Diastereoselective Tandem Michael Additions of Indoles to 3-Nitrocoumarin Derivatives and Methyl Vinyl Ketone

Abstract

Tandem Michael additions of indole derivatives to 3-nitrocoumarins 2, followed by MVK, in one pot, has been developed for the synthesis of multi-functionalized 3,4-dihydrocoumarins bearing a quaternary stereocenter. The reaction proceeds with high diastereoselectivities in good to excellent yields.

Key words

α,β-unsaturated nitroesters - tandem Michael additions - one-pot reactions - 3,4-dihydrocoumarins

References and Notes

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10

Typical Procedure: To a stirred solution of Mg(OTf)₂ (0.01 mmol) and 3-nitrocoumarin 2 (0.50 mmol) in i-PrOH (3 mL) at 20 °C in air was added indole derivative 1 (0.51 mmol). After the reaction was complete (ca. 3-12 h, monitored by TLC), MVK (124 µL, 1.50 mmol) and Ph₃P (26.2 mg, 0.10 mmol) were added in turn, then DME (3 mL) was added in ca. five minutes. The resulting mixture was stirred for the required time (TLC), concentrated, and purified by flash chromatography on silica gel (PE-EtOAc, 2:1) to give the product 4.
Selected spectral data:
4a: IR (neat): 3418, 1773, 1710, 1554, 1458, 1356, 1226, 1169, 747 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.43 (br s, 1 H), 7.40-7.33 (m, 3 H), 7.25-7.20 (m, 2 H), 7.14-7.07 (m, 4 H), 4.98 (s, 1 H), 2.86-2.73 (m, 2 H), 2.66-2.44 (m, 2 H), 2.09 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 205.75, 161.25, 149.76, 135.81, 129.64, 128.56, 126.70, 125.60, 124.70, 122.83, 122.60, 120.41, 117.88, 116.78, 111.72, 107.69, 92.98, 43.96, 38.12, 29.87, 28.42. LRMS-EI: m/z (%) = 378 (M⁺), 274 (100). Anal. Calcd for C₂₁H₁₈N₂O₅: C, 66.66; H, 4.79; N, 7.40. Found: C, 66.67; H, 4.84; N, 7.40.
4b: IR (neat): 3052, 2926, 1774, 1718, 1554, 1487, 1456, 1338, 1226, 1166, 742 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.38-7.32 (m, 3 H), 7.28-7.20 (m, 2 H), 7.13-7.07 (m, 3 H), 6.97 (s, 1 H), 4.97 (s, 1 H), 3.78 (s, 3 H), 2.80-2.71 (m, 2 H), 2.60-2.44 (m, 2 H), 2.08 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 205.62, 161.22, 149.75, 136.66, 129.56, 128.99, 128.52, 127.41, 125.54, 122.90, 122.37, 120.00, 117.89, 116.75, 109.78, 105.91, 93.04, 43.81, 38.11, 33.07, 29.83, 28.40. LRMS-ESI: m/z = 393 (M + H⁺). HRMS: m/z calcd for C₂₂H₂₀N₂O₅Na (M + Na⁺): 415.1270; found: 415.1267.
4c: IR (neat): 3418, 1770, 1716, 1587, 1556, 1509, 1455, 1360, 1264, 1237, 1169, 1091, 735 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.27 (s, 1 H), 7.41-7.30 (m, 3 H), 7.05-6.94 (m, 3 H), 6.73-6.61 (m, 2 H), 5.44 (s, 1 H), 3.52 (s, 3 H), 3.00-2.49 (m, 4 H), 2.05 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 206.94, 161.87, 150.40, 137.42, 136.24, 130.01, 129.87, 125.64, 121.95, 121.13, 119.26, 119.20, 116.90, 111.76, 103.26, 92.88, 44.23, 38.33, 30.34, 28.41, 12.27. LRMS-ESI: m/z = 393 (M + H⁺). HRMS: m/z calcd for C₂₂H₂₀N₂O₅Na (M + Na⁺): 415.1270; found: 415.1265.
4d: IR (neat): 3421, 1767, 1716, 1554, 1509, 1361, 1264, 1092, 736 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.50 (br s, 1 H), 7.34-7.30 (m, 1 H), 7.20-7.05 (m, 4 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 1.8 Hz, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 5.86 (br s, 1 H), 3.88 (br s, 3 H), 2.94-2.48 (m, 4 H), 2.08 (s, 3 H). ¹³C NMR (75 MHz, acetone-d ₆): δ = 205.15, 161.57, 154.03, 149.97, 137.47, 128.96, 128.48, 125.23, 124.71, 123.42, 122.72, 117.42, 116.20, 107.21, 105.25, 99.92, 94.32, 54.42, 42.54, 37.47, 28.85, 27.69. LRMS-ESI: m/z = 409 (M + H⁺). HRMS: m/z calcd for C₂₂H₂₀N₂O₅Na (M + Na⁺): 431.1219; found: 431.1217.
Spectral data for compound 3: ¹H NMR (300 MHz, CDCl₃): δ = 8.27 (br s, 1 H), 7.46-7.04 (m, 9 H), 5.84 (d, J = 9.3 Hz, 1 H), 5.40 (d, J = 9.3 Hz, 1 H).