钯/降冰片烯协同催化精准合成多取代吲哚

doi:10.6023/cjoc202511008

摘要/Abstract

多取代吲哚化合物是自然界中广泛分布的一类杂环化合物, 大部分具有重要的生物活性. 然而, 吲哚丰富的化学反应性导致多取代吲哚的精准高效合成存在较大的挑战. 此文报道了以单官能化吲哚为底物、烷基卤化物和烯烃为反应试剂, 基于钯/降冰片烯(Pd/NBE)协同催化策略, 高位点选择性和高区域选择性地合成复杂多取代吲哚衍生物. 该合成方法底物适用范围广, 且可实现克级规模制备. 此外, 该反应具有良好的官能团兼容性, 为多取代吲哚产物的进一步转化提供了可能. 值得一提的是, 从机理上推断, 该反应经历了关键的六元环钯中间体, 进而实现了吲哚的跨环 C—H键活化和多位点修饰.

关键词: 多取代吲哚, 钯/降冰片烯(Pd/NBE), 位点选择性, 区域选择性, 六元环钯中间体

Multisubstituted indoles are a class of heterocyclic compounds widely distributed in nature, and most of them exhibit significant biological activities. However, the rich chemical reactivity of indoles poses significant challenges for the precise and efficient synthesis of multisubstituted indoles. This article reports the highly site-selective and regioselective synthesis of complex multisubstituted indoles via a palladium/norbornene cooperative catalysis strategy, with readily available monofunctionalized indoles, alkyl halides, and alkenes as the building blocks. This method features broad substrate scope and good scalability. In addition, the reaction demonstrates excellent functional group tolerance, thus offering opportunities for the further modification of the obtained multisubstituted indole products. It is worth mentioning that a key six-membered palladacycle intermediate is presumed to exist in the reaction mechanism, enabling remote modifications of indole across the ring.

Key words: multisubstituted indole, palladium/norbornene (Pd/NBE), site-selectivity, regioselectivity, six-membered palladacycle

引用此文

付雪鹏, 汪建树, 陈树清, 程鸿刚, 周强辉. 钯/降冰片烯协同催化精准合成多取代吲哚[J]. 有机化学, 2026, 46(8): 3053-3067.

Xuepeng Fu, Jianshu Wang, Shuqing Chen, Honggang Cheng, Qianghui Zhou. Precise Synthesis of Multisubstituted Indoles Enabled by Palladium/Norbornene Cooperative Catalysis[J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3053-3067.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 7

图1. 含多取代吲哚骨架的生物活性分子

Figure 1. Bioactive molecules containing multisubstituted indole scaffolds

图式1. 多取代吲哚的合成方法(a), 钯/降冰片烯协同催化合成吲哚和咔唑(b)以及本文研究内容(c)

Scheme 1. Synthesis methods of multisubstituted indoles (a), palladium/norbornene cooperative catalysis of indoles and carbazoles (b) and the research contents of this paper (c)

Entry	NBE¹ (x/equiv.)	Ligand	2a (y/equiv.)	Yield^b/%
Entry	NBE¹ (x/equiv.)	Ligand	2a (y/equiv.)	4a 5a
1	2.0	PPh₃	2.5	9	45
2	2.0	L1	2.5	24	2
3	2.0	L2	2.5	26	21
4	2.0	L3	2.5	22	57
5	2.0	L4	2.5	55	29
6	2.0	L5	2.5	60	19
7	1.0	L5	2.5	43	37
8	3.0	L5	2.5	58	29
9	2.0	L5	4.0	75 (70^c)	5
10	2.0	L5	5.0	75	5

表1. 反应条件的优化a

Table 1. Optimization of the reaction conditions

图式3. 基于Pd0/NBE协同催化制备2,3,4-三取代吲哚可能的反应机理

Scheme 3. Proposed mechanism of synthesizing 2,3,4-trisubstituted indoles via Pd0/NBE cooperative catalysis

表2. 基于Pd0/NBE协同催化制备2,3,4-三取代吲哚a

Table 2. Synthesis of 2,3,4-trisubstituted indoles via Pd0/NBE cooperative catalysis

表3. 基于PdII/NBE协同催化制备3,4,5-三取代吲哚a

Table 3. Synthesis of 3,4,5-trisubstituted indoles via PdII/NBE cooperative catalysis

图式2. 克级实验及产物转化

Scheme 2. Gram-scale experiment and product conversion

参考文献 20

[1]	(a) Borman, R. A.; Tilford, N. S.; Harmer, D. W.; Day, N.; Ellis, E. S.; Sheldrick, R. L. G.; Carey, J.; Coleman, R. A.; Baxter, G. S. Br. J. Pharmacol. 2009, 135, 1144.
	(b) Moore, R. E.; Cheuk, C.; Yang, G.-X.; Patterson, G. M. L.; Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones, N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52, 1036.
	(c) Plenge, P.; Yang, D.-X.; Salomon, K.; Laursen, L.; Kalenderoglou, I. E.; Newman, A. H.; Gouaux, E.; Coleman, J. A.; Loland, C. J. Nat. Commun. 2021, 12, 5063.
	(d) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc. 2010, 132, 4894.
	(e) Medley, J. W.; Movassaghi, M. Angew. Chem. Int. Ed. 2012, 51, 4572.
	(f) Shao, L.; Liao, C.; Gregg, I.; Davoudian, P. A.; Savalia, N. K.; Delagarza, K.; Kwan, A. C. Neuron 2021, 109, 2535.
	(g) Dupeyre, G.; Lemoine, P.; Ainseba, N.; Michela, S.; Cachet, X. Org. Biomol. Chem. 2011, 9, 7780.
	(h) Spence, K. A.; Chari, J. V.; Niro, D. M.; Susick, R. B.; Ukwitegetse, N.; Djurovich, P. I.; Thompson, M. E.; Garg, N. K. Chem. Sci. 2022, 13, 5884.
	(i) Suárez, A.; García-García, P.; Fernández-Rodríguez, M. A.; Sanz, R. Adv. Synth. Catal. 2014, 356, 374.
	(j) Tian, Z.-Y.; Liao, A.-C.; Kang, J.; Gao, Y.-Y.; Lu, A.-D.; Wang, Z.-W.; Wang, Q.-M. J. Agric. Food Chem. 2021, 69, 9754.
	(k) Boriskin, Y. S.; Leneva, I. A.; Pécheur, E. I.; Polyak, S. J. Curr. Med. Chem. 2008, 15, 997.
[2]	(a) Mao, P.-F.; Zhou, L.-J.; Zheng, A.-Q.; Miao, C.-B.; Yang, H.-T. Org. Lett. 2019, 21, 3153.
	(b) Zhou, L.-J.; Wang, K.; Guan, H.-R.; Zheng, A.-Q.; Yang, H.-T.; Miao, C.-B. J. Org. Chem. 2020, 85, 7925.
	(c) Huang, X.; Shi, Y.; Wang, Y.; Jiao, J.; Tang, Y.; Li, J.; Xu, S.; Li, Y. Org. Lett. 2021, 23, 8365.
	(d) Zhang, Y.-R.; Qiu, Z.-W.; Fu, Z.-J.; Chen, S.-S.; Pan, H.-P.; Li, B.-Q.; Ma, A.-J.; Zhang, X.-Z. Adv. Synth. Catal. 2024, 366, 1320.
	(e) Lai, B.-W.; Qu, S.-Y.; Yin, Y.-X.; Li, R.; Dong, K.; Shi, F. J. Org. Chem. 2024, 89, 10197.
	(f) Pi, C.; Qu, Y.; Cui, X.; Wu, Y. Chin. J. Org. Chem. 2020, 40, 740 (in Chinese).
	(皮超, 曲亚平, 崔秀灵, 吴养洁, 有机化学, 2020, 40, 740.)
	(g) Wang, Y.; Zhang, J.; Liu, Y.; Luo, X.; Deng, W. Chin. J. Org. Chem. 2023, 43, 2864 (in Chinese).
	(王熠, 张键, 刘飏子, 罗晓燕, 邓卫平, 有机化学, 2023, 43, 2864.)
[3]	(a) Coste, A.; Toumi, M.; Wright, K.; Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841.
	(b) Vadola, P. A.; Sames, D. J. Org. Chem. 2012, 77, 7804.
	(c) Liang, K.; Yang, J.; Tong, X.; Shang, W.; Pan, Z.; Xia, C. Org. Lett. 2016, 18, 1474.
	(d) Shrestha, R.; Khanal, H. D.; Lee, Y. R. RSC Adv. 2019, 9, 17347.
[4]	(a) Banerjee, S.; Kumar, S. V.; Punniyamurthy, T. J. Org. Chem. 2020, 85, 2793.
	(b) Chen, C.; Wang, Y.; Shi, X.; Sun, W.; Zhao, J.; Zhu, Y.-P.; Liu, L.; Zhu, B. Org. Lett. 2020, 22, 4097.
	(c) Wang, D.; Li, M.; Chen, X.; Wang, M.; Liang, Y.; Zhao, Y.; Houk, K. N.; Shi, Z. Angew. Chem. Int. Ed. 2021, 60, 7066.
[5]	Shinde, V. N.; Rangan, K.; Kumar, D.; Kumar, A. J. Org. Chem. 2021, 86, 2328.
[6]	Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. 1997, 36, 119.
[7]	(a) Ye, J.; Lautens, M. Nat. Chem. 2015, 7, 863.
	(b) Zhu, H.; Ye, C.; Chen, Z. Chin. J. Org. Chem. 2015, 35, 2291 (in Chinese).
	(朱辉, 叶长青, 陈知远, 有机化学, 2015, 35, 2291.)
	(c) Della Ca', N.; Fontana, M.; Motti, E.; Catellani, M. Acc. Chem. Res. 2016, 49, 1389.
	(d) Wang, J.; Dong, Z.; Yang, C.; Dong, G. Nat. Chem. 2019, 11, 1106.
	(e) Shi, H.; Lu, Y.; Weng, J.; Bay, K. L.; Chen, X.; Tanaka, K.; Verma, P.; Houk, K. N.; Yu, J.-Q. Nat. Chem. 2020, 12, 399.
	(f) Dong, Z.; Wang, J.; Dong, G. J. Am. Chem. Soc. 2015, 137, 5887.
	(g) Chen, S.; Liu, Z.-S.; Yang, T.; Hua, Y.; Zhou, Z.; Cheng, H.-G.; Zhou, Q. Angew. Chem. Int. Ed. 2018, 57, 7161.
	(h) Shi, G.; Shao, C.; Ma, X.; Gu, Y.; Zhang, Y. ACS Catal. 2018, 8, 3775.
	(i) Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing, W. R.; Yu, J.-Q. J. Am. Chem. Soc. 2019, 141, 14870.
	(j) Li, R.; Zhou, Y.; Xu, X.; Dong, G. J. Am. Chem. Soc. 2019, 141, 18958.
	(k) Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing, W. R.; Yu, J.-Q. Angew. Chem. Int. Ed. 2020, 59, 13831.
	(l) Wu, Z.; Fatuzzo, N.; Dong, G. J. Am. Chem. Soc. 2020, 142, 2715.
	(m) Dong, S.; Luan, X. Chin. J. Chem. 2021, 39, 1690.
	(n) Shang, Y.; Wu, C.; Gao, Q.; Liu, C.; Li, L.; Zhang, X.; Cheng, H.-G.; Liu, S.; Zhou, Q. Nat. Commun. 2021, 12, 2988.
	(o) Zhou, L.; Cheng, H.-G.; Li, L.; Wu, K.; Hou, J.; Jiao, C.; Deng, S.; Liu, Z.; Yu, J.-Q.; Zhou, Q. Nat. Chem. 2023, 15, 815.
	(p) Cheng, H.; Jia, S.; Zhou, Q. Acc. Chem. Res. 2023, 56, 573.
	(q) Wang, J.-S.; Liu, Z.; Qian, G.; Chen, X.; Cao, L.; Yu, T.; Ye, J.; Ma, Y.; Chen, S.; Yang, Z.; Cheng, H.-G.; Yang, Y.-F.; Zhou, Q. Angew. Chem. Int. Ed. 2025, 64, e202509300.
[8]	(a) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.
	(b) Mitsudo, K.; Thansandote, P.; Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939.
[9]	(a) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990.
	(b) Potukuchi, H. K.; Bach, T. J. Org. Chem. 2013, 78, 12263.
[10]	Liu, X.; Zhou, Y.; Qi, X.; Li, R.; Liu, P.; Dong, G. Angew. Chem. Int. Ed. 2023, 62, e202310697.
[11]	Gao, Y.; Zhu, W.; Yin, L.; Dong, B.; Fu, J.; Ye, Z.; Xue, F.; Jiang, C. Tetrahedron Lett. 2017, 58, 2213.
[12]	(a) Elsaid, M.; Ge, R.; Liu, C.; Maiti, D.; Ge, H. Angew. Chem. Int. Ed. 2023, 62, e202303110.
	(b) Herington, F.; Achal, F. J.; Figueroa-Agosto, D.; Liu, C.; Ge, H. J. Org. Chem. 2025, 90, 12485.
[13]	Li, W.; Tao, J.; Sheng, H.; Cao, M.; Chen, M.; Gao, W.; Zhang, X.; Li, W.; Yu, Y.; Li, T. Org. Chem. Front. 2025, 12, 4332.
[14]	Liu, S.; Tian, L.; Zhang, M.; Liang, C.; Gong, X.; Wang, X.; Nan, J. Org. Lett. 2025, 27, 8293.
[15]	Wang, F.-Y.; Tan, Y.-F.; Jiao, L. ChemRxiv 2024, DOI: 10.26434/chemrxiv-2024-xn57p.
[16]	Wang, Z.; Hu, L.; Chekshin, N.; Zhuang, Z.; Qian, S.; Qiao, J. X.; Yu, J.-Q. Science 2021, 374, 1281.
[17]	Wang, J.; Zhou, Y.; Xu, X.; Liu, P.; Dong, G. J. Am. Chem. Soc. 2020, 142, 3050.
[18]	Shohji, N.; Kawaji, T.; Okamoto, S. Org. Lett. 2011, 13, 2626.
[19]	Stahl, G. L.; Walter, R.; Smith, C. W. J. Org. Chem. 1978, 43, 2285.
[20]	Cao, L.; Hua, Y.; Cheng, H.-G.; Zhou, Q. Org. Chem. Front. 2021, 8, 3883.