Compound 26

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Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

2-Methoxy-6-phenylnaphthalene, 130: by analogy to a modified literature procedure (Lee, C.-Y. & Cheon, C.-H. Diastereomeric Resolution of rac-1,1^l–Bi-2-naphthol Boronic Acid with a Chiral Boron Ligand and its Application to Simultaneous Synthesis of (R)- and (S)-3,3^l-Disubstituted 1,1^l–Bi-2-naphthol Derivatives. The Journal of Organic Chemistry 78, 7086‑7092 (2013)), degassed 2 M aqueous Na₂CO₃ (42 mL, 83.2 mmol) was added to a suspension of 6-bromo-2-methoxynaphthalene (3.80 g, 16.0 mmol), phenylboronic acid (3.90 g, 32.0 mmol) and Pd(PPh₃)₄ (925 mg, 0.8 mmol) in degassed 1,2-dimethoxyethane (160 mL). The reaction mixture was then stirred at reflux for 18 hours. After cooling to room temperature the reaction was quenched with saturated aqueous ammonium chloride and the majority of 1,2‑dimethoxyethane was removed under reduced pressure. Ethyl acetate was added and the aqueous layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification via column chromatography eluting with 1:3 dichloromethane/petrol 40-60 afforded the title compound 130 as a white solid (3.34 g, 89 %). The spectral data matched that previously reported in the literature (Liu, W., Cao, H. & Lei, A. Iron-Catalyzed Direct Arylation of Unactivated Arenes with Aryl Halides. Angewandte Chemie International Edition 49, 2004-2008 (2010)). ¹H NMR (400 MHz, CDCl₃) δ_H = 8.00 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.77-7.71 (m, 3H), 7.53-7.47 (m, 2H), 7.41-7.36 (m, 1H), 7.23-7.17 (m, 2H), 3.96 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C = 157.9, 141.3, 136.5, 133.9, 129.8, 129.3, 128.9, 127.4, 127.3, 127.2, 126.2, 125.7, 119.3, 105.7, 55.5; LRMS (ESI⁺): calculated for C₃₄H₂₉O₂⁺ = 469, mass found = 469.

1-Bromo-2-methoxy-6-phenylnaphthalene, 131: by analogy to a modified literature procedure (Carreno, M. C., Garcia Ruano, J. L., Sanz, G., Toledo, M. A. & Urbano, A. N-Bromosuccinimide in Acetonitrile: A Mild and Regiospecific Nuclear Brominating Reagent for Methoxybenzenes and Naphthalenes. The Journal of Organic Chemistry 60, 5328-5331 (1995)), a suspension of 130 (3.29 g, 14 mmol) in acetonitrile (70 mL) was stirred at reflux for 10 minutes. N-bromosuccinimide (2.74 g, 15.4 mmol) was added and the mixture was stirred at reflux for 15 minutes. After cooling to room temperature the mixture was filtered and the precipitate washed with acetonitrile. After drying the precipitate under reduced pressure for 4 hours (c.a. 0.1 mbar) the title compound 131 was afforded as a white solid (3.92 g, 89 %). The spectral data matched that previously reported in the literature (Marchais-Oberwinkler, S. et al. New Drug-Like Hydroxyphenylnaphthol Steroidomimetics As Potent and Selective 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Estrogen-Dependent Diseases. Journal of Medicinal Chemistry 54, 534-547 (2011)). ¹H NMR (400 MHz, CDCl₃) δ_H = 8.29 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.84 (dd, J = 9.0, 2.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.53-7.46 (m, 2H), 7.42-7.36 (m, 1H), 7.30 (d, J = 9.0 Hz, 1H), 4.05 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C = 153.9, 140.6, 137.2, 132.5, 130.2, 129.4, 129.0, 127.5, 127.5, 127.4, 126.9, 125.9, 114.1, 108.7, 57.2; HRMS (CI⁺): calculated for C₁₇H₁₄BrO⁺ = 313.0223, mass found = 313.0223.

2'-Methoxy-6'-phenyl-3,4-dihydro-1,1'-binaphthalene, 132: magnesium turnings (365 mg, 15.0 mmol) were stirred vigorously under vacuum (c.a. 0.1 mbar) at 150 °C for 1 hour. After cooling to room temperature THF (5 mL) followed by a solution of 131 (3.13 g, 10.0 mmol) in THF (20 mL) were added. The reaction mixture was heated to 60 °C. The reaction was then initiated by addition of 1,2-dibromoethane (0.1 mL) and subsequently stirred at reflux for 3 hours. The resulting Grignard reagent was then used immediately according to general procedure A, as outlined in the synthesis of 1, with 1-tetralone (1.6 mL, 12 mmol), anhydrous cerium chloride (5.92 g, 24.0 mmol), THF (75 mL) and 3M HCl (75 mL). Purification via column chromatography eluting with a gradient from 1:4 dichloromethane/petrol 40-60 to 1:2 dichloromethane/petrol 40-60 afforded the title compound 132 as an off white solid (2.62 g, 72 %). Melting point: 156-157 °C (dichloromethane/petrol 40-60); ¹H NMR (400 MHz, CDCl₃) δ_H = 8.04 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.41 (d, J = 9.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.28-7.23 (m, 1H), 7.14 (td, J = 7.4, 1.3 Hz, 1H), 6.98 (td, J = 7.6, 1.4 Hz, 1H), 6.56 (dd, J = 7.6, 1.3 Hz, 1H), 6.09 (t, J = 4.5 Hz, 1H), 3.87 (s, 3H), 3.07 (t, J = 8.1 Hz, 2H), 2.62 (m 2H); ¹³C NMR (101 MHz, CDCl₃) δ_C = 154.6, 141.3, 136.4, 135.9, 135.6, 133.7, 133.2, 130.1, 129.5, 129.4, 128.9, 127.6, 127.3, 127.2, 127.0, 126.6, 126.1, 126.1, 125.9, 124.7, 123.6, 114.5, 57.1, 28.3, 23.8; FTIR (neat) λ/cm^-1 = 3060, 3025, 2934, 2883, 2835, 1623, 1593, 1492, 1461, 1427, 1255, 1176, 1089; HRMS (CI⁺): calculated for C₂₇H₂₃O⁺ = 363.1743, mass found = 363.1743.

2'-Methoxy-6'-phenyl-3,4-dihydro-[1,1'-binaphthalen]-2(1H)-one, 133: according to general procedure B, as outlined in the synthesis of 1, with 132 (2.52 g, 6.95 mmol), dichloromethane (70 mL), sodium bicarbonate (1.46 g, 17.4 mmol), meta-chloroperbenzoic acid (75 % w/w, 3.20 g, 13.9 mmol); then 1:1 diethyl ether/dichloromethane (140 mL), boron trifluoride diethyl etherate (1.37 mL, 11.1 mmol). Purification via column chromatography eluting with a gradient from 10:89:1 ethyl acetate/petrol 40‑60/triethylamine to 20:79:1 ethyl acetate/petrol 40-60/triethylamine followed by recrystallization from hexane/ethyl acetate afforded the title compound 133 as a white solid (1.37 g, 52 %). Melting point: 168-169 °C (ethyl acetate/hexane); ¹H NMR (400 MHz, CDCl₃) δ_H = 8.06 (d, J = 1.8 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.73-7.69 (m, 2H), 7.67 (dd, J = 8.9, 1.9 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 8.4, 6.9 Hz, 2H), 7.41-7.34 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.19 (tt, J = 7.5, 1.1 Hz, 1H), 7.01 (td, J = 7.7, 1.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 5.59 (s, 1H), 3.79 (s, 3H), 3.39-3.24 (m, 2H), 2.98 (dt, J = 16.3, 5.4 Hz, 1H), 2.85 (ddd, J = 16.3, 10.1, 6.1 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ_C = 210.5, 155.0, 141.0, 137.6, 136.3, 136.2, 132.6, 130.1, 130.0, 128.9, 127.6, 127.4, 127.3, 127.3, 126.9, 126.7, 126.6, 126.5, 124.3, 121.2, 114.3, 56.6, 50.5, 38.8, 28.7; FTIR (neat) λ/cm^-1 = 3063, 3026, 2904, 2841, 1714, 1625, 1596, 1494, 1456, 1410, 1255, 1084; HRMS (ESI⁺): calculated for C₂₇H₂₃O₂⁺ = 379.1693, mass found = 379.1687.

Asymmetric synthesis of the title compound (0.200 mmol scale): according to general procedure C, as outlined in the synthesis of 9, with 133 (75.7 mg, 0.200 mmol), N‑(2,3,4‑trifluoro-benzyl) quinidinium bromide 6 (11 mg, 0.020 mmol), K₃PO₄ (425 mg, 2.00 mmol), dichloromethane (0.40 mL), benzene (0.60 mL), benzyl iodide (131 mg, 0.60 mmol) in benzene (1.0 mL); then dichloromethane (2.0 mL), DDQ (136 mg, 0.60 mmol). Purification via column chromatography eluting with a gradient from 0:1 ethyl acetate/petrol 40-60 to 1:19 ethyl acetate/petrol 40-60 afforded the title compound 26 as a white solid (92.8 mg, 99 %, 98:2 e.r.).

Asymmetric (1.00 gram scale): a Schlenk tube was sequentially charged with N-(2,3,4-trifluorobenzyl)quinidinium bromide 6 (145 mg, 0.264 mmol), 133 (1.00 g, 2.64 mmol) and K₃PO₄ (5.60 g, 26.4 mmol). The atmosphere was evacuated and backfilled with argon three times. Dichloromethane (2.5 mL) and benzene (10 mL) were added. The suspension was cooled to 0 °C and stirred for 5 minutes. A solution of benzyl iodide in dichloromethane (2.5mL) and benzene (10 mL) was prepared at 0 °C and subsequently added. The resulting suspension was stirred rapidly at a rate of 1000-1400 rpm in the dark at 0 °C for 48 hours. A further catalytic amount of N-(2,3,4-trifluorobenzyl)quinidinium bromide 6 (145 mg, 0.264 mmol) was added and the reaction mixture stirred rapidly at a rate of 1000-1400 rpm in the dark at 0 °C for 48 hours. The crude reaction mixture was then filtered through a plug of celite which was subsequently washed with dichloromethane. The filtrate was concentrated under reduced pressure and dissolved in dichloromethane (25 mL) and DDQ (1.80 g, 7.92 mmol) was subsequently added. After stirring at room temperature for 2 hours, saturated aqueous sodium thiosulfate and ethyl acetate were added. The aqueous later was separated and the organic layer was washed twice with saturated aqueous sodium bicarbonate. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue via column chromatography eluting with a gradient from 1:2 dichloromethane/petrol 40-60 to 1:1 dichloromethane/petrol 40-60 afforded the title compound 26 as a white solid (1.16 g, 96 %, 98:2 e.r.). The e.r. could be improved via the following procedure: a suspension of 26 (1.16 g, 2.49 mmol) in hexane (100 mL) was stirred rapidly at reflux for 5 minutes. Benzene was added dropwise until complete dissolution of the precipitate was observed. The stirrer bar was removed and the solution was allowed to cool to room temperature. The racemic precipitate was isolated via filtration and the mother liquor was concentrated under reduced pressure to afford the title compound 26 (1.14 g, 92 %, 99:1 e.r.).

Racemic synthesis of the title compound: according to general procedure D, as outlined in the synthesis of 11, with 133 (66.5 mg, 0.200 mmol), tetrabutylammonium bromide (6.4 mg, 0.020 mmol), K₃PO₄ (425 mg, 7.5 mmol), dichloromethane (2.0 mL), benzyl bromide (72 µL, 2.25 mmol); then dichloromethane (2.0 mL), DDQ (136 mg, 0.60 mmol). Purification via column chromatography eluting with a gradient from 0:1 ethyl acetate/petrol 40-60 to 1:19 ethyl acetate/petrol 40-60 afforded the title compound 26 as a white solid (86.1 mg, 92 %). Melting point: 178-179 °C (ethyl acetate/petrol 40-60); 1H NMR (400 MHz, CDCl₃) δ_H = 8.09 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.72-7.66 (m, 2H), 7.52-7.41 (m, 5H), 7.38-7.31 (m, 2H), 7.26 (dd, J = 8.5, 1.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.18-7.12 (m, 3H), 7.06-6.99 (m, 2H), 5.11 (d, J 12.7 Hz, 1H), 5.07 (d, J 12.7 Hz, 1H), 3.78 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C = 155.3, 154.2, 141.4, 137.7, 136.3, 134.2, 133.5, 129.9, 129.6, 129.5, 129.4, 128.9, 128.3, 128.1, 127.5, 127.3, 127.1, 126.9, 126.5, 126.2, 126.1, 125.9, 125.5, 123.9, 120.8, 119.5, 116.3, 114.4, 71.4, 56.8; FTIR (neat) λ/cm^-1 = 3060, 6030, 2934, 2838, 1622, 1592, 1478, 1454, 1330, 1252, 1176, 1093, 1019; HRMS (EI⁺): calculated for C₃₄H₂₆O₂⁺ = 466.1927, mass found = 466.1922; [α]_D²⁵ = –44.3 (c = 1.00, CHCl₃, at 99:1 e.r.).