Passerini/Friedel–Crafts Route towards Indole Derivatives

Abstract

The Passerini adducts of various electron-rich aromatic aldehydes with pivalic acid were used as electrophiles towards indoles in a Friedel–Crafts-type reaction. The Friedel–Crafts step was performed under microwave conditions using a catalytic amount of FeCl₃.

Key words

Passerini - Friedel–Crafts - indoles - iron chloride catalyst

• References and Notes

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Solventless conditions were adopted for all Passerini reactions. For references, see:
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• 6 Passerini Adduct 1b; Typical Procedure: A mixture of p-anisaldehyde (0.37 mL, 3.0 mmol), pivalic acid (0.31 g, 3.0 mmol), and cyclohexyl isocyanide (0.38 mL, 3.0 mmol) was stirred at r.t. for 3 d. Purification by flash chromatography with a gradient (Et₂O–PE, 40:60 then 60:40 and 80:20) gave the desired 1b as a white solid in 70% isolated yield (729 mg, 2.1 mmol); mp 142–143 °C; R_f 0.43 (Et₂O–petroleum ether, 70:30). ¹H NMR (400 MHz, CDCl₃): δ = 7.31 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 6.03 (d, J = 7.8 Hz, 1 H), 5.96 (s, 1 H), 3.70–3.86 (m, 4 H), 1.80–1.91 (m, 2 H), 1.52–1.69 (m, 3 H), 1.29–1.40 (m, 2 H), 1.23 (s, 9 H), 1.04–1.19 (m, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 176.4, 167.7, 159.8, 128.6, 128.0, 114.0, 74.8, 55.2, 47.9, 38.7, 32.8, 27.0, 25.4, 24.6. HRMS: m/z calcd for C₂₀H₂₉NO₄: 374.2097; found: 374.2103. IR (thin film): 3435, 3041, 3003, 2946, 2857, 1734, 1679, 1613, 1587, 1533, 1526, 1513, 1453, 1305, 1249, 1186, 1142, 1035, 941, 834 cm^–1. Friedel-Crafts Product 3a; Typical Procedure: To a solution of Passerini adduct 1b (100 mg, 0.29 mmol) in toluene (1 mL, 0.33 M) were added indole 2a (34 mg, 0.29 mmol) and FeCl₃ (0.05 equiv). The resulting mixture was heated at 130 °C for 15 min under microwave conditions (CEM Discover microwave, 150 W). After removal of the solvent under reduced pressure, the crude was purified by flash chromatography (gradient EtOAc–PE, 40:60 to 50:50) to afford 3a as a red oil in 70% isolated yield (83 mg, 0.229 mmol); R_f 0.25 (EtOAc–petroleum ether, 40:60). ¹H NMR (400 MHz, CDCl₃): δ = 8.72 (s, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.28–7.32 (m, 2 H), 7.21 (dd, J = 11.2, 4.0 Hz, 1 H), 7.11 (dd, J = 11.0, 4.0 Hz, 1 H), 6.84–6.92 (m, 3 H), 5.84 (d, J = 8.2 Hz, 1 H), 5.09 (s, 1 H), 3.87–3.97 (m, 1 H), 3.83 (s, 1 H), 1.83–1.96 (m, 2 H), 1.57–1.67 (m, 3 H), 1.27–1.39 (m, 2 H), 0.97–1.12 (m, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 171.9, 158.6, 136.7, 131.8, 129.6, 126.5, 124.1, 122.3, 119.7, 119.1, 114.8, 114.1, 111.5, 55.3, 50.5, 48.4, 33.0, 32.9, 25.4, 24.8. HRMS: m/z calcd for C₂₃H₂₆N₂O₂: 362.1994; found: 362.1985. IR (thin film): 3478, 3406, 3009, 2936, 2857, 1652, 1611, 1514, 1457, 1416, 1338, 1303, 1250, 1179, 1095, 1035, 909 cm^–1.
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