Nickel-Catalyzed Radical Hydroalkylative Dearomatization of Indoles with Alkyl Bromides

Abstract

Dearomatization of indole derivatives offers a straightforward approach to accessing the indoline framework. However, highly efficient dearomatization of indoles bearing electron-deficient groups remains underdeveloped. Herein, a nickel-catalyzed intermolecular hydroalkylative dearomatization reaction of indoles with simple alkyl bromides through a single-electron-transfer process is reported. A wide variety of indole derivatives bearing various functional groups were compatible with this protocol and reacted with primary, secondary, or tertiary alkyl bromides to afford a series of indolines in good yields (up to 82%) and with excellent diastereoselectivity (up to >20:1). Notably, a nickel-mediated hydrogen-atom-transfer process was observed when terminal alkyl bromides were employed as the radical precursors, which resulted in branched products.

Key words

alkyl bromides - dearomatization - hydroalkylation - indoles - nickel catalysis

Publication History

Received: 23 July 2024

Accepted after revision: 07 August 2024

Accepted Manuscript online:
07 August 2024

Article published online:
04 September 2024

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• 15 Radical Hydroalkylative Dearomatization; General Procedure A flame-dried sealed tube was charged with Ni(ClO₄)₂·6 H₂O (7.3 mg, 0.02 mmol, 10 mol%), ligand L1 (4.4 mg, 0.024 mmol, 12 mol%), and DMA (1 mL), and the resulting mixture was stirred for 10 min. The appropriate indole derivative 1 (0.2 mmol, 1.0 equiv), alkyl bromide 2 (0.7 mmol, 3.5 equiv), and Mn powder (27.5 mg, 0.5 mmol, 2.5 equiv) were added. The mixture was thoroughly degassed by three freeze–pump–thaw cycles and then stirred for 4 h at r.t. The tube was then placed in a glove box and additional 2 (0.2 mmol, 1.0 equiv) was added. The mixture was then stirred for another 24 h until the reaction was complete (TLC). The mixture was filtered through a short column of silica gel, which was washed with EtOAc, and the organic phase was concentrated in vacuo to afford a crude product. The dr values were determined by ¹H NMR analysis of the crude product, which was then subjected to further purification by column chromatography [silica gel, PE–EtOAc (15:1 to 10:1)]. Methyl (trans)-1-Acetyl-3-isopropylindoline-2-carboxylate (3aa) Yellow oil; yield: 42.9 mg (82%, >20:1 dr). IR (thin film): 2955, 2922, 2853, 1748, 1666, 1597, 1461, 1392, 1281, 1253, 1200, 1027, 996, 755 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.22 and 7.13 (d, J = 8.0 Hz, 1 H), 7.27–7.16 (m, 2 H), 7.06–7.02 (m, 1 H), 4.94 and 4.58 (d, J = 2.4 Hz, 1 H), 3.76 and 3.71 (s, 3 H), 3.30 and 3.15 (dd, J = 4.8, 2.4 Hz, 1 H), 2.48 and 2.17 (s, 3 H), 2.09–1.96 (m, 1 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.83 and 0.80 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 168.6, 168.4, 141.4, 133.9, 131.3, 128.4, 128.1, 125.9, 124.5, 123.8, 123.3, 117.2, 113.8, 64.4, 62.9, 52.9, 52.5, 52.4, 50.2, 33.5, 33.2, 24.5, 23.8, 19.5, 17.8, 17.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₉NNaO₃: 284.1257; found: 284.1257.

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