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Synlett 2016; 27(18): 2571-2574
DOI: 10.1055/s-0035-1561497
DOI: 10.1055/s-0035-1561497
letter
Passerini/Friedel–Crafts Route towards Indole Derivatives
Further Information
Publication History
Received: 10 April 2016
Accepted after revision: 10 June 2016
Publication Date:
03 August 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201618/lookinside/thumbnails/st-2016-b0247-l_10-1055_s-0035-1561497-1.jpg)
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561497.
- Supporting Information
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References and Notes
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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; Rf 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); Rf 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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For reviews, see:
For some reviews, see:
For reduction of Passerini adducts, see:
Solventless conditions were adopted for all Passerini reactions. For references, see:
For some examples, see: