位阻调控的吲哚C4位甲基化和C4甲基化/羰基重排反应

doi:10.6023/cjoc202510028

摘要/Abstract

甲基化反应的发展因其在药物发现中“神奇甲基效应”而备受关注. 同时, 吲哚骨架在天然产物和药效团中广泛存在. 尽管其他位点选择性甲基化反应取得了进展, 但关于吲哚C4位甲基化的报道寥寥无几, 且尚未见吲哚环上 C—H甲基化与羰基迁移的协同研究. 本研究实现了吲哚C4位甲基化, 并开发了位阻控制的C4甲基化/羰基重排反应. 羰基处的大位阻基团可促进其迁移, 为合成C2/C4双取代吲哚提供了一条简洁高效的合成路径.

关键词: 甲基化, 羰基迁移, 钯催化, 神奇甲基效应

The development of methylation protocol has attracted intense attention owing to “magic methyl effect” in drug discovery. Meanwhile, the indole scaffold is prevalence in the natural products and pharmacophores. Despite the advances in other site selective methylation, there is scarce reports for C4 methylation of indoles and combination of a carbonyl group rearrangement with C—H methylation on indole ring. Herein, the C4 methylation of indoles and the steric controlled C4-methylation/carbonyl group migration are reported. The large steric hindrance at carbonyl group facilitates the carbonyl group migration, which provides a straightforward protocol for the synthesis of C2/C4 disubstituted indoles.

Key words: methylation, carbonyl group dancing, Pd catalysis, magic methyl effect

引用此文

谢赫男, 程瑶航, 安光辉. 位阻调控的吲哚C4位甲基化和C4甲基化/羰基重排反应[J]. 有机化学, 2026, 46(2): 475-485.

Henan Xie, Yaohang Cheng, Guanghui An. C4-Methylation and C4-Methylation/Carbonyl Migration of Indoles via Steric Control[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 475-485.

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图/表 9

Scheme 1. C—H methylation of indoles

Entry	Catalyst	Acid	Temp/℃	Yield^b/%
Entry	Catalyst	Acid	Temp/℃	3a	4a
1	Pd(OAc)₂	TFA	50	74	—
2	Pd(TFA)₂	TFA	50	72	—
3	—	TFA	50	—	—
4	Pd(OAc)₂	HOAc	50	16	—
5	Pd(OAc)₂	TsOH•H₂O	50	—	—
6	Pd(OAc)₂	—	50	—	—
7	Pd(OAc)₂	TFA	60	53	4
8	Pd(OAc)₂	TFA	70	26	8
9	Pd(OAc)₂	TFA	80	19	12
10^c	Pd(OAc)₂	TFA	50	86	—
11^c^,^d	Pd(OAc)₂	TFA	50	88	—

Table 1. Optimization of the reaction conditionsa

Scheme 2. Substrate scope of C4-methylation Standard conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (3.0 equiv.), Pd(OAc)2 (10 mol%), Cu(OAc)2 (20 mol%), TFA (2.0 equiv.), DCE (2.0 mL), air, 50 ℃, 3 h, isolated yields. a 5 h.

Scheme 3. Effect of substituents at aliphatic carbonyl group

Entry	Acid	Temp./℃	Yield^b/%
Entry	Acid	Temp./℃	3p	6a
1	TFA	50	18	53
2	TFA	40	15	25
3	TFA	60	16	52
4	PivOH	50	0	0
5	TsOH•H₂O	50	0	0
6	—	50	0	0
7^c	TFA	50	9	65
8^c^,^d	TFA	50	0	75

Table 2. Optimization of the reaction conditionsa

Scheme 4. Substrate scope of C4-methylation/carbonyl group dance reaction Standard conditions: 1 (0.2 mmol, 1 equiv.), 2 (3.0 equiv.), Pd(OAc)2 (10 mol%), Cu(OAc)2 (20 mol%), TFA (2.0 equiv.), KOAc (1.0 equiv.), DCE (2.0 mL), air, 50 ℃, 6 h, isolated yields.

Entry	Catalyst	Additive	Acid	Time/h	Yield^b/%
1	—	—	—	6	0
2	Pd(OAc)₂	—	—	6	0
3	—	Cu(OAc)₂	—	6	0
4	—	—	TFA	6	79
5^c	—	—	TFA	6	88
6^c			TFA	12	90

Table 3. Control reactionsa

Scheme 5. Mechanism studies

Scheme 6. Proposed mechanism

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