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

Fenglian Ge; Zengxue Wang; Wen Wan; Jian Hao

doi:10.1055/s-2007-967950

LETTER

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

Fenglian Ge^a, Zengxue Wang^a, Wen Wan^a, 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

Abstract

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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

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References

References and Notes

For recent reviews on the synthesis of indoles, see:

1a Humphrey GR. Kuethe JT. Chem. Rev. 2006, 106: 2875

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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.

6 Tamura K. Mizukami H. Maeda K. Watanabe H. Uneyama K. J. Org. Chem. 1993, 58: 32

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.

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