Nickel-Catalyzed Radical Hydroalkylative Dearomatization of Indoles with Alkyl Bromides
Hao-Tian Dai
a
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
,
Xu-Lun Huang
a
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
,
Yuan-Zheng Cheng∗
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
,
Shu-Li You∗
a
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. of China
› Author AffiliationsFinancial support for this work was provided by the National Natural Science Foundation of China (22201291, 21821002, 22261132511, and 22031012), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2023000046), and the Science and Technology Commission of Shanghai Municipality (22JC1401103 and 2023000285). S.-L.Y. acknowledges support from the New Cornerstone Science Foundation.
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.
15Radical 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.
For recent reviews on the nickel-mediated chain-walking process, see:
16a
Wang Y,
He Y,
Zhu S.
Acc. Chem. Res. 2022; 55: 3519
