C4-Methylation and C4-Methylation/Carbonyl Migration of Indoles via Steric Control

doi:10.6023/cjoc202510028

Abstract

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

Cite this article

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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Fig. & Tab. 6

Scheme 1. C—H methylation of indoles

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

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.

Scheme 5. Mechanism studies

Scheme 6. Proposed mechanism

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位阻调控的吲哚C4位甲基化和C4甲基化/羰基重排反应