Organocatalytic Fischer Indolization Using the 2,2′-Biphenol/ B(OH)₃ System

Abstract

An organocatalyzed Fischer indolization is established by combining 2,2′-biphenol (10 mol%) and B(OH)₃ (30 mol%) as weak, readily available, and easy-to-handle acids. The inclusion of MgSO₄, which efficiently scavenges NH₃ (a possible acid catalyst poison), appears to be key to the success of this process. The corresponding indoles are obtained in yields of up to 91% using this method.y

Key words

Fischer indolization - 2,2′-biphenol - boric acid - organocatalyst - indoles

Publication History

Received: 15 February 2024

Accepted after revision: 03 May 2024

Article published online:
17 May 2024

• References and Notes

• 1 Present address: Faculty of Science and Technology, Kyoto Prefectural University, 1-5 Hangi-cho, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan; [e-mail]
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pK _a1 = 7.6 for 2,2′-biphenol:
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pK _a = 9.1 for B(OH)₃:
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• 14 9-Benzyl-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (12a); Typical Procedure A screw-top test tube equipped with a magnetic stir bar was charged with 1-benzyl-1-phenylhydrazine (13a) (1 equiv, 27.9 mg, 0.141 mmol) and toluene (0.28 mL, 0.5 M). To the solution were added 4-phenylcyclohexanone (14a) (1 equiv, 24.6 mg, 0.141 mmol), 2,2′-biphenol (10 mol%, 2.62 mg, 0.0141 mmol), B(OH)₃ (30 mol%, 2.63 mg, 0.0432 mmol), and MgSO₄ (anhydrous, 3 equiv, 50.0 mg, 0.417 mmol) at room temperature. After stirring in refluxing toluene for 4 h using a heating block, the reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 90:10) to afford the indole 12a (42.4 mg, 89%) as a yellow solid. R_f = 0.68 (n-hexane/EtOAc = 80:20). ¹H NMR (500 MHz, CDCl₃): δ = 7.48 (dd, J = 6.6, 1.6 Hz, 1 H), 7.34–7.29 (m, 4 H), 7.26–7.17 (m, 5 H), 7.13–7.06 (m, 2 H), 6.99 (d, J = 6.9 Hz, 2 H), 5.26 (d, J = 16.9 Hz, 1 H), 5.20 (d, J = 16.9 Hz, 1 H), 3.15–3.01 (m, 2 H), 2.88–2.84 (m, 1 H), 2.74–2.73 (m, 2 H), 2.21–2.17 (m, 1 H), 2.13–2.05 (m, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 146.6, 138.1, 136.8, 135.1, 128.7, 128.4, 127.2, 127.0, 126.2, 126.1, 120.9, 119.0, 117.8, 109.7, 109.0, 46.3, 40.9, 30.3, 29.4, 22.2. The ¹H and ¹³C NMR spectra were identical with those previously reported.^8a