1528 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 7
Momose et al.
8 Hz). 11d : 1H NMR (CDCl3): δ 2.43 (3H, s), 3.91 (3H, s), 5.11
(2H, s), 6.5-6.7 (2H, m), 6.97 (1H, d, J ) 3 Hz), 7.05-7.2 (3H,
m), 7.42 (1H, d, J ) 16 Hz), 7.5-7.6 (1H, m), 9.67 (1H, d, J )
8 Hz). IR (KBr) (cm-1): 1670, 1620, 1595, 1510. 11e: 1H NMR
(CDCl3): δ 2.45 (3H, s), 5.04 (2H, s), 6.72 (1H, dd, J ) 16, 7.5
Hz), 7.05-7.5 (8H, m), 7.95-8.1 (2H, m), 9.71 (1H, d, J ) 7.5
Hz). 11f: 1H NMR (CDCl3): δ 2.43 (3H, s), 5.10 (2H, s), 6.76
(1H, dd, J ) 16, 8 Hz), 7.04 (1H, t, J ) 7.5 Hz), 7.15 (1H, d, J
) 8 Hz), 7.35-7.5 (4H, m), 7.58 (1H, dd, J ) 8, 1.5 Hz), 7.88
(1H, d, J ) 16 Hz), 7.95-8.1 (2H, m), 9.66 (1H, d, J ) 8 Hz).
IR (KBr) (cm-1): 1665, 1615, 1595, 1555. 11h : 1H NMR
(CDCl3): δ 2.50 (3H, s), 5.36 (2H, s), 6.64 (1H, dd, J ) 16, 7.5
Hz), 6.89 (1H, d, J ) 9 Hz), 7.35-7.5 (4H, m), 7.82 (1H, dd, J
) 9, 2.5 Hz), 7.95-8.1 (2H, m), 8.35 (1H, d, J ) 2.5 Hz), 9.68
(1H, d, J ) 7.5 Hz). IR (KBr) (cm-1): 1680, 1640, 1620, 1595,
1555. 11i: 1H NMR (CDCl3): δ 1.37 (6H, d, J ) 6 Hz), 4.5-
4.7 (1H, m), 6.61 (1H, dd, J ) 16, 8 Hz), 6.92 (2H, d, J ) 9
Hz), 7.42 (1H, d, J ) 16 Hz), 7.51 (2H, d, J ) 9 Hz), 9.65 (1H,
d, J ) 8 Hz). IR (neat) (cm-1): 1670, 1620, 1600, 1565, 1505.
11j: 1H NMR (CDCl3): δ 1.36 (6H, d, J ) 6 Hz), 4.5-4.7 (1H,
m), 6.22 (1H, dd, J ) 15, 8 Hz), 6.8-7.05 (4H, m), 7.26 (1H,
dd, J ) 15, 10 Hz), 7.44 (2H, d, J ) 9 Hz), 9.59 (1H, d, J ) 8
Hz). IR (neat) (cm-1): 1670, 1615, 1590, 1565, 1505. 11k : 1H
NMR (CDCl3): δ 2.38 (3H, s), 3.00 (2H, t, J ) 7 Hz), 4.28 (2H,
t, J ) 7 Hz), 6.22 (1H, dd, J ) 15, 8 Hz), 6.75-7.05 (4H, m),
7.15-7.5 (4H, m), 7.9-8.05 (2H, m), 9.59 (1H, d, J ) 8 Hz).
IR (KBr) (cm-1): 1670, 1645, 1615, 1590, 1550, 1505.
solvents, melting points, and elemental analyses were listed
in Tables 4-6. 17b: 1H NMR (CDCl3): δ 1.32 (6H, d, J ) 6
Hz), 1.6-2.3 (4H, m), 2.61 (2H, t, J ) 7.5 Hz), 4.28 (1H, dd, J
) 8.5, 4.5 Hz), 4.4-4.65 (1H, m), 6.82 (2H, d, J ) 8.5 Hz),
7.06 (2H, d, J ) 8.5 Hz), 8.34 (1H, br s). IR (neat) (cm-1): 3200,
3060, 1750, 1700, 1690, 1605, 1575, 1505. 17d : 1H NMR
(CDCl3): δ 1.2-1.75 (6H, m), 1.32 (6H, d, J ) 6 Hz), 1.8-2.3
(2H, m), 2.54 (2H, t, J ) 7.5 Hz), 4.26 (1H, dd, J ) 9, 4.5 Hz),
4.4-4.6 (1H, m), 6.80 (2H, d, J ) 8.5 Hz), 7.05 (2H, d, J ) 8.5
Hz), 8.06 (1H, br s). IR (neat) (cm-1): 3200, 1750, 1700, 1690,
1605, 1505. 17e: 1H NMR (CDCl3): δ 1.32 (6H, d, J ) 6 Hz),
1.65-2.15 (4H, m), 2.62 (2H, t, J ) 7 Hz), 4.4-4.6 (1H, m),
4.84 (1H, dd, J ) 7, 4.5 Hz), 6.81 (2H, d, J ) 8.5 Hz), 7.06
(2H, d, J ) 8.5 Hz), 8.00 (1H, br s). IR (neat) (cm-1): 3210,
3050, 1820, 1750, 1605, 1505. 17g: 1H NMR (CDCl3): δ 1.32
(6H, d, J ) 6 Hz), 1.3-2.1 (8H, m), 2.54 (2H, t, J ) 7.5 Hz),
4.4-4.6 (1H, m), 4.84 (1H, dd, J ) 7.5, 4.5 Hz), 6.80 (2H, d, J
) 8.5 Hz), 7.05 (2H, d, J ) 8.5 Hz), 7.98 (1H, br s). IR (neat)
(cm-1): 3230, 1825, 1750, 1610, 1505. 37: 1H NMR (CDCl3):
δ 1.55-2.3 (4H, m), 2.41 (3H, s), 2.63 (2H, t, J ) 7 Hz), 3.86
(3H, s), 4.27 (1H, dd, J ) 8, 4.5 Hz), 5.03 (2H, s), 6.6-6.75
(2H, m), 6.97 (1H, d, J ) 8.5 Hz), 7.35-7.5 (3H, m), 7.95-
8.05 (2H, m), 8.14 (1H, br s). IR (KBr) (cm-1): 3160, 3050, 1745,
1690, 1510. 40: 1H NMR (CDCl3): δ 1.6-2.1 (4H, m), 2.37 (3H,
s), 2.60 (2H, t, J ) 7 Hz), 2.97 (2H, t, J ) 6.5 Hz), 4.21 (2H, t,
J ) 6.5 Hz), 4.81 (1H, dd, J ) 7, 4.5 Hz), 6.82 (2H, d, J ) 8.5
Hz), 7.05 (2H, d, J ) 8.5 Hz), 7.3-7.5 (3H, m), 7.9-8.05 (2H,
m), 8.40 (1H, br s). 42: 1H NMR (CDCl3): δ 1.25-2.1 (8H, m),
2.38 (3H, s), 2.54 (2H, t, J ) 7.5 Hz), 2.97 (2H, t, J ) 6.5 Hz),
4.22 (2H, t, J ) 6.5 Hz), 4.81 (1H, dd, J ) 7, 4.5 Hz), 6.82 (2H,
d, J ) 8.5 Hz), 7.05 (2H, d, J ) 8.5 Hz), 7.35-7.5 (3H, m),
7.9-8.0 (2H, m), 8.14 (1H, br s). IR (KBr) (cm-1): 1820, 1745,
1645, 1605, 1545, 1510. 45: 1H NMR (CDCl3): δ 1.6-2.1 (4H,
m), 2.43 (3H, s), 2.62 (2H, t, J ) 7 Hz), 4.80 (1H, dd, J ) 7, 4.5
Hz), 4.97 (2H, s), 6.94 (2H, d, J ) 8.5 Hz), 7.09 (2H, d, J ) 8.5
Hz), 7.35-7.5 (3H, m), 7.9-8.05 (2H, m), 8.55 (1H, br s). 49:
1H NMR (CDCl3): δ 1.75-2.1 (4H, m), 2.38 (3H, s), 2.73 (2H,
t, J ) 7 Hz), 2.93 (2H, t, J ) 7 Hz), 3.39 (2H, t, J ) 7 Hz), 4.85
(1H, dd, J ) 6.5, 4.5 Hz), 7.25 (2H, d, J ) 8 Hz), 7.35-7.5
(3H, m), 7.9-8.1 (5H, m). IR (KBr) (cm-1): 1820, 1740, 1685,
1655, 1605, 1550. 52: 1H NMR (DMSO-d6): δ 2.47 (3H, s),
5.06 (2H, s), 6.55-7.2 (5H, m), 7.45-7.6 (3H, m), 7.60 (2H, d,
J ) 9 Hz), 7.9-8.0 (2H, m), 12.26 (1H, br s). 53: 1H NMR
(CDCl3): δ 1.6-2.1 (4H, m), 2.45 (3H, s), 2.66 (2H, t, J ) 7
Hz), 4.79 (1H, dd, J ) 6.5, 4.5 Hz), 4.99 (2H, s), 6.7-6.9 (3H,
m), 7.15-7.3 (1H, m), 7.4-7.5 (3H, m), 7.95-8.1 (2H, m), 8.46
(1H, br s). 54: 1H NMR (DMSO-d6): δ 1.5-1.9 (4H, m), 2.44
(3H, s), 2.60 (2H, t, J ) 7 Hz), 4.96 (1H, dd, J ) 6.5, 4.5 Hz),
5.03 (2H, s), 6.85-6.95 (1H, m), 7.1-7.25 (3H, m), 7.45-7.6
(3H, m), 7.9-8.0 (2H, m), 11.81 (1H, br s). IR (KBr) (cm-1):
3420, 1820, 1745. 62: 1H NMR (CDCl3): δ 1.7-2.15 (4H, m),
2.48 (3H, s), 2.61 (2H, t, J ) 7 Hz), 4.84 (1H, dd, J ) 6.5, 4.5
Hz), 5.27 (2H, s), 6.76 (1H, d, J ) 8.5 Hz), 7.3-7.5 (4H, m),
7.95-8.1 (3H, m), 8.84 (1H, br s). IR (KBr) (cm-1): 1820, 1745,
1600, 1565, 1550. 63: 1H NMR (CDCl3): δ 1.7-2.1 (4H, m),
2.41 (3H, s), 2.63 (2H, t, J ) 7 Hz), 3.86 (3H, s), 4.82 (1H, dd,
J ) 7, 4.5 Hz), 5.03 (2H, s), 6.65-6.75 (2H, m), 6.96 (1H, d, J
) 9 Hz), 7.35-7.5 (3H, m), 7.95-8.1 (2H, m), 8.11 (1H, br s).
IR (KBr) (cm-1): 3050, 1815, 1745, 1515. 64: 1H NMR
(CDCl3): δ 1.7-2.15 (4H, m), 2.40 (3H, s), 2.62 (2H, t, J ) 7
Hz), 3.85 (3H, s), 4.82 (1H, dd, J ) 7, 4.5 Hz), 5.03 (2H, s),
6.51 (1H, dd, J ) 3.5, 2 Hz), 6.65-6.75 (2H, m), 6.85-7.05
(2H, m), 7.5-7.6 (1H, m), 8.53 (1H, br s). IR (KBr) (cm-1):
3000, 1820, 1745, 1515.
4-(5-Meth yl-2-p h en yl-4-oxa zolep r op ion yl)cin n a m a ld e-
h yd e (11g). A mixture of 4-(5-methyl-2-phenyl-4-oxazolepro-
pionyl)benzaldehyde (6.00 g, 18.8 mmol), formylmethylene
triphenylphosphorane (6.29 g, 20.7 mmol), and benzene (100
mL) was refluxed for 24 h. After the solvent was removed, the
residue was purified by column chromatography on SiO2 (200
g). Elution with AcOEt-hexane (1:2, v/v) gave the title
compound as crystals (11g, 4.08 g, 63%). Recrystallization from
CH2Cl2-isoPr2O gave colorless prisms; mp 119-120 °C. 1H
NMR (CDCl3): δ 2.38 (3H, s), 2.95 (2H, t, J ) 7 Hz), 3.42 (2H,
t, J ) 7 Hz), 6.77 (1H, dd, J ) 16, 7.5 Hz), 7.35-7.5 (3H, m),
7.5 (1H, d, J ) 16 Hz), 7.64 (2H, d, J ) 8.5 Hz), 7.9-8.0 (2H,
m), 8.04 (2H, d, J ) 8.5 Hz). IR (KBr) (cm-1): 1675, 1640, 1620,
1600, 1550. Anal. (C22H19NO3) C, H, N.
Gen er a l P r oced u r e for 5-P r op yl- or 5-P en tyl-2,4-th ia -
(oxa )zolid in ed ion es 12 (n ) 3 or 5 in Ta bles 4-6). 5-[3-
[4-[2-(5-Meth yl-2-p h en yl-4-oxa zolyl)eth oxy]p h en yl]p r o-
p yl]-2,4-th ia zolid in ed ion e (32). A mixture of 11b (2.50 g,
7.50 mmol), 2,4-thiazolidinedione (878 mg, 7.50 mmol), pip-
eridine (192 mg, 2.25 mmol), and EtOH (50 mL) was refluxed
for 3 h. The reaction mixture was poured into water, acidified
with 2 N HCl, and extracted with AcOEt. The extract was
washed with water, dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography on SiO2
(60 g). Elution with AcOEt-CHCl3 (1:10, v/v) gave 5-[3-[4-[2-
(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propenylidene]-
2,4-thiazolidinedione as crystals (38, 780 mg, 24%). Recrys-
tallization from CHCl3-MeOH gave yellow needles; mp 222-
223 °C. 1H NMR (dimethyl sulfoxide (DMSO)-d6): δ 2.37 (3H,
s), 2.95 (2H, t, J ) 6.5 Hz), 4.27 (2H, t, J ) 6.5 Hz), 6.76 (1H,
dd, J ) 7.5, 5.5 Hz), 6.98 (2H, d, J ) 8.5 Hz), 7.22 (1H, d, J )
7.5 Hz), 7.4-7.55 (4H, m), 7.60 (2H, d, J ) 8.5 Hz), 7.85-8.0
(2H, m). Anal. (C24H20N2O4S) C, H, N.
A solution of 38 (433 mg, 1.0 mmol) in 1,4-dioxane (40 mL)-
EtOH (40 mL) was hydrogenated on 5% Pd-C (50% wet, 1.50
g) under atmospheric pressure. After the catalyst was removed
by filtration, the filtrate was concentrated in vacuo to give the
title compound as crystals (32, 235 mg, 54%). Recrystallization
from AcOEt-hexane gave colorless prisms; mp 151-152 °C.
1H NMR (CDCl3): δ 1.06-2.3 (4H, m), 2.38 (3H, s), 2.61 (2H,
t, J ) 7 Hz), 2.97 (2H, t, J ) 6.5 Hz), 4.15-4.3 (3H, m), 6.83
(2H, d, J ) 8.5 Hz), 7.06 (2H, d, J ) 8.5 Hz), 7.35-7.5 (3H,
m), 7.9-8.0 (2H, m), 8.18 (1H, br s). Anal. (C24H24N2O4S) C,
H, N. Compounds 17b, 17d , and 37 were obtained similarly.
Compounds 17e, 17g, 40, 42, 45, 49, 52-54, and 62-64 were
also prepared similarly by treatment with 2,4-oxazolidinedione
instead of 2,4-thiazolidinedione. The yields, recrystallization
Meth od B. 4-[2-[4-[3-(1,3-Dioxa n -2-yl)p r op yl]p h en oxy]-
eth yl]-5-m eth yl-2-p h en yloxa zole (13a ). Sodium hydride
(60% in oil, 780 mg, 19.5 mmol) was added gradually to a
stirred solution of [2-(1,3-dioxan-2-yl)ethyl]triphenylphospho-
nium bromide (8.93 g, 19.5 mmol) in DMF (100 mL) at room
temperature. After the mixture was stirred for 30 min, 4-[2-
(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.00 g)
was added to the mixture. The resultant was stirred at room
temperature for 15 h and at 70 °C for 5 h. The reaction mixture
was poured into water, acidified with 2 N HCl, and extracted