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Synlett 2006(7): 1090-1094  
DOI: 10.1055/s-2006-939074
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Synthesis of Substituted Indole N-Oxides: TiCl4-Mediated Baylis-Hillman Reaction of α-Oxo Cyclic Ketene-S,S-acetal with o-Nitrobenz­aldehydes and Subsequent Intramolecular Cyclization

Wei Pan, Dewen Dong*, Shaoguang Sun, Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax: +86(431)5098635; e-Mail: dongdw663@nenu.edu.cn;
Further Information

Publication History

Received 21 January 2006
Publication Date:
24 April 2006 (online)

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Abstract

One-pot synthesis of substituted indole N-oxides 3 has been developed based on the TiCl4-mediated Baylis-Hillman reaction of α-oxo cyclic ketene-S,S-acetal 1 with o-nitrobenzaldehydes 2 and subsequent intramolecular cyclization reaction.

Key words

Baylis-Hillman reaction - indole N-oxides - α-oxo ketene-S,S-acetals - TiCl4

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Typical Procedure for the Synthesis of Substituted Indole N -Oxides 3 (3b as an Example).
To a solution of 1 (4.0 mmol) and 2b (1.0 mmol) in mixed solvent of CH2Cl2 (5 mL) and MeCN (5 mL) was added TiCl4 (1.5 mmol) at 0 °C. The mixture was stirred at 0 °C for about 45 min until substrate 1 was consumed as indicated by TLC. The reaction was then allowed to warm to r.t. and stirred for 6 h. The reaction mixture was quenched with sat. aq Na2CO3 (10 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were washed with sat. aq NaCl (3 × 20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellowish solid. Purification was carried out by flash silica gel chromatography using PE-Et2O (4:1) as eluent to give product 3b (0.17 g, 43%). Compound 3b: yellowish solid; mp 140-142 °C. 1H NMR (500 MHz, CDCl3): δ = 1.80 (s, 3 H), 3.34-3.59 (m, 8 H), 6.85 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.52 (d, J = 7.5 Hz,1 H), 7.70 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 26.04, 35.88, 37.82, 38.18, 41.10, 109.81, 119.87, 120.53, 121.49, 124.75, 127.10, 134.88, 139.40, 149.26, 171.57, 179.55, 193.97. IR (KBr): 3424, 2924, 2361, 1645, 1521, 1465, 1368 cm-1. MS (EI): m/z = 393.9 [M + 1]+. Anal. Calcd for C17H15NO2S4: C, 51.88; H, 3.84; N, 3.56. Found: C, 51.83; H, 3.88; N, 3.53.
Selected Data for Other Compounds. Compound 3a: yellowish solid; mp 138-140 °C. 1H NMR (500 MHz, CDCl3): δ = 1.93 (s, 3 H), 3.30-3.58 (m, 8 H), 6.00 (s, 2 H), 6.28 (s, 1 H), 7.20 (s 1 H). 13C NMR (125 MHz, CDCl3): δ = 25.67, 35.57, 37.49, 37.79, 40.82, 90.57, 101.87, 102.29, 114.33, 119.66, 127.50, 138.27, 143.22, 147.66, 154.55, 171.54, 177.59, 193.58. IR (KBr): 3424, 2924, 2361, 1645, 1521, 1465, 1386 cm-1. MS (EI): m/z = 438.0 [M + 1]+. Anal. Calcd for C18H15NO4S4: C, 49.41; H, 3.46; N, 3.20. Found: C, 49.46; H, 3.48; N, 3.23.
Selected crystal data for 3a: empirical formula: C18H15O4NS4; formula weight: 437.0; crystal color, habit: yellow, rectangular; crystal dimensions: 0.24 × 0.19 × 0.09 mm; crystal system: orthorhombic; lattice type: primitive; lattice parameters: a = 12.5378 (17), b = 10.4037 (14), c = 17.058 (2) Å, V = 2187.0(5) Å3; β = 100.618 (3)°; space group: P21/c (#33); Z = 4; D calc = 1.373 g cm-3; F(000) = 936.00; residuals: R = 0.0816, wR = 0.2024.
CCDC 285048.
Compound 3c: yellowish solid; mp 153-155 °C. 1H NMR (500 MHz, CDCl3): δ = 1.93 (s, 3 H), 3.31-3.59 (m, 8 H), 6.80 (d, J = 7.0 Hz, 1 H), 7.41 (d, J = 7.0 Hz, 1 H), 7.82 (m, 1 H). 13C NMR (125 MHz, CDCl3): δ = 25.55, 35.45, 37.40, 37.81, 40.67, 110.65, 118.91, 121.92, 123.73, 125.62, 126.69, 134.26, 141.02, 146.80, 171.61, 177.54, 193.18. IR (KBr): 3415, 2924, 1647, 1607, 1520, 1462 cm-1. MS (EI): m/z = 428.0 [M + 1]+. Anal. Calcd for: C17H14ClNO2S4: C, 47.70; H, 3.30; Cl, 8.28; N, 3.27. Found: C, 47.75; H, 3.33; Cl, 8.24; N, 3.23. Compound 3d: amethyst solid; mp 127-129 °C. 1H NMR (500 MHz, CDCl3): δ = 1.94 (s, 3 H), 3.34-3.63 (m, 8 H), 7.70 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 26.02, 36.07, 38.03, 38.55, 41.26, 105.75, 115.21, 118.56, 125.21, 125.70, 127.83, 145.04, 147.89, 152.12, 173.18, 177.27, 193.04. IR (KBr): 3436, 2924, 1618, 1529, 1454, 1348 cm-1. MS (EI): m/z = 439.0 [M + 1]+. Anal. Calcd for C17H14N2O4S4: C, 46.56; H, 3.22; N, 6.39. Found: C, 46.59; H, 3.17; N, 6.43. Compound 4b: yellowish solid; mp 152-154 °C. 1H NMR (500 MHz,CDCl3): δ = 2.23 (s, 3 H), 3.11-3.37 (m, 4 H), 6.62 (d, J = 8.0 Hz, 1 H), 7.68 (m, 1 H), 7.56 (m, 2 H), 7.84 (d, J = 8.0 Hz,1 H). 13C NMR (125 MHz, CDCl3): δ = 29.07, 36.67, 38.58, 71.42, 124.87, 125.03, 128.95, 129.01, 132.69, 135.79, 149.44, 165.95, 194.99. IR (KBr): 3430, 2925, 1615, 1528, 1455 cm-1. Anal. Calcd for: C13H13NO4S2: C, 50.14; H, 4.21; N, 4.50. Found: C, 50.19; H, 4.25; N, 4.45.
Compound 5b: yellowish solid; mp 149-151 °C. 1H NMR (500 MHz, CDCl3): δ = 2.10 (s, 6 H), 3.25 (m, 8 H), 6.55 (s, 1 H), 7.43 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.54 (m, 1 H), 7.89 (d, J = 8.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 28.33, 37.59, 37.87, 49.22, 125.22, 129.10, 132.13, 133.27, 135.07, 150.42, 195.14. IR (KBr): 3446, 2921, 2361, 1636, 1522, 1235 cm-1. Anal. Calcd for: C19H19NO4S4: C, 50.31; H, 4.22; N, 3.09. Found: C, 50.35; H, 4.17; N, 3.05.
Compound 6b: yellowish solid; mp 101-103 °C. 1H NMR (500 MHz, CDCl3): δ = 2.15 (s, 3 H), 2.43 (s, 3 H,), 3.21-3.32 (m, 4 H), 6.28 (d, J = 8.5 Hz 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.45 (m, 1 H), 7.58 (m, 2 H), 7.79 (d, J = 8.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 23.19, 28.31, 37.31, 38.48, 52.25, 124.11, 125.00, 128.79, 129.17, 132.59, 134.15, 149.08, 164.48, 169.66, 195.03. IR (KBr): 3262, 2970, 1653, 1529, 1457, 1364, 1242, 1175 cm-1. Anal. Calcd for: C15H16N2O4S2: C, 51.12; H, 4.58; N, 7.95. Found: C, 51.15; H, 4.62; N, 7.90. Compound 4c: yellowish solid; mp 138-140 °C. 1H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3 H), 3.01 (d, J = 6.5 Hz, 1 H), 3.29-3.36 (m, 4 H), 6.56 (d, J = 6.5 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.68 (s, 1 H), 7.82 (d, J = 8.5 Hz,1 H). 13C NMR (125 MHz, CDCl3): δ = 28.70, 36.59, 38.35, 70.89, 124.18, 126.22, 128.69, 129.03, 138.10, 139.05, 149.66, 165.44, 194.08. IR (KBr): 3467, 1522, 1458, 1465, 1349 cm-1. Anal. Calcd for C13H12ClNO4S2: C, 45.15; H, 3.50; Cl, 10.25; N, 4.05. Found: C, 45.19; H, 3.46; Cl, 10.29; N, 4.00.
Compound 5c: yellowish solid; mp: 119-120 °C. 1H NMR (500 MHz, CDCl3): δ = 2.14 (s, 6 H), 3.23-3.29 (m, 8 H), 6.54 (s, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.44 (dd, J 1 = 2.0 Hz, J 2 = 9.0 Hz, 1 H), 7.88 (d, J = 9.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 28.10, 37.34, 37.66, 48.91, 122.57, 126.45, 128.94, 131.59, 137.06, 139.55, 148.15, 165.11, 194.57. IR (KBr): 3853, 2734, 2360, 1635, 1521, 1235 cm-1. Anal. Calcd for C19H18ClNO4S4: C, 46.76; H, 3.72; Cl, 7.26; N, 2.87; found: C, 46.80; H, 3.76; Cl, 7.21; N, 2.83.
Compound 6c: yellowish solid, mp 109-111 °C, 1H NMR (500 MHz, CDCl3): δ = 2.18 (s, 3 H), 2.44 (s, 3 H), 3.24-3.35 (m, 4 H), 6.25 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.41 (dd, J 1 = 2.0 Hz, J 2 = 8.5 Hz, 1 H), 7.57 (s, 1 H), 7.78 (d, J = 8.5 Hz, 1 H). Anal. Calcd for C15H15ClN2O4S2: C, 46.57; H, 3.91; Cl, 9.16; N, 7.24. Found: C, 46.61; H, 3.87; Cl, 9.22; N, 7.29.