Metal-Free Directed C–H Borylation of Indoles at the Sterically Congested C2 Position

Wang Jiang; Jingyi Bai; Jiahang Lv; Yue Zhao; Chaoguo Yan; Zhuangzhi Shi

doi:10.1055/a-2126-1750

Synlett, Inhaltsverzeichnis

Synlett 2023; 34(18): 2220-2226
DOI: 10.1055/a-2126-1750

cluster

Modern Boron Chemistry: 60 Years of the Matteson Reaction

Metal-Free Directed C–H Borylation of Indoles at the Sterically Congested C2 Position

Wang Jiang

^aCollege of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China

^bState Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China

,

Jingyi Bai

^bState Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China

,

Jiahang Lv

^bState Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China

,

Yue Zhao

^bState Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China

,

Chaoguo Yan∗

^aCollege of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China

,

Zhuangzhi Shi∗

^aCollege of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, P. R. of China

^bState Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. of China

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Abstract

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Abstract

During the past few decades, transition metal-catalyzed C–H borylation has been one of the most notable advances in synthetic chemistry and has been widely employed in the preparation of organoboron reagents. Due to economic and heavy-metal-residue concerns, there is significant interest in the development of metal-free processes to mimic metallic systems. Here, we disclose a highly efficient metal-free approach for the directed C–H borylation of C3-substituted indoles at the sterically congested C2 position that uses the inexpensive boron reagent BBr₃. Compared with the conventional methods using transition metals, this practical protocol provides an ideal pathway to obtain numerous C2-borylated indoles. The benefit of the synthesis of complex molecules and their applicability to medicinal chemistry is also shown through the construction of key intermediates of (–)-goniomitine and bazedoxifene and by a total synthesis of the drug fluvastatin. Mechanistic experiments demonstrate the site selectivity of this C–H borylation process.

Key words

C–H bond activation - borylation - indoles - BBr₃ - site selectivity - metal-free reaction

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References and Notes

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24 1-(1-Adamantylcarbonyl)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1c); Typical Procedure A flame-dried 25-mL Schlenk tube was flushed with argon and then charged with indole 1a (58.6 mg, 0.2 mmol, 1.0 equiv) and dry DCM (1 mL, 0.2 M). A 1.0 M solution of BBr₃ in DCM, (0.22 mL, 1.1 equiv) was added slowly under argon. Pyridine (2.0 mmol) and pinacol (0.30 mmol) were then added sequentially, and the resulting mixture was stirred at rt for another 2 h until the reaction was complete (TLC). The solvent was removed directly under vacuum, and the crude product was purified by flash column chromatography [silica gel, EtOAc–PE (1:20)] to give a white solid; yield: 64.9 mg (77%). ATR-FTIR: 3023, 2976, 1685, 1352, 952, 728 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 8.3 Hz, 1 H), 7.52–7.50 (m, 1 H), 7.28–7.24 (m, 1 H), 7.19–7.15 (m, 1 H), 2.42 (s, 3 H), 2.16 (d, J = 3.0 Hz, 6 H), 2.10–2.08 (m, 3 H), 1.76–1.74 (m, 6 H), 1.36 (s, 12 H). ¹³C NMR (126 MHz, CDCl₃): δ = 183.2, 136.4, 132.5, 125.9, 124.1, 121.6, 119.7, 113.8, 83.1, 44.1, 38.0, 36.3, 28.0, 25.1, 9.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₃₅BNO₃: 420.2705; found: 420.2708.

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