Precise Synthesis of Multisubstituted Indoles Enabled by Palladium/Norbornene Cooperative Catalysis

doi:10.6023/cjoc202511008

Abstract

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

Cite this article

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.

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Fig. & Tab. 7

Figure 1. Bioactive molecules containing multisubstituted indole scaffolds

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

Table 1. Optimization of the reaction conditions

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

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

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

Scheme 2. Gram-scale experiment and product conversion

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