Intramolecular Friedel-Crafts Reaction of Indoles with Carbonyl Groups: A Simple Synthesis of 3- and 4-Substituted β-Carbolin-1-ones

Abstract

The intramolecular Friedel-Crafts reaction of indole-2-carboxylic acid β-oxoamides catalyzed by trifluoroacetic acid or InCl₃, is a convenient method for the synthesis of 3-aryl-, 4-aryl-, and 4-alkyl-β-carbolin-1-ones.

heterocycles - indoles - ring closure - Friedel-Crafts reaction - β-carbolinones

References and Notes

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17

General Procedure for the Synthesis of Hydroxyamides 3 and 7: The appropriate amino alcohol 2 (3 mmol) was dissolved in anhyd THF (12 mL) and then EDC (3 mmol), HOBt (3 mmol) and the corresponding indole-2-carboxylic acid (2 mmol) were added sequentially at 25 °C. After stirring overnight at r.t., evaporating the solvent, pouring the product into sat. aq NaHCO₃, extracting with EtOAc, washing with 1 N HCl, sat. aq NaHCO₃, brine, drying over Na₂SO₄ and concentrating the combined extract gave the amide.
General Procedure for the Synthesis of Ketoamides 4a,e,g, and 8c: A suspension of the appropriate amide 3 or 7c (0.45 mmol) in EtOAc (6 mL) was added with IBX (1.35 mmol), then immersed in an oil bath set to 80 °C and stirred vigorously open to the atmosphere. After 2.5 h (TLC monitoring) the reaction was cooled to r.t. and filtered through a medium glass frit. The filter cake was washed with EtOAc-CH₂Cl₂ (50:50, 2 × 6 mL) and the combined filtrates were concentrated to yield the product.
General Procedure for the Synthesis of Ketoamides 4b-d: To a well-stirred suspension of the appropriate amide 3 (2 mmol) in anhyd CH₂Cl₂ (10 mL) was added PCC (4 mmol) and the mixture was stirred at 40-50 °C, under nitrogen, for 8 h. Silica gel was added, the solvent evaporated and the residue was purified by flash chromatography (CH₂Cl₂-acetone, 90:10).
General Procedure for the Synthesis of β-Carbolin-1-ones 5 and 9c: Trifluoroacetic acid (0.6 mmol) was added to a suspension of the appropriate ketoamide 4 or 8c (0.4 mmol) in MeCN (6 mL) and the mixture was refluxed for 16 h. Evaporating the solvent, extracting with EtOAc, washing with sat. aq NaHCO₃, drying over Na₂SO₄ and concentrating the extract gave a crude product that was purified by crystallization or by flash chromatography.
General Procedure for the Synthesis of β-Carbolin-1-ones 9a,b,d: To a solution of IBX (1 mmol) in DMSO (1.5 mL) the appropriate hydroxyamide 7 (0.521 mmol) was added and the solution was stirred overnight at r.t. under N₂. The solution was diluted with H₂O and extracted with EtOAc. The combined organic layers were washed with sat. aq NaHCO₃, H₂O, dried over Na₂SO₄ and evaporated. The crude product was crystallized from EtOAc (9a,d) or chromatographed on flash silica gel (CH₂Cl₂-MeOH, 99:1; 9b).
Deprotection of 5f: To an ice-cooled suspension of 5f (170 mg, 0.399 mmol) in anisole (16 mL), AlCl₃ (319 mg, 2.39 mmol) was added and the mixture was stirred for 30 min at 110 °C. Addition of H₂O, extraction with EtOAc, washing with NaHCO₃, H₂O and brine, then drying, filtering and evaporating of solvent, followed by flash chromatography with CH₂Cl₂-MeOH (94:6) as an eluent, gave 5h (59 mg, 52%); mp 280 °C (MeOH). ¹H NMR (300 MHz, DMSO-d ₆): d = 11.86 (s, 1 H), 11.31 (s, 1 H), 9.55 (s, 1 H), 7.34 (d, J = 8.6 Hz, 2 H), 6.72-6.94 (m, 5 H), 3.81 (s, 3 H), 3.53 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 157.3, 155.1, 150.3, 144.5, 135.1, 130.7, 127.8, 127.2, 123.2, 122.5, 116.8, 115.6, 114.2, 104.2, 94.9, 55.8.
Spectral data for relevant compounds [unless otherwise noted: ¹H NMR (300 MHz, DMSO-d ₆) and ¹³C NMR (75 MHz, DMSO-d ₆)]
5a: mp 260 °C (dec.). ¹H NMR: δ = 11.4 (d, J = 4.5 Hz, 1 H), 7.57-7.40 (m, 5 H), 7.15 (s, 1 H), 6.85 (d, J = 4.5 Hz, 1 H), 6.65 (s, 1 H), 4.27 (s, 3 H), 3.88 (s, 3 H), 3.45 (s, 3 H). ¹³C NMR: δ = 155.9, 150.5, 144.9, 137.2, 136.3, 129.8 (2 × C), 128.8 (2 × C), 127.9, 125.8, 123.4, 122.7, 116.6, 112.8, 103.8, 93.6, 56.2, 56.05, 31.6.
5b: mp 258 °C. ¹H NMR: δ = 11.30 (d, J = 4.8 Hz, 1 H), 9.57 (s, 1 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.12 (s, 1 H), 6.90 (d, J = 8.2 Hz, 2 H), 6.77 (d, J = 4.8 Hz, 1 H), 6.75 (s, 1 H), 4.27 (s, 3 H), 3.87 (s, 3 H), 3.50 (s, 3 H). ¹³C NMR: δ = 157.2, 155.6, 150.7, 144.7, 136.6, 130.9 (2 × C), 128.3, 125.9, 123.9, 122.6, 116.7, 115.5 (2 × C), 113.0, 104.3, 93.8, 56.2, 55.8, 31.6.
5c: mp 271 °C. ¹H NMR: δ = 11.35 (d, J = 5.2 Hz, 1 H), 9.55 (br s, 1 H), 7.30 (t, J = 8.2 Hz, 1 H), 7.16 (s, 1 H), 6.95 (d, J = 5.2 Hz, 1 H), 6.93 (d, J = 1.5 Hz, 1 H), 6.80-6.86 (m, 3 H), 4.45 (s, 3 H), 3.90 (s, 3 H), 3.50 (s, 3 H). ¹³C NMR: δ = 157.8, 155.9, 150.6, 144.7, 138.3, 136.5, 129.9, 125.8, 123.1, 120.0, 116.8, 116.5, 116.4, 114.8, 112.9, 104.1, 93.5, 56.2, 55.7, 31.7.
5d: mp 252 °C. ¹H NMR (300 MHz, acetone-d ₆): δ = 7.51 (d, J = 8.9 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 2 H), 7.11 (dd, J = 2.6, 8.9 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 2 H), 6.91 (s, 1 H), 6.86 (d, J = 2.6 Hz, 1 H), 4.35 (s, 3 H), 3.67 (s, 3 H).
5e: mp >300 °C. ¹H NMR: δ = 11.04 (d, J = 5.2 Hz, 1 H), 7.46 (s, 1 H), 7.17 (s, 1 H), 6.75 (d, J = 5.2 Hz, 1 H), 4.21 (s, 3 H), 4.18 (s, 3 H), 3.84 (s, 3 H), 2.50 (s, 3 H). ¹³C NMR: δ = 155.9, 150.7, 145.3, 136.3, 125.5, 125.1, 122.1, 113.9, 110.6, 104.3, 93.5, 56.4, 56.2, 31.5, 16.6.
5f: mp 153 °C. ¹H NMR: δ = 11.39 (d, J = 4.5 Hz, 1 H), 9.57 (s, 1 H), 7.13-7.38 (m, 7 H), 6.90 (d, J = 7.4 Hz, 2 H), 6.82 (d, J = 4.5 Hz, 1 H), 6.74 (s, 1 H), 6.10 (s, 1 H), 3.79 (s, 3 H), 3.49 (s, 3 H). ¹³C NMR: δ = 157.4, 155.7, 150.6, 144.8, 139.2, 135.8, 130.9, 129.9, 128.8, 127.5, 125.3, 124.3, 116.8, 115.3, 114.7, 113.7, 94.0, 56.3.
9a: mp 156 °C. ¹H NMR: δ = 7.65-8.12 (m, 5 H), 7.15 (br s, 1 H), 7.05 (s, 1 H), 7.02 (s, 1 H), 7.00 (s, 1 H), 3.95 (s, 3 H), 3.83 (s, 3 H), 3.75 (s, 3 H). ¹³C NMR: δ = 168.5, 164.3, 148.9, 145.8, 135.1 (2 × C), 134.1, 131.6 (2 × C), 130.9, 129.9, 126.7, 120.8, 118.4, 105.6, 102.9, 93.6, 56.1 (2 × C), 32.0.
9b: mp 201 °C. ¹H NMR: δ = 7.55 (s, 1 H), 7.44 (d, J = 7.1 Hz, 1 H), 7.22-7.38 (m, 5 H), 7.15 (s, 1 H), 6.97 (d, J = 7.1 Hz, 1 H), 5.22 (s, 2 H), 4.21 (s, 3 H), 3.91 (s, 3 H), 3.83 (s, 3 H). ¹³C NMR: δ = 155.6, 151.0, 145.6, 138.7, 136.4, 129.2, 128.9 (2 × C), 128.0 (2 × C), 127.7, 125.7, 124.5, 113.3, 102.9, 100.4, 93.6, 56.3 (2 × C), 50.8, 31.7.
9c: mp 255 °C. ¹H NMR (300 MHz, acetone-d ₆): δ = 11.0 (br s, 1 H), 10.63 (br s, 1 H), 7.85 (d, J = 8.5 Hz, 2 H), 7.60 (s, 1 H), 7.31-7.54 (m, 3 H), 7.28 (s, 1 H), 7.15 (s, 1 H), 3.88 (s, 6 H).
9d: mp 199 °C, ¹H NMR: δ = 8.08 (br s, 1 H), 7.71-7.90 (m, 4 H), 7.64 (d, J = 8.6 Hz, 2 H), 7.37-7.56 (m, 6 H), 7.04-7.29 (m, 4 H), 6.07 (s, 2 H).