Molecules 2020, 25, 2640
23 of 32
128.0, 124.9, 119.6, 117.3, 114.0, 90.8, 57.2, 57.1, 55.4, 47.1, 44.9, 41.8, 40.1, 35.3, 33.4, 25.5, 21.0; HRMS
(TOF MS ES+) calcd for C25H28NO4 [M + H]+ 406.2018, found 406.2014. An HCl salt was prepared by
dissolving 2d free base in hot i-PrOH (5.0 mL) followed by the addition of concentrated aqueous HCl
(0.10 mL, 3 equiv) and cooling to 5 ◦C. The crystals were filtered and air-dried to give 2d as its HCl salt.
Anal. Calcd for C25H27NO4
·
HCl
·
0.5H2O
·
0.5C3H8O (2d·HCl
·
0.5H2O 0.5C3H8O): C, 66.19; H, 6.83; N,
·
2.77; found: C, 66.17; H, 6.92; N, 2.91%. [α]2D0 −136.5 (c 0.68, MeOH, HCl·0.5H2O·0.5i-PrOH).
(7aR,12bS)-9-Hydroxy-3-(4-fluorophenethyl)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]-
isoquinolin-7(7aH)-one (2e): The general procedure with S10 (0.406 g, 1.5 mmol), 1-(2-bromoethyl)-4-
fluorobenzene (0.460 mL, 3.3 mmol), NaHCO3 (0.504 g, 6 mmol), and DMF (10 mL). Purification by
1
column chromatography afforded 2e free base (0.290 g, 50%) as a colorless oil. H-NMR (CD3OD):
δ
7.24 (dd, J = 8.2 Hz, 5.4 Hz, 2H), 6.99 (t, J = 8.8 Hz, 2H), 6.60 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 8.4 Hz,
1H), 4.77 (s, 1H), 3.30 (s, 1H), 2.97 (d, J = 18.4 Hz, 1H), 2.83–2.66 (m, 5H), 2.61 (dt, J = 12.8 Hz, 3.4 Hz,
1H), 2.52 (td, J = 14.2 Hz, 4.6 Hz, 1H), 2.37 (dd, J = 18.6 Hz, 5.8 Hz, 1H), 2.29 (dt, J = 14.0 Hz, 2.8 Hz,
1H), 2.22 (td, J = 12.0 Hz, 3.0 Hz, 1H), 2.12 (td, J = 12.0 Hz, 4.4 Hz, 1H), 1.88–1.82 (m, 1H), 1.69 (d,
J = 12.4 Hz, 1H), 1.15 (ddd, J = 27.2 Hz, 13.2 Hz, 2.4 Hz, 1H); 13C-NMR (CD3OD):
δ 210.3, 162.7, 160.2,
144.1, 139.2, 136.0(2), 130.0(2), 127.0, 124.9, 119.6, 117.3, 114.6, 114.4, 91.0, 57.2, 56.6, 47.2, 45.0, 41.5, 39.4,
34.7, 32.8, 25.4, 20.4; HRMS (TOF MS ES+) calcd for C24H25FNO3 (M + H+) 394.1818, found 394.1825.
An HCl salt was prepared by dissolving 2e free base in hot i-PrOH (5.0 mL) followed by the addition
of concentrated aq HCl (0.10 mL, 3 equiv) and cooling to 5 ◦C. The crystals were filtered and air-dried
to give 2e as its HCl salt. Anal. Calcd for C24H24FNO3
·
HCl
·
1.5H2O (2e·HCl
·
1.5H2O): C, 63.14; H, 6.03;
N, 2.98; found: C, 63.09; H, 6.18; N, 3.07%. [α]2D0 − 137.8 (c 0.65, MeOH, HCl·1.5H2O).
(7aR,12bS)-9-Hydroxy-3-(3-fluorophenethyl)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]-
isoquinolin-7(7aH)-one (2f): The general procedure with 10 (0.406 g, 1.5 mmol), 1-(2-bromoethyl)-3-
fluorobenzene (0.460 mL, 3.3 mmol), NaHCO3 (0.504 g, 6 mmol), and DMF (10 mL). Purification by
1
column chromatography afforded 2f free base (0.270 g, 46%) as colorless oil. H-NMR (CD3OD):
δ 7.27
(dd, J = 14.0 Hz, 8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 10.4 Hz, 1H), 6.90 (td, J = 8.6 Hz,
2.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 4.76 (s, 1H), 3.34–3.32 (m, 1H), 2.96 (d,
J = 18.4 Hz, 1H), 2.85–2.68 (m, 5H), 2.60 (dt, J = 12.6 Hz, 3.4 Hz, 1H), 2.52 (td, J = 14.0 Hz, 4.6 Hz, 1H),
2.36 (dd, J = 18.4 Hz, 5.6 Hz, 1H), 2.28 (dt, J = 13.8 Hz, 2.1 Hz, 1H), 2.21 (td, J = 12.4 Hz, 3.2 Hz, 1H),
2.11 (td, J = 12.2 Hz, 4.4 Hz, 1H), 1.87–1.81 (m, 1H), 1.67 (d, J = 12.4 Hz, 1H), 1.14 (ddd, J = 26.8 Hz,
13.4 Hz, 2.4 Hz, 1H); 13C-NMR (CD3OD):
δ 210.4, 164.1, 161.7, 144.1, 143.1, 143.0, 139.2, 129.7, 129.6,
127.0, 124.9, 124.3, 124.2, 119.7, 117.4, 115.1, 114.9, 112.5, 112.2, 91.0, 57.2, 56.1, 47.2, 44.9, 41.5, 39.4,
34.7, 33.3, 25.3, 20.4; HRMS (TOF MS ES+) calcd for C24H25FNO3 [M + H]+ 394.1818, found 394.1821.
An HCl salt was prepared by dissolving 2f free base in hot i-PrOH (5.0 mL) followed by the addition
of concentrated aqueous HCl (0.10 mL, 3 equiv) and cooling to 5 ◦C. The crystals were filtered and
air-dried to give 2f as its HCl salt. Anal. Calcd for C24H24FNO3
·
HCl
·
1.25H2O (2f·HCl
·
1.25H2O): C,
63.71; H, 6.13; N, 3.10; found: C, 63.71; H, 6.11; N, 3.11%. [α]2D0 −149.2 (c 0.48, MeOH, HCl·1.25H2O).
(7aR,12bS)-9-Hydroxy-3-(2-fluorophenethyl)-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]-
isoquinolin-7(7aH)-one (2g): The general procedure with S10 (0.406 g, 1.5 mmol), 1-(2-bromoethyl)-2-
fluorobenzene (0.460 mL, 3.3 mmol), NaHCO3 (0.504 g, 6 mmol), and DMF (10 mL). Purification by
1
column chromatography afforded 2g free base (0.260 g, 45%) as a colorless oil. H-NMR (CD3OD):
δ 7.31–7.27 (m, 1H), 7.24–7.19 (m, 1H), 7.11–7.01 (m, 2H), 6.61 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.0 Hz,
1H), 4.77 (s, 1H), 3.36 (dd, J = 5.2 Hz, 2.8 Hz, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.94–2.66 (m, 5H), 2.61
(dt, J = 12.8 Hz, 3.4 Hz, 1H), 2.40 (td, J = 14.0 Hz, 4.6 Hz, 1H), 2.38 (dd, J = 18.6 Hz, 5.8 Hz, 1H),
2.29 (dt, J = 14.0 Hz, 3.0 Hz, 1H), 2.23 (td, J = 12.4 Hz, 3.2 Hz, 1H), 2.12 (td, J = 12.2 Hz, 4.6 Hz, 1H),
1.89–1.82 (m, 1H), 1.70–1.67 (m, 1H), 1.15 (ddd, J = 27.2 Hz, 13.4 Hz, 2.4 Hz, 1H); 13C-NMR (CD3OD):
δ
210.4, 162.4, 160.0, 144.0, 139.2, 130.9, 130.8, 127.8, 127.7, 127.0, 126.8, 126.6, 124.9, 123.9(2), 119.6,
117.3, 114.7, 114.5, 91.0, 57.2, 55.0, 47.2, 45.0, 41.5, 39.4, 34.7, 26.9(2), 25.4, 20.4; HRMS (TOF MS ES+)
calcd for C24H25FNO3 [M + H]+ 394.1818, found 394.1822. An HCl salt was prepared by dissolving 2g
free base in hot i-PrOH (5.0 mL) followed by the addition of concentrated aq HCl (0.10 mL, 3 equiv)