Construction of Indole Skeletons through Direct Catalytic Three-Component Domino Reactions of Vinylarenes, Aldehydes, and Pronucleophiles

Abstract

A synthesis of 3-alkyl-2-arylindoles was performed by sequential oxidation and reduction of 2-(2-nitrophenyl)ethanols that were prepared by base-catalyzed three-component reactions of vinylarenes, aldehydes, and various pronucleophiles, including nitroalkanes, thiols, and malonates. In addition to indoles, a selective synthesis of an N-hydroxyindole was accomplished. The highly nucleophilic character of transient benzylic anions in DMSO was also clarified for the three-component reactions.

Key words

indole - multicomponent reaction - catalytic reaction - direct reaction - domino reaction

Publication History

Received: 09 May 2022

Accepted after revision: 31 May 2022

Accepted Manuscript online:
31 May 2022

Article published online:
23 June 2022

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• 19 Diethyl {3-Hydroxy-2-(2-nitrophenyl)-3-[2-(trifluoromethyl)phenyl]propyl}(methyl)malonate (4j); Typical Procedure A mixture of diethyl methylmalonate (104.5 mg, 0.6 mmol), a 0.5 M solution of KHMDS in toluene (0.06 mL, 0.03 mmol), and anhyd DMSO (0.5 mL) was added to a stirred solution of 2-nitrostyrene (89.5 mg, 0.60 mmol) and 2-(trifluoromethyl)benzaldehyde (52.2 mg, 0.30 mmol) in dry DMSO (0.5 mL) at rt. The resulting solution was stirred at rt for 18 h, and then the reaction was quenched by addition of sat. aq NH₄Cl. The mixture was extracted with EtOAc, and the organic extracts were washed with H₂O, dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (5:1)] to give a yellow solid; yield: 107.7 mg (0.216 mmol, 72%); mp 98.3–99.0 °C (CHCl₃). IR (CHCl₃): 3602, 3029, 2987, 1725, 1608, 1527, 1351 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.0 Hz, 1 H), 7.67–7.60 (m, 3 H), 7.44–7.35 (m, 3 H), 7.28 (d, J = 8.0 Hz, 1 H), 5.18 (t, J = 6.0 Hz, 1 H), 4.12–4.00 (m, 3 H), 3.98–3.77 (m, 1 H), 3.67–3.59 (m, 1 H), 2.65 (d, J = 5.2 Hz, 1 H), 2.55 (dd, J = 14.4, 10.8 Hz, 1 H), 2.20 (dd, J = 14.4, 2.8 Hz, 1 H), 1.19–1.15 (m, 6 H), 1.07 (t, J = 6.8 Hz, 3 H).¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 171.4, 151.6, 140.9, 134.8, 132.0, 132.0, 130.1, 128.0, 127.7, 127.7 (q, split by C–F coupling, J = 29.6 Hz), 127.6, 125.6 (q, split by C–F coupling, J = 5.7 Hz), 124.3 (q, split by C–F coupling, J = 272.7 Hz), 124.0, 73.2, 61.5, 61.1, 52.8, 40.9, 37.4, 19.9, 13.8, 13.7. HRMS (DART+): m/z [M + H]⁺ calcd for C₂₄H₂₇F₃NO₇: 498.1740; found: 498.1732.
• 20 Diethyl Methyl({2-[2-(trifluoromethyl)phenyl]-1H-indol-3-yl}methyl)malonate (5j) and Diethyl ({1-Hydroxy-2-[2-(trifluoromethyl)phenyl]-1H-indol-3-yl}methyl)(methyl)malonate (7j); Typical Procedure PCC (43.1 mg, 0.20 mmol) was added to a stirred suspension of 4j (24.8 mg, 0.05 mmol) and Celite (27.7 mg) in CH₂Cl₂ (2.0 mL) at 0 °C, and the mixture was stirred at rt for 24 h. The mixture was then filtered through a silica gel pad by washing with Et₂O, and the filtrate was concentrated to give a crude product (26.5 mg) that was used in the next step without purification. To a stirred solution of the resulting ketone (26.5 mg) in CH₂Cl₂ (1.0 mL) were added Zn (49 mg) and AcOH (0.08 mL, 1.40 mmol) at 0 °C. The resulting mixture was refluxed for 3 h, cooled to rt, and filtered through Celite pad. Sat. aq NaHCO₃ was added, and the mixture was extracted with CH₂Cl₂. The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by preparative TLC (benzene–EtOAc, 10:1) to give 5j as a yellow oil [yield: 19.5 mg (43.6 μmol, 87% for 2 steps)] and 7j as a white solid [yield: 0.9 mg (1.94 μmol, 4% for 2 steps)]. 5j IR (CHCl₃): 3471, 2985, 2938, 1725, 1606 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 8.16 (br s, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.65–7.52 (m, 4 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.23–7.10 (m, 2 H), 4.04–3.96 (m, 2 H), 3.89–3.82 (m, 2 H), 3.54 (s, 2 H), 1.13 (s, 3 H), 1.08 (t, J = 6.8 Hz, 6 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 172.2, 135.4, 133.7, 133.2, 131.8, 131.5, 129.4 (q, split by C–F coupling, J = 30.5 Hz), 128.9, 128.6, 126.6 (q, split by C–F coupling, J = 4.7 Hz), 123.9 (q, split by C–F coupling, J = 272.7 Hz), 122.5, 119.7, 119.6, 110.7, 109.2, 61.1, 54.8, 29.3, 19.9, 13.7. HRMS (FAB+): m/z [M⁺] calcd for C₂₄H₂₄F₃NO₄: 447.1657; found: 447.1652. 7j mp 174.0–175.0 °C (MeOH). IR (CHCl₃): 3029, 2985, 1724 cm^–1. ¹H NMR (CD₃OD, 400 MHz): δ = 7.83 (d, J = 7.6 Hz, 1 H), 7.74–7.63 (m, 2 H), 7.50–7.46 (m, 2 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.17 (t, J = 8.4 Hz, 1 H), 7.03 (t, J = 6.8 Hz, 1 H), 4.05–3.90 (m, 3 H), 3.86–3.78 (m, 1 H), 3.48 (d, J = 14.8 Hz, 1 H), 3.20 (d, J = 14.8 Hz, 1 H), 1.13–1.04 (m, 9 H). ¹³C NMR (CD₃OD, 100 MHz): δ = 173.8, 173.7, 135.8, 135.4, 134.9, 132.4, 132.0 (q, split by C–F coupling, J = 30.5 Hz), 130.5, 130.3, 127.6 (q, split by C–F coupling, J = 4.8 Hz), 125.3 (q, split by C–F coupling, J = 272.7 Hz), 125.3, 123.1, 120.2, 120.2, 109.3, 105.3, 62.5, 62.4, 56.0, 31.0, 20.8, 14.1, 14.1. HRMS (FAB+): m/z [M⁺] calcd for C₂₄H₂₄F₃NO₅: 463.1607; found: 463.1598.