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Synlett 2003(10): 1447-1450
DOI: 10.1055/s-2003-40864
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 5-Acylindoles via Regioselective Acylation of 3-Trifluoroacetylindole

Jun Lia,b, Bogang Lia, Xiaozhen Chena, Guolin Zhang*a
a Chengdu Institute of Biology, the Chinese Academy of Sciences, Chengdu 610041, P. R. China
b Chengdu Institute of Organic Chemistry, the Chinese Academy of Sciences, Chengdu 610041, P. R. China
Fax: +86(28)85225401; e-Mail: zhanggl@cib.ac.cn;
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Publication History

Received 4 June 2003
Publication Date:
24 July 2003 (online)

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Abstract

5-Acylindoles were synthesized by regioselective acylation of 3-trifluoroacetylindole with acyl chloride under the catalysis of Lewis acids, followed by hydrolysis of trifluoroacetyl and decarboxylation. Polar solvents were beneficial to the acylation and most of the Lewis acids tested showed good catalytic activities.

Key words

regioselectivity - acylation - 3-trifluoroacetylindole - 5-acylindole-3-carboxylic acid - 5-acylindole

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Friedel-Crafts Acylation of 3-Trifluoroacetylindole (1); General Procedure: To an ice cold solution of 1 (0.107 g, 0.5 mmol) in nitromethane (4 mL) was added acyl chloride (2, 1.5 mmol) under a N2 atmosphere, and the mixture was stirred for 15 min. Then AlCl3 (0.2 g, 1.5 mmol) was rapidly added and the reaction proceeded 4 h at r.t. To the reaction mixture H2O (5 mL) was added to quench the reaction. Nitromethane was removed under reduced pressure. The residue was resolved in EtOAc (30 mL) and washed with sat. aq NaHCO3 solution (three times) and NaCl solution(twice). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give a solid residue, which was purified by silica gel column chromatography with petroleum ether/acetone or petroleum ether/EtOAc as eluent to afford the acylated products.

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Acylated Indole Compounds: A mixture of 5-acetyl-3-trifluoroacetylindole (3a) and 6-acetyl-3-trifluoroacetylindole (4a) (72:28) was obtained by chromatography in total yield 85%. Recrystallization of the mixture from EtOAc resulted in pure 3a, but pure 4a could not be obtained.
Compound 3a: Mp 195-196 °C (EtOAc). ESI-MS (negative mode): m/z = 254 [(M - 1)-], 255 [(M)-]. IR (KBr): 3222, 1676, 1642, 1439, 1376, 1276, 1190, 1142, 896 cm-1. 1H NMR (400 MHz, CD3COCD3): δ = 11.86 (br s, 1 H, N-H), 8.97 (dd, 1 H, J = 2.0 Hz, 0.8 Hz, H-4), 8.54 (m, 1 H, H-2), 8.02 (dd, 1 H, J = 8.8 Hz, 2.0 Hz, H-6), 7.73 (dd, 1 H, J = 8.8 Hz, 0.8 Hz, H-7), 2.68 (s, 3 H, CH3).
Compound 4a: The 1H NMR data of 4a came from the 1H NMR spectra of the mixture of 3a and 4a. 1H NMR (400 MHz, CD3COCD3): δ = 11.92 (br s, 1 H, N-H), 8.61 (m, 1 H, H-2); 8.37 (dd, 1 H, J = 8.8 Hz, 0.8 Hz, H-4), 8.29 (dd, 1 H, J = 2.0 Hz, 0.8 Hz, H-7), 8.02 (dd, 1 H, J = 8.8 Hz, 2.0 Hz, H-5), 2.66 (s, 3 H, CH3).
7-Acetyl-3-trifluoroacetylindole (5a): Mp 173-174 °C (petroleum ether:EtOAc = 6:1). ESI-MS (negative mode): m/z = 254 [(M - 1)-], 255 [(M)-]. IR (KBr): 3312, 2924, 1674, 1658, 1521, 1431, 1364, 1269, 1198, 895 cm-1. 1H NMR (400 MHz, CD3COCD3): δ = 12.03 (br s, 1 H, N-H), 8.56 (dd, 1 H, J = 8.0 Hz, 0.8 Hz, H-4), 8.41 (m, 1 H, H-2), 8.09 (dd, 1 H, J = 8.0 Hz, 0.8 Hz, H-6), 7.49 (t, 1 H, J = 8.0 Hz, H-5), 2.73 (s, 3 H, CH3).
5-Chloroacetyl-3-trifluoroacetylindole (3b): Mp 231-232 °C (petroleum ether:acetone = 5:1); ESI-MS (negative mode): m/z = 288 [(M - 1)-], 290 [(M + 1)-]. IR (KBr): 3238, 2924, 1684, 1667, 1139, 895 cm-1. 1H NMR (500 MHz, CD3COCD3): δ = 11.92 (br s, 1 H, N-H), 8.98 (s, 1 H, H-4), 8.56 (s, 1 H, H-2), 8.03 (dd, 1 H, J = 8.5 Hz, 2.0 Hz, H-6), 7.77 (d, 1 H, J = 8.5 Hz, H-7), 5.10 (s, 2 H, CH2).
6-Chloroacetyl-3-trifluoroacetylindole (4b): Mp 198-199 °C (petroleum ether:acetone = 5:1). ESI-MS (negative mode: m/z = 288 [(M - 1)-], 290 [(M + 1)-]. IR (KBr): 3315, 2925, 1674, 1446, 1269, 1147, 892, 728 cm-1. 1H NMR (400 MHz, CD3COCD3): δ = 12.02 (br s, 1 H, N-H), 8.63 (m, 1 H, H-2), 8.40 (dd, 1 H, J = 8.4 Hz, 0.4 Hz, H-4), 8.34 (dd, 1 H, J = 1.6 Hz, 0.4 Hz, H-7), 8.04 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-5), 5.09 (s, 2 H, CH2).
5-( n -Butyryl)-3-trifluoroacetylindole (3c): Mp 185-186 °C (petroleum ether:acetone = 7:1). ESI-MS (negative mode): m/z = 282 [(M - 1)-], 283 [(M)-]. IR (KBr): 3230, 2966, 1664, 1638, 1524, 1439, 1380, 1205, 1139, 1077, 897 cm-1. 1H NMR (400 MHz, CD3COCD3): δ = 11.85 (br s, 1 H, N-H), 8.98 (dd, 1 H, J = 1.6 Hz, 0.8 Hz, H-4), 8.54 (br s, 1 H, H-2), 8.03 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.72 (dd, 1 H, J = 8.4 Hz, 0.8 Hz, H-7), 3.10 (t, 2 H, J = 7.2 Hz, CH2), 1.77 (m, 2 H, J = 7.6 Hz, 7.2 Hz, CH2), 1.02 (t, 3 H, J = 7.6 Hz, CH3).
5-( iso -Butyryl)-3-trifluoroacetylindole (3d): Mp 169-170 °C (petroleum ether:EtOAc = 6:1). ESI-MS (negative mode): m/z = 282 [(M - 1)-], 283 [(M)-]. IR (KBr): 3249, 2975, 1659, 1615, 1525, 1465, 1385, 1345, 1276, 1138, 1075, 897 cm-1. 1H NMR (400 MHz, CD3COCD3): δ = 11.86 (br s, 1 H, N-H), 8.98 (dd, 1 H, J = 1.6 Hz, 0.8 Hz, H-4), 8.55 (m, 1 H, H-2), 8.03 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.74 (dd, 1 H, J = 8.4 Hz, 0.8 Hz, H-7), 3.78 (m, 1 H, CH), 1.21 (d, 6 H, J = 7.2 Hz, CH3).
5-Benzoyl-3-trifluoroacetylindole (3e): Mp 207-208 °C (petroleum ether:EtOAc = 6:1). ESI-MS (negative mode): m/z = 316 [(M - 1)-], 317 [(M)-]. IR (KBr): 3219, 3056, 2941, 1645, 896, 712 cm-1. 1H NMR (500 MHz, CD3COCD3): δ = 11.91 (br s, 1 H, N-H), 8.76 (d, 1 H, J = 1.5 Hz, H-4), 8.56 (br d, 1 H, J = 1.5 Hz, H-2), 7.87 (dd, 1 H, J = 8.0 Hz, 1.5 Hz, H-6), 7.82 (d, 2 H, J = 7.5 Hz, H-2′ and H-6′ in phenyl), 7.79 (d, 1 H, J = 8.5 Hz, H-7), 7.67 (td, 1 H, J = 7.5, 1.5 Hz, H-4′ in phenyl), 7.57 (t, 2 H, J = 7.5 Hz, H-3′ and H-5′ in phenyl).
5-(4′-Methylbenzoyl)-3-trifluoroacetylindole (3f): Mp 225 °C (petroleum ether:acetone = 6:1). ESI-MS (negative mode): m/z = 330 [(M - 1)-], 331 [(M)-]. IR (KBr): 3363, 2925, 1679, 1642, 1604, 1525, 1437, 1312, 1288, 1192, 1142, 891, 758 cm-1. 1H NMR (500 MHz, CD3COCD3): δ = 11.90 (br s, 1 H, N-H), 8.74 (d, 1 H, J = 1.5 Hz, H-4), 8.55 (m, 1 H, H-2), 7.85 (dd, 1 H, J = 8.5 Hz, 1.5 Hz, H-6), 7.78 (d, 1 H, J = 8.5 Hz, H-7), 7.73 (dd, 2 H, J = 7.5 Hz, 1.5 Hz, H-2′ and H-6′ in phenyl), 7.38 (dd, 2 H, J = 7.5 Hz, 1.5 Hz, H-3′ and H-5′ in phenyl), 3.45 (s, 3 H, CH3).
5-(4′-Nitrobenzoyl)-3-trifluoroacetylindole (3g): The acylation of 1 with p-nitrobenzoyl chloride was catalyzed by FeCl3 in nitromethane. The operation was the same as the acetylation catalyzed by AlCl3.
Compound 3g: Mp 237-238 °C (petroleum ether:acetone = 6:1). ESI-MS (negative mode): m/z = 361 [(M - 1)-], 362 [(M)-]. IR: 3222, 3055, 1651, 1619, 1521, 1435, 1193, 900, 849, 729, 687 cm-1. 1H NMR (500 MHz, CD3COCD3): δ = 11.97 (br s, 1 H, N-H), 8.75 (d, 1 H, J = 1.5 Hz, H-4), 8.59 (br d, 1 H, J = 1.0 Hz, H-2), 8.43 (dt, 2 H, J = 9.0 Hz, 2.0 Hz, H-3′ and H-5′ in phenyl), 8.05 (dt, 2 H, J = 9.0 Hz, 2.0 Hz, H-2′ and H-6′ in phenyl), 7.91 (dd, 1 H, J = 9.0 Hz, 1.5 Hz, H-6), 7.82 (d, 1 H, J = 9.0 Hz, H-7).
6-(4′-Nitrobenzoyl)-3-trifluoroacetylindole (4g): Mp 250 °C (petroleum ether:acetone = 6:1). ESI-MS (negative mode): m/z = 361 [(M - 1)-], 362 [(M)-]. IR (KBr): 3358, 3129, 1656, 1617, 1521, 1350, 1283, 1193, 885, 848, 719 cm-1. 1H NMR (500 MHz, CD3COCD3): δ = 11.92 (br s, 1 H, N-H), 8.64 (br d, 1 H, J = 1.5 Hz, H-2), 8.43 (d, 1 H, J = 8.5 Hz, H-4), 8.42 (dt, 2 H, J = 8.5 Hz, 2.0 Hz, H-3′ and H-5′ in phenyl), 8.14 (d, J = 1.5 Hz, H-7), 8.05 (dt, 2 H, J = 8.5 Hz, 2.0 Hz, H-2′ and H-6′ in phenyl), 7.86 (dd, 1 H, J = 8.5 Hz, 1.5 Hz, H-5).

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The acylation of 1 with chloroacetyl chloride catalyzed by ionic liquid produced not only 5-acylated product 3b but also 6-acylated isomer 4b. The procedure was as follows: The mixture of 1-methyimidazole (5 mL, 0.062 mol) and excess n-butyl chloride (15 mL) was stirred at reflux for 24 h under a N2 atmosphere. Superfluous n-butyl chloride was evaporated under reduced pressure to give 8.96 g of
1-methyl-3-butylimidazolium chloride (MeBuImCl), yield = 82%. A dry flask was charged with 2.62 g of MeBuImCl (15 mmol). With vigorous stirring AlCl3 (4 g, 30 mmol) was added to the flask in four portions under a N2 atmosphere and a liquid formed (MeBuImCl-AlCl3). When the ionic liquid was cooled to r.t., 1 (0.107 g, 0.5 mmol) was then dissolved in the ionic liquid, followed by adding chloroacetyl chloride (2b, 1.5 mmol). Stirring was continued for another 3 h and H2O was added slowly to quench the reaction. The mixture was extracted by EtOAc. The following work-up was the same as that of acetylation of 1 catalyzed by AlCl3. The residue was chromatographed on a silica gel colum with 5:1 petroleum ether:acetone to result in 3b (yield = 86%) and 4b (yield = 4%).

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Hydrolysis of 3a, 3c-f; General Procedure: To a aq 4.4 M KOH solution was added 5-acyl-3-trifluoroacetylindole (3a, 3c-f, 1 mmol). The mixture was refluxed until 3 disappeared (0.5-2 h). The mixture was adjusted to pH = 5-6 with 5.5 M HCl(aq) to precipitate carboxylic acid, which was extracted with EtOAc or n-butanol (3 × 20 mL). The combined extracts were washed with brine and dried (Na2SO4). Removal of the solvent in vacuum gave a solid residue, which was purified by silica gel column chromatography (petroleum ether:acetone = 2:1).
5-Acetylindole-3-carboxylic Acid (6a): Mp 198-200 °C (petroleum ether:acetone = 2:1). ESI-MS (negative mode): m/z = 202 [(M - 1)-], 203 [(M)-]. IR (KBr): 3210, 2925, 1681, 1646, 1449, 1311, 1176, 700 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ = 12.25 (s, 1 H, -COOH), 12.16 (s, 1 H, N-H), 8.66 (br s, 1 H, H-4), 8.14 (d, 1 H, J = 2.4 Hz, H-2), 7.82 (dd, 1 H, J = 8.4 Hz, 1.2 Hz, H-6), 7.55 (d, 1 H, J = 8.4 Hz, H-7), 2.62 (s, 3 H, CH3).
5- n -Butyrylindole-3-carboxylic Acid (6c): Mp 174-175 °C (petroleum ether:acetone = 2:1). ESI-MS (negative mode): m/z = 230 [(M - 1)-], 231 [(M)-]. IR (KBr): 3237, 2961, 1669, 1533, 1444, 1169 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ = 12.24 (s, 1 H, -COOH), 12.14 (br s, 1 H, N-H), 8.68 (br s, 1 H, H-4), 8.14 (d, 1 H, J = 2.9 Hz, H-2), 7.83 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.55 (d, 1 H, J = 8.4 Hz, H-7), 3.05 (t, 2 H, J = 7.2 Hz, CH2), 1.67 (m, 2 H, J = 7.2 Hz, CH2), 0.95 (t, 3 H, J = 7.2 Hz, CH3).
5- iso -Butyrylindole-3-carboxylic Acid (6d): Mp 171-172 °C (petroleum ether:acetone = 2:1). ESI-MS (negative mode): m/z = 230 [(M)-]. IR (KBr): 3281, 2973, 1657, 1537, 1446, 1186, 1128, 759 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ = 12.10 (s, 2 H, -COOH and N-H), 8.67 (br s, 1 H, H-4), 8.12 (d, 1 H, J = 2.7 Hz, H-2), 7.83 (dd, 1 H, J = 8.4 Hz, 0.9 Hz, H-6), 7.55 (d, 1 H, J = 8.4 Hz, H-7), 3.70 (t, 2 H, J = 6.6 Hz, CH), 1.14 (d, 6 H, J = 6.6 Hz, CH3).
5-Benzoylindole-3-carboxylic Acid (6e): Mp 178-179 °C (petroleum ether:acetone = 2:1). ESI-MS (negative mode): m/z = 264 [(M)-], 220 [(M - 1 - CO2 -)]. IR (KBr): 3184, 2925, 1668, 1639, 1499, 1201, 1138, 705 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ = 12.23 (s, 1 H, -COOH), 12.10 (br s, 1 H, N-H), 8.44 (br s, 1 H, H-4), 8.17 (d, 1 H, J = 3.3 Hz, H-2), 7.73 (d, 2 H, J = 7.8 Hz, H-2′ and H-6′ in phenyl), 7.67 (d, 1 H, J = 8.4 Hz, H-6), 7.66 (t, 1 H, J = 7.8 Hz, H-4′ in phenyl), 7.62 (d, 1 H, J = 8.4 Hz, H-7), 7.57 (t, 2 H, J = 7.8 Hz, H-3′ and H-5′ in phenyl).
5-(4′-Methylbenzoyl)indole-3-carboxylic Acid (6f): Mp 193-194 °C (petroleum ether:acetone = 2:1). ESI-MS (negative mode): m/z = 278 [(M - 1)-], 279 [(M)-]. IR (KBr): 3423, 3187, 2924, 1662, 1530, 1454, 1292, 1198, 1130, 759 cm-1. 1H NMR (600 MHz, DMSO-d 6): δ = 12.21 (s, 1 H, -COOH), 12.08 (br s, 1 H, N-H), 8.42 (br s, 1 H, H-4), 8.16 (d, 1 H, J = 2.4 Hz, H-2), 7.65 (d, 3 H, J = 7.8 Hz, H-6 and H-2′ and H-6′ in phenyl), 7.61 (d, 1 H, J = 8.4 Hz, H-7), 7.38 (d, 2 H, J = 7.8 Hz, H-3′ and H-5′ in phenyl), 2.42 (s, 3 H, CH3).

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Decarboxylation; General Procedure: Quinoline (0.5 mL), 6 (0.5 mmol) and its cupric salt (0.02 mmol) were added to a flask fitted with a magnetic bar and a reflux condenser connected to an oil bubbler. The mixture was heated until gas evolution (CO2) occurred and kept at this temperature until gas evolution ceased (45-120 min). The reaction mixture was cooled to r.t. To the mixture was added 20 mL EtOAc and washed with 1 N HCl(aq) (three times). The organic layer was washed with sat. aq NaHCO3 solution (three times), brine(once) and dried over Na2SO4. Removal of the solvent gave a solid residue, which was purified by silica gel column chromatography (petroleum ether:acetone = 8:1 to 2:1).
5-Acetylindole (7a): Mp 69-71 °C (petroleum ether:acetone = 8:1). ESI-MS (negative mode): m/z = 158 [(M - 1)-], 159 [(M)-]. IR (KBr): 3271, 1661, 1600, 1429, 1351, 1273, 914, 771, 731 cm-1. 1H NMR (600 MHz, CDCl3): δ = 10.65 (br s, 1 H, N-H), 8.35 (s, 1 H, H-4), 7.83 (dd, 1 H, J = 8.4 Hz, 1.5 Hz, H-6), 7.52 (d, 1 H, J = 8.4 Hz, H-7), 7.48 (t, 1 H, J = 2.2 Hz, H-2), 6.66 (br d, 1 H, J = 2.2 Hz, H-3), 2.62 (s, 3 H, CH3).
5- n -Butyrylindole (7c): Mp 104-105 °C (petroleum ether:acetone = 8:1). ESI-MS (negative mode): m/z = 186 [(M - 1)-]. IR (KBr): 3269, 2963, 1664, 1605, 1380, 1367, 1329, 1223, 1154, 892, 759 cm-1. 1H NMR (600 MHz, CDCl3): δ = 10.48 (br s, 1 H, N-H), 8.37 (br d, 1 H, J = 0.8 Hz, H-4), 7.84 (dd, 1 H, J = 8.4 Hz, 1.0 Hz, H-6), 7.52 (d, 1 H, J = 8.4 Hz, H-7), 7.47 (t, 1 H, J = 2.8 Hz, 2.4 Hz, H-2), 6.66 (br d, 1 H, J = 2.0 Hz, H-3), 3.06 (t, 2 H, J = 7.2 Hz, CH2), 1.77 (m, 2 H, J = 7.2 Hz, CH2), 1.01 (t, 3 H, J = 7.2 Hz, CH3).
5- iso -Butyrylindole (7d): Mp 65-66 °C (petroleum ether:acetone = 8:1). ESI-MS (negative mode): m/z = 186 [(M - 1)-]. IR (KBr): 3300, 2975, 1663, 1603, 1430, 1383, 1346, 1228, 1139, 1097, 1007, 749 cm-1. 1H NMR (600 MHz, CDCl3): δ = 10.65 (br s, 1 H, N-H), 8.38 (s, 1 H, H-4), 7.85 (dd, 1 H, J = 8.4 Hz, 1.5 Hz, H-6), 7.54 (d, 1 H, J = 8.4 Hz, H-7), 7.48 (t, 1 H, J = 2.4 Hz, H-2), 6.66 (d, 1 H, J = 2.4 Hz, H-3), 3.78 (m, 1 H, J = 7.2 Hz, CH), 1.20 (d, 6 H, J = 7.2 Hz, CH3).
5-Benzoylindole (7e): Mp 148-149 °C (petroleum ether:acetone = 5:1). ESI-MS (negative mode): m/z = 220 [(M - 1)-]. IR (KBr): 3292, 1623, 1607, 1571, 1322, 880, 737 cm-1. 1H NMR (600 MHz, CDCl3): δ = 10.72 (br s, 1 H, N-H), 8.10 (br s, 1 H, H-4), 7.80 (dd, 2 H, J = 7.4 Hz, 1.2 Hz, H-2′ and H-6′ in phenyl), 7.71 (dd, 1 H, J = 8.4 Hz, 1.5 Hz, H-6), 7.66 (t, 1 H, J = 7.4 Hz, H-4′ in phenyl), 7.59 (t, 2 H, J = 7.4 Hz, H-3′ and H-5′ in phenyl), 7.57 (d, 1 H, J = 8.4 Hz, H-7), 7.51 (t, 1 H, J = 2.4 Hz, H-2), 6.67 (br d, 1 H, J = 2.4 Hz, H-3).
5-(4′-Methylbenzoyl)indole (7f): Mp 168-169 °C (petroleum ether:acetone = 8:1). ESI-MS (negative mode): m/z = 234 [(M - 1)-]. ESI-MS (positive mode): m/z = 258 [(M + Na)+], 274 [(M + K)+]. IR (KBr): 3235, 1631, 1606, 1329, 1316, 1177, 754 cm-1. 1H NMR (600 MHz, CDCl3): δ = 10.70 (br s, 1 H, N-H), 8.08 (br s, 1 H, H-4), 7.71 (d, 2 H, J = 7.8 Hz, H-2′ and H-6′ in phenyl), 7.69 (dd, 1 H, J = 8.4 Hz, 1.2 Hz, H-6), 7.59 (d, 1 H, J = 8.4 Hz, H-7), 7.51 (t, 1 H, J = 2.2 Hz, H-2), 7.38 (d, 2 H, J = 7.8 Hz, H-3′ and H-5′ in phenyl), 6.66 (br d, 1 H, J = 2.2 Hz, H-3), 2.47 (s, 3 H, CH3).