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

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.

indoles - sulfides - sulfones - Grignard reagents - lithiation

References and Notes

For some examples, see:

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10

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.

11

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: [phone] or email: [e-mail]].

12

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.

13

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]¯.

14 Woodbridge RG. Dougherty G. J. Am. Chem. Soc.  1950,  72:  4320 

15a Illi VO. Synthesis  1979,  136 

15b Conway SC. Gribble GW. Heterocycles  1990,  30:  627 

16

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.

17

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.

18

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.

19

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.

20 Katritzky AR. Akutagawa K. Tetrahedron Lett.  1985,  26:  5935 

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22

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.

23 Hünig S. Steinmetzer H.-C. Liebigs Ann. Chem.  1976,  1039 

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25 Janosik T. Bergman J. Stensland B. Stålhandske C. J. Chem. Soc., Perkin Trans. 1  2002,  330