Synlett 2006(15): 2459-2463  
DOI: 10.1055/s-2006-950427
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Routes to 3-(Arylthio)indoles: Application to the Synthesis of the 3,3′-Bis(indolyl) Sulfone Core of the Marine Alkaloid Echinosulfone A

Hamid Shirania, Birgitta Stenslandb, Jan Bergman*a,c, Tomasz Janosik*a
a Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, 14157 Huddinge, Sweden
b Preformulation and Biopharmaceutics, Solid State Analysis, AstraZeneca PAR & D / SBBG B341:3, 15185 Södertälje, Sweden
c Södertörn University College, 14104 Huddinge, Sweden
Fax: +46(8)6081501; e-Mail: jabe@biosci.ki.se; e-Mail: toja@biosci.ki.se;
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Publikationsverlauf

Received 15 May 2006
Publikationsdatum:
08. September 2006 (online)

Abstract

A new approach to 3-(arylthio)indoles and related compounds has been developed, based on the reactions of aryl Grignard reagents or lithiated heteroaromatics with a phenylsulfonyl-protected 3,3′-bis(indolyl) disulfide. In addition, a rational approach to the 3,3′-bis(indolyl) sulfone core of the alkaloid echinosulfone A has been accomplished, involving treatment of a 3-lithioindole with bis(phenylsulfonyl) sulfide as the key step.

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Data for compound 4: Colorless crystals, mp 160.5-161.5 °C; 1H NMR (300.1 MHz, CDCl3): δ = 7.81-7.75 (m, 2 H), 7.48-7.42 (m, 2 H), 7.39 (s, 2 H), 7.17-7.08 (m, 4 H), 0.91 (s, 18 H), 0.59 (s, 12 H); 13C NMR (75.5 MHz, CDCl3): δ = 141.6, 134.9, 132.0, 122.0, 120.3, 119.7, 114.2, 109.1, 26.4, 19.6, -3.8; Anal. Calcd for C28H40N2SSi2: C, 68.23; H, 8.18; N, 5.68. Found: C, 68.25; H, 8.06; N, 5.59.

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Crystallographic data (excluding structure factors) for compound 4 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 606016. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44 (1223)336033 or email: deposit@ccdc.cam.ac.uk].

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Data for compound 5: Colorless crystals, mp 227.5-229 °C (Lit.6b 232 °C); IR (neat): 3409, 3393, 1452, 1405, 1335, 1236, 1085, 1002, 739 cm -1; 1H NMR (300.1 MHz, DMSO-d 6): δ = 11.26 (s, 2 H), 7.74-7.70 (m, 2 H), 7.65 (d, J = 2.6 Hz, 2 H), 7.36-7.33 (m, 2 H), 7.10-7.00 (m, 2 H); 13C NMR (75.5 MHz, DMSO-d 6): δ = 136.2, 129.7, 128.5, 121.5, 119.4, 118.6, 111.9, 105.3; ESI-MS: m/z = 263 [M - H]- . The IR and 1H NMR data are in good agreement with those discussed in reference 6c.

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Data for compound 6: Colorless crystals, mp 304-306 °C; 1H NMR (300.1 MHz, DMSO-d 6): δ = 12.02 (s, 2 H), 8.22 (s, 2 H), 7.81-7.79 (m, 2 H), 7.44 (d, J = 7.4 Hz, 2 H), 7.21-7.11 (m, 4 H); 13C NMR (75.5 MHz, DMSO-d 6): δ = 136.3, 130.1, 122.9, 122.8, 121.2, 118.7, 117.2, 112.6; ESI-MS: m/z = 295 [M - H]¯.

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Preparation of disulfide 8: A stirred suspension of finely powdered KOH (12.5 g, 0.22 mol) in CH2Cl2 (155 mL) under N2 was cooled to 0 °C, followed by sequential addition of the disulfide 7 (14.8 g, 50 mmol), and tetrabutylammo-nium hydrogen sulfate (0.88 g, 2.6 mmol). To this mixture was added a solution of benzenesulfonyl chloride (16.0 mL, 0. 125 mol) in CH2Cl2 (25 mL) at 0 °C over 1.25 h. The resulting mixture was stirred at 0 °C for 1 h, and thereafter at r.t. for 1.5 h, whereupon it was filtered, and the filter cake was washed with several portions of CH2Cl2. Evaporation of the combined filtrates and washings gave a solid residue, which was recrystallized from MeCN (using activated carbon), to give 8 (20.9 g, 72%) as pinkish crystals, mp 165-166.5 °C; 1H NMR (300.1 MHz, CDCl3): δ = 8.02-7.98 (m, 2 H), 7.91-7.88 (m, 4 H), 7.62-7.48 (m, 10 H), 7.42-7.36 (m, 2 H), 7.27-7.22 (m, 2 H); 13C NMR (75.5 MHz, CDCl3): δ = 137.8, 135.3, 134.5, 130.6, 130.4, 129.8, 127.1, 125.9, 124.1, 120.6, 115.8, 113.8; Anal. Calcd for C28H20N2O4S4: C, 58.31; H, 3.50; N, 4.86. Found: C, 58.46; H, 3.58; N, 4.78.

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Compound 11 (Table [1] , entry 3): To a solution of benzo[b]thiophene (0.24 g, 2.0 mmol) in anhydrous THF (10 mL) was added BuLi (2.5 M in hexanes, 0.80 mL, 2.0 mmol) over 10 min under N2 at -78 °C. The solution was stirred for 30 min at -78 °C, followed by addition of a solution of the disulfide 8 (1.15 g, 2.0 mmol) in anhydrous THF (10 mL) over ˜15 min at -78 °C. The mixture was allowed to warm to r.t. over 16 h, and was thereafter treated with sat. aq NH4Cl (20 mL). The resulting mixture was extracted with Et2O (2 × 30 mL). The combined organic layers were washed with H2O (30 mL), brine (30 mL) and dried over Na2SO4. Evaporation of the solvents gave a residue, which was subjected to column chromatography on silica gel, initially using n-heptane followed by EtOAc-n-heptane (1:9 ® 1:4), to provide 11 (0.64 g, 76%), as colorless crystals, mp 140-143 °C; 1H NMR (300.1 MHz, CDCl3): δ = 8.02-7.99 (m, 1 H), 7.93-7.90 (m, 2 H), 7.86 (s, 1 H), 7.65-7.56 (m, 4 H), 7.50-7.45 (m, 2 H), 7.39-7.23 (m, 5 H); 13C NMR (75.5 MHz, CDCl3): δ = 141.4, 139.9, 138.0, 136.9, 135.4, 134.4, 130.8, 130.1, 129.6, 127.1, 126.4, 125.8, 124.7, 124.6, 124.2, 123.2, 122.0, 120.4, 114.0, 113.7; Anal. Calcd for C22H15NO2S3: C, 62.68; H, 3.59; N, 3.32. Found: C, 62.61; H, 3.68; N, 3.25.

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Compound 14 (Table [1] , entry 5): A solution of 2-bromo-biphenyl (0.56 g, 2.4 mmol) in anhydrous THF (5 mL) was added dropwise to a suspension of magnesium turnings (53 mg, 2.2 mmol) in anhydrous THF (5 mL) at r.t. under N2. The mixture was heated at reflux for 1 h and was thereafter cooled to 0 °C, whereupon a solution of the disulfide 8 (1.15 g, 2.0 mmol) in anhydrous THF (10 mL) was added drop-wise during ˜15 min at 0 °C. The mixture was allowed to warm to r.t. over 16 h, followed by addition of 50% aq NH4Cl (20 mL). Workup as for compound 11, followed by column chromatography on silica gel, initially using n-heptane, followed by Et2O-n-heptane (1:19 ® 15:85), gave 14 (0.67 g, 76%) as colorless crystals, mp 128-130 °C; 1H NMR (300.1 MHz, CDCl3): δ = 8.03-8.00 (m, 1 H), 7.90-7.87 (m, 2 H), 7.69 (s, 1 H), 7.59-7.32 (m, 10 H), 7.26-7.15 (m, 3 H), 7.08-7.03 (m, 1 H), 6.84 (dd, J = 7.9, 0.9 Hz, 1 H); 13C NMR (75.5 MHz, CDCl3): δ = 141.0, 140.4, 138.0, 135.6, 135.0, 134.3, 131.3, 131.1, 130.5, 129.6, 129.5, 128.4, 128.1, 127.9, 127.5, 127.0, 125.9, 125.7, 124.1, 120.7, 114.0, 112.6; Anal. Calcd for C26H17NO2S2: C, 70.72; H, 4.34; N, 3.17. Found: C, 70.83; H, 4.39; N, 3.14.

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Compound 17 (Table [1] , entry 8): A solution of i-PrMgCl (2.0 M in Et2O, 1.2 mL, 2.4 mmol,) was added slowly (over ˜10 min) to a solution of ethyl 2-iodobenzoate (0.55 g, 2.0 mmol) in anhydrous THF (10 mL) at -20 °C under N2. The mixture was stirred at -20 °C for 30 min, and was then allowed to warm to 0 °C over 30 min. After cooling to -78 °C, a solution of the disulfide 8 (1.15 g, 2.0 mmol) in THF (10 mL) was added over ˜15 min. The resulting mixture was allowed to warm to r.t. over 16 h, and was subsequently treated with sat. aq NH4Cl (25 mL). Workup as for compound 11, followed by column chromatography on silica gel using n-heptane-EtOAc (8:1), afforded 17 (0.60 g, 69%) as a colorless viscous oil, which solidified upon standing. 1H NMR (300.1 MHz, CDCl3): δ = 8.08-8.02 (m, 2 H), 7.97-7.93 (m, 2 H), 7.90 (s, 1 H), 7.62-7.56 (m, 1 H), 7.51-7.46 (m, 2 H), 7.41-7.36 (m, 2 H), 7.25-7.19 (m, 1 H), 7.14-7.09 (m, 2 H), 6.69-6.66 (m, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3): δ = 166.6, 141.6, 138.0, 135.8, 134.4, 132.5, 132.3, 131.4, 131.3, 129.6, 127.1, 126.8, 126.6, 125.8, 124.5, 124.2, 120.7, 114.0, 111.9, 61.5, 14.5.

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Data for compound 18: Off-white crystalline solid, mp 138-140 °C; 1H NMR (300.1 MHz, DMSO-d 6): δ = 11.55 (s, 1 H), 11.17 (s, 1 H), 7.75 (d, J = 2.5 Hz, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 7.16-7.11 (m, 1 H), 7.08-6.96 (m, 2 H), 6.93-6.88 (m, 1 H), 6.31 (d, J = 1.7 Hz, 1 H); 13C NMR (75.5 MHz, DMSO-d 6) δ = 137.0, 136.3, 131.4, 131.1, 128.4, 128.0, 121.9, 121.0, 119.8, 119.1, 119.1, 118.4, 112.1, 110.8, 103.7, 100.8; ESI-MS: m/z = 265 [M + H]+; Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N, 10.60. Found: C, 72.48; H, 4.65; N, 10.36.