Methyl 3-(4-Substituted-phenyl)tropane-2-carboxylates
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6407
line from a nitrogen source. THF was distilled just prior to its
use (sodium benzophenone ketyl) or was purchased.
under N2. (1R)-3â-(4-Bromophenyl)tropane-2â-carboxylic acid
methyl ester 2d16 (2.07 g, 6.12 mmol) was then added and the
reaction was heated at reflux for 27 h. The solution was cooled
and concentrated under reduced pressure and water was
added. The mixture was extracted with CH2Cl2 (3 × 100 mL),
and the organic extracts were combined, dried (NaSO4), and
concentrated under reduced pressure to provide an oil. The
oil was purified using medium-pressure column chromatog-
raphy on silica (EtOAc/TEA/hexane, 9:1:10) to provide a white
solid (1.37 g, 66%). The solid was converted to the fumarate
salt with fumaric acid in MeOH. The mixture was heated until
all of the solid dissolved, the solution cooled, and Et2O was
added slowly until a precipitate formed. The solid precipitate
was collected and dried to provide 4d as a white powder. Mp:
(1R)-3r-Phenyltropane-2â-carboxylic Acid Methyl Es-
ter Tosylate (3a). Sodium borohydride (2.55 g, 67.3 mmol)
in MeOH (75 mL) was added to a solution of nickel(II) acetate
(16.75 g, 67.3 mmol) in MeOH (75 mL) at room temperature.
(1R)-3R-Phenyl-2â-(3-methyl-[1,2,4]oxadiazole-5-yl)tropane (7a)20
(3.80 g, 13.46 mmol) in MeOH (50 mL) was then added to the
mixture followed by concentrated HCl (5.6 mL, 67 mmol). The
black suspension was heated at reflux for 4 h, cooled to room
temperature, filtered through Celite, and concentrated under
reduced pressure. Water and ammonium hydroxide were
added, and the green suspension was extracted with Et2O (3
× 100 mL). The Et2O extracts were combined, dried (MgSO4),
and concentrated under reduced pressure to provide an oil.
The oil was purified using medium-pressure column chroma-
tography on silica, with 50% (Et2O/TEA, 9:1), 50% (hexane),
to provide an oil (0.77 g, 22%). The oil was dissolved in EtOAc
and 1.1 equiv of p-toluenesulfonic acid was added. The solution
was heated until the solid dissolved, the solution cooled, and
the solid precipitate was collected to provide 3a as a white
solid. Mp: 172-173 °C. [R]22D: -31.6° (c 1.16, EtOH). 1H NMR
(DMSO-d6): δ 1.90 (m, 3H), 2.19, (m, 1H), 2.24 (s, 3H), 2.26
(m, 1H), 2.42 (m, 1H), 2.66 (s, 3H), 3.25 (m, 2H), 3.52 (s, 3H),
3.85 (m, 1H), 4.09 (m, 1H), 7.08 (m, 2H), 7.31 (m, 2H), 7.42
(m, 2H), 9.38 (brs, 1H). Anal. (C23H29NSO5): C, H, N.
(1R)-3r-(4-Bromophenyl)-2â-(3-methyl-[1,2,4]oxadi-
azole-5-yl)tropane (7b). A 2.5 M solution of n-butyllithium
(14 mL, 35 mmol) in hexane was added at -78 °C under N2 to
1-bromo-4-iodobenzene (9.65 g, 34 mmol) in THF (250 mL).
The solution was allowed to stir for 15 min and (1R)-2-(3-
methyl-[1,2,4]oxadiazole-5-yl)trop-2-ene30 (3.5 g, 17 mmol) in
THF (25 mL) was slowly added. The reaction was then allowed
to stir for 3 h at -78 °C and a solution of TFA (4.4 mL, 57
mmol) in Et2O (10 mL) was added in a dropwise manner. The
slurry was concentrated under reduced pressure and am-
monium hydroxide (100 mL) was added. The mixture was
extracted with CH2Cl2 (3 × 100 mL), and the organic layers
were combined, dried (MgSO4), and concentrated under re-
duced pressure to provide an orange oil. The oil was purified
using medium-pressure column chromatography on silica
(Et2O/TEA, 9:1) to provide a mixture of the 3R,2â- and 3R,3R-
isomers (2.12 g) which were used in the next step without
further purification.
1
152-153 °C. [R]22D: +9.05° (c 0.42, MeOH). H NMR (D2O):
δ 2.08 (m, 2H), 2.20 (m, 1H), 2.31 (m, 2H), 2.40 (m, 1H), 2.86
(s, 3H), 3.40 (m, 2H), 3.55 (s, 3H), 4.02 (m, 1H), 4.34 (m, 1H),
7.30 (d, J ) 9 Hz, 2H), 7.55 (d, J ) 9 Hz, 2H). Anal. (C20H26-
BrNO8): C, H, N.
(1R)-3r-(4-Chlorophenyl)tropane-2r-carboxylic Acid
Methyl Ester tosylate (5b). (1R)-3-(4-Chlorophenyl)trop-2-
ene-2-carboxylic acid methyl ester (8a) (0.40 g, 1.37 mmol) in
anhydrous MeOH (20 mL) was added to a 100 mL Parr
hydrogenation bottle containing Raney nickel (0.40 g, washed
free from water with MeOH) in MeOH (5 mL). The suspension
was hydrogenated at 50 psi for 14 h. The suspension was
filtered through a Celite pad and the filtrate was concentrated
under reduced pressure to provide a colorless oil. The oil was
purified using medium-pressure column chromatography (CH2-
Cl2/MeOH 9.5:0.5) to provide a colorless oil (0.17 g, 0.58 mmol,
42%). The oil was dissolved in EtOAc (20 mL) and p-
toluenesulfonic acid (0.10 g, 0.58 mmol) was added. The
suspension was heated until the solid dissolved and concen-
trated under reduced pressure. The semisolid residue was then
recrystallized from 2-propanol/Et2O to provide 5b as a white
solid. Mp: 189-190 °C. [R]22D: +7.8° (c 0.43, MeOH). 1H NMR
(CD3OD): δ 1.6 (m, 1H), 2.15 (m, 1H), 2.30 (m, 1H), 2.32 (s,
3H), 2.48 (m, 2H), 2.65 (m, 1H), 2.85 (s, 3H), 3.60 (s, 3H), 3.61
(m, 1H), 3.83 (dd, J ) 7.5, 14.5 Hz, 1H), 3.90 (m, 1H), 4.25 (m,
1H), 7.23 (d, J ) 6 Hz, 2H), 7.30 (m, 4H), 7.70 (d, J ) 6 Hz,
2H). Anal. (C23H28ClNSO5): C, H, N.
(1R)-3r-(4-Methylphenyl)tropane-2r-carboxylic Acid
Methyl Ester Tosylate (5c). (1R)-3-(4-Methylphenyl)trop-2-
ene-2-carboxylic acid methyl ester (8b)21 (0.69 g, 2.53 mmol)
in anhydrous MeOH (20 mL) was added to a 100 mL Parr
hydrogenation bottle containing Raney nickel (0.69 g, washed
free from water with MeOH) in MeOH (5 mL). The suspension
was hydrogenated at 50 psi for 14 h. The suspension was
filtered through a Celite pad and the filtrate was concentrated
under reduced pressure to provide a colorless oil. The oil was
purified using medium-pressure column chromatography (CH2-
Cl2/MeOH 9.5:0.5) to provide a colorless oil (0.39 g, 1.43 mmol,
55%). The oil was dissolved in EtOAc (20 mL), and p-
toluenesulfonic acid (0.28 g, 1.62 mmol) was added. The
suspension was heated until the solid dissolved and concen-
trated under reduced pressure. The semisolid residue was then
recrystallized from 2-propanol/Et2O to provide 5c as a white
solid. Mp: 145-146 °C. [R]22D: +10.7° (c 0.59, MeOH). 1H NMR
(CD3OD): δ 1.6 (m, 1H), 2.15 (m, 1H), 2.28 (m, 1H), 2.30 (s,
3H), 2.39 (s, 3H), 2.50 (m, 2H), 2.68 (m, 1H), 2.85 (s, 3H), 3.60
(m, 1H), 3.61 (s, 3H), 3.8 (m, 1H), 3.93 (m, 1H), 4.25 (m, 1H),
7.20 (m, 6H), 7.71 (d, J ) 8 Hz, 2H). Anal. (C24H31NSO5): C,
H, N.
(1R)-3r-(4-Bromophenyl)tropane-2â-carboxylic Acid
Methyl Ester Tosylate (3d). Sodium borohydride (1.0 g, 27.6
mmol) in MeOH (30 mL) was added to a solution of nickel(II)
acetate (6.9 g, 27.6 mmol) in MeOH (30 mL) at room temper-
ature. A mixture of (1R)-3R-(4-bromophenyl)-2â-(3-methyl-
[1,2,4]oxadiazole-5-yl)tropane (7b) and (1R)-3R-(4-bromophenyl)-
2R-(3-methyl-[1,2,4]oxadiazole-5-yl)tropane, (2.0 g, 5.5 mmol)
in MeOH (50 mL) was then added to the mixture followed by
concentrated HCl (2.4 mL, 27.6 mmol). The black suspension
was heated at reflux for 4 h, cooled to room temperature,
filtered through Celite, and concentrated under reduced pres-
sure. Water and ammonium hydroxide were added, and the
green suspension was extracted with Et2O (3 × 100 mL). The
Et2O extracts were combined, dried (MgSO4), and concentrated
under reduced pressure to provide an oil. The oil was purified
using medium-pressure column chromatography on silica, with
75% (Et2O/TEA, 9:1), 30% (hexane), to provide an oil (0.36 g,
20%). The oil was dissolved in EtOAc and 1.1 equiv of
p-toluenesulfonic acid was added. The solution was heated
until the solid dissolved, the solution cooled, and the solid
precipitate was collected to provide 3d as a white solid. Mp:
(1R)-3-(4-Chlorophenyl)trop-2-ene-2-carboxylic Acid
Methyl Ester (8a). 4-(Chlorophenyl)boronic acid (0.65 g, 4.13
mmol) was added to a suspension of LiCl (0.29 g, 6.84 mmol),
Pd(Ph3)4 (0.13 g, 0.08 mmol), and (1R)-3-trifluoromethane-
sulfonyloxy-trop-2-ene-2-carboxylic acid methyl ester31 (1.11
g, 3.18 mmol) in 1,2-dimethoxyethane (13 mL). The suspension
was allowed to stir for 5 min and Na2CO3 (2.0 M, 1.65 mL)
was added. The reaction was heated at reflux (2 h) and allowed
to cool to room temperature. Water (20 mL) and concentrated
NH4OH (25 mL) were added, and the suspension was extracted
with CHCl3 (3 × 50 mL). The extracts were combined, dried
1
191-192 °C. [R]22D: -40.12° (c 0.81, MeOH). H NMR (CD3-
OD): δ 2.0 (m, 2H), 2.32 (m, 3H), 2.39 (s, 3H), 2.57 (m, 1H),
2.82 (s, 3H), 3.34 (m, 2H), 3.68 (s, 3H), 3.93 (m, 1H), 4.18 (m,
1H), 7.22 (d, J ) 9 Hz, 2H), 7.35 (d, J ) 9 Hz, 2H), 7.49 (d, J
) 9 Hz, 2H), 7.72 (d, J ) 9 Hz, 2H). Anal. (C23H28BrNSO5):
C, H, N.
(1R)-3â-(4-Bromophenyl)tropane-2r-carboxylic Acid
Methyl Ester Fumarate (4d). Sodium metal (0.70 g, 30
mmol) was added in small portions to MeOH (25 mL) at 0 °C
Carroll, F. Ivy
