4726 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Haadsma-Svensson et al.
5,6-Dim eth oxy-2-(m or p h olin o)in d a n (12c). This com-
pound was prepared from amine 8 (1.15 g, 5.0 mmol) and
2-bromoethyl ether (0.63 mL, 5.0 mmol) using the same
procedure described in the preparation of 12b to yield the
product as a light yellow solid (1.07 g, 81% yield). The solid
was dissolved in hot Et2O, filtered through folded filter paper
and concentrated. Recrystallized from Et2O/hexane gave a
light yellow, needle-shaped solid: mp 113-114 °C. 1H NMR
(CDCl3 δ): 6.72 (s, 2 H), 3.84 (s, 6 H), 3.78 (t, J ) 4.7 Hz, 4
H), 3.22 (quint, J ) 8.0 Hz, 1 H), 3.03 (dd, J ) 7.2, 14.6 Hz, 2
H), 2.88 (dd, J ) 8.3, 14.8 Hz, 2 H), 2.57 (m, 4 H). 13C NMR
(δ): 148.2, 132.8, 107.8, 67.6, 66.8, 56.0, 51.9, 36.6. IR (mull):
2798, 1508, 1333, 1307, 1270, 1263, 1244, 1233, 1221, 1187,
1149, 1119, 1100, 888, 857, cm-1. MS (EI): m/z 263 (M+), 264,
263, 248, 177, 176, 161, 133, 105, 91, 55. Anal. (C15H21NO3)
C, H, N.
concentrated to give a clear oil. Purification was done on silica
gel (200 g), eluting with 4:1 hexane/EtOAc afforded two
products; one was the desired product, and the other was a
borane complex of the desired product. The two products were
combined, dissolved in 50 mL of 3:1 acetone/3 N HCl, and
stirred for 15 min. The solution was concentrated, and the
residue was basified and worked up as before. A single desired
product was afforded by TLC as a yellowish oil (0.59 g, 89%).
The oil was converted to an HCl salt and recrystallized from
hot MeOH/EtOAc to give a white solid that was dried in a
vacuum oven: mp 221-222 °C. 1H NMR (CDCl3 δ): 7.26 (m, 1
H), 7.13 (m, 1 H), 7.08 (dd, J ) 1.1, 4.9 Hz, 1 H), 6.72 (s, 2 H),
3.84 (s, 6 H), 3.79-3.68 (m, 3 H), 3.02-2.85 (m, 4 H), 2.47 (m,
2 H), 1.52 (sextet, J ) 7.5 Hz, 2 H), 0.86 (t, J ) 7.3 Hz, 3 H).
13C NMR (CDCl3 δ): 148.0, 133.5, 128.4, 125.3, 122.1, 107.9,
62.7, 56.1, 52.9, 50.3, 36.2, 20.3, 11.9. IR (mull): 3040, 2437,
2401, 2374, 1504, 1441, 1314, 1301, 259, 1223, 1185, 1104,
1083, 826, 816, cm-1. MS (EI): m/z 331 (M+), 331, 303, 302,
204, 203, 177, 176, 165, 98, 97. Anal. (C19H26ClNO2S) C, H, N.
N-(2,3-Dih ydr o-5,6-dim eth oxy-1H-in den -2-yl)-N-pr opyl-
2-th iop h en em eth a n a m in e (13a ). A solution of 9 (0.50 g, 2.1
mmol), 2-thiophenecarboxylic acid (0.35 g, 2.8 mmol), and Et3N
(0.74 mL, 5.3 mmol) in CH2Cl2 (25 mL) was treated dropwise
with diethyl cyanophosphonate (DEPC) (0.42 mL, 2.8 mmol).
The dark solution was stirred at room temperature for 24 h
(gradually turned from orange to black). The reaction was
quenched with H2O and extracted with CH2Cl2 (2 × 100 mL).
The organic layers were washed with brine, dried (MgSO4),
and concentrated to give a brown oil. The crude oil was purified
on silica gel (200 g), eluting with 20:1 CH2Cl2/MeOH saturated
with NH3 to give a light yellow oil (0.58 g, 79%). 1H NMR
(CDCl3 δ): 7.40 (dd, J ) 1.1, 4.9 Hz, 1 H), 7.31 (dd, J ) 1.1,
3.7 Hz, 1 H), 7.02 (m, 1 H), 6.73 (s, 2 H), 5.12 (quintet, J ) 8.0
Hz, 1 H), 3.84 (s, 6 H), 3.35 (m, 2 H), 3.11 (d, J ) 8.0 Hz, 4 H),
1.69 (m, 2 H), 0.85 (t, J ) 7.4 Hz, 3 H). 13C NMR (CDCl3 δ):
164.8, 148.5, 138.5, 132.2, 128.2, 128.0, 126.7, 107.7, 59.3, 56.1,
37.3, 22.6, 11.5. To a slurry of LAH (0.12 g, 3.2 mmol) in THF
(50 mL) was added dropwise a solution of the amide (0.55 g,
1.6 mmol) in THF (50 mL). The reaction was stirred at room
temperature for 1.5 h followed by a slow quench with 5 N
NaOH. The mixture was transferred to an Erlenmeyer flask,
diluted with THF (300 mL), Na2SO4 was added, the mixture
was filtered and concentrated to give a yellow oil. The crude
material was purified on silica gel (200 g), eluting with hexane/
EtOAc (3:2) to give a yellow oil (0.44 g, 83%). 1H NMR (CDCl3
δ): 7.20 (dd, J ) 1.2, 5.0 Hz, 1 H), 6.95-6.90 (m, 2 H), 6.72 (s,
2 H), 3.88 (s, 2 H), 3.84 (s, 6 H), 3.77 (quintet, J ) 7.9 Hz, 1
H), 3.01 (dd, J ) 7.8, 15.1 Hz, 2 H), 2.90 (dd, J ) 7.9, 15.3 Hz,
2 H), 2.50 (m, 2 H), 1.56 (sextet, J ) 7.5 Hz, 2 H), 0.90 (t, J )
7.3 Hz, 3 H). 13C NMR (CDCl3 δ): 148.0, 144.1, 133.5, 126.4,
124.9, 124.4, 107.9, 62.4, 56.1, 52.8, 49.7, 36.4, 20.6, 11.9. The
oil was converted into an HCl salt and crystallized from hot
EtOAc/MeOH to give a white solid that was dried in a vacuum
oven: mp 210-212 °C. IR (mull): 3055, 2361, 2321, 1504, 1442,
N-(2,3-Dih ydr o-5,6-dim eth oxy-1H-in den -2-yl)-N-pr opyl-
2-th iop h en eeth a n a m in e (13c). The amide was prepared
from 9 (0.50 g, 2.1 mmol) and 2-thiopheneacetic acid (0.39 g,
2.8 mmol) using the same procedure as 13a to give a brown
oil (1.04 g). The crude product was purified on silica gel (200
g), eluting with hexane/EtOAc (1:1) to give the desired product
as a light yellow oil (0.8 g, 100%). 1H NMR indicated two
1
conformations in a 1:1 ratio. H NMR (CDCl3 δ): 7.20 (dd, J
) 1.0, 5.2 Hz, 1 H), 6.94 (m, 2 H), 6.72 (m, 2 H), 5.11 (m, 0.5
H), 4.80 (m, 0.5 H), 3.98 (s, 1 H), 3.89 (s, 1 H), 3.84 (s, 6 H),
3.22-2.91 (m, 6 H), 1.67-1.59 (m, 2 H), 0.84 (m, 3 H).13C NMR
(CDCl3 δ): 170.0, 169.6, 148.6, 148.3, 137.1, 132.8, 131.8, 126.8,
126.7, 125.9, 124.8, 124.7, 107.7, 58.9, 56.4, 56.1, 47.9, 44.9,
37.1, 36.7, 36.1, 35.6, 24.4, 22.0, 11.6, 11.4. To a slurry of LAH
(0.08 g, 2.2 mmol) in THF (10 mL) was added dropwise a
solution of the amide (0.40 g, 1.1 mmol) in THF (10 mL). The
slurry stirred at room temperature for 3.5 h, then slowly
quenched with 5 N NaOH, transferred to an Erlenmeyer flask,
and diluted with more THF (300 mL). Na2SO4 was added to
dry, then the slurry was filtered and concentrated to give an
orange oil (0.50 g). The crude material was purified on silica
gel (200 g), eluting with hexane/EtOAc (3:2) to give a yellow
oil (0.24 g, 63%). 1H NMR (CDCl3 δ): 7.13 (dd, J ) 1.1, 5.2
Hz, 1 H), 6.93 (m, 1 H), 6.81 (m, 1 H), 6.73 (s, 2 H), 3.85 (s, 6
H), 3.75 (quintet, J ) 8.0 Hz, 1 H), 2.98 (m, 4 H), 2.85 (m, 4
H), 2.55 (m, 2 H), 1.56 (m, 2 H), 0.91 (t, J ) 7.3 Hz, 3 H). 13C
NMR (CDCl3 δ): 148.1, 143.1, 133.4, 126.7, 124.5, 123.3, 107.9,
63.5, 56.1, 53.6, 53.3, 36.6, 28.1, 20.8, 12.1. The oil was
converted to the HCl salt and crystallized from hot EtOAc/
hexane. The resulting tan solid was recrystallized from hot
EtOAc to give an off-white solid: mp 84-86 °C. IR (mull):
2589, 2523, 2489, 2386, 1508, 1330, 1314, 1257, 1238, 1222,
1189, 1102, 1090, 990, 852, cm-1. % water (KF) ) 2.0; melt
solvate ) 0.02% EtOAc. MS (FAB): m/z 346 (MH+), 348, 347,
346, 248, 177, 176, 139, 111, 105, 91. HRMS (FAB) calcd for
1315, 1302, 1287, 1256, 1225, 1186, 1104, 1033, 858, 754, cm-1
.
% water (KF) ) 0.13; melt solvate ) 0.17% MeOH, 0.05%
EtOAc. MS (EI): m/z 331 (M+), 331, 303, 302, 234, 204, 203,
177, 176, 165, 97. Anal. (C19H25NO2S‚HCl‚0.13% H2O) C, H,
N.
C20H27NO2S+H: 346.1841. Found: 346.1842. Anal. (C20H27
NO2S‚HCl‚2.0% H2O) C, H, N.
-
N-(2,3-Dih ydr o-5,6-dim eth oxy-1H-in den -2-yl)-N-pr opyl-
3-th iop h en em eth a n a m in e (13b). The amide was prepared
from 9 (0.51 g, 2.2 mmol) and 3-thiophenecarboxylic acid (0.37
g, 2.9 mmol) using the same procedure as 13a to give an orange
oil. The crude product was purified on silica gel (200 g), eluting
with 4:1 hexane/EtOAc (2 L), 3:2 hexane/EtOAc (2 L) to give
the desired product as a clear oil (0.71 g, 93%). 1H NMR (CDCl3
δ): 7.49 (dd, J ) 1.2, 2.9 Hz, 1 H), 7.31 (m, 1 H), 7.20 (dd, J
) 1.3, 5.1 Hz, 1 H), 6.72 (s, 2 H), 4.92 (m, 1 H), 3.85 (s, 6 H),
3.30 (m, 2 H), 3.06 (m, 4 H), 1.66 (m, 2 H), 0.84 (m, 3 H). To
a solution of amide (0.70 g, 2.0 mmol) in THF (30 mL) was
slowly added dropwise BH3‚THF (1M, 10.0 mL, 10.0 mmol).
The yellow solution was stirred at room temperature for 2 h
and then warmed to reflux. After 2 h, the reaction was cooled
to room temperature and slowly quenched with 1 N HCl and
then concentrated. The residue was basified with saturated
Na2CO3 and then extracted with EtOAc (2 × 100 mL). The
organic layers were washed with brine, dried (MgSO4), and
N-(2,3-Dih ydr o-5,6-dim eth oxy-1H-in den -2-yl)-N-pr opyl-
3-th iop h en eeth a n a m in e (13d ). The amide was prepared
from 9 (0.50 g, 2.1 mmol) and 3-thiopheneacetic acid (0.60 g,
4.2 mmol) using the same procedure as 13a to give an orange
oil. The crude product was purified on silica gel (200 g), eluting
with 4:1 hexane/EtOAc to give the desired product as a light
yellow oil (0.75 g, 99%). NMR indicated two different confor-
1
mations in a 1:1.25 ratio. H NMR (CDCl3 δ): 7.28 (m, 1 H),
7.05 (m, 2 H), 6.70 (m, 2 H), 5.09 (quintet, J ) 8.0 Hz, 0.44
H), 4.75 (quintet, J ) 8.2 Hz, 0.56 H), 3.84 (s, 6 H), 3.81 (s, 1
H), 3.71 (s, 1 H), 3.20-2.77 (m, 6 H), 1.64 (m, 2 H), 0.84 (t, J
) 7.4 Hz, 3 H). To a solution of the amide (0.75 g, 2.1 mmol)
in THF (25 mL) was slowly added dropwise BH3‚THF (1M,
10.5 mL, 10.5 mmol). The yellow solution was warmed to reflux
for 2 h and then cooled to room temperature. The reaction was
slowly quenched with H2O and then concentrated. The residue
was diluted with 40 mL of 3:1 acetone/3N HCl, stirred for 15
min, and concentrated. The resulting residue was basified with