Synthesis and Monoamine Transporter Binding Properties
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3855
optical rotations were determined at the sodium D line using
a Rudolph Research Autopol III polarimeter (1 dm cell). Thin-
layer chromatography was carried out on Whatman silica gel
60 TLC plates. Visualization was accomplished under UV or
in an iodine chamber. Microanalyses were carried out by
Atlantic Microlab Inc. The compounds were purified by flash
chromatography on silica gel 60 (230-400 mesh) or prepara-
tive-layer chromatography (radial PLC) on a chromatotron
(Harrison Association, Palo Alto, CA) using glass plates coated
with 1-, 2-, or 4 mm thickness of Kissel gel 60 pF254 containing
gypsum. Glassware was oven- or flame-dried and cooled under
nitrogen. All reactions were performed under nitrogen or
argon. Samarium iodide was purchased from Fluka Chemical
Corp. All other chemicals were purchased from Aldrich Chemi-
cal Company, Inc. THF and ether were freshly distilled from
sodium benzophenone. All other reagents were used without
further purification. CMA is a mixture of 95% chloroform, 4%
methanol, and 1% concentrated ammonium hydroxide.
131.72, 131.65, 123.34, 123.30, 123.05, 114.61, 114.31, 64.66,
59.79, 49.91, 41.42, 39.49, 37.88, 37.87, 29.31, 29.24, 14.51,
14.4611.96; [R]20D -68.29° (c 22.7 CH3OH). This material was
used without further purification to prepare 7d.
3r-(4-Fluoro-3-methylphenyl)-2â-(3′-methyl-1′,2′,4′-oxa-
diazol-5′-yl)tropane (10b). A flame-dried 100 mL round-
bottomed flask equipped with a magnetic stirrer was charged
with a solution of 4-bromo-2-fluorotoluene (0.922 g, 4.87 mmol)
in 20 mL of anhydrous ether, and the solution was cooled to
-78 °C via a dry ice/acetone bath. To this was added slowly a
solution of n-BuLi (2.5 M in hexane, 1.95 mL, 4.87 mmol) over
15 min, maintaining the temperature below -70 °C. The
solution was stirred at -78 °C for 30 min, and then a solution
of anhydroecgonine oxadiazole (9, 0.500 g, 2.43 mmol) in
anhydrous ether (10 mL) was added slowly over 10 min. The
resulting solution was stirred at -78 °C for 4 h and quenched
with 1 N HCl at the same temperature. The mixture was
allowed to warm to room temperature, then washed with ether.
The ether layer was discarded, and the aqueous layer was
basified to pH 11 with concentrated NH4OH at 0 °C (via an
ice bath) and extracted with chloroform (3 × 15 mL). The
combined organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure to afford the crude
product as a light-yellow oil. Purification by flash column
chromatography [silica, 1:1 CMA/(1:1 hexane/ethyl acetate)]
General Procedure for the Synthesis of 3r-(Substi-
tuted phenyl)nortropane-2â-carboxylic Acid Methyl Es-
ters (8a-h). A representative experimental procedure is given
below. The percent yields, salts prepared, and analytical data
for each compound are in Table 1.
3r-(3-Fluoro-4-methylphenyl)nortropane-2â-carboxy-
lic Acid Methyl Ester (8d) Hydrochloride. To a solution
of tropane 7d (0.820 g, 2.817 mmol) in 1,2-dichloroethane
(20 mL) was added 1-chloroethyl chloroformate (2.01 g,
14.1 mmol). The mixture was refluxed for 12 h under N2.
Cooling to room temperature was followed by concentration
of the solvent in vacuo to afford a light-yellow oil. The oil was
dissolved in anhydrous CH3OH (15 mL), and the mixture was
refluxed for 4 h. The mixture was concentrated in vacuo, and
the residue was dissolved in CH2Cl2 (25 mL). The solution was
washed with NH4OH (5%, 10 mL). The aqueous layer was
separated and extracted with CH2Cl2 (2 × 15 mL). The
combined organic layer was dried (Na2SO4). Concentration in
vacuo gave a light-yellow oil. Purification of the oil via radial
PLC (silica, 10:1 Et2O/Et3N) gave the product (0.515 g, 66%)
as a light-yellow oil. The free base was converted to the
hydrochloride salt: mp 204-205 °C; [R]20D -62.50° (c 12.5 CH3-
OH); 1H NMR (CDCl3) δ 7.02-7.16 [m, 2 H], 6.84-6.98 [m,
2 H], 3.59-3.65 [m, 4 H], 3.10 [q, 1 H], 2.45 [d, 1 H, J ) 9.0
Hz], 2.21-2.28 [m, 4 H], 1.91-2.00 [m, 1 H], 1.85-1.90 [m,
2 H], 1.57-1.68 [m, 3 H], 1.32 [t, 1 H, J ) 12.0 Hz]; 13C NMR
((CDCl3) δ 175.45, 162.82, 159.58, 143.47, 131.28, 123.05,
114.27, 114.20, 113.97, 113.91, 56.20, 55.57, 51.74, 51.55,
36.13, 36.11, 32.83, 32.38, 14.15. Anal. C16H21ClFNO2‚0.5H2O)
C, H, N.
gave the pure product (0.120 g, 16%) as a light-yellow oil:
1
[R]20 -58.4° (c 12, CHCl3); H NMR (CDCl3) δ 6.91 [m, 3 H],
D
3.34 [m, 3 H], 3.03 [d, 1 H, J ) 9.0 Hz], 2.39 [m, 1 H], 2.29
[s, 3 H], 2.20 [s, 3 H], 2.16 [m, 4 H], 1.70 [m, 1 H], 1.55 [m,
1 H], 1.33 [m, 1 H]. This material was used without further
purification to prepare 7e.
3r-(3-Fluoro-4-methylphenyl)tropane-2â-carboxylic
Acid Methyl Ester (7d) Hydrochloride. A 100 mL round-
bottomed flask equipped with a magnetic stirrer was charged
with a solution of nickel acetate tetrahydrate (0.853 g,
3.42 mmol) in 15 mL of methanol. To this was added solid
NaBH4 (0.129 g, 3.42 mmol) cautiously because the reaction
is exothermic. A black colloidal suspension formed immedi-
ately. A solution of 10a (0.22 g, 0.68 mmol) in 5 mL of methanol
was added, and the reaction mixture was refluxed for 4 h. The
mixture was allowed to cool to room temperature, filtered
through Celite, and washed with methanol. The filtrate was
concentrated under reduced pressure to give a green solid,
which was dissolved in 15 mL of H2O. The aqueous layer was
basified at 0-5 °C to pH 11 with concentrated NH4OH and
extracted with ether (3 × 10 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure
1
to give the product as a colorless oil: 0.170 g (85%); H NMR
(CDCl3) δ 7.13 [m, 1 H], 6.84 [m, 2 H], 3.60 [s, 3 H], 3.29
[m, 3 H], 2.46 [m, 2 H], 2.24 [s, 3 H], 2.21 [s, 3 H], 2.10 [m,
1 H], 1.53 [m, 4 H]; 13C NMR 175.34, 163.16, 159.92, 144.47,
144.37, 131.54, 131.46, 123.34, 123.30, 114.54, 114.25, 63.49,
59.86, 56.75, 56.53, 52.11, 41.36, 39.42, 39.19, 35.96, 35.94,
35.70, 29.12, 29.04, 14.49, 14.45. The hydrochloride salt had
3r-(3-Fluoro-4-methylphenyl)-2â-(3′-methyl-1′,2′,4′-oxa-
diazol-5′-yl)tropane (10a). A flame-dried 100 mL round-
bottomed flask equipped with a magnetic stirrer was charged
with a solution of 4-bromo-2-fluorotoluene (0.92 g, 4.9 mmol)
in 20 mL of anhydrous ether, and the solution was cooled to
-78 °C via a dry ice/acetone bath. To this was added slowly a
solution of n-BuLi (2.5 M in hexane, 1.95 mL, 4.9 mmol) over
15 min, maintaining the temperature below -70 °C. The
solution was stirred at -78 °C for 30 min, and then a solution
of anhydroecgonine oxadiazole (9, 0.500 g, 2.43 mmol) in
anhydrous ether (10 mL) was added slowly over 10 min. The
resulting solution was stirred at -78 °C for 4 h and quenched
with 1 N HCl at the same temperature. The mixture was
allowed to warm to room temperature, then washed with ether.
The ether layer was discarded, and the aqueous layers were
basified to pH 11 with concentrated NH4OH at 0 °C (via an
ice bath) and extracted with chloroform (3 × 15 mL). The
combined organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure to afford the product as
a light-yellow oil. Purification by flash column chromatography
[silica, 1:1 CMA/(1:1 hexane/ethyl acetate)] gave the pure
product (0.278 g, 36%) as a light-yellow oil: 1H NMR (CDCl3)
δ 7.02 [m, 1 H], 6.81 [m, 2 H], 3.43 [m, 1 H], 3.34 [m, 2 H],
3.05 [d, 1 H, J ) 9 Hz], 2.49 [m, 1 H], 2.72 [s, 3 H], 2.27 [s,
3 H], 2.18 [s, 3 H], 2.14 [m, 2 H], 1.68 [m, 1 H], 1.55 [m, 1 H],
1.41 [m, 1 H]; 13C NMR 167.34, 163.17, 159.93, 143.31, 143.22,
[R]20 -18.6° (c 2.5, CHCl3). Anal. (C17H23ClFNO2) C, H, N.
D
3r-(4-Fluoro-3-methylphenyl)tropane-2â-carboxylic
Acid Methyl Ester (7e) Hydrochloride. A 100 mL round-
bottomed flask equipped with a magnetic stirrer was charged
with a solution of nickel acetate tetrahydrate (1.97 g,
7.93 mmol) in 20 mL of methanol. To this was added solid
NaBH4 (0.300 g, 7.9 mmol) cautiously because the reaction is
exothermic. A black colloidal suspension formed immediately.
A solution of 10b (0.500 g, 1.6 mmol) in 5 mL of methanol
was added, and the reaction mixture was refluxed for 4 h. The
mixture was allowed to cool to room temperature, filtered
through Celite, and washed with methanol. The filtrate was
concentrated under reduced pressure to give a green solid,
which was dissolved in 15 mL of H2O. The aqueous layer was
basified at 0-5 °C to pH 11 with concentrated NH4OH and
extracted with ether (3 × 10 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure
to give the crude product as a yellow oil: 0.370 g (80%);
1H NMR (CDCl3) δ 7.04 [m, 2 H], 6.87 [m, 1 H], 3.58 [s, 3 H],
3.29 [m, 3 H], 2.42 [m, 2 H], 2.23 [m, 7 H], 1.52 [m, 3 H], 1.31
Carroll, F. Ivy
