6
764 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
Stehouwer et al.
to the Grignard solution over a period of 15 min. The reaction
mixture was stirred at -43 °C under Ar for 3 h, cooled to -78 °C,
and quenched by dropwise addition of TFA (28.6 mL, 0.37 mol,
EtOAc/NEt
3
v/v/v 75:20:5 (100 mL), 50:45:5 (300 mL), 20:75:5
(300 mL). The solvent was removed to give 0.46 g (79%) of a
colorless residue: TLC R ) 0.19 (silica, 20:75:5 v/v/v hexane/
); H NMR (600 MHz, CDCl ) δ 7.33 (s, 1 H), 7.32
f
1
1
0.2 equiv) in anhydrous CH
2
Cl
2
(75 mL) over a period of 3.5
EtOAc/NEt
3
3
min (temperature rose to -35 °C). The reaction mixture was
warmed to room temperature and the solvent removed to give an
(m, 1 H), 7.14 (m, 2 H), 3.73 (m, 1 H), 3.71 (m, 1 H), 3.42 (s, 3
H), 3.21 (dt, 1 H, J ) 6.0 Hz, J ) 12.6 Hz), 2.73 (m, 1 H), 2.37
(td, 1 H, J ) 12.6 Hz, J ) 3.0 Hz), 2.12 (m, 1 H), 2.01 (m, 1 H),
orange oil that was dissolved in CH
addition of H O (100 mL). The mixture was cooled to 0 °C, the
aqueous layer was basified to pH 10 with concentrated NH OH-
aq), the mixture was filtered, and the layers separated. The aqueous
layer was extracted with CH Cl Cl
(25 mL × 2), the combined CH
layers were dried over MgSO , and the solvent was removed to
give an orange oil that was vacuum flash chromatographed on silica
13 cm high × 4 cm i.d.; eluted with CH Cl (200 mL), hexane/
EtOAc/NEt v/v/v 90:8:2 (100 mL), 75:20:5 (400 mL)) to afford
.90 g (65%) of a faint yellow oil: TLC R
2 2
Cl (100 mL) followed by
1.75 (m, 1 H), 1.65 (m, 2 H); 13C NMR (150 MHz, CDCl
) δ
2
3
4
173.79, 144.94, 130.77, 130.01, 129.85, 126.19, 122.61, 56.54,
53.78, 51.44, 51.09, 35.73, 33.75, 29.22, 27.83; HRMS (APCI)
(
+
79
2
2
2
2
[MH] Calcd for C15
H
19
O
2
N Br: 324.0594, Found: 324.0594;
8
1
4
Calcd for C15H O N Br: 326.0578, Found: 326.0574.
19 2
(Z)-1,2-Bis(trimethylstannyl)ethene. Purified acetylene (passed
successively through a -78 °C cold trap, concentrated H SO (aq),
NaOH(s), CaCl (s), and then Drierite) was bubbled through a
solution of hexamethylditin (2.52 g, 7.69 mmol), Pd(PPh ) (0.89
g, 0.77 mmol), and 1,4-dioxane (20 mL, purged with Ar for 45
(
2
2
2
4
3
2
7
f
) 0.34 (silica, 75:20:5
); H NMR (600 MHz, CDCl ) δ 7.37
3
4
1
v/v/v hexane/EtOAc/NEt
3
3
(s, 1 H), 7.32 (m, 1 H), 7.31 (m, 1 H), 7.27 (s, 1 H), 3.55 (m, 1 H),
min prior to use) at 65 °C for 4 h. The solution was cooled to
room temperature, stirred at room temperature for 20 min, and
3
.48 (s, 3 H), 3.37 (m, 1 H), 3.01 (dt, 1 H, J ) 5.4 Hz, J ) 13.2
Hz), 2.91 (m, 1 H), 2.61 (td, 1 H, J ) 3.0 Hz, J ) 12.6 Hz), 2.23
filtered. The filtrate was poured onto silica gel (14 cm high × 4
(s, 3 H), 2.19 (m, 1 H), 2.10 (m, 1 H), 1.75 (m, 1 H), 1.70 (m, 1
cm i.d.) that had been pretreated with 10% NEt /hexane (100 mL)
3
13
H), 1.62 (m, 1 H), 0.24 (s, 9 H); C NMR (150 MHz, CDCl
1
6
3
) δ
72.46, 142.18, 139.80, 132.50, 131.07, 128.25, 127.53, 65.59,
2.48, 53.09, 51.27, 42.17, 34.33, 34.12, 26.16, 25.36, -0.89;
and then 1% NEt /hexane (100 mL). The product was eluted under
vacuum with 1% NEt /hexane (200 mL), and the solvent was
removed to give a dark orange oil that was briefly dried under
3
3
+
1
HRMS (APCI) [MH] Calcd for C19
32.2039.
â-Carbomethoxy-3â-(3′-bromophenyl)tropane (5). 2â-Car-
H30NO
2
Si: 332.2040, Found:
vacuum (2.48 g, 91%). TLC R ) 0.66 (1% NEt /hexane); H NMR
f
3
2
3
(400 MHz, CDCl ) δ 7.33 (s, 2 H), 0.17 (t, 18 H, J
) 26.6
3
SnH
Hz); 13C NMR (150 MHz, CDCl
2
3
) δ 155.17, -8.10.
bomethoxy-3â-(3′-(trimethylsilyl)phenyl)tropane (4) (1.02 g, 3.08
mmol) was dissolved in MeOH (20 mL) followed by addition of
AcOH (40 mL), then NBS (1.74 g, 9.78 mmol, 3.2 equiv), and
2â-Carbomethoxy-3â-(3′-((Z)-2-trimethylstannylethenyl)-
phenyl)nortropane (7). 2â-Carbomethoxy-3â-(3′-bromophenyl)-
-4
nortropane (6) (0.25 g, 0.77 mmol), Pd(PPh ) (89 mg, 0.77 × 10
3
4
4
then n-Bu NBr (3.01 g, 9.34 mmol, 3.0 equiv). (Caution: addition
mol, 0.1 equiv), (Z)-1,2-bis(trimethylstannyl)ethene (1.00 g, 2.83
mmol, 3.7 equiv), and Ar-purged toluene (25 mL) were stirred at
reflux under Ar for 18 h, cooled to room temperature, and poured
onto silica (43 mm h × 43 mm i.d.) that had been pretreated with
10% NEt /hexane (100 mL). Elution under vacuum with CH Cl
2
of NBS last may result in an explosive release of gas!). The solution
was stirred at 77 °C under Ar for 20 h, cooled to room temperature,
diluted with CH
2
Cl
2 2
(150 mL) and H O (150 mL), and cooled to
0
°C. The aqueous phase was basified to pH 11 with concentrated
3
2
NH
4
OH(aq), the layers were separated, and the aqueous layer was
Cl Cl layers
(25 mL × 2). The combined CH
were dried over MgSO , and the solvent was removed to give a
yellow oil that was purified by vacuum flash chromatography on
silica (11.5 cm high × 4 cm i.d.) eluted with CH Cl (200 mL)
and then 75:20:5 v/v/v hexane/EtOAc/NEt to afford 0.66 g (63%)
of a viscous, colorless syrup: TLC R ) 0.27 (silica, 75:20:5 v/v/v
); H NMR (600 MHz, CDCl ) δ 7.37 (s, 1
H), 7.28 (d, 1 H, J ) 7.8 Hz), 7.20 (d, 1 H, J ) 7.8 Hz), 7.14 (dd,
H, J ) 7.8 Hz), 3.57 (m, 1 H), 3.52 (s, 3 H), 3.36 (m, 1 H), 2.97
dt, 1 H, J ) 5.4 Hz, J ) 12.6 Hz), 2.90 (m, 1 H), 2.53 (td, 1 H,
J ) 3.0 Hz, J ) 12.6 Hz), 2.22 (s, 3 H), 2.19 (m, 1 H), 2.10 (m,
(100 mL), then hexane/EtOAc/NEt v/v/v 75:20:5 (100 mL), 50:
45:5 (200 mL), 20:75:5 (500 mL) gave a crude brown oil that was
3
extracted with CH
2
2
2
2
4
∼76:24 cis/trans by integration of the vinyl proton NMR reso-
nances. Purification by radial chromatography (2 mm silica; hexane/
2
2
EtOAc/NEt v/v/v 90:8:2 (1 L), 85:12:3 (100 mL), 80:14:6 (100
3
3
mL)) afforded 56 mg (17%) of a yellow oil that was ∼92:8 cis/
f
trans, 71 mg (21%) of a yellow oil that was ∼88:12 cis/trans, and
1
hexane/EtOAc/NEt
3
3
68 mg (20%) of a yellow oil that was ∼73:27 cis/trans. TLC R )
f
1
0.21 (silica, 20:75:5 v/v/v hexane/EtOAc/NEt ); cis-7: H NMR
3
3
3
1
(
(600 MHz, CDCl ) δ 7.54 (td, 1 H, J ) 13.2 Hz, J ) 73.1
3
HH
SnH
Hz), 7.23 (dd, 1 H, J ) 7.8 Hz), 7.10 (m, 2 H), 7.06 (s, 1 H), 6.19
3 2
(td, 1 H, J ) 13.2 Hz, J
HH
SnH
) 32.0 Hz), 3.78 (m, 1 H), 3.74
H), 1.69 (m, 2 H), 1.60 (m, 1 H); 1 C NMR (150 MHz, CDCl
δ 172.13, 145.90, 130.74, 129.71, 129.12, 126.12, 122.35, 65.48,
2.35, 52.83, 51.44, 42.14, 34.12, 33.82, 26.06, 25.39; HRMS
3
)
1
3
(m, 1 H), 3.37 (s, 3 H), 3.25 (dt, 1 H, J ) 5.4 Hz, J ) 13.2 Hz),
2.74 (m, 1 H), 2.44 (td, 1 H, J ) 2.6 Hz, J ) 12.9 Hz), 2.17 (m,
1 H), 2.07 (m, 1 H), 1.77 (m, 1 H), 1.71 (m, 1 H), 1.65 (m, 1 H),
6
+
79
2
13
(
3
APCI) [MH ] Calcd for C16
38.0752; Calcd for C16
2
H
O
21 2
N Br: 338.0750, Found:
N Br: 340.0734, Found: 340.0732.
â-Carbomethoxy-3â-(3′-bromophenyl)nortropane (6). 2â-
Carbomethoxy-3â-(3′-bromophenyl)tropane (5) (0.61 g, 1.80 mmol),
,2,2-trichloroethyl chloroformate (2.5 mL, 18.2 mmol, 10.1 equiv),
Na CO (s) (0.11 g, 1.04 mmol, 0.6 equiv), and toluene (12 mL)
0.07 (s, 9 H, J
) 27.0 Hz); C NMR (150 MHz, CDCl ) δ
SnH
3
8
1
H O
21 2
174.03, 147.51,142.42, 141.24, 133.78, 128.32, 127.00, 126.40,
125.57, 56.52, 53.82, 51.30, 36.06, 33.98, 29.31, 27.86, -7.88. cis/
+
120
trans-7: HRMS (ESI) [MH] Calcd for C20
H
30
O
2
N
Sn: 436.1293,
1
18
2
Found:436.1290; Calcd for C20
434.1284.
H O N Sn: 434.1287, Found:
30 2
2
3
were stirred at reflux under Ar for 21 h, cooled, poured onto dry
2â-Carbomethoxy-3â-(3′-((Z)-2-iodoethenyl)phenyl)nortro-
pane (mZIENT, 1). 2â-Carbomethoxy-3â-(3′-((Z)-2-trimethylstan-
nylethenyl)phenyl)nortropane (7) (∼75:25 cis/trans, 0.17 g, 0.39
silica (33 mm high × 43 mm i.d.), and eluted under vacuum with
2 2 3
CH Cl (75 mL) and then 75:20:5 v/v/v/hexane/EtOAc/NEt (150
mL). The solvent was removed to give a colorless residue that was
dried under vacuum (0.94 g). To the residue were added Zn dust
2 2
mmol) was dissolved in CH Cl (25 mL) and cooled to 0 °C under
2 2
Ar. ICl (1 M CH Cl , 0.75 mL, 1.9 equiv) was added dropwise
(
1.24 g), AcOH (25 mL), and H
stirred at room temperature for 16 h. The reaction mixture was
filtered, the filtrate was diluted with CH Cl (75 mL) and H O (75
mL), and the mixture was cooled to 0 °C. The aqueous phase was
basified to pH 11 with concentrated NH OH(aq), the layers were
separated, and the aqueous layer was extracted with CH Cl (25
mL × 2). The combined CH Cl layers were dried over MgSO
and the solvent was removed to give a colorless oil. The oil was
dissolved in CH Cl
, poured onto dry silica (38 mm high × 43
mm i.d.), and eluted under vacuum: CH Cl (100 mL), then hexane/
2
O (0.7 mL), and the mixture was
until a faint red color persisted, the reaction mixture was stirred at
0 °C under Ar for 10 min, and the reaction was quenched by
2
2
2
addition of Na
mixture was stirred at room temperature for 10 min and diluted
with CH Cl (25 mL) and H O (25 mL), and the layers separated.
The aqueous layer was extracted with CH Cl
(10 mL × 2), the
combined CH Cl layers were dried over MgSO , and the solvent
2 2 3 2
S O (aq) (0.60 g in 10 mL of H O). The reaction
4
2
2
2
2
2
2
2
2
2
4
,
2
2
4
was removed to give a yellow foam (0.18 g). Purification by radial
chromatography (2 mm silica, elution:hexane (15 mL), hexane/
EtOAc/NEt v/v/v 95:4:1 (100 mL), 90:8:2 (200 mL), 75:20:5 (800
3
2
2
2
2