Compound 60

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Compound data: 1H NMR

Compound data: 1H{19F} NMR

Compound data: 13C NMR

Compound data: 13C{19F} NMR

Compound data: 19F NMR

Compound data: 19F{1H} NMR

Compound data: 1H{31P} NMR

Compound data: 1H{19F,31P} NMR

Compound data: 19F{1H,31P} NMR

Compound data: 19F{31P} NMR

Compound data: 31P NMR

Compound data: 31P{1H} NMR

Compound data: Crystallographic data

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

Following a modified literature procedure (Huang, H., Liu, X., Zhou, L., Chang, M. & Zhang, X. Direct asymmetric reductive amination for the synthesis of chiral β‐arylamines. Angew. Chem. Int. Ed. 55, 5309–5312 (2016)), a 25 mL Schlenk flask was charged with (R)-(+)-1,1’-bi(2-naphthol) (78.7 mg, 0.275 mmol, 1.1 equiv.), phosphorus trichloride (0.24 mL, 2.75 mmol, 11 equiv.), dimethylformamide (1.5 μL, 0.02 mmol, 0.08 equiv.) under argon. The reaction mixture was heated to 50 °C for 15 min and all volatiles were removed under reduced pressure. CH₂Cl₂ (3×2 mL) was used to remove the traces of phosphorus trichloride. The resulting oil was kept under vacuum for 1 h and was used directly in next step. In a separate 25 mL Schlenk flask, a mixture of cis-3,5-difluoropiperidine hydrochloride (4) (39.4 mg, 0.25 mmol, 1.0 equiv.), triethylamine (0.1 mL, 0.75 mmol, 3.0 equiv.) and THF (1 mL, 0.25M) was stirred at room temperature for 1 h. Then, the above made chlorophosphite was dissolved in THF (3×2 mL) and was transferred to the reaction flask. The reaction mixture was warmed to 60 °C and stirring was continued for 18 h. The resulting precipitate was removed by filtration and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography (0-10% EtOAc in pentane) to yield the desired ligand as a white solid (70.5 mg, 0.162 mmol, 65%). Single crystals of the title compound suitable for X-ray diffraction analysis were obtained by crystallization at room temperature from (1:1) a mixture of n-hexane and ethyl acetate (slow evaporation of solvents). ¹H NMR (600 MHz, C₆D₆, 299 K) δ 7.66 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.15 – 7.11 (m, 2H), 6.95 – 6.91 (m, 2H), 3.89 (dm, J = 47.4 Hz, 1H), 3.79 (dm, J = 47.4 Hz, 1H), 3.16 – 3.02 (m, 2H), 2.69 (dq, J = 13.3, 6.2 Hz, 1H), 2.53 (dq, J = 13.1, 6.5 Hz, 1H), 1.85 – 1.73 (m, 1H), 1.52 (h, J = 11.6 Hz, 1H); ¹H{¹⁹F} NMR (600 MHz, C₆D₆, 299 K) δ 7.66 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.15 – 7.11 (m, 2H), 6.93 (tdd, J = 8.2, 4.6, 2.6 Hz, 2H), 3.87 (tt, J = 7.8, 4.1 Hz, 1H), 3.81 (tt, J = 8.6, 4.1 Hz, 1H), 3.11 (dt, J = 12.8, 4.6 Hz, 1H), 3.07 (ddd, J = 13.4, 7.9, 4.3 Hz, 1H), 2.69 (ddd, J = 13.4, 7.8, 5.5 Hz, 1H), 2.53 (ddd, J = 12.8, 7.8, 5.5 Hz, 1H), 1.78 (dt, J = 12.7, 4.1 Hz, 1H), 1.52 (dt, J = 12.7, 8.6 Hz, 1H); ¹H{³¹P} NMR (600 MHz, C₆D₆, 299 K) δ 7.66 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.13 (t, J = 7.4 Hz, 2H), 6.95 – 6.91 (m, 2H), 3.89 (d, J = 47.4 Hz, 1H), 3.80 (d, J = 47.4 Hz, 1H), 3.09 (dt, J = 28.5, 12.7 Hz, 2H), 2.69 (dt, J = 13.6, 6.7 Hz, 1H), 2.53 (dt, J = 13.6, 7.1 Hz, 1H), 1.78 (td, J = 16.5, 12.4 Hz, 1H), 1.59 – 1.48 (m, 1H); ¹H{¹⁹F, ³¹P} NMR (600 MHz, C₆D₆, 299 K) δ 7.66 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.13 (t, J = 7.4 Hz, 2H), 6.95 – 6.91 (m, 2H), 3.87 (tt, J = 7.8, 4.1 Hz, 1H), 3.81 (tt, J = 8.6, 4.1 Hz, 1H), 3.11 (dd, J = 12.8, 4.1 Hz, 1H), 3.07 (dd, J = 13.4, 4.3 Hz, 1H), 2.69 (dd, J = 13.4, 7.8 Hz, 1H), 2.53 (dd, J = 12.8, 7.8 Hz, 1H), 1.78 (dt, J = 12.7, 4.1 Hz, 1H), 1.52 (dt, J = 12.7, 8.6 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃, 299 K) δ 149.04 (×2), 149.00, 132.87 (d, J = 1.6 Hz), 132.70 (d, J = 1.1 Hz), 131.63 (d, J = 0.6 Hz), 131.05, 130.61, 130.40, 128.52 (d, J = 1.8 Hz), 127.09, 127.07, 126.47, 126.37, 125.14, 125.05, 123.96 (d, J = 5.0 Hz), 122.95 (d, J = 2.3 Hz), 121.89 (d, J = 1.7 Hz), 121.60, 84,95 (ddd, J = 180.7, 8.2, 5.3 Hz), 84.70 (ddd, J = 181.4, 8.8, 3.5 Hz), 47.91 (t, J = 25.0 Hz), 47.48 (dd, J = 26.2, 14.8 Hz), 37.12 (t, J = 20.3 Hz); ¹³C{¹⁹F} NMR (151 MHz, CDCl₃, 299 K) δ 149.04 (×2), 149.00, 132.87 (d, J = 1.5 Hz), 132.70 (d, J = 1.1 Hz), 131.63, 131.05, 130.61, 130.40, 128.52 (d, J = 1.8 Hz), 127.09, 127.07, 126.47, 126.37, 125.14, 125.05, 123.96 (d, J = 5.0 Hz), 122.95 (d, J = 2.2 Hz), 121.89 (d, J = 1.7 Hz), 121.60, 84.95 (d, J = 5.4 Hz), 84.70 (d, J = 3.3 Hz), 47.91 (d, J = 24.9 Hz), 47.48 (d, J = 14.6 Hz), 37.12; ¹⁹F NMR (564 MHz, C₆D₆, 299 K) δ -180.67 – -180.91 (m), -181.68 – -181.94 (m); ¹⁹F{¹H} NMR (564 MHz, C₆D₆, 299 K) δ -180.80 (d, J = 6.2 Hz), -181.80 (d, J = 6.2 Hz); ¹⁹F{³¹P, ¹H} NMR (564 MHz, C₆D₆, 299 K) δ -180.80 (d, J = 6.2 Hz), -181.80 (d, J = 6.2 Hz); ¹⁹F{^{31P} NMR (564 MHz, C6D6, 299 K) δ -180.80 (dm, J = 47.4 Hz), -181.80 (dm, J = 47.4 Hz); 31P NMR (243 MHz, C6D6, 299 K) δ 144.8; 31P{1H} NMR (243 MHz, C6D6, 299 K) δ 144.8. ESI-MS: calculated [C25H20F2NO2P +Na]+: 458.1097, found: 458.1094. IR ν = 3055.3 (w), 2939.6 (w), 1735.9 (w), 1589.4 (w), 1504.5 (w), 1465.9 (w), 1327.1 (m), 1226.7 (m), 1195.9 (m), 1141.9 (m), 1072.5 (m), 1010.7 (m), 941.3 (s), 902.7 (m), 825.6 (s), 802.4 (m), 748.4 (s), 686.7 (m), 632.7 (m), 594.1 (m), 555.5 (s). M.p.: 154-156 °C. [α]D25 = -446.4 (0.011 M in CH3Cl). In order to prove whether the fluorine atoms are occupying axial or equatorial positions, we conducted a series of NMR studies that includes NOE and HF-HetNOE experiments. HF-HetNOE experiment showed unequivocally that the fluorine atoms are occupying equatorial positions}