Preparation of Symmetrical and Nonsymmetrical Fluorene ­Sulfonamide Scaffolds

Abstract

Methods for the preparation of symmetrical and nonsymmetrical 2,7-disubstituted 9H-fluorene derivatives are described.

Key words

fluorene - sulfonamide - microwave-assisted synthesis

• References and Notes

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• 19 General Procedure for the Microwave-Assisted Formation of Sulfonamides 9H-Fluorene-2,7-disulfonyl dichloride (4, 100 mg, 0.28 mmol), acetone (1.52 mL), THF (0.28 mL), amine (0.56 mmol), and 2 M NaOH (aq, 0.32 mL) were added to a 5 mL microwave vial equipped with a magnetic stirrer bar. The mixture was heated in a Biotage Initiator at 100 °C for 15 min and allowed to cool to r.t. CH₂Cl₂ (10 mL) was added, and the mixture washed with water (10 mL), sat. Na₂CO₃ solution (10 mL), 2 M HCl (aq) solution (10 mL),and brine (10 mL). The organic extract was dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude product. N,N-Diisopropyl-9H-fluorene-2,7-disulfonamide (13) Prepared by the General Procedure, using isopropylamine (0.05 mL, 0.58 mmol). Purified by column chromatography on silica (PE–EtOAc = 2:1, followed by 1:1) to give 13 as a yellow-orange solid (80 mg, 71%); mp 194–195 °C. IR (ATR): 3054, 2990, 1456, 1403, 1304, 1235, 1181, 1103 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.21 ( 2H, d, J = 8.1 Hz), 8.06 (2 H, d, J = 0.8 Hz), 7.89 (2 H, dd, J = 8.1, 1.5 Hz), 7.61 (2 H, d, J = 7.2 Hz), 4.18 (2 H, s), 3.22–3.35 (2 H, m), 0.96 (12 H, d, J = 6.5 Hz). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 144.7 (C_q), 143.0 (C_q), 141.1 (C_q), 125.5 (CH), 123.4 (CH), 121.5 (CH), 45.2 (CH), 36.7 (CH₂), 23.2 (CH₃). LC–MS: m/z = 407.1 [M – 1]⁺. HRMS: m/z calcd for C₁₉H₂₃O₄N₂S₂: 407.1105; found: 407.1107. Palladium-Catalysed Procedures 7-(Morpholinosulfonyl)-N-(p-tolyl)-9H-fluorene-2-sulfonamide (21) A microwave vial was charged with 20 (30.0 mg, 0.062 mmol), K₂S₂O₅ (33.0 mg, 0.148 mmol), TBAB (26.3 mg, 0.082 mmol), NaO₂CH (12.0 mg, 0.176 mmol), Pd(OAc)₂ (1.0 mg, 5 mol%), Ph₃P (3.0 mg, 0.013 mmol), 1,10-phenanthroline (2.0 mg, 0.011 mmol), and DMSO (0.2 mL). The mixture was degassed by bubbling nitrogen through the solvent for 10 min, and then heated under argon at 70 °C for 3 h. Following cooling to r.t., a solution of morpholine (12.6 mg, 0.145 mmol) in anhydrous THF (1.0 mL) was added, and the mixture cooled to 0 °C. A solution of NBS (25.8 mg, 0.145 mmol) in THF (1.0 mL) was added dropwise and the mixture left to warm to r.t. over 1 h. Water (10 mL) was added, and the mixture extracted with EtOAc (3 × 10 mL). The organics were combined and washed with water (20 mL), brine (20 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE–EtOAc = 1:1) to give 21 as a yellow solid (27 mg, 77%). ¹H NMR (400 MHz, acetone-d ₆): δ = 8.87 (1 H, s), 8.19 (1 H, d, J = 8.0 Hz), 8.11 (1 H, d, J = 8.4 Hz), 8.01–8.06 (2 H, m), 7.81–7.88 (2 H, m), 7.11 (2 H, d, J = 8.4 Hz), 7.04 (2 H, d, J = 8.4 Hz), 4.14 (2 H, s), 3.62–3.72 (4 H, m), 2.93–3.03 (4 H, m), 2.21 (3 H, s). ¹³C NMR (101 MHz, acetone-d ₆): δ = 146.2 (C_q), 145.9 (C_q), 145.2 (C_q), 144.8 (C_q), 140.5 (C_q), 136.1 (C_q), 135.7 (C_q), 135.3 (C_q), 130.5 (CH), 128.0 (CH), 127.3 (CH), 125.8 (CH), 125.1 (CH), 122.5 (CH), 122.3 (CH), 122.2 (CH), 66.7 (CH₂), 47.1 (CH₂), 37.7 (CH₂), 20.7 (CH₃). LC–MS m/z = 483.2 [M – 1]⁺. HRMS: m/z calcd for C₂₅H₂₅N₂O₅S₂: 485.1199; found: 485.1189. 7-Morpholino-N-(p-tolyl)-9H-fluorene-2-sulfonamide (22) A mixture of RuPhos palladacycle (7 mg, 0.05 equiv), RuPhos (5 mg, 0.05 equiv), NaOt-Bu (29 mg, 0.30 mmol), 7-bromo-N-(p-tolyl)-9H-fluorene-2-sulfonamide (83 mg, 0.20 mmol), and morpholine (0.021 mL, 0.24 mmol) in 1,4-dioxane (0.50 mL) was sealed and heated in a Biotage Initiator at 120 °C for 30 min. After cooling, the sample was passed through a plug of Celite using MeOH (10.0 mL), then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE–EtOAc = 1:1) to give 21 (59 mg, 72%) as a yellow solid; mp 170 °C (decomp.); IR (ATR): 2922, 1612, 1512, 1451, 1419, 1243, 1189, 1111 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (1 H, d, J = 1.2 Hz), 7.70 (1 H, dd, J = 8.0, 0.8 Hz), 7.67 (1 H, d, J = 8.8 Hz), 7.64 (1 H, d, J = 8.4 Hz), 7.10 (1 H, d, J = 2.0 Hz), 6.99–7.04 (2 H, m), 6.92–6.98 (3 H, m), 6.41 (1 H, s), 3.86–3.92 (4 H, m), 3.83 (2 H, s), 3.20–3.28 (4 H, m), 2.26 (3 H, s). ¹³C NMR (101 MHz, CDCl₃): δ = 152.1 (C_q), 146.8 (C_q), 146.2 (C_q), 143.1 (C_q), 135.6 (C_q), 135.4 (C_q), 134.0 (C_q), 133.3 (C_q), 130.0 (CH), 126.7 (CH), 123.8 (CH), 122.7 (CH), 121.8 (CH), 118.9 (CH), 115.2 (CH), 112.1 (CH), 67.0 (CH₂), 49.5 (CH₂), 37.1 (CH₂), 21.0 (CH₃). LC–MS: m/z = 421.1 [M + 1]⁺. HRMS: m/z calcd for C₂₄H₂₅N₂O₃S: 422.1580; found: 422.1577. 7-(Morpholine-4-carbonyl)-N-(p-tolyl)-9H-fluorene-2-sulfonamide (23) A mixture of Pd(OAc)₂ (2.0 mg, 0.05 equiv), Xantphos (6.0 mg, 0.05 equiv), Mo(CO)₆ (53.0 mg, 0.05 equiv), DMAP (37.0 mg, 0.30 mmol), 7-bromo-N-(p-tolyl)-9H-fluorene-2-sulfonamide (83.0 mg, 0.20 mmol), and morpholine (0.034 mL, 0.39 mmol) in 1,4-dioxane (0.50 mL) was sealed and heated in a Biotage Initiator at 90 °C for 30 min. After cooling, the reaction mixture was passed through Celite using MeOH (10.0 mL), then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE–EtOAc = 4:1) to give 22 as a yellow solid (0.068 g, 76%); mp 210 °C (decomp.). IR (ATR): 2925, 2853, 1619, 1605, 1445, 1332, 1243, 1191, 1148, 1111, 1049 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (1 H, d, J = 0.7 Hz), 7.82 (1 H, d, J = 8.0 Hz), 7.75–7.80 (2 H, m), 7.62 (1 H, d, J = 0.8 Hz), 7.45 (1 H, dd, J = 8.0, 1.2 Hz, 1 H), 7.02 (2 H, d, J = 8.0 Hz), 6.96 (2 H, d, J = 8.0 Hz), 6.77 (1 H, br s), 3.91 (2 H, s), 3.50–3.87 (8 H, m), 2.25 (3 H, s). ¹³C NMR (101 MHz, CDCl₃): δ = 170.5 (C_q), 145.3 (C_q), 144.6 (C_q), 144.1 (C_q), 141.6 (C_q), 137.9 (C_q), 135.7 (C_q), 135.2 (C_q), 133.8 (C_q), 130.0 (CH), 126.7 (CH), 126.4 (CH), 124.4 (CH), 124.2 (CH), 122.7 (CH), 121.0 (CH), 120.6 (CH), 67.0 (CH₂), 37.1 (CH₂), 21.0 (CH₃), one carbon missing. LC–MS: m/z = 449.1 [M + 1]⁺. HRMS: m/z calcd for C₂₅H₂₅N₂O₄S: 449.1530; found: 449.1530.