D. Passarella et al. / Bioorg. Med. Chem. 11 (2003) 1007–1014
1011
General procedure for the preparation of 2-benzyl-7-[1-[2
(trimethylsilyl)ethoxymethyl]indol-2-yl]-3-oxo-2-aza-car-
2-Benzyl-7-[1-[2-(trimethylsilyl)ethoxymethyl]-indol-2-
yl]-(5-endo)-carbomethoxy-3-oxo-2-azabicyclo [2.2.2]oct-
7-ene (16). Yield: 51%. Oil; Rf (EtOAc/hexane
-
bomethoxybicyclo[2.2.2]oct-7-ene by zinc halide cross-
coupling reaction. To a dry solution of 1-[2-(trimethylsi-
lyl)ethoxymethyl]-indole 10a (1.2 mmol) in THF (3
mL), BuLi 1.6 M in hexane (830 mL, 1.33 mmol, 1.1
ꢁ
1
1
3:1)=0.3; IR (nujol) 1730, 1669 cm
;
H NMR
(CDCl ) d 7.45 (1H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz),
3
7.31–7.19 (5H, m), 7.21 (1H, t, J=8 Hz), 7.09 (1H, t,
J=8 Hz), 6.68 (1H, dd, J=7, 2 Hz), 5.94 (1H, s), 5.31
(2H, s), 4.73 (1H, A portion of AB system), 4.53 (1H,
ddd, J=3, 3, 2 Hz), 4.42 (1H, B portion of AB system),
4.03 (1H, dd, J=6, 2 Hz), 3.70 (3H, s), 3.58 (2H, t, J=8
Hz), 3.14 (1H, ddd, J=10, 5, 2 Hz), 2.15 (1H, ddd,
J=12, 10, 3 Hz), 1.90 (1H, ddd, J=12, 5, 1 Hz), 0.93–
ꢀ
equiv) was slowly added at ꢁ15 C and the mixture was
stirred for 10 min at this temperature. The resulting
orange solution was then cooled to ꢁ78 C and treated
ꢀ
with a 0.6 M solution of anhydrous ZnCl (fused by
2
flame-drying under reduced pressure for 5 min) in THF
(
2 mL, 1.2 mmol, 1.0 equiv) and the stirring was con-
tinued for 5 min at this temperature. In a separate flask,
Pd(PPh ) (0.036 mmol, 3%) and bromo alkene (mix-
1
3
0.90 (2H, m), 0.00 (9H, s); C NMR (CDCl ) d 173.2,
3
171.8, 139.3, 137.6, 136.7, 135.0, 129.8, 128.6 (2C), 128.4
(2C), 127.8, 127.6, 123.0, 120.7, 120.6, 109.6, 103.6,
72.8, 65.9, 57.9, 52.1, 47.9, 44.2, 39.7, 31.1, 17.9, ꢁ1.49
(3C). Anal. calcd for C H N O Si: C 69.73, H 7.03, N
3
4
ture of 5 and 8 or mixture of 6 and 7, 1.2 mmol) were
dissolved in dry THF (2 mL) and stirred for 20 min at
room temperature. Then the resulting solution was
added to the solution of 1-[2-(trimethylsilyl)ethoxy-
3
0
36
2
4
5.42. Found: C 69.77, H 7.05, N 5.36.
methyl]indol-2-ylzinc chloride 10b prepared above, at
ꢁ
ꢀ
and then refluxed. After the reaction was complete, the
78 C. The mixture was allowed to stir at rt for 5 min
2-Benzyl-7-[1-[2-(trimethylsilyl)ethoxymethyl]-indol-2-
yl]-(5-exo)-carbomethoxy-3-oxo-2-azabicyclo [2.2.2]oct-
7-ene (17). Yield: 58%. Oil; Rf (EtOAc/hexane
mixture was cooled to rt, added to 20 mL of NH Cl 5%
4
ꢁ
1
1
and extracted with EtOAc. The combined organic layers
were washed with brine and dried over Na SO . After
3:1)=0.4; IR (nujol) 1734, 1670 cm
;
H NMR
(CDCl ) d 7.49 (1H, d, J=8 Hz), 7.38 (1H, d, J=8 Hz),
2
4
3
vacuum concentration, the mixture was directly chro-
matographed (EtOAc/hexane 1:2).
7.30-7.15 (6H, m), 7.10 (1H, t, J=8 Hz), 6.84 (1H, dd,
J=7, 2 Hz), 6.08 (1H, s), 5.31 (2H, s), 4.67 (1H, A por-
tion of AB system), 4.53 (1H, B portion of AB system),
4.58–4.52 (1H, m), 3.98 (1H, dd, J=7, 3 Hz), 3.79 (3H,
s), 3.60 (2H, t, J=8 Hz), 2.87 (1H, ddd, J=10, 5, 3 Hz),
2.35 (1H, ddd, J=13, 5, 4 Hz), 1.81 (1H, ddd, J=13, 10,
2-Benzyl-7-[1-[2-(trimethylsilyl)ethoxymethyl]-indol-2-
yl]-(6-endo)-carbomethoxy-3-oxo-2-azabicyclo [2.2.2]oct-
7
-ene (14). Yield: 65%. Oil; Rf (EtOAc/hexane
1
ꢁ
1
13
1
:1)=0.46; IR (nujol) 1730, 1668 cm
;
H NMR
3 Hz), 0.91 (2H, t, J=8 Hz),-0.05 (9H, s); C NMR
(
CDCl ) d 7.46 (1H, d, J=8 Hz), 7.39 (1H, d, J=8 Hz),
(CDCl ) d 173.2, 170.9, 139.5, 138.4, 136.8, 135.5, 128.6,
3
3
7
.36–7.22 (5H, m), 7.21 (1H, t, J=8 Hz), 7.10 (1H, t,
J=8 Hz), 6.92 (1H, dd, J=7, 2 Hz), 5.91 (1H, s), 5.28
2H, s), 4.89 (1H, dd, J=4, 2 Hz), 4.81 (1H, A portion
of AB system), 4.43 (1H, B portion of AB system), 3.75
128.3 (2C), 128.0, 127.7 (2C), 126.9, 123.2, 120.8, 120.7,
109.5, 103.5, 72.8, 66.1, 59.3, 52.4, 47.8, 44.2, 43.9, 30.7,
18.0, ꢁ1.4 (3C). Anal. calcd for C H N O Si: C 69.73,
(
3
0
36
2
4
H 7.03, N 5.42. Found: C 69.79, H 7.07, N 5.40.
(
1H, ddd, J=7, 3, 3 Hz), 3.65 (2H, t, J=8 Hz), 3.27
3H, s), 3.07 (1H, ddd, J=4, 6, 10 Hz), 2.18 (1H, dd,
(
J=6, 4 Hz), 1.75–1.58 (1H, m), 0.91 (2H, t, J=8 Hz),
0
1
1
5
2-Benzyl-7-[1-[2-(trimethylsilyl)ethoxymethyl]-5-methoxy-
indol - 2 - yl]-(6 - exo) - carbomethoxy - 3 - oxo - 2 - azabicy-
clo[2.2.2]oct-7-ene (18). Obtained following the general
procedure described for compounds 14–17 and using as
starting materials 5-methoxy-1-[2-(trimethylsilyl)ethox-
ymethyl]-indole 11a (0.5 mmol) and bromo alkene 5 (0.5
1
3
.00 (9H, s); C NMR (CDCl ) d 173.4, 171.5, 139.2,
3
36.6, 136.1, 134.1, 129.1, 128.8 (2C), 128.3 (2C), 127.8,
27.4, 123.0, 120.7, 120.4, 109.5, 103.3, 72.7, 66.0, 59.9,
1.7, 47.9, 44.6, 44.3, 29.6, 18.0, ꢁ1.4 (3C). Anal. calcd
for C H N O Si: C 69.73, H 7.03, N 5.42. Found: C
mmol, as pure product). Yield: 53%. Oil; R (EtOAc/
f
3
0
36
2
4
ꢁ
1 1
6
9.72, H 7.17, N 5.49.
hexane 3:1)=0.4; IR (nujol) 1732, 1669, 1239 cm ; H
NMR (CDCl ) d 7.35-7.15 (8H, m), 6.78 (1H, dd,
3
2-Benzyl-7-[1-[2-(trimethylsilyl)ethoxymethyl]-indol-2-
yl]-(6-exo)-carbomethoxy-3-oxo-2-azabicyclo [2.2.2]oct-
J=14, 2 Hz), 5.78 (1H, s), 5.32–5.19 (2H, AB system),
5.09 (1H, A portion of AB system), 4.90–4.85 (1H, m),
4.09 (1H, B portion of AB system), 3.85 (3H, s), 3.75–
3.69 (1H, m), 3.65 (3H, s), 3.58 (2H, t, J=8 Hz), 2.80–
2.70 (1H, m), 2.10–1.80 (2H, m), 0.92–0.85 (2H, m), 0.00
7
-ene (15). Yield: 61%. Oil; Rf (EtOAc/hexane
ꢁ
1
1
3
:1)=0.3; IR (nujol) 1731, 1666 cm
;
H NMR
(
CDCl ) d 7.40 (1H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz),
3
1
3
7
.21 (1H, t, J=8 Hz), 7.30–7.19 (5H, m), 7.08 (1H, t,
J=8 Hz), 6.80 (1H, dd, J=7, 2 Hz), 5.86 (1H, s), 5.26
2H, s), 5.09 (1H, A portion of AB system), 4.90 (1H,
(9H, s); C NMR (CDCl ) d 173.0, 171.9, 154.6, 137.0–
3
134.0 (4C), 128.0–120.0 (9C), 110.3, 103.2, 72.9, 65.9,
60.0, 55.7, 52.0, 47.9, 44.7, 40.0, 26.4, 17.6,-1.3 (3C).
Anal. calcd for C H N O Si: C 68.10, H 7.01, N 5.12.
(
bs), 4.09 (1H, B portion of AB system), 3.72–3.69 (1H,
m), 3.58 (2H, t, J=8 Hz), 3.66 (3H, s), 2.78 (1H, ddd,
J=10, 6, 3 Hz), 2.41 (1H, ddd, J=12, 5, 2 Hz), 2.03 (1H,
3
1
38
2
5
Found: C 68.13, H 7.03, N 5.13.
1
3
ddd, J=12, 10, 3 Hz), 0.93–0.89 (2H, m), 0.00 (9H, s);
C
2 - Benzyl - 7 - [1 - [2 - (trimethylsilyl)ethoxymethyl]- 5 -
methoxyindol-2-yl]-(5-exo)-carbomethoxy-3-oxo-2-azabi-
cyclo[2.2.2]oct-7-ene (19). Obtained following the gen-
eral procedure described for compounds 14–17 and
using as starting materials 5-methoxy-1-[2-(trimethylsi-
lyl)ethoxymethyl]-indole 11a (0.5 mmol) and bromo
NMR (CDCl ) d 173.2, 172.7, 139.3, 137.1, 136.9, 135.5,
3
1
1
2
6
28.6, 128.4 (2C), 128.1 (2C), 127.8, 127.6, 125.5, 120.7,
20.6, 109.4, 103.5, 72.7, 66.0, 60.0, 52.0, 48.8, 44.7, 40.0,
6.4, 17.6, ꢁ1.49 (3C). Anal. calcd for C H N O Si: C
3
0
36
2
4
9.73, H 7.03, N 5.42. Found: C 69.80, H 7.10, N 5.39.