To the
5 (0.330 g, 1.166 mmol) in 5 mL DCE was added MgSO
4 (0.280 g, 2.332 mmol) and slowly 1-(4-chloro-2-fluorobezyl)piperidin-4-one (
12, 0.420 g, 1.749 mmol) dissolved in 3 mL DCE and stirred for 60 min at RT. Following this time, sodium triacetoxyborohydride (0.500 g, 1.749 mmol) was added in 4 portions, and the slurry was stirred for 60 h. The reaction was quenched with NaHCO
3 solution (1.2 g in 70 mL water) and extracted with DCM (3 × 40 mL). Combined organic layers were dried over anhydrous Na
2SO
4, and the crude was purified using column chromatography. 0–5% MeOH in DCM was used to elute
13 as a yellow gummy solid. Yield: 0.310 g, 0.610 mmol, 53%.
1H NMR (500 MHz, CDCl
3) δ 8.72 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.33 (td, J = 8.1, 2.8 Hz, 1H), 7.13–7.09 (m, 1H), 7.06 (dt, J = 9.6, 2.2 Hz, 1H), 3.89 (s, 3H), 3.87–3.78 (m, 2H), 3.69 (tt, J = 9.2, 4.4 Hz, 1H), 3.54 (dd, J = 4.3, 1.5 Hz, 4H), 3.30 (ddd, J = 12.4, 9.2, 2.8 Hz, 1H), 3.17 (dd, J = 12.5, 8.1 Hz, 1H), 2.92 (dddt, J = 25.1, 11.4, 5.0, 2.7 Hz, 3H), 2.81–2.66 (m, 4H), 2.63 (ddd, J = 11.7, 9.2, 3.0 Hz, 2H), 2.19 (ddd, J = 12.5, 10.0, 2.9 Hz, 2H), 2.09 (td, J = 11.5, 2.6 Hz, 1H), 2.05–1.97 (m, 2H), 1.93–1.84 (m, 1H), 1.68–1.45 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).
13C NMR (126 MHz, CDCl
3) δ 165.23, 162.03, 160.05, 159.84, 147.77, 139.82, 133.38 (d, J = 10.8 Hz), 132.13 (dd, J = 8.8, 5.5 Hz), 124.25 (t, J = 3.1 Hz), 123.79 (d, J = 11.7 Hz), 119.03 (d, J = 63.5 Hz), 115.96 (d, J = 26.0 Hz), 57.24, 55.47, 54.58 (d, J = 10.0 Hz), 53.31, 52.87, 52.06, 51.84, 50.70, 48.83, 44.46, 34.46, 30.59, 24.83, 20.97 (d, J = 14.9 Hz), 14.18. HR-ESI–MS [M + H]
+ C
25H
31Cl
2FN
4O
2, calcd 509.18863, found 509.18700. (Additional file
1: Fig. S4(g)).