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Synlett 2007(3): 0447-0450  
DOI: 10.1055/s-2007-967950
LETTER
© Georg Thieme Verlag Stuttgart · New York

Grignard Cyclization Reaction of Fluorinated N-Arylimidoyl Chlorides: A Novel and Facile Access to 2-Fluoroalkyl Indoles

Fenglian Gea, Zengxue Wanga, Wen Wana, Jian Hao*a,b
a Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. of China
Fax: +86(21)66133380; e-Mail: jhao@mail.shu.edu.cn;
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
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Publication History

Received 24 August 2006
Publication Date:
07 February 2007 (online)

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Abstract

2-Fluoroalkyl-substituted indole derivatives were simply prepared via the Grignard cyclization reaction (GCR) of corresponding fluorinated N-aryl imidoyl chlorides in good yields. This approach provides a novel and facile access to the biologically ­important 2-fluoroalkylindole derivatives.

Key words

fluorine-containing Indoles - Grignard cyclizations - imidoyl chlorides - aryl amines - heterocycles

5

General Procedure for the Synthesis of 2-Fluoroalkyl-Substituted Indoles 3.
To a flame-dried 100 mL three-necked round-bottomed flask equipped with condenser and magnetic stir bar was added magnesium ribbon (0.3 g, 12.1 mmol) and anhydrous THF (25 mL) under a nitrogen atmosphere. A solution of the appropriate fluorinated N-[(2-bromoalkyl)phenyl]imidoyl chloride 2 (10.1 mmol) dissolved in THF (6 mL) was added dropwise at 0 °C. The reaction started within a few minutes. After addition, the reaction mixture was stirred for 2 h at 0 °C (monitored by TLC). Upon completion of the reaction, the reaction mixture was quenched with 10 mL sat. solution of NH4Cl and extracted with EtOAc (15 mL, 3 ×). The combined organic layer was washed with brine, dried over Mg2SO4, and concentrated by rotary evaporator. The residue was then purified by column chromatography (20:1 hexane-EtOAc) on neutral Al2O3 to yield products 3.
2-Trifluoromethylindole ( 3a).
Compound 3a was obtained as a light yellow solid in 78% yield; mp 107-108 °C. 1H NMR (500 MHz): δ = 8.30 (br, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.32 (t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 6.92 (s, 1 H). 13C NMR (125 MHz): δ = 136.1, 126.6, 125.7 (q, J C-C-F = 38.8 Hz), 124.8, 122.1, 121.2 (q, J C-F = 266.2 Hz), 121.1, 111.7, 104.3 (q, J C-C-C-F = 3.3 Hz). 19F NMR (470 MHz): δ = -60.50 (s, 3 F). IR (neat): 3389, 2921, 1375, 1306, 1196, 1168, 1103, 940, 818, 754 cm-1. Anal. Calcd for C9H6F3N: C, 58.38; H, 3.27; N, 7.57. Found: C, 58.39; H, 3.32; N, 7.55. HRMS: m/z calcd for C9H6F3N [M+]: 185.0452; found: 185.0452. 3-Methyl-2-trifluoromethylindole ( 3b).
Compound 3b was obtained as a yellow solid in 82% yield, using 1.5 equiv of magnesium ribbon; mp 73-74 °C. 1H NMR (500 MHz): δ = 8.16 (br, 1 H) 7.64 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 2.44 (q, J = 1.7 Hz, 3 H). 13C NMR (125 MHz): δ = 135.2, 128.1, 124.8, 122.1 (q, J C-F = 266.3 Hz), 121.6 (q, J C-C-F = 36.7 Hz), 120.4, 120.1, 114.1 (q, J C-C-C-F = 2.9 Hz), 111.6, 8.3. 19F NMR (470 MHz): δ = -58.61 (s, 3 F). IR (neat): 3393, 2925, 1454, 1321, 1263, 1166, 1116, 756 cm-1. HRMS: m/z calcd for C10H8F3N [M+]: 199.0609; found: 199.0610. 5-Methoxy-2-trifluoromethylindole ( 3c).
Compound 3c was obtained as a light yellow solid in 75% yield; mp 50-51 °C. 1H NMR (500 MHz): δ = 8.30 (br, 1 H), 7.32 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 7.00 (dd, J = 9.0, 2.5 Hz, 1 H), 6.85 (s, 1 H), 3.86 (s, 3 H). 13C NMR (125 MHz): δ = 154.8, 131.3, 127.1, 126.2 (q, J C-C-F = 38.4 Hz), 121.2 (q, J C-F = 265.9 Hz), 115.7, 112.6, 103.8 (q, J C-C-C-F = 3.3 Hz), 102.8, 55.7. 19F NMR (470 MHz): δ = -60.45 (s, 3 F). IR (neat): 3402, 2949, 1559, 1461, 1384, 1224, 1174, 1117, 1023, 801 cm-1. HRMS: m/z calcd for C10H8F3NO [M+]: 215.0558; found: 215.0557.
6-Fluoro-2-trifluoromethylindole ( 3d).
Compound 3d was obtained as a yellow viscous liquid in 62% yield; mp 126 °C (dec.). 1H NMR (500 MHz): δ = 8.40 (br, 1 H), 7.58 (dd, J = 8.8, 5.2 Hz, 1 H), 7.06 (dd, J = 9.0, 1.8 Hz, 1 H), 6.96 (td, J = 9.0, 2.2 Hz, 1 H), 6.88 (s, 1 H). 13C NMR (125 MHz): δ = 161.2 (d, J C-F = 240.0 Hz), 136.2 (d, J C-C-C-F = 12.5 Hz), 126.2 (q, J C-C-F = 39.2 Hz), 123.2 (d, J C-C-C-F = 10.0 Hz), 123.1, 121.0 (q, J C-F = 265.8 Hz), 110.4 (d, J C-C-F = 25.0 Hz), 104.4 (q, J C-C-C-F = 3.3 Hz), 97.9 (d, J C-C-F = 26.2 Hz). 19F NMR (470 MHz): δ = -60.66 (s, 3 F), -116.7 (m, 1 F). IR (neat): 3463, 2929, 1567, 1323, 1258, 1174, 835 cm-1. HRMS: m/z calcd for C9H5F4N [M+]: 203.0358; found: 203.0361. 6-Chloro-2-trifluoromethylindole ( 3e). Compound 3e was obtained as a yellow viscous liquid in 45% yield, using 1.5 equiv of magnesium ribbon; mp 145 °C (dec.). 1H NMR (500 MHz): δ = 8.41 (br, 1 H), 7.59 (d, J = 8.5 Hz, 1 H), 7.43-7.16 (m, 2 H), 6.91 (s, 1 H). 13C NMR (125 MHz): δ = 136.4, 130.7, 126.4 (q, J C-C-F = 38.8 Hz), 125.1, 123.0, 122.1, 120.9 (q, J C-F = 266.3 Hz), 111.6, 104.3 (q, J C-C-C-F = 3.5 Hz). 19F NMR (470 MHz): δ = -60.71 (s, 3 F). IR (neat): 3425, 2965, 1554, 1417, 1356, 1313, 1239, 1125, 922, 826 cm-1. HRMS: m/z calcd for C9H5ClF3N [M+]: 219.0063; found: 219.0059. 2-Difluoromethyl-5-methoxyindole ( 3h). Compound 3h was obtained as a yellow solid in 78% yield, using 1.5 equiv of magnesium ribbon; mp 76-78 °C. 1H NMR (500 MHz): δ = 8.33 (br, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 7.08 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 9.0, 2.5 Hz, 1 H), 6.77 (t, J H-F = 55.0 Hz, 1 H), 6.66 (d, J = 2.0 Hz, 1 H), 3.84 (s, 3 H). 13C NMR (125 MHz): δ = 154.6, 131.5, 130.6 (t, J C-C-F = 24.2 Hz), 127.4, 114.8, 112.4, 110.4 (t, J C-F = 233.8 Hz), 103.6 (t, J C-C-C-F = 6.8 Hz), 102.7, 55.7. 19F NMR (470 MHz): δ = -109.8 (d, J F-H = 55.0 Hz, 2 F). IR (neat): 3459, 2959, 1561, 1456, 1372, 1206, 1173, 1134, 1070, 983, 809 cm-1. HRMS: m/z calcd for C10H9F2NO [M+]: 197.0652; found: 197.0654. 3-Methyl-2-perfluoropropylindole ( 3i). Compound 3i was obtained as a light yellow solid in 79% yield, using 1.5 equiv of magnesium ribbon; mp 73-75 °C. 1H NMR (500 MHz): δ = 8.18 (br, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.35 (m, 1 H), 7.22 (m, 1 H), 2.45 (t, J = 2.2 Hz, 3 H). 13C NMR (125 MHz): δ = 136.0, 128.3, 124.9, 120.4, 120.1, 119.3 (t, J C-C-F = 28.1 Hz), 118.0 (qt, J C-F = 286.2 Hz, J C-C-F = 33.8 Hz), 116.6 (t, J C-C-C-F = 3.8 Hz), 114.1 (tt, J C-F = 253.1 Hz, J C-C-F = 31.9 Hz), 111.5, 109.2 (m), 8.5 (q, J = 2.1 Hz). 19F NMR (470 MHz): δ = -80.26 (t, J = 9.4 Hz, 3 F), -109.60 (q, J = 9.4 Hz, 2 F),
-126.66 (s, 2 F). IR (neat): 3387, 2928, 1343, 1225, 1196, 1112, 903, 748 cm-1. HRMS: m/z calcd for C12H8F7N [M+]: 299.0545; found: 299.0548. 5-Methoxy-2-perfluoropropylindole ( 3j). Compound 3j was obtained as a light yellow solid in 76% yield, using 1.5 equiv of magnesium ribbon; mp 44-46 °C. 1H NMR (500 MHz): δ = 8.54 (br, 1 H), 7.27 (d, J = 9.0 Hz, 1 H), 7.10 (d, J = 2.0 Hz, 1 H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H), 6.87 (s, 1 H), 3.84 (s, 3 H). 13C NMR (125 MHz): δ = 155.0, 132.0, 127.5, 124.4 (t, J C-C-F = 29.4 Hz), 118.0 (qt, J C-F = 286.2 Hz, J C-C-F = 33.8 Hz), 116.1, 112.8 (tt, J C-F = 251.9 Hz, J C-C-F = 31.2 Hz), 112.7, 108.8 (m), 106.0 (t, J = 5.0 Hz), 102.7, 55.8. 19F NMR (470 MHz): δ = -80.20 (t, J = 9.4 Hz, 3 F), -109.47 (q, J = 9.4 Hz, 2 F), -126.70 (s, 2 F). IR (neat): 3308, 2953, 1628, 1548, 1459, 1343, 1222, 1180, 976, 792 cm-1. HRMS: m/z calcd for C12H8F7NO [M+]: 315.0494; found: 315.0496.

7

General Procedure for the Synthesis of Fluorinated N -(2-Alkylphenyl)Imidoyl Chlorides ( 1).
To a 200 mL three-necked round-bottomed flask equipped with condenser and magnetic stir bar was added Ph3P (34.5 g, 132 mmol), Et3N(7.3 mL, 53 mmol), CCl4 (21.1 mL, 220 mmol), and TFA, difluoroacetic acid or perfluorocarboxylic acid (44 mmol) at 0 °C under a nitrogen atmosphere and stirred for 10 min. A solution of o-alkylaniline (44 mmol) dissolved in CCl4 (21.1 mL, 220 mmol) was added dropwise to the reaction mixture. Upon completion of the addition, the reaction mixture was allowed to reflux for 3 h. After cooling, the solvent was removed by rotary evaporator, the residue was then carefully washed with PE (3 ×), and the precipitation was removed via filtration. The filtrate was combined and concentrated by rotary evaporator. The residue was then purified by flash column chromatography (10:1 hexane-EtOAc) or distillation under reduced pressure to offer the products 1.

8

General Procedure for the Synthesis of Fluorinated N -[(2-Bromoalkyl)phenyl]imidoyl Chlorides ( 2).
To a 200 mL three-necked round-bottomed flask equipped with condenser and magnetic stir bar was added the appropriate fluorinated N-arylimidolyl chloride 1 (46 mmol), NBS (8.6 g, 48 mmol), benzoyl peroxide (0.6 g, 2.3 mmol), and anhydrous CCl4 (80 mL) under a nitrogen atmosphere. This reaction mixture was stirred and heated to reflux for 2-5 h (monitored by TLC) until a complete conversion of 1. After cooling down to r.t., the precipitate was removed via filtration. Then, the filtrate was combined and concentrated by rotary evaporator. The residue was then purified by flash column chromatography (10:1 hexane-EtOAc) or distillation under reduced pressure to yield products 2.