´
´
L. Czibula, A. Nemes, F. Sebök, C. Szantay, Jr., M. Mak
FULL PAPER
of sodium hydroxide (5.5 g) in water (66 mL) was added whilst stir-
12.9 Hz, 1 H, 7-Hy), 5.81 (s, 2 H, ϪCHϪCHϪ), 7.07Ϫ8.04 (m, 19
ring. After 30 min, the organic layer was separated, and the aque- H, ArH) ppm. After suspending the salt in a mixture of water
ous layer was washed with dichloromethane (40 mL). The organic
layers were washed with brine (20 mL) and concentrated to give
solvent-free 5 (34.5 g, 97%) as a pale-yellow viscous oil. HRMS for
C19H20FNO: calcd. 297.1523; found 297.1525. LRMS: m/z (%) ϭ
297 (11), 266 (37), 206 (24), 120 (33), 91 (100).
(100 mL) and dichloromethane (100 mL), the pH of the mixture
was adjusted to 9 with aqueous ammonia (25%) solution. After
separation, the aqueous layer was extracted with dichloromethane
(30 mL). The combined organic layers were concentrated to give
(ϩ)-6 (22.6 g, 76%). M.p. 65Ϫ66 °C. [α]2D0 ϭ ϩ54.1 (c ϭ 1, chloro-
form). IR (KBr): ν˜ ϭ 3280, 2790, 1597, 1510, 1232, 1130, 1090,
831, 760, 733, 697, 549 cmϪ1. 1H NMR (CDCl3, δTMS ϭ 0.00 ppm):
δ ϭ 1.63 (m, 1 H, 5-He), 1.66 (m, 1 H, 3-H), 2.05 (td, J6a,6e ϭ 12.0,
(3R)-1-Benzyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,2,3,6-tetra-
hydropyridine [(؊)-5]: (Ϫ)--Dibenzoyltartaric acid monohydrate
(56.4 g, 0.15 mol) in acetone (180 mL) was added to a solution of
5 (44.7 g, 0.15 mol) in acetone (70 mL) at room temperature, and
the mixture was then stirred at room temperature for 5 h. The pre-
cipitated crystals were filtered at 10 °C, washed with acetone (2 ϫ
20 mL), and dried in air to give (Ϫ)-5 (as -dibenzoyltartaric acid
salt; 42 g, 85.6%). M.p. 126Ϫ128 °C. [α]2D0 ϭ Ϫ93.5 (c ϭ 2, meth-
anol). IR (KBr): ν˜ ϭ 1727, 1680, 1270, 1103, 1225, 1069, 1602,
812, 730, 714, 701 cmϪ1. 1H NMR ([D6]DMSO, δTMS ϭ 0.00 ppm):
J
6a,5a ϭ 12.0, J6a,5e ϭ 3.0 Hz, 1 H, 6-Ha), 2.42 (m, 1 H, 2-Ha), 2.45
(qd, J5a,6e ϭ 12.0, J5a,4a ϭ 12.0, J5a,5e ϭ 12.0, J5a,6e ϭ 4.5 Hz, 1 H,
5-Ha), 2.80 (dt, J4a,5a ϭ 12.0, J4a,5e ϭ 4.5, J4a,3e ϭ 4.5 Hz, 1 H, 4-
H), 3.01 (dm, J6e,6a ϭ 12.0 Hz, 1 H, 6-He), 3.14 (dt, J2e,2a ϭ 12.0,
J2e,3e ϭ 2.1, J2e,6e ϭ 2.1 Hz, 1 H, 2-He), 3.42 (d, J7x,7y ϭ 12.9 Hz,
1 H, 7-Hx), 3.47 (d, J7x,7y ϭ 12.9 Hz, 1 H, 7-Hy), 3.48 (dt, J8x,8y
11.1 Hz, J8x,3 ϭ 2.4, J8x,2a ϭ 2.4 Hz, 1 H, 8-Hx), 3.55 (dd, J8x,8y
ϭ
ϭ
11.1 Hz, J8y,3 ϭ 3.0 Hz, 1 H, 8-Hy), 6.91 (m, 2 H, 3ЈЈ-H ϩ 5ЈЈ-H),
7.13Ϫ7.28 (m, 7 H, ArH) ppm. HRMS for C19H22FNO: calcd.
299.1680; found 299.1686. LRMS: m/z (%) ϭ 299 (24), 268 (24),
208 (16), 176 (19), 120 (47), 91 (100). C19H22FNO (299.39): calcd.
C 76.28, H 7.41, N 4.68; found C 75.91, H 7.38, N 4.66.
δ ϭ 2.80Ϫ3.48 (m, 7 H, 2,6,8-H2 and 3-H), 3.90 (d, J8x,8y
ϭ
12.9 Hz, 1 H, 7-Hx), 3.96 (d, J7x,7y ϭ 12.9 Hz, 1 H, 7-Hy), 5.82 (s,
2 H, ϪCHϪCHϪ), 5.92 (t, 1 H, 5-H), 7.12Ϫ8.03 (m, 19 H, ArH)
ppm. C37H34FNO9 (655.68): calcd. C 67.82, H 5.23, N 2.14; found
C 67.45, H 5.23, N 2.12. The obtained salt was suspended in a
mixture of water (200 mL) and dichloromethane (200 mL), and the
solution was made basic by a solution of sodium hydroxide (4.5 g)
in water (20 mL) whilst stirring. After separation, the aqueous layer
was extracted with dichloromethane (50 mL). The combined or-
ganic phases were dried (MgSO4), and the filtrate was concentrated
under reduced pressure to yield the (Ϫ)-5 (18.5 g, 97%). M.p.
67Ϫ68.5 °C (diisopropyl ether). [α]2D0 ϭ Ϫ73.1 (c ϭ 1, chloroform).
(3R,4R)-1-Benzyl-4-(4-fluorophenyl)-3-{[(methylsulfonyl)oxy]-
methyl}piperidine (7): Triethylamine (5.8 g, 0.0574 mol) and meth-
anesulfonyl chloride (6.6 g, 0.0576 mol) were added to a solution
of (ϩ)-6 (14.9 g, 0.05 mol) in dichloromethane (75 mL). The mix-
ture was stirred at room temperature for 3 h, water (40 mL) was
added, and the pH of the solution was then adjusted to 8 by ad-
dition of sodium hydrogencarbonate (10%) solution. After separat-
IR (KBr): ν˜ ϭ 3270, 1651, 1602, 1509, 1234, 1162, 1043, 817, 739, ing the phases, the aqueous layer was extracted with dichlorometh-
699, 513 cmϪ1 1H NMR (CDCl3, δTMS ϭ 0.00 ppm): δ ϭ 2.67
ane (20 mL). The combined organic phases were washed with water
(dddd, J2x,2y ϭ 10.8, J2x,3 ϭ 3.9, J2x,6x ϭ 2.1, J2x,8x ϭ 2.1 Hz, 1 H, (20 mL), dried (MgSO4) and concentrated to afford solvent-free 7
2-Hx), 2.75 (m, 1 H, 3-H), 2.83 (dt, J6x,6y ϭ 17.1, J6x,5 ϭ 2.1, (18.3 g, 97%) as a pale-yellow viscous oil. IR (KBr): ν˜ ϭ 2930,
J6x,2x ϭ 2.1 Hz, 1 H, 6-Hx), 3.18 (dt, J2x,2y ϭ 10.8, J2y,3 ϭ 1.5 Hz, 1510, 1336, 1225, 1178, 1160, 945, 833, 743, 700 cmϪ1. H NMR
.
1
1 H, 2-Hy), 3.38 (dd, J6x,6y ϭ 17.1, J6y,5 ϭ 4.8 Hz, 1 H, 6-Hy), 3.59
(ddd, 1 H, J8x,8y ϭ 10.7, J8x,3 ϭ 3.0, J2x,8x ϭ 2.1 Hz, 8-Hx), 3.60
(d, J7x,7y ϭ 12.6 Hz, 1 H, 7-Hx), 3.66 (d, J7x,7y ϭ 12.6 Hz, 1 H, 7-
([D6]DMSO, δTMS ϭ 0.00 ppm): δ ϭ 1.63 (m, 1 H, 5-He),
1.91Ϫ2.13 (m, 2 H, 5-Ha and 6-Ha), 2.20 (m, 1 H, 2-He), 2.26 (m,
1 H, 3-H), 2.91Ϫ3.04 (m, 3 H, 2-Ha, 6-He, 4-H), 2.95 (s, 3 H,
Hy), 3.77 (dd, J8x,8y ϭ 10.7, J7y,3 ϭ 3.0 Hz, 1 H, 8-Hy), 6.02 (dd, SO2Me), 3.50 (d, J7x,7y ϭ 13.5 Hz, 1 H, 7-Hx), 3.54 (d, J7x,7y
ϭ
J6x,5 ϭ 2.1, J6y,5 ϭ 4.8 Hz, 1 H, 5-H), 7.00 (m, 2 H, 3ЈЈ-H ϩ 5ЈЈ-
H), 7.25Ϫ7.40 (m, 7 H, ArH) ppm.
13.5 Hz, 1 H, 7-Hy), 3.62 (dd, 1 H, J8x,8y ϭ 9.6 Hz; J8x,3 ϭ 3.3 Hz,
8-Hx), 4.55 (t, J8x,8y ϭ 9.6 Hz, J8y,3 ϭ 9.6 Hz, 1 H, 8-Hy), 7.15 (m,
2 H, 3ЈЈ-H ϩ 5ЈЈ-H), 7.22Ϫ7.36 (m, 7 H, ArH) ppm. HRMS for
C20H24FNO3S: calcd. 377.1455; found 377.1460. LRMS: m/z (%) ϭ
377 (31), 298 (15), 282 (23), 268 (29), 134 (25), 91 (100).
(3R,4R)-1-Benzyl-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine
[(؉)-6]: Compound (Ϫ)-5 (65.6 g,0.1 mol) was dissolved in a mix-
ture of water (120 mL), acetic acid (12 mL), and hydrochloric acid
(37%, 6 mL), and was hydrogenated at 45 °C in the presence of Pd/
C catalyst (10%,1.5 g). After completion of the reaction, the cata-
lyst was filtered off at room temperature. Dichloromethane (80 mL)
(3S,4R)-1-Benzyl-4-(4-fluorophenyl)-3-{[3,4-(methylenedioxy)-
phenoxy]methyl}piperidine Hydrochloride (9·HCl): Sesamol (3 g,
0.022 mol) and sodium hydroxide (3.6 g, 0.09 mol) in water
was added to the filtrate and the solution was adjusted to pH ϭ (5.5 mL) were added to a solution of 7 (7.54 g, 0.02 mol) in xylene
9 with sodium hydroxide (40%) solution. The organic phase was
separated, and the aqueous layer was extracted with dichlorometh-
(30 mL) and sec-butanol (15 mL), and the mixture was heated to
reflux for 10 h. The reaction mixture was chilled, and water
ane (20 mL). The combined organic layers were concentrated, the (30 mL) was added. After separation, the organic phase was
residue was dissolved in acetone (100 mL), and (Ϫ)--dibenzoyltar-
taric acid monohydrate (36.9 g, 0.098 mol) in acetone (150 mL) was
added. The precipitated crystals were filtered at 5 °C to obtain (Ϫ)-
6-(Ϫ) (as -dibenzoyltartaric acid salt; 51.2 g, 78%). M.p. 118Ϫ119
°C. [α]2D0 ϭ Ϫ29.5 (c ϭ 1, methanol). IR (KBr): ν˜ ϭ 1728, 1714,
washed with water until neutral and concentrated to afford solvent-
free product under reduced pressure. The residue was dissolved in
2-propanol (35 mL) and acidified to pH ϭ 2 by concentrated aque-
ous hydrochloric acid (37%). The precipitated product was filtered
at 0 °C and washed with acetone (2 ϫ 20 mL) to give 9·HCl (7.13 g,
78.5%). M.p. 236Ϫ238 °C. [α]2D0 ϭ Ϫ38 (c ϭ 1, methanol). IR
1
1267, 1104, 1224, 1070, 1601, 842, 730, 712, 702 cmϪ1. H NMR
([D6]DMSO, δTMS ϭ 0.00 ppm): δ ϭ 1.64 (m, 1 H, 5-He), (KBr): ν˜ ϭ 2850Ϫ2200, 1184, 1036, 1218, 1630, 1602, 825 cmϪ1
1.94Ϫ2.10 (m, 2 H, 3-H and 5-Ha), 2.60Ϫ2.76 (m, 2 H, 2-Ha, 6-
Ha), 2.86 (dd, J8x,8y ϭ 10.5 Hz, J8x,3 ϭ 3.9 Hz, 1 H, 8-Hx), 2.97
.
1H NMR (CDCl3, δTMS ϭ 0.00 ppm): δ ϭ 1.97 (m, 1 H, 5-Hx),
2.72Ϫ3.36 (m, 5 H, 5-Hy, 2-Hx, 6-Hx, 3-H, 4-H), 3.45 (dd, J8x,8y
ϭ
(dt, J4a,5a ϭ 12.6, J4a,5e ϭ 3.6, J4a,3e ϭ 3.6 Hz, 1 H, 4-H), 3.27Ϫ3.35 9.6 Hz, J8x,3 ϭ 3.9 Hz, 1 H, 8-Hx), 3.53Ϫ3.64 (m, 3 H, 2-Hy, 6-Hy,
(m, 2 H, 2-He, 6-He), 3.50 (t, J8x,8y ϭ 10.5 Hz, J8x,3 ϭ 10.5 Hz, 1 8-Hy), 4.21 (d, J7x,7y ϭ 12.9 Hz, 1 H, 7-Hx), 4.28 (d, J7x,7y
H, 8-Hy), 3.94 d (d, J7x,7y ϭ 13.2 Hz, 1 H, 7-Hx), 4.10 (d, J7x,7y 12.9 Hz, 1 H, 7-Hy), 5.89 (s, 2 H, OCH2O), 6.10 (dd, J6Ј,5Ј ϭ 8.4 Hz,
ϭ
ϭ
3338
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 3336Ϫ3339