Indan Derivatives as Melatonin Receptor Agonists
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4233
1
was dissolved in ethyl acetate. This solution was washed with
water and saturated aqueous NaHCO3 and dried over anhy-
drous magnesium sulfate. The filtrate was concentrated, and
the residue was purified by column chromatography to yield
0.163 g (89%) of 19; mp 133-134 °C (from ethyl acetate/
acetate). H NMR (CDCl3): δ 1.16 (t, 3H, J ) 7.5), 1.50-1.80
(m, 2H), 1.90-2.12 (m, 1H), 2.20-2.40 (m, 1H), 2.24 (q, 2H, J
) 7.5), 2.65-2.95 (m, 2H), 3.00-3.18 (m, 1H), 3.38 (q, 2H, J
) 7.1), 5.82 (br s, 1H), 6.86 (s, 1H), 7.27 (s, 1H), hidden (1H).
Anal. (C14H18BrNO2) C, H, N, Br.
1
hexane). H NMR (CDCl3): δ 2.68 (t, 2H, J ) 5.9), 3.08 (t, 2H,
N-[2-(5-Br om o-6-(isop r op en yloxy)-2,3-d ih yd r o-1H -in -
d en -1-yl)eth yl]p r op ion a m id e (29). A 60% suspension of
sodium hydride in mineral oil (0.648 g, 16.2 mmol) was added
slowly to an ice-cooled solution of 28 (4.21 g, 13.5 mmol) in
DMF (50 mL). After 30 min, by which time gas evolution had
ceased, 3-chloro-2-methylpropane (3.67 g, 40.5 mmol) was
added cautiously, and stirring was continued at 0 °C for 90
min. The mixture was made slightly acidic by the careful
addition of a few drops of dilute HCl and then partitioned
between ethyl acetate and H2O. The organic layer was washed
with water and dried over anhydrous magnesium sulfate. The
filtrate was concentrated, and the residue was purified by
column chromatography with hexane/ethyl acetate (1:2) as
eluent to yield 4.15 g (84%) of 29; mp 105-108 °C (from ethyl
acetate/hexane). 1H NMR (CDCl3): δ 1.16 (t, 3H, J ) 7.6), 1.86
(s, 3H), 1.9-2.4 (m, 6H), 2.80 (m, 2H), 3.08 (m, 1H), 3.38 (q,
2H, J ) 7.6), 4.47 (s, 2H), 5.00 (s, 1H), 5.17 (s, 1H), 5.40 (br s,
1H), 6.76 (s, 1H), 7.37 (s, 1H). Anal. (C18H24BrNO2) C, H, N,
Br.
N-[2-(5-Br om o-6-h yd r oxy-7-(2-m eth yl-2-p r op en yl)-2,3-
d ih yd r o-1H-in d en -1-yl)eth yl]p r op ion a m id e (30). A sus-
pension of 29 (4.29 g, 11.7 mmol) in N,N-diethylaniline (30
mL) was heated at 200-205 °C for 2.5 h under an atmosphere
of argon. The excess N,N-diethylaniline was removed in vacuo.
The residual oil was taken up in ethyl acetate, washed
successively with a brine solution and H2O, and then dried
over anhydrous magnesium sulfate. The filtrate was concen-
trated, and the residue was purified by column chromatogra-
phy with hexane/ethyl acetate (2:1) as eluent to yield 3.90 g
(91%) of 30; mp 89-91 °C (from ethyl acetate/hexane). 1H NMR
(CDCl3): δ 1.14 (t, 3H, J ) 7.6), 1.40-1.80 (m, 2H), 1.80 (s,
3H), 1.90-2.10 (m, 2H), 2.17 (q, 2H, J ) 7.6), 2.60-3.50 (m,
7H), 4.49 (s, 1H), 4.79 (s, 1H), 5.32 (br s, 1H), 5.47 (s, 1H),
7.21 (s, 1H). Anal. (C18H24BrNO2) C, H, N, Br.
J ) 5.9), 3.47 (t, 2H, J ) 8.8), 4.65 (t, 2H, J ) 8.8), 7.01 (d,
1H, J ) 8.1), 7.21 (d, 1H, J ) 8.1). Anal. (C11H10O2) C, H.
2-(1,2,6,7-Tetr a h yd r o-8H-in d en o[5,4-b]fu r a n -8-ylid en e-
)a ceton itr ile (20). Compound 20 was prepared in 60% yield
from 19 by a method similar to that described for 10; mp 149-
151 °C (from methanol). 1H NMR (CDCl3): δ 3.00-3.20 (m,
4H), 3.31 (t, 2H, J ) 8.8), 4.67 (t, 2H, J ) 8.8), 5.45 (t, 1H, J
) 2.4), 6.86 (d, 1H, J ) 8.1), 7.11 (d, 1H, J ) 8.1). Anal. (C13H11
-
NO) C, H, N.
2-(1,6,7,8-Tetr a h yd r o-2H-in d en o[5,4-b]fu r a n -8-yl)eth yl-
a m in e (21). Compound 21 was prepared in 81% yield from
1
20 by a method similar to that described for 11 as an oil. H
NMR (CDCl3): δ 1.42-2.35 (m, 4H), 2.64-2.98 (m, 4H), 3.01-
3.38 (m, 3H), 4.41-4.70 (m, 2H), 6.61 (d, 1H, J ) 8.1), 6.95 (d,
1H, J ) 8.1), hidden (2H).
N-[2-(1,6,7,8-Tet r a h yd r o-2H -in d en o[5,4-b]fu r a n -8-yl)-
eth yl]a ceta m id e (22a ). Acetic anhydride (0.050 mL, 0.528
mmol) was added all at once to a vigorously stirred solution
of 21 (71.6 mg, 0.352 mmol) and aqueous 1 N NaOH (1.5 mL)
in tetrahydrofuran (1.5 mL) at room temperature. After the
mixture was stirred for 30 min at room temperature, ethyl
acetate and water were added. The organic layer was washed
with brine and dried over anhydrous magnesium sulfate. The
filtrate was concentrated to give a solid, which was recrystal-
lized from a mixture of ethyl acetate and hexane to yield 57.0
mg (66%) of 22a ; mp 78-79 °C (from ethyl acetate/hexane).
1H NMR (CDCl3): δ 1.53-2.12 (m, 3H), 1.96 (s, 3H), 2.20-
2.38 (m, 1H), 2.70-2.96 (m, 2H), 3.02-3.40 (m, 5H), 4.45-
4.68 (m, 2H), 5.46 (br s, 1H), 6.62 (d, 1H, J ) 8.0), 6.96 (d, 1H,
J ) 8.0). Anal. (C15H19NO2) C, H, N.
N-[2-(1,6,7,8-Tet r a h yd r o-2H -in d en o[5,4-b]fu r a n -8-yl)-
eth yl]p r op ion a m id e (22b). Compound 22b was prepared in
78% yield from propionyl chloride and 21 by a method similar
to that described for 22a ; mp 102-104 °C (from isopropyl
ether/hexane). 1H NMR (CDCl3): δ 1.14 (t, 3H, J ) 7.6), 1.55-
2.38 (m, 4H), 2.18 (q, 2H, J ) 7.6), 2.69-2.99 (m, 2H), 3.02-
3.40 (m, 5H), 4.42-4.63 (m, 2H), 5.61 (br s, 1H), 6.62 (d, 1H,
J ) 7.8), 6.95 (d, 1H, J ) 7.8). Anal. (C16H21NO2) C, H, N.
N-[2-(1,6,7,8-Tet r a h yd r o-2H -in d en o[5,4-b]fu r a n -8-yl)-
et h yl]b u t a n a m id e (22c). Compound 22c was prepared in
67% yield from butyryl chloride and 21 by a method similar
to that described for 22a ; mp 55-57 °C (from ethyl acetate).
1H NMR (CDCl3): δ 0.94 (t, 3H, J ) 7.3), 1.51-1.90 (m, 4H),
1.92-2.08 (m, 1H), 2.12 (t, 2H, J ) 7.3), 2.17-2.38 (m, 1H),
2.68-2.98 (m, 2H), 3.00-3.40 (m, 5H), 4.41-4.68 (m, 2H), 5.43
(br s, 1H), 6.62 (d, 1H, J ) 8.0), 6.96 (d, 1H, J ) 8.0). Anal.
(C17H23NO2) C, H, N.
N-[2-(2,2-Dim eth yl-1,6,7,8-tetr a h yd r o-2H-in d en o[5,4-b]-
fu r a n -8-yl)eth yl]p r op ion a m id e (31). Boron trifluoride di-
ethyl etherate (4.12 mL, 32.5 mmol) was added slowly to an
ice-cooled solution of 30 (2.38 g, 6.50 mmol) in dichloromethane
(40 mL), and stirring was continued at 0 °C for 3 h. The
reaction mixture was poured into ice-water and extracted with
ethyl acetate. The organic layer was washed with water and
saturated aqueous NaHCO3 and dried over anhydrous mag-
nesium sulfate. The filtrate was concentrated to give a solid,
which was recrystallized from a mixture of ethyl acetate and
isopropyl ether to yield 2.12 g (89%) of N-[2-(4-bromo-2,2-
dimethyl-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]-
propionamide; mp 98-101 °C (from ethyl acetate/isopropyl
1
ether). H NMR (CDCl3): δ 1.15 (t, 3H, J ) 7.5), 1.48 (s, 3H),
1.54 (s, 3H), 1.76-2.02 (m, 2H), 2.19 (q, 2H, J ) 7.5), 2.25-
2.38 (m, 1H), 2.62-3.16 (m, 6H), 3.32 (q, 2H, J ) 5.3), 5.41
(br s, 1H), 7.11 (s, 1H). Anal. Calcd for C18H24BrNO2: C, 59.02;
H, 6.60; N, 3.82; Br, 21.81. Found: C, 58.94; H, 6.48; N, 3.98;
Br, 21.97.
A solution of the propionamide (1.06 g, 2.90 mmol) and Et3N
(0.808 mL, 5.80 mmol) in ethanol (15 mL) was subjected to
hydrogenation in the presence of 10% palladium on carbon
(0.11 g, containing 50% water) in a hydrogen atmosphere at
room temperature for 1 h and 50 °C for 30 min. After hydrogen
absorption had ceased, the catalyst was removed by filtration.
N-[2-(5-Br om o-6-m eth oxy-2,3-d ih yd r o-1H-in d en -1-yl)-
eth yl]p r op ion a m id e (27). Compound 27 was prepared in
86% yield from bromine and N-[2-(6-methoxy-2,3-dihydro-1H-
inden-1-yl)ethyl]propionamide (26) by a method similar to that
described for 15; mp 105-107 °C (from ethyl acetate). 1H NMR
(CDCl3): δ 1.16 (t, 3H, J ) 7.6), 1.49-1.82 (m, 2H), 1.98-
2.41 (m, 2H), 2.21 (q, 2H, J ) 7.6), 2.71-2.90 (m, 2H), 3.00-
3.20 (m, 1H), 3.39 (q, 2H, J ) 7.1), 3.88 (s, 3H), 5.50 (br s,
1H), 6.78 (s, 1H), 7.37 (s, 1H). Anal. (C15H20BrNO2) C, H, N.
N-[2-(5-Br om o-6-h yd r oxy-2,3-d ih yd r o-1H-in d en -1-yl)-
eth yl]p r op ion a m id e (28). A solution of 27 (26.0 g, 79.7
mmol) in dichloromethane (400 mL) was cooled to -20 °C in
a solid CO2-CCl4 bath, and BBr3 (40.1 g, 0.160 mol) was then
added slowly by syringe. The reaction was allowed to proceed
for 1 h as the cooling bath gradually warmed to room
temperature. The reaction mixture was poured into ice-water
and extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium
sulfate. The filtrate was concentrated, and the residue was
purified by column chromatography with ethyl acetate as
eluent to yield 21.4 g (86%) of 28; mp 149-151 °C (from ethyl
The filtrate was concentrated and recrystallized from
a
mixture of ethyl acetate and isopropyl ether to yield 0.635 g
(76%) of 31; mp 69-72 °C (from ethyl acetate/isopropyl ether).
1H NMR (CDCl3): δ 1.14 (s, 3H), 1.43 (s, 3H), 1.50 (s, 3H),
1.60-2.10 (m, 2H), 2.13 (q, 2H, J ) 7.5), 2.24-2.40 (m, 1H),
2.60-3.20 (s, 6H), 3.35 (q, 2H, J ) 5.3), 5.39 (br s, 1H), 6.55
(d, 1H, J ) 7.6), 6.95 (d, 1H, J ) 7.6). Anal. (C18H25NO2) C, H,
N.
2-(6,7-Dim e t h oxy-2,3-d ih yd r o-1H -in d e n -1-ylid e n e )-
a ceton itr ile (33). Compound 33 was prepared in 81% yield