Scandium-Catalyzed Intramolecular Friedel–Crafts Reactions of 2-[(2-Alkyl-1H-indol-3-yl)methylene]malonates

Abstract

We have synthesized a variety of 2-[(2-alkyl-1H-indol-3-yl)methylene]malonates and studied their scandium-catalyzed intramolecular Friedel–Crafts reactions leading to the corresponding polycyclic compounds such as indeno[1,2-b]indoles and benzo[1,2-b]carbazoles.

Key words

scandium triflate - indole - Friedel–Crafts reaction - carbazole - polycycle

• References and Notes

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• 20 General Procedure for Cu-Catalyzed Synthesis of (1H-Indole-3-yl)methylenemalonate (3a): A solution of 2-(hex-1-ynyl)aniline (1a, 191.1 mg, 0.99 mmol) and triethyl orthoformate (0.3 mL, 1.8 mmol) in toluene (1.0 mL) was refluxed for 2 h under argon atmosphere. Then the mixture was concentrated under reduced pressure and treated with copper(II) triflate (35.7 mg, 0.10 mmol, 10 mol%) and dimethyl malonate (130.7 mg, 0.99 mmol) in anhyd toluene (1.0 mL) under argon atmosphere. The resulting mixture was refluxed for 6 h at 120 °C in a preheated oil-bath. Upon completion of the reaction, the solvent was removed under vacuum and the residue was subjected to silica gel column chromatography (EtOAc–n-hexane, 1:2) to afford the pure product 2a (208.6 mg, 73%) as a yellow oil. Tosylation of 2a was carried out to give 3a in over 95% yield. Typical Procedure for the Sc-Catalyzed Cyclization of 3b–n: Scandium(III) triflate (19.0 mg, 0.04 mmol, 20 mol%) was added to a mixture of N-protected indole 3b (100.0 mg, 0.19 mmol) in anhyd 1,4-dioxane (1.0 mL) under argon atmosphere. The resulting mixture was stirred for 12 h at 120 °C in a preheated oil-bath. Upon completion of the reaction, the solvent was removed under vacuum and the residue was subjected to silica gel column chromatography (EtOAc–n-hexane, 1:4) to afford the pure product 4b (87.1 mg, 87%) as a yellow solid. Diethyl 2-(5-Tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)malonate (4b): yellow solid; mp 110–112 °C. FTIR (neat): 3052.0, 2981.8, 2935.9, 1731.1, 1371.9, 1178.1 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 8.0 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 2 H), 7.51–7.57 (m, 2 H), 7.43 (t, J = 7.6 Hz, 1 H), 7.22–7.31 (m, 3 H), 7.10 (d, J = 8.4 Hz, 2 H), 4.57 (d, J = 4.8 Hz, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 3.97 (d, J = 4.8 Hz, 1 H), 3.79–3.88 (m, 2 H), 2.26 (s, 3 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.22, 167.78, 148.45, 144.84, 143.16, 141.07, 135.27, 134.35, 130.80, 129.85, 128.35, 126.80, 126.59, 126.29, 124.73, 124.69, 124.24, 122.14, 120.24, 115.68, 61.72, 61.48, 54.06, 41.103, 21.62, 13.95, 13.64. HRMS (EI): m/z [M] calcd for C₂₉H₂₇NO₆S: 517.1559; found: 517.1558. Diethyl 2-[Nitro(2-phenyl-1-tosyl-1H-indol-3-yl)methyl]malonate (5b): yellow solid; mp 126–128 °C. FTIR (neat): 3054.1, 2982.9, 2937.1, 1733.2, 1554.9, 1450.5, 1376.7, 1177.1 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.20 (d, J = 7.6 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.43–7.50 (m, 3 H), 7.29–7.39 (m, 6 H), 7.12 (d, J = 8.0 Hz, 2 H), 4.56–4.72 (m, 2 H), 4.38–4.44 (m, 1 H), 4. 07–4.22 (m, 2 H), 3.74 (d, J = 10.4 Hz, 1 H), 3.58–3.67 (m, 2 H), 2.32 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H), 0.70 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.38, 166.50, 144.90, 136.88, 135.65, 131.60, 131.48, 130.16, 129.65, 129.57, 127.91, 127.82, 126.83, 125.35, 123.99, 119.65, 117.04, 115.88, 76.18, 62.36, 61.69, 53.47, 34.69, 21.65, 13.97, 13.39. HRMS (EI): m/z [M] calcd for C₃₀H₃₀N₂O₈ S: 578.1723; found: 578.1723.Diethyl 2-(2,3-Dimethoxy-5-tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)malonate (4c): yellow solid; mp 121–124 °C. FTIR (neat): 2980.4, 2935.4, 1730.5, 1368.1, 1256.1, 1177.5, 1142.5 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.35 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H), 7.36 (d, J = 8.8 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 2 H), 6.95 (s, 1 H), 6.60–6.92 (m, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 3.98 (s, 3 H), 3.93 (s, 1 H), 3.88 (s, 3 H), 3.83 (q, J = 7.2 Hz, 2 H), 2.29 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 0.59 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.05, 167.97, 148.95, 147.87, 144.82, 143.28, 141.21, 140.62, 135.09, 129.82, 129.77, 129.41, 127.31, 127.06, 126.84, 126.74, 124.24, 123.99, 119.60, 115.62, 108.84, 105.90, 61.61, 61.52, 56.27, 56.22, 54.25, 40.90, 21.60, 13.96, 13.70. HRMS (EI): m/z [M] calcd for C₃₁H₃₁NO₈S: 577.1770; found: 577.1769. Diethyl 2-(2,3-Dimethoxy-8-nitro-5-tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)malonate (4d): yellow solid; mp 128–130 °C. FTIR (neat): 3109.8, 2934.7, 2854.2, 1730.1, 1521.4, 1392.9, 1343.7, 1215.2 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.44 (d, J = 2.0 Hz, 1 H), 8.32 (d, J = 8.6 Hz, 1 H), 8.14 (s, 1 H), 8.11 (dd, J = 8.6, 3.0 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.15 (s, 1 H), 4.54 (d, J = 4.8 Hz, 1 H), 4.16–4.27 (m, 2 H), 4.03 (s, 3 H), 4.00 (d, J = 4.8 Hz, 1 H), 3.96 (s, 3 H), 3.80–3.86 (m, 2 H), 2.30 (s, 3 H), 1.16 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.17, 167.06, 149.04, 148.64, 146.18, 145.63, 144.73, 143.13, 141.32, 134.58, 130.06, 128.69, 126.59, 125.95, 118.56, 115.64, 115.33, 108.35, 105.93, 62.07, 61.39, 56.17, 56.11, 53.92, 40.92, 21.55, 13.89, 13.55. HRMS (EI): m/z [M] calcd for C₃₁H₃₀N₂O₁₀S: 622.1621; found: 622.1621. 1-(5-Tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)propan-2-one (4e): yellow solid; mp 108–110 °C. FTIR (neat): 3053.5, 2981.5, 2918.8, 1717.7, 1596.8, 1451.5, 1372.8, 1177.7 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 7.6 Hz, 1 H), 8.27 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.41–7.45 (m, 3 H), 7.23–7.33 (m, 3 H), 7.11 (d, J = 8.4 Hz, 2 H), 4.39 (t, J = 6.8 Hz, 1 H), 2.88 (d, J = 6.8 Hz, 2 H), 2.27 (s, 3 H), 2.16 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 207.55, 151.33, 144.90, 142.15, 141.14, 135.23, 134.03, 133.49, 129.88, 129.85, 127.93, 126.77, 126.40, 126.35, 126.19, 124.66, 124.38, 124.27, 122.04, 119.72, 115.82, 115.73, 46.39, 37.02, 30.74, 21.65. HRMS (EI): m/z [M] calcd for C₂₅H₂₁NO₃S: 415.1242; found: 415.1243. 1-Phenyl-2-(5-tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)ethanone (4f): yellow solid; mp 130–132 °C. FTIR (neat): 3065.4, 2922.2, 2852.0, 1713.2, 1597.7, 1448.9, 1377.9, 1176.9 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.34 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 6.6 Hz, 1 H), 7.28–7.55 (m, 10 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.02 (d, J = 7.6 Hz, 2 H), 6.52 (t, J = 7.2 Hz, 1 H), 4.45 (br s, 1 H), 2.79–2.97 (m, 2 H), 2.36 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 205.29, 156.72, 144.87, 136.79, 135.48, 135.21, 131.60, 130.80, 129.49, 129.22, 128.10, 127.91, 127.01, 126.24, 125.12, 123.91, 123.71, 123.02, 119.65, 116.35, 43.85, 35.49, 35.46, 21.74. HRMS (EI): m/z [M] calcd for C₃₀H₂₃NO₃S: 477.1399; found: 477.1396. (Z)-4-Hydroxy-3-(5-tosyl-5,10-dihydroindeno[1,2-b]indol-10-yl)pent-3-en-2-one (4h): yellow solid; mp 142–145 °C. FTIR (neat): 3524.2, 3064.0, 2917.0, 2848.7, 1706.7, 1597.1, 1373.3, 1177.7 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 8.0 Hz, 1 H), 8.34 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.24–7.37 (m, 6 H), 7.05 (d, J = 8.0 Hz, 2 H), 4.66 (s, 1 H), 2.53 (s, 3 H), 2.25 (s, 3 H), 0.83 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.76, 188.35, 150.77, 145.11, 141.99, 141.41, 135.14, 133.93, 133.31, 129.84, 128.19, 126.70, 126.62, 126.34, 125.23, 124.61, 123.98, 122.35, 118.96, 116.36, 106.88, 41.10, 31.73, 23.41, 23.27, 22.80, 21.63, 14.27. HRMS (EI): m/z [M] calcd for C₂₇H₂₃NO₄S: 457.1348; found: 457.1346. 5-Tosyl-5H-benzo[b]carbazole (5j):²¹ yellow solid; mp 155–158 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.73 (s, 1 H), 8.31–8.34 (m, 2 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H) 7.95 (d, J = 8.0 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.46–7.55 (m, 3 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 2 H), 2.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.97, 140.17, 137.42, 134.79, 133.09, 130.67, 129.74, 128.59, 128.48, 128.12, 126.66, 126.46, 126.04, 125.24, 124.28, 120.73, 118.49, 115.49, 112.35, 21.57. 9-Phenyl-5-tosyl-5H-benzo[b]carbazole (5k):¹⁹ yellow solid; mp 175–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (s, 1 H), 8.34–8.37 (m, 2 H), 8.11–8.16 (m, 2 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.71–7.76 (m, 4 H), 7.49–7.55 (m, 3 H), 7.37–7.42 (m, 2 H), 7.05 (d, J = 8.0 Hz, 2 H), 2.21 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.99, 141.06, 140.23, 137.99, 137.51, 134.81, 132.27, 130.94, 129.75, 129.09, 129.03, 128.55, 127.51, 127.48, 126.66, 126.42, 125.90, 125.86, 124.32, 120.77, 118.76, 115.53, 112.16, 21.57. 9-Methoxy-5-tosyl-5H-benzo[b]carbazole (5l):¹⁹ yellow solid; mp 159–161 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.66 (s, 1 H), 8.32 (d, J = 8.4 Hz, 1 H), 8.22 (s, 1 H), 7.93–7.99 (m, 2 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.21–7.24 (m, 2 H), 7.04 (d, J = 8.0 Hz, 2 H), 3.95 (s, 3 H), 2.22 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.16, 144.72, 140.04, 135.88, 134.66, 131.68, 129.85, 129.56, 128.60, 128.24, 127.29, 126.52, 126.42, 124.07, 120.50, 119.29, 116.91, 115.44, 112.40, 105.41, 55.34, 21.45. 8,9-Dimethoxy-5-tosyl-5H-benzo[b]carbazole (5m):²² yellow solid; mp 163–165 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.59 (s, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 7.93 (d, J = 7.2 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H), 7.38 (s, 1 H), 7.22 (s, 1 H), 7.05 (d, J = 8.0 Hz, 2 H), 4.07 (s, 3 H), 4.02 (s, 3 H), 2.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.85, 149.15, 144.70, 139.53, 136.39, 134.74, 129.57, 129.07, 127.66, 126.67, 126.50, 126.40, 125.20, 124.02, 120.12, 120.09, 116.71, 115.33, 110.93, 106.61, 105.97, 55.94, 55.89, 21.46. 12-Tosyl-12H-naphtho[1,2-b]carbazole (5n):¹⁹ yellow solid; mp 179–181 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.65 (s, 1 H), 8.92 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 8.33 (s, 1 H), 8.02 (d, J = 7.2 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.71–7.77 (m, 4 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 2 H), 2.19 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.89, 139.82, 137.89, 134.72, 132.05, 130.57, 130.09, 129.63, 129.05, 128.62, 128.10, 126.91, 126.87, 126.78, 126.50, 126.35, 126.28, 124.20, 123.15, 120.48, 119.09, 115.49, 108.19, 21.42.
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