Compound (S,M)-1

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

(S,M)-1 was synthesised in analogy to procedures developed by Schlosser, Leroux and Colobert (Leroux, F. & Schlosser, M. The “aryne” route to biaryls featuring uncommon substitution patterns. Angew. Chem. Int. Ed. 22, 4272–4274 (2002); Leroux, F. R., Bonnafoux, L., Heiss, C., Colobert, F. & Lanfranchi, D. A. A practical transition metal-free aryl-aryl coupling method: arynes as key intermediates. Adv. Synth. Catal. 349, 2705–2713 (2007); Leroux, F. R., Berthelot, A., Bonnafoux, L., Panossian, A. & Colobert, F. Transition-metal-free atrop-selective synthesis of biaryl compounds based on arynes. Chem. Eur. J. 18, 14232–14226 (2012)).

1-bromo-3-fluoro-2-iodobenzene, 5: to a solution of diisopropylamine (3.36 mL, 24.0 mmol) in tetrahydrofuran (50 mL) under nitrogen at –78 °C was added n-butyllithium (1.6 M in hexanes, 15 mL, 24.0 mmol) via syringe. After stirring at this temperature for 15 minutes 1-bromo-3-fluorobenzene (2.55 mL, 22.9 mmol) was added via syringe. The reaction mixture was then stirred at this temperature for two hours, after which it was treated with a solution of iodine (6.13 g, 24.2 mmol) in tetrahydrofuran (20 mL). The reaction mixture was then allowed to slowly warm to room temperature, at which point it was treated with a 10% aqueous solution of sodium thiosulfate (25 mL). The organic and aqueous phases were then separated and the aqueous phase was extracted into diethyl ether (20 mL, three times). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by distillation using Kugelrohr apparatus to provide the title compound 1-bromo-3-fluoro-2-iodobenzene 5 (6.49 g, 21.6 mmol, 94%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ: 7.44 (d, J = 8.2 Hz, 1H), 7.21 (ddd, J = 5.8, 8.2, 8.2 Hz, 1H), 6.99 (app. t, J = 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.7 (d, J_C–F = 249.1 Hz), 131.0 (d, J_C–F = 1.5 Hz), 130.8 (d, J_C–F = 8.8 Hz), 128.5 (d, J_C–F = 3.3 Hz), 114.0 (d, J_C–F = 24.9 Hz), 90.7 (d, J_C–F = 27.5 Hz, C₇); ¹⁹F NMR (376 MHz, CDCl₃) δ: −82.71 ppm (t, J = 6.6 Hz).

2,2'-dibromo-6-fluoro-1,1'-biphenyl, 6: to a solution of 1-bromo-3-fluoro-2-iodobenzene 5 (3.01 g, 10.0 mmol) in tetrahydrofuran (30 mL) under nitrogen at –78 °C was added n-butyllithium (1.6 M in hexanes, 12.5 mL, 20 mmol) via syringe. The reaction mixture was then allowed to stir at this temperature for 45 minutes, after which 1,2-dibromobenzene (1.30 mL, 10 mmol) was added via syringe. The reaction was stirred for a further 2 hours at –78 °C after which it was slowly warmed to room temperature and quenched by the cautious addition of water (30 mL). The organic and aqueous phases were separated and the aqueous phases was extracted into diethyl ether (20 mL, two times). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by flash column chromatography (silica, pentane, isocratic 100%) to provide the title compound 2,2'-dibromo-6-fluoro-1,1'-biphenyl 6 (2.75 g) as a mixture with two other minor components (see Supplementary Section 12) as a white solid. All attempts to further purify this mixture by flash column chromatography or crystallisation were unsuccessful. It was thus decided that this mixture would be carried through into the subsequent steps. R_f (pentane, 100%): 0.63; m.p. 68.9 – 70.1 °C; major signals consistent with literature (Leroux, F. R., Bonnafoux, L., Heiss, C., Colobert, F. & Lanfranchi, D. A. A practical transition metal-free aryl-aryl coupling method: arynes as key intermediates. Adv. Synth. Catal. 349, 2705–2713 (2007)); ¹H NMR (400 MHz, CDCl₃, signals in square brackets [ ] correspond to unidentified impurities, see also Supplementary Section 12 for spectra) δ: [7.97 (d, J = 7.9 Hz)], 7.71 (d, J = 8.2 Hz, 1H), [7.68 (d, J = 8.3 Hz)], 7.49 (d, J = 8.1 Hz, 1H), [7.46 (app s)], 7.42 (t, J = 7.6 Hz, 1H), [7.37 (app d, J = 7.4 Hz)], 7.31 (td, J = 1.8, 8.1 Hz, 1H), 7.26 (t, J = 7.6 Hz, 2H), 7.14 (t, J = 8.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 160.1 (d, J = 250.4 Hz), [142.2], [140.6], [139.2], 136.2, 132.8, [132.7], 131.5 (d, J = 0.9 Hz), [131.1], 130.6, 130.5, [130.4], 130.2, [130.1], [129.5], [128.42], 128.37 (d, J = 3.6 Hz), [128.3], 127.5, [127.3], 124.9 (d, J = 3.2 Hz), 124.2, [123.7], [115.0], 114.82 (d, J = 27.7 Hz), [114.81]; ¹⁹F NMR (376 MHz, CDCl₃) δ: [–108.52 ppm (dd, J = 6.1, 8.7 Hz)], –108.61 ppm (dd, J = 5.8, 8.6 Hz).

(S,M)-1: a 250 mL round bottom flask with stirring bar was charged with 2,2'-dibromo-6-fluoro-1,1'-biphenyl 6 (2.52 g, 7.62 mmol) (2,2'-dibromo-6-fluoro-1,1'-biphenyl 6 contains two unidentified impurities, which could not be removed by flash column chromatography or crystallization, see Supplementary Section 12 for spectra) and evacuated and back-filled with nitrogen (three times). Tetrahydrofuran (30 mL) was added via syringe and the solution was cooled to –78 °C. n-Butyllithium (1.6 M in hexanes, 4.73 mL, 7.58 mmol) was then added via syringe and the reaction mixture was allowed to stir at this temperature for 30 minutes. After this time the solution was cannulated into a solution of (–)-menthyl-(S)-p-toluenesulfinate (2.38 g, 8.07 mmol) in toluene (55 mL) at –78 °C (a further 15 mL of tetrahydrofuran was used to ensure efficient transfer). The reaction mixture was then allowed to stir for two hours at –78 °C, after which the reaction mixture was warmed to room temperature, followed by the cautious dropwise addition of water (30 mL). The organic and aqueous phases were then separated and the aqueous phase was extracted into ethyl acetate (20 mL, two times). The combined organic phases were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by flash column chromatography (silica, ethyl acetate in pentane, gradient 10 – 30%) to provide a mixture of (S,M)1 and (S,P)-1 (approximately 2.55 g, some residual dichloromethane and heptane visible in ¹H NMR spectrum) as a colourless oil ((S,M)-1 : (S,P)-1, 1.00 : 1.04 as determined by ¹⁹F NMR). Some other minor signals not corresponding to (S,M)-1 or (S,P)-1 are clearly evident in both the ¹H and ¹⁹F NMR spectra, including signals corresponding to (S)-4 – Supplementary Section 9. HPLC analysis of this mixture suggests that (S,P)-1 is formed with 86% ee and accurate determination of the ee of (S,M)-1 at this point is inhibited by overlap of signals (see Supplementary Section 12).

Some of this mixture (2.185 g) was then subjected to vapour diffusion: heptane into ethyl acetate at room temperature. After two days large colourless crystals formed. These crystals were washed with ethyl acetate (three times), dissolved in a dichloromethane : heptane solvent mixture and concentrated under reduced pressure to provide the title compound (S,M)-1 (0.460 g, 1.18 mmol, (S,M)-1 : (S,P)-1, > 50 : 1.0 by ¹⁹F NMR; > 98% ee for (S,M)-1, where there is no evidence of (R,P)-1 but the impurity discussed below is evident as a shoulder on the peak corresponding to (S,M)-1 (HPLC traces are provided in Supplementary Section 12) as a white solid. The mother liquor and ethyl acetate washings could be re-submitted to vapour diffusion conditions to provide further batches of (S,M)-1.

It should be noted that (S,M)-1 was synthesised a number of times according to the procedure described above. Different batches gave varying ratios of (S,M)-1 : (S,P)-1 (30.0 : 1.0 to > 200 : 1.0). Varying quantities of a minor unidentified impurity were also always evident by 1H NMR, where this impurity is also evident in the HPLC trace and appears as a shoulder on the signal corresponding to (S,M)-1. (S,M)-1 was always formed in > 98% ee following crystallisation, although the minor unidentified impurity prevents accurate determination of the ee. To account for these observations the exact starting ¹H and ¹⁹F NMR spectra and HPLC traces are provided for all the procedures described in Supplementary Sections 4, 6, 7 and 8.

R_f (ethyl acetate in pentane, 30%): 0.61; m.p. 134.3 – 136.6 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, J = 8.3 Hz, 1H, H₃), 7.74 (d, J = 8.0 Hz, 1H, H₄), 7.65 (ddd, J = 8.1, 8.1, 5.2 Hz, 1H, H₂), 7.32-7.24 (m, 2H, H₅ & H₁), 7.17 (t, J = 7.6 Hz, 1H, H₆), 7.09 (d, J = 8.3 Hz, 2H, H₈), 7.04 (d, J = 8.3 Hz, 2H, H₉), 6.59 (d, J = 7.7 Hz, 1H, H₇), 2.33 (s, 3H, H₁₀); ¹³C NMR (100 MHz, CDCl₃) δ: 159.2 (d, ¹J_C–F = 250.3 Hz, C₁₅), 146.8 (d, ³J_C–F = 1.3 Hz, C₁₃), 142.2 (C₁₁), 141.5 (C₁₂), 133.2 (C₄), 132.7 (d, 4J_C–F = 1.2 Hz, C₇), 131.9 (C₁₆), 130.7 (d, ³J_C–F = 8.1 Hz, C₂), 130.6 (C₅), 129.8 (C₈), 127.2 (C₆), 126.3 (C₉), 126.2 (d, ²J_C–F = 16.8 Hz, C₁₄), 124.4 (C₁₇), 119.5 (d, 4J_C–F = 3.6 Hz, C₃), 118.2 (d, ²J_C–F = 22.6 Hz, C1), 21.6 (C₁₀); [α]²⁰_D = –217.6 (c = 0.60, CHC_l3); HRMS (ESI): calcd. for C₁₉H₁₅BrFOS 389.00055, found 388.99979; HPLC analysis: OZ-H column, 40 °C, 0.5 mL min–1, heptane/isopropanol = 80/20, λ = 215 nm, t₁= 20.2 min, t₂ = 26.7 min, t₃ = 34.4 min, t4 = 42.2 min.

A single crystal could be grown by vapour diffusion: heptane into ethyl acetate at room temperature. A single crystal of compound (S,M)-1, was mounted on top of a cryoloop and transferred into the cold nitrogen stream (100 K) of a Bruker-AXS D8 Venture diffractometer. Data collection and reduction was done using the Bruker software suite APEX2 (Bruker, (2012). APEX2 (v2012.4-3), SAINT (Version 8.18C) and SADABS (Version 2012/1). Bruker AXS Inc., Madison, Wisconsin, USA). The final unit cell was obtained from the xyz centroids of 9998 reflections after integration. A multiscan absorption correction was applied, based on the intensities of symmetry-related reflections measured at different angular settings (SADABS) (Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122). The structures were solved by direct methods using SHELXS, and refinement of the structure was performed using SHELXL. The hydrogen atoms were generated by geometrical considerations, constrained to idealised geometries and allowed to ride on their carrier atoms with an isotropic displacement parameter related to the equivalent displacement parameter of their carrier atoms. The absolute configuration that was chosen was suggested based on the anomalous scattering; refinement of the inverted structure resulted in significantly higher R-values. Final refinement gave a Flack x-parameter of 0.015(2). While this Flack x value is slightly too high (7.5 x s.u.) (resulting in a B-level alert when using the online IUCr CheckCIF routine), its small absolute value together with a comparison to the inverted structure (which refined to Flack x = 0.990(2) indicates the model to be correct. An additional B-level alert is generated that is due to a short intermolecular O…Br contact of 3.04 Å: this short contact is likely due to weak charge-transfer bonding in the solid state between O and Br atoms of neighboring molecules. Crystal data and details on data collection and refinement are presented in Supplementary Table 1. The data have been deposited in the Cambridge Crystallographic Data Centre, CCDC deposition number: 1473303.