Base-Promoted Tandem Cyclization for the Synthesis of Polyfunctional 2-Hydroxy-2,3-dihydrofurans from Arylglyoxal Monohydrates and 3-(1H-Indol-3-yl)-3-oxopropanenitrile

Abstract

An efficient base-promoted tandem cyclization for the synthesis of polyfunctional 2-hydroxy-2,3-dihydrofurans from arylglyoxal monohydrates and 3-(1H-indol-3-yl)-3-oxopropanenitrile has been established. The investigation of the mechanism suggested that this reaction proceeds through a Knoevenagel condensation–Michael addition–oxidation–cyclization sequence. This method demonstrates the compatibility with a wide range of functional groups to produce the 2-hydroxy-2,3-dihydrofuran scaffolds in good to excellent yields in one pot.

Key words

2-hydroxy-2,3-dihydrofurans - tandem cyclization - arylglyoxal monohydrates - 3-(1H-indol-3-yl)-3-oxopropanenitrile - one pot

• References and Notes

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• 14 Typical Procedure for the Synthesis of 3a A mixture of phenylglyoxal monohydrate (1a, 0.5 mmol), 3-(1H-indol-3-yl)-3-oxopropanenitrile (2a, 1.0 mmol), and K₂CO₃ (1.0 mmol) in DMSO (3 mL) was stirred at 80 °C for 2 h till almost completed conversion of the substrates by TLC analysis, then 30% NaCl solution (50 mL) was added to the mixture, which was then extracted with EtOAc three times (3 × 50 mL). The extract was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc) to afford the product 3a (221.7 mg, 92%) as a yellow solid. (E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-indol-3-yl)-5-phenyl-4,5-dihydrofuran-3-carbonitrile (3a) Yield 92%, 221.7 mg; yellow solid; mp 255.5–257.3 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 12.75 (s, 1 H), 12.21 (s, 1 H), 9.65 (s, 1 H), 8.68 (s, 1 H), 8.22 (s, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.72–7.64 (m, 2 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.54–7.44 (m, 3 H), 7.33–7.23 (m, 4 H).¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.1, 173.8, 159.6, 137.0, 136.7, 136.1, 136.0, 135.2, 129.6, 128.3, 125.6, 125.0, 124.7, 123.9, 123.3, 123.0, 122.2, 121.3, 121.2, 116.8, 115.7, 114.5, 113.2, 113.0, 112.4, 103.4, 96.6, 79.4. IR (KBr): 3424, 3265, 2208, 1610, 1523, 1483, 1430, 1307, 1235, 745 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₁₉N₄O₃: 483.1452; found: 483.1449. (E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-indol-3-yl)-5-(4-nitrophenyl)-4,5-dihydrofuran-3-carbonitrile (3e) Yield 85%, 224.0 mg; yellow solid; mp 249.3–250.1 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 12.84 (s, 1 H), 12.25 (s, 1 H), 10.07 (s, 1 H), 8.74 (s, 1 H), 8.44–8.34 (m, 2 H), 8.26 (s, 1 H), 8.20–8.13 (m, 1 H), 8.03–7.93 (m, 2 H), 7.86 (d, J = 6.0 Hz, 1 H), 7.68–7.61 (m, 1 H), 7.58–7.53 (m, 1 H), 7.35–7.22 (m, 4 H).¹³C NMR (150 MHz, DMSO-d ₆): δ = 180.1, 174.1, 159.1, 148.4, 143.4, 137.0, 136.3, 135.8, 127.6, 125.3, 124.8, 124.3, 123.9, 123.6, 123.4, 122.5, 122.3, 121.5, 121.4, 116.9, 115.8, 114.4, 113.5, 112.6, 111.7, 103.5, 96.9, 79.8. IR (KBr): 3387, 3256, 2205, 1607, 1563, 1525, 1427, 1348, 1304, 1235, 1206, 1143, 979, 744 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₁₈N₅O₅: 528.1302; found: 528.1296. (E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-(4-chlorophenyl)-5-hydroxy-2-(1H-indol-3-yl)-4,5-dihydrofuran-3-carbonitrile (3h) Yield 80%, 206.4 mg; yellow solid; mp 245.0–246.3 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 12.77 (s, 1 H), 12.20 (s, 1 H), 9.78 (s, 1 H), 8.68 (s, 1 H), 8.21 (s, 1 H), 8.14 (d, J = 5.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 7.2 Hz, 2 H), 7.63–7.49 (m, 4 H), 7.34–7.22 (m, 4 H).¹³C NMR (150 MHz, DMSO-d ₆): δ = 180.4, 174.2, 159.6, 136.4, 136.2, 135.6, 134.7, 128.7, 128.0, 125.4, 124.9, 124.3, 123.6, 123.3, 122.5, 121.5, 117.0, 115.9, 114.6, 113.5, 113.3, 112.6, 103.6, 96.8, 79.7, 56.2. IR (KBr): 3427, 2208, 1610, 1570, 1525, 1486, 1427, 1308, 1235, 1140, 745 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₁₇ClN₄NaO₃: 539.0881; found: 539.0885. (E)-4-[2-(1H-Indol-3-yl)-2-oxoethylidene]-5-hydroxy-2-(1H-indol-3-yl)-5-(thiophen-3-yl)-4,5-dihydrofuran-3-carbonitrile (3j) Yield 75%, 183.0 mg; yellow solid; mp 267.9–269.3 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 12.77 (s, 1 H), 12.26 (s, 1 H), 9.63 (s, 1 H), 8.73 (s, 1 H), 8.31 (s, 1 H), 8.25–8.18 (m, 1 H), 7.97 (d, J = 6.0 Hz, 1 H), 7.90 (s, 1 H), 7.67–7.61 (m, 2 H), 7.58 (d, J = 5.4 Hz, 1 H), 7.34–7.26 (m, 5 H).¹³C NMR (150 MHz, DMSO-d ₆): δ = 180.6, 173.8, 159.4, 138.8, 137.1, 136.4, 135.5, 135.4, 127.5, 125.8, 125.5, 125.0, 124.2, 123.6, 123.3, 122.6, 121.5, 117.1, 116.1, 116.0, 114.8, 113.5, 112.6, 111.7, 103.8, 96.8, 79.3. IR (KBr): 3260, 2204, 1613, 1568, 1509, 1481, 1434, 1304, 1237, 1207, 1146, 1023, 742 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₁₈N₄O₃S: 489.1016; found: 489.1015. (E)-5-Hydroxy-2-(1-methyl-1H-indol-3-yl)-4-[2-(1-methyl-1H-indol-3-yl)-2-oxoethylidene]-5-phenyl-4,5-dihydro­furan-3-carbonitrile (3k) Yield 91%, 232.1 mg; yellow solid; mp 244.1–245.2 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.65 (s, 1 H), 8.67 (s, 1 H), 8.20 (s, 1 H), 8.15 (d, J = 5.4 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.75–7.63 (m, 3 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.55–7.46 (m, 3 H), 7.39–7.33 (m, 2 H), 7.32–7.27 (m, 2 H), 3.98 (s, 3 H), 3.91 (s, 3 H).¹³C NMR (150 MHz, DMSO-d ₆): δ = 179.9, 173.6, 160.2, 139.0, 138.3, 137.6, 137.2, 137.0, 129.8, 128.5, 125.8, 125.7, 125.3, 124.2, 123.6, 123.5, 122.7, 121.6, 116.9, 114.7, 114.4, 113.1, 111.9, 111.0, 102.5, 96.5, 79.6, 34.1, 33.6. IR (KBr): 3437, 3226, 2189, 1580, 1535, 1471, 1365, 1244, 746 cm^-1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₂₂N₄NaO₃: 533.1584; found: 533.1576. (E)-5-(3-Bromophenyl)-5-hydroxy-2-(1-methyl-1H-indol-3-yl)-4-[2-(1-methyl-1H-indol-3-yl)-2-oxoethylidene]-4,5-dihydrofuran-3-carbonitrile (3p) Yield 80%, 235.6 mg; yellow solid; mp 235.4–237.1 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.85 (s, 1 H), 8.68 (s, 1 H), 8.19 (s, 1 H), 8.15 (d, J = 6.6 Hz, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.72 (d, J = 5.4 Hz, 1 H), 7.69 (d, J = 6.6 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.50–7.45 (m, 1 H), 7.43–7.24 (m, 5 H), 3.99 (s, 3 H), 3.91 (s, 3 H).¹³C NMR (150 MHz, DMSO-d ₆): δ = 179.7, 173.6, 159.8, 139.5, 139.1, 138.6, 138.5, 137.6, 137.5, 137.1, 132.9, 131.0, 128.7, 125.7, 125.2, 125.0, 124.3, 123.7, 123.6,122.6, 121.6, 116.9, 114.7, 114.3, 111.9, 111.1, 102.5, 96.5, 79.8, 34.2, 33.6. IR (KBr): 3443, 2197, 1522, 1462, 1363, 1321, 1226, 1087, 748 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₂BrN₄O₃: 589.0870; found: 589.0877. (E)-5-Hydroxy-2-(1-methyl-1H-indol-3-yl)-4-[2-(1-methyl-1H-indol-3-yl)-2-oxoethylidene]-5-(naphthalen-2-yl)-4,5-dihydrofuran-3-carbonitrile (3r) Yield 88%, 246.4 mg; yellow solid; mp 228.8–230.0 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 9.84 (s, 1 H), 8.68 (s, 1 H), 8.18 (s, 1 H), 8.14 (d, J = 7.2 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.73–7.68 (m, 2 H), 7.60 (t, J = 8.4 Hz, 3 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.44–7.25 (m, 6 H), 3.99 (s, 3 H), 3.91 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 179.7, 173.6, 159.8, 139.6, 139.0, 138.6, 137.6, 137.1, 132.8, 130.9, 128.8, 125.8, 125.2, 125.0, 124.2, 123.7, 123.6, 122.8, 121.7, 121.6, 116.9, 114.7, 114.3, 111.9, 111.0 , 102.5, 96.6, 79.8, 79.2, 59.8, 34.1, 33.6, 20.8, 14.1. IR (KBr): 3235, 2188, 1650, 1387, 1232, 1125, 1085, 748 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₂₅N₄O₃: 561.1921; found: 561.1915. (E)-5-Hydroxy-2-(6-methyl-1H-indol-3-yl)-4-[2-(6-methyl-1H-indol-3-yl)-2-oxoethylidene]-5-phenyl-4,5-dihydro­furan-3-carbonitrile (3u) Yield 84%, 214.2 mg; yellow solid; mp 230.1–232.1 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 12.64 (s, 1 H), 12.08 (s, 1 H), 9.63 (s, 1 H), 8.62 (s, 1 H), 8.15 (s, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 6.0 Hz, 2 H), 7.53–7.48 (m, 3 H), 7.41 (s, 1 H), 7.33 (s, 1 H), 7.08 (d, J = 8.4 Hz, 2 H), 2.44 (s, 3 H), 2.41 (s, 3 H).¹³C NMR (100 MHz, DMSO-d ₆): δ = 180.1, 173.7, 159.6, 139.1, 136.7, 136.0, 135.9, 134.1, 128.7, 125.5, 125.1, 124.6, 123.8, 123.2, 122.9, 122.1, 121.2, 116.7, 115.6, 114.4, 113.1, 112.3, 103.4, 96.5, 79.3, 56.0, 21.0, 18.7. IR (KBr): 3265, 2205, 1571, 1536, 1503, 1440, 1237, 1018, 765 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₂₂N₄NaO₃: 533.1584; found: 533.1580.