Regioselective Suzuki–Miyaura Cross-Coupling Reactions of the Bis(triflate) of 1,4-Dihydroxy-9H-fluoren-9-one

Dedicated to Professor Steven V. Ley on the occasion of his 70^th birthday

Abstract

1,4-Diaryl-9H-fluoren-9-ones were prepared by regioselective Suzuki–Miyaura cross-coupling reaction of the bis(triflate) of 1,4-dihydroxy-9H-fluoren-9-one. The reactions proceeded with excellent site selectivity. The first attack occurs at position 1, due to electronic reasons.

Key words

Catalysis - Suzuki–Miyaura reaction - regioselectivity - palladium - heterocycles

• References and Notes

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For Suzuki–Miyaura reactions of bis(triflates) from our laboratory, see, for example:
• 13a Methyl 2,5-dihydroxybenzoate: Nawaz M, Ibad MF, Abid O.-U.-R, Khera RA, Villinger A, Langer P. Synlett 2010; 150
• 13b Alizarin: Mahal A, Villinger A, Langer P. Synlett 2010; 1085 3,4
• 13c Dihydroxybenzophenone: Nawaz M, Khera RA, Malik I, Ibad MF, Abid O.-UR, Villinger A, Langer P. Synlett 2010; 979
• 13d Phenyl 1,4-dihydroxynaphthoate: Abid O.-U.-R, Ibad MF, Nawaz M, Ali A, Sher M, Rama NH, Villinger A, Langer P. Tetrahedron Lett. 2010; 51: 1541
• 13e 5,10-Dihydroxy-11H-benzo[b]fluoren-11-one: Ali A, Hussain MA, Villinger A, Langer P. Synlett 2010; 3031
• 14 Synthesis of 9-Oxo-9H-fluorene-1,4-diaryl-bis(trifluoromethanesulfonate) (2) To a CH₂Cl₂ solution (150 mL) of 1 (1.8 g, 8.543 mmol) was added dry pyridine (10 mL), and the solution was cooled to –78 °C under argon atmosphere. Then Tf₂O (5.785 g, 20.503 mmol, 2.4 equiv) was added dropwise to the solution and stirred for 20 h at r.t. After removal of the solvent with reduced pressure H₂O (100 mL) was added to the resulting oil, and the precipitate was filtered off and recrystallized with hot heptane. After cooling to r.t., the precipitated pure product 2 was filtered and washed with heptane. To obtain the residual product, the heptane was concentrated under vacuum, and the product 2 was isolated by column chromatography (silica gel; heptane–EtOAc, 3:1) as a yellow fluffy solid (3.318 g, 82%); mp 131–133 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.88 (d, ³ J = 7.6 Hz, 1 H, ArH), 7.78 (d, ³ J = 7.4 Hz, 1 H, ArH), 7.64 (dt, ³ J = 7.6 Hz, ⁴ J = 1.2 Hz, 1 H, ArH), 7.53 (d, ³ J = 9.1 Hz, 1 H, ArH), 7.48 (dt, ³ J = 7.5 Hz, ⁴ J = 0.9 Hz, 1 H, ArH), 7.21 (d, ³ J = 9.1 Hz, 1 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 187.40 (CO), 144.29, 143.06, 139.32, 138.13 (C), 136.09 (CH), 133.49 (C), 131.48 (CH), 129.39 (C), 127.62 (CH), 125.70, 124.5, 124.38 (C), 118.85 (q, J _F,_C = 321.00 Hz, CF₃), 118.66 (q, J _F,_C = 321.00 Hz, CF₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –73.02 (CF₃), –73.17 (CF₃). IR (ATR): ν = 3104.6 (w), 3089 (w), 2921 (w), 2849 (w), 1726 (s), 1427 (s), 1224 (s), 1207 (s), 1166 (m), 1134 (s), 1104 (m), 905 (s), 886 (s), 845 (s), 812 (m), 803 (s), 762 (m), 754 (s), 598 (s) cm^–1. MS (EI, 70eV): m/z = 476 (52) [M⁺], 343 (13), 279 (100), 251 (49), 223 (35), 185 (14), 154 (16), 128 (33), 100 (12), 69 (43). HRMS (EI): m/z calcd for C₁₅H₆F₆O₇S₂ [M⁺]: 475.94536; found: 475.94491. Anal. Calcd for C₁₅H₆F₆O₇S₂ (476.32): C, 37.82; H, 1.27. Found: C, 37.92; H, 1.08.
• 15 General Procedure for the Synthesis of 4a–h In a pressure tube 2 (0,315 mmol), K₃PO₄ (3.0 equiv), Pd(PPh₃)₄ (6.0 mol%), and arylboronic acid (2.4 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH₂Cl₂, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the bis-substituted fluorenone 4a–h in good yields.
• 16 1,4-Bis-(3,4-dimethoxyphenyl)-9H-fluoren-9-one (4a) Starting with 2 (150 mg, 0.315 mmol), 3a (138 mg, 0.756 mmol, 2.4 equiv), Pd(PPh₃)₄ (22 mg, 0.018 mmol, 6 mol%), K₃PO₄ (200 mg, 0.945 mmol, 3.0 equiv), and 1,4-dioxane (5 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 1:1) 4a was isolated as an orange solid (138 mg, 97%); mp 192–194 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.62–7.58 (m, 1 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.23 (d, J = 7.9 Hz, 1 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.15–7.11 (m, 2 H, ArH), 7.02 (s, 2 H, ArH), 6.97 (d, J = 9.2 Hz, 2 H, ArH), 6.81–6.75 (m, 1 H, ArH), 4.00 (s, 3 H, OCH₃), 3.95 (s, 3 H, OCH₃), 3.94 (s, 3 H, OCH₃), 3.89 (s, 3 H, OCH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 193.09 (CO), 149.35, 149.18, 149.11, 148.43, 143.72, 142.41, 141.17, 136.87 (C), 136.41 (CH), 134.80 (C), 134.20 (CH), 132.29 (C), 131.35 (CH), 130.18 (C), 128.85, 124.03, 123.30, 121.88, 121.20, 113.09, 112.26, 111.57, 110.82 (CH), 56.15, 5615 (OCH₃), 56.06, 56.06 (OCH₃). IR (ATR): ν = 3008 (w), 2955 (w), 2933 (w), 2905 (w), 2838 (w), 2627 (w), 2577 (w), 1701 (m), 1519 (m), 1441 (s), 1251 (s), 1222 (s), 1146 (s), 1020 (s), 746 (s) cm^–1. MS (EI, 70 eV): m/z = 452 (100) [M⁺], 437 (9), 263 (4); 250 (4), 226 (5), 132 (4). HRMS (ESI-TOF/MS): m/z calcd for C₂₉H₂₄O₅ [M + H]⁺: 453.16965; found: 453.16995; m/z calcd for C₂₉H₂₄O₅ [M + Na]⁺: 475.15159; found: 475.15191.
• 17 General Procedure for the Synthesis of 5a–h In a pressure tube 2 (0.525 mmol), K₃PO₄ (2.0 equiv), Pd(PPh₃)₄ (3.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon und stirred for 12 h at 60 °C. After cooling to r.t., the solution was filtered through Celite, washed with CH₂Cl₂, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the monosubstituted fluorenone 5a–h in good yields.
• 18 1-(4′-Hydroxyphenyl)-9-oxo-9H-fluoren-4-yl-trifluoromethanesulfonate (5f) Starting with 2 (150 mg, 0.315 mmol), 3f (53 mg, 0.378 mmol, 1.2 equiv), Pd(PPh₃)₄ (11 mg, 0.009 mmol, 3 mol%), K₃PO₄ (134 mg,0.63 mmol, 2.0 equiv), and 1,4-dioxane (9 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 6:1) 5f was isolated as deep yellow solid (112 mg, 86%); mp 194–196 °C. ¹H NMR (300 MHz, DMSO): δ = 9.75 (s, 1 H, OH), 7.80–7.69 (m, 2 H, ArH), 7.64 (t, J = 7.2 Hz, 2 H, ArH), 7.51 (t, J = 7.2 Hz, 1 H, ArH), 7.40 (m, 3 H, ArH), 6.83 (d, J = 8.6 Hz, 2 H, ArH). ¹³C NMR (63 MHz, CDCl₃): δ = 190.03 (CO), 158.21, 142.34, 141.91, 138.63, 135.74 (C), 135.49, 134.00 (CH), 133.54, 133.58 (C), 130.81, 130.81, 130.68, 127.34 (CH), 126.01 (C), 124.47, 123.03 (CH), 118.06 (q, J _F,_C = 320.70 Hz, CF₃), 114.73, 114.73 (CH). ¹⁹F NMR (282 MHz, CDCl₃): δ = –73.13 (CF₃). IR (ATR): ν = 3320 (w), 3019 (w), 2920 (w), 2850 (w), 1699 (m), 1422 (s), 1205 (s), 1137 (s), 825 (s), 608 (s), 585 (s), 567 (s), 547 (m), 527 (s) cm^–1. MS (EI, 70eV): m/z = 420 (28) [M⁺], 287 (100), 259 (22), 231 (7), 202 (22), 176 (4), 150 (2), 101 (5), 69 (8). HRMS (EI): m/z calcd for C₂₀H₁₁F₃O₅S₁ [M⁺]: 420.02738; found: 420.02764. Anal. Calcd for C₂₀H₁₁F₃O₅S (420.36): C, 57.15; H, 2.64. Found: C, 57.23; H, 2.52.
• 19 CCDC-1416855 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: [phone]; or [e-mail].
• 20 General Procedure for the Synthesis of 6a–g In a pressure tube 5a–e,g, K₃PO₄ (2.0 equiv), Pd(PPh₃)₄ (5.0 mol%), and arylboronic acid (1.2 equiv) were mixed with dry 1,4-dioxane, degassed with argon and stirred for 12 h at 100 °C. After cooling to r.t. the solution was filtered through Celite, washed with CH₂Cl₂, and the filtrate was concentrated by reduced pressure. The residue was purified by column chromatography to receive the cross-substituted fluorenone 6a–g in good yields.
• 21 1-(5′-Fluoro-2′-methoxyphenyl)-4-(4′′-methoxyphenyl)-9H-fluoren-9-one (6a) Starting with 5g (75 mg, 0.166 mmol), 3b (30 mg, 0.199 mmol, 1.2 equiv), Pd(PPh₃)₄ (9 mg, 0.008 mmol, 5 mol%), K₃PO₄ (67 mg, 0.315 mmol, 2.0 equiv), and 1,4-dioxane (3 mL). After purification by column chromatography (silica gel; heptane–EtOAc, 4:1) 6a was isolated as a deep yellow solid (67 mg, 99%); mp 193–195 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.58–7.52 (m, 1 H, ArH), 7.45–7.39 (m, 2 H, ArH), 7.34 (d, J = 7.9 Hz, 1 H, ArH), 7.20–7.14 (m, 3 H, ArH), 7.13–7.03 (m, 3 H, ArH), 7.01 (dd, J = 8.7, 3.1 Hz, 1 H, ArH), 6.93 (dd, J = 9.0, 4.4 Hz, 1 H, ArH), 6.84–6.78 (m, 1 H, ArH), 3.92 (OCH₃), 3.74 (OCH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 192.72 (CO), 159.71 (OCH₃), 156.92 (d, ² J _F,_C = 238.5 Hz, CF), 153.52 (d, ⁴ J = 2.0 Hz, COCH₃), 144.11, 137.45 (C), 136.57 (CH), 135.42 (d, ⁴ J _F,_C = 3.1 Hz, CH), 134.72 (C), 134.16 (CH), 131.95, 131.61 (C), 131.25, 130.22, 130.22 (CH), 128.68 (d, J = 6.6 Hz, CH), 123.94, 123.24 (CH), 117.23 (d, ² J _F,_C = 23.7 Hz, CH), 115.33 (d, ² J _F,_C = 22.6 Hz, CH), 114,29 (CH), 111.67 (d, ³ J _F,_C = 8.2 Hz, CH), 56.33 (OCH₃), 55.52 (OCH₃). ¹⁹F NMR (282 MHz, CDCl₃): δ = –124.53 (CF). IR (ATR): ν = 3392 (w), 3068 (w), 3000 (w), 2957 (w), 2945 (w), 2914 (w), 2835 (w), 1704 (s), 1483 (s), 1469 (s), 1175 (s), 1026 (s), 940 (s), 764 (s) cm^–1. MS (EI, 70eV): m/z = 410 (35) [M⁺], 379 (100), 294 (6), 190 (8), 153 (5). HRMS (EI): m/z calcd for C₂₇H₁₉F₁O₃ [M⁺]: 410.13127; found: 410.13077.
• 22 Handy ST, Zhang Y. Chem. Commun. 2006; 299