—	—	—	—

Fig. 2. Substrate scope of reverse-prenylated oxindoles and contiguous quaternary substituted oxindoles.

Fig. 3. Substrate scope of α-hydroxy-(reverse-)prenylated oxindoles and consecutive (hetero)arylated oxindoles.

Fig. 4. Mechanism studies for unified construction of prenylated and reverse-prenylated oxindoles.

Fig. 5. Scale-up preparation and divergent transformations.

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镍催化吲哚酮的选择性异戊烯化和反异戊烯基化反应

Unified construction of prenylated and reverse-prenylated oxindoles from isoprene launched by Ni catalysis

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