332
Vol. 55, No. 2
7-Isopropoxy-5,6-dimethoxy-2-{{4-[(morphorinocarbonyl)- 100%). 1H-NMR (CDCl3) d: 1.42 (6H, d, Jꢄ6.0 Hz), 1.50 (4.5H, s), 1.51
oxy]phenyl}thio}-4H-chromen-4-one (2k) Yield from 1: 80%. 1H-NMR (4.5H, s), 3.07 (1.5H, s), 3.17 (1.5H, s), 3.84 (3H, s), 3.92 (3H, s), 4.00 (1H,
(CDCl3) d: 1.42 (6H, d, Jꢄ6.4 Hz), 3.59 (2H, br s), 3.70 (2H, br s), 3.77 (4H,
m), 3.85 (3H, s), 3.92 (3H, s), 4.62 (1H, septet, Jꢄ6.4 Hz), 5.81 (1H, s),
s), 4.03 (1H, s), 4.62 (1H, septet, Jꢄ6.0 Hz), 5.83 (0.5H, s), 5.85 (0.5H, s),
6.58 (1H, s), 7.19 (1H, d, Jꢄ8.7 Hz), 7.24 (1H, d, Jꢄ8.7 Hz), 7.58 (2H, d,
6.60 (1H, s), 7.23 (2H, d, Jꢄ8.8 Hz), 7.59 (2H, d, Jꢄ8.8 Hz). IR (KBr) Jꢄ8.7 Hz). EI-MS m/z: 559 (Mꢃ).
cmꢁ1
:
1724, 1632, 1612. EI-MS m/z: 501 (Mꢃ). Anal. Calcd for
2) To a solution of the above compound (740 mg, 1.32 mmol) in
dichloromethane (7 ml) was added trifluoroacetic acid (1 ml), and the mix-
C25H27NO8S: C, 59.87; H, 5.43; N, 2.79. Found: C, 59.57; H, 5.54; N, 2.80.
7-Isopropoxy-5,6-dimethoxy-2-{{4-{[(4-methyl-1-piperazinyl)car- ture was stirred at room temperature for 24 h. After adding H2O (20 ml), the
1
bonyl]oxy}phenyl}thio}-4H-chromen-4-one (2l) Yield from 1: 90%. H-
NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.0 Hz), 2.36 (3H, s), 2.48 (4H, t,
Jꢄ5.1 Hz), 3.65 (4H, m), 3.85 (3H, s), 3.92 (3H, s), 4.62 (1H, septet,
Jꢄ6.1 Hz), 5.82 (1H, s), 6.60 (1H, s), 7.22 (2H, d, Jꢄ8.7 Hz), 7.58 (2H, d,
Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1726, 1634, 1610. EI-MS m/z: 514 (Mꢃ). Anal.
mixture was extracted with chloroform (20 mlꢀ2), dried over Na2SO4
and concentrated. The residue was purified by recrystallization from
EtOAc–hexane to give the title compound (551.3 g, 83%). 1H-NMR (ace-
tone-d6) d: 1.40 (6H, d, Jꢄ6.0 Hz), 3.06 (1.5H, s), 3.21 (1.5H, s), 3.79 (3H,
s), 3.81 (3H, s), 4.15 (1H, s), 4.27 (1H, s), 4.81 (1H, septet, Jꢄ6.0 Hz), 5.68
Calcd for C26H30NO7S: C, 60.69; H, 5.88; N, 5.44. Found: C, 60.55; H, 6.06; (0.5H, s), 5.70 (0.5H, s), 6.84 (1H, s), 7.30 (1H, d, Jꢄ8.7 Hz), 7.36 (1H, d,
N, 5.51.
Jꢄ8.7 Hz), 7.71 (1H, d, Jꢄ8.7 Hz), 7.72 (1H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1
7-Isopropoxy-5,6-dimethoxy-2-{{4-{[methyl(2-pyridyl)car- 1728, 1608. FAB-MS m/z: 504 (MHꢃ). Anal. Calcd for C24H25NO9S: C,
:
bamoyl]oxy}phenyl}thio}-4H-chromen-4-one (2m) Yield from 1: 93%.
1H-NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 3.63 (3H, s), 3.85 (3H, s), 3.92
(3H, s), 4.62 (1H, septet, Jꢄ6.1 Hz), 5.84 (1H, s), 6.59 (1H, s), 7.13 (1H, dd,
Jꢄ4.2, 8.4 Hz), 7.28 (2H, d, Jꢄ8.7 Hz), 7.61 (2H, d, Jꢄ8.7 Hz), 7.73 (2H,
57.25; H, 5.00; N, 2.78. Found: C, 57.08; H, 5.18; N, 2.78.
N-{{4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-
yl)thio]phenoxy}carbonyl}-L-proline (2u) Yield from 1: 53%. 1H-NMR
(CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 2.01—2.59 (4H, m), 3.53—3.81 (2H,
m), 8.47 (1H, m). IR (KBr) cmꢁ1: 1732, 1628, 1612, 1588. EI-MS m/z: 522 m), 3.84 (3H, s), 3.91 (1.5H, s), 3.92 (1.5H, s), 4.47—4.68 (2H, m), 5.77
(Mꢃ). Anal. Calcd for C27H26N2O7S: C, 62.06; H, 5.01; N, 5.36. Found: C, (0.5H, s), 5.86 (0.5H, s), 6.59 (0.5H, s), 6.60 (0.5H, s), 7.23 (1H, d,
61.92; H, 5.13; N, 5.39.
Jꢄ8.7 Hz), 7.27 (1H, d, Jꢄ8.7 Hz), 7.54 (1H, d, Jꢄ8.7 Hz), 7.58 (1H, d,
7-Isopropoxy-5,6-dimethoxy-2-{{4-[(methoxymethycarbamoyl)- Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1722, 1606. EI-MS m/z: 529 (Mꢃ).
oxy]phenyl}thio}-4H-chromen-4-one (2n) Yield from 1: 90%. 1H-NMR
(CDCl3) d: 1.43 (6H, d, Jꢄ6.0 Hz), 3.31 (3H, s), 3.82 (3H, s), 3.85 (3H, s),
Typical Procedure for the Preparation of the Carbamates 2v—z
(Method G). 2-{{4-{[(2-Hydroxyethyl)methylcarbamoyl]oxy}phenyl}
3.92 (3H, s), 4.62 (1H, septet, Jꢄ6.0 Hz), 5.85 (1H, s), 6.55 (1H, s), 7.28 thio}-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one (2v) 1) A mix-
(2H, d, Jꢄ8.6 Hz), 7.60 (2H, d, Jꢄ8.6 Hz). IR (KBr) cmꢁ1: 1720, 1638. EI- ture of 1 (500 mg, 1.29 mmol) and 3v (974 mg, 3.87 mmol) in pyridine
MS m/z: 475 (Mꢃ).
(5 ml) was stirred at room temperature for 24 h. After adding 3 N-HCl
7-Isopropoxy-5,6-dimethoxy-2-{{4-{[(2-methoxyethyl)methylcar- (30 ml), the mixture was extracted with EtOAc (30 mlꢀ2), dried over
bamoyl]oxy}phenyl}thio}-4H-chromen-4-one (2o) Yield from 1: 97%.
Na2SO4 and concentrated. The residue was purified by flash chromatography
1H-NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.0 Hz), 3.08 (1.5H, s), 3.18 (1.5H, s), on silica gel (hexane/EtOAcꢄ2/1) to give 2-{{4-{{[2-(tert-butyldimethyl-
3.40 (3H, s), 3.50—3.75 (4H, m), 3.85 (3H, s), 3.92 (3H, s), 4.62 (1H, siloxy)ethyl]methylcarbamoyl}oxy}phenyl}thio}-7-isopropoxy-5,6-
septet, Jꢄ6.1 Hz), 5.83 (1H, s), 6.59 (1H, s), 7.26—7.39 (2H, m), 7.57 (2H, dimethoxy-4H-chromen-4-one (793.8 mg, 100%). 1H-NMR (CDCl3) d:
d, Jꢄ8.6 Hz). IR (KBr) cmꢁ1: 1728, 1632. EI-MS m/z: 503 (Mꢃ).
0.090 (3H, s), 0.092 (3H, s), 0.92 (9H, s), 1.43 (6H, d, Jꢄ6.1 Hz), 3.09
7-Isopropoxy-5,6-dimethoxy-2-{{4-{{[(S)-2-(methoxymethyl)-1-pyrro- (1.5H, s), 3.19 (1.5H, s), 3.47 (1H, t, Jꢄ5.5 Hz), 3.56 (1H, t, Jꢄ5.5 Hz),
lidinyl]carbonyl}oxy}phenyl}thio}-4H-chromen-4-one (2p) Yield from 3.80—3.88 (2H, m), 3.84 (3H, s), 3.92 (3H, s), 4.62 (1H, septet, Jꢄ6.1 Hz),
1
1: 83%. H-NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 1.85—2.15 (4H, m),
5.82 (0.5H, s), 5.83 (0.5H, s), 6.59 (1H, s), 7.21 (1H, d, Jꢄ8.7 Hz), 7.22
3.38 (3H, s), 3.45—3.70 (4H, m), 3.85 (3H, s), 3.92 (3H, s), 4.20—4.25 (1H, d, Jꢄ8.7 Hz), 7.58 (d, 2H, Jꢄ8.7 Hz). EI-MS m/z: 603 (Mꢃ).
(1H, m), 4.62 (1H, septet, Jꢄ6.1 Hz), 5.82 (1H, s), 6.59 (1H, s), 7.25 (2H, d,
2) A solution of the above compound (716.1 mg, 1.19 mmol) in a 1%
Jꢄ8.7 Hz), 7.58 (2H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1726, 1630, 1612. EI- solution of 36% HCl in EtOH (10 ml) was stirred at room temperature for
MS m/z: 529 (Mꢃ). Anal. Calcd for C27H31NO8S: C, 61.23; H, 5.90; N, 2.64. 1 h. After adding H2O (30 ml), the mixture was extracted with EtOAc
Found: C, 61.27; H, 5.96; N, 2.74.
(30 mlꢀ2), dried over Na2SO4 and concentrated. The residue was purified by
{{{4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl)thio]phe- flash chromatography on silica gel (hexane/EtOAcꢄ1/5) to give the title
1
noxy}carbonyl}methylamino}acetonitrile (2q) Yield from 1: 100%. H-
compound (467.5 mg, 80%). Recrystallization from EtOAc–hexane afforded
1
NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 3.16 (1.2H, s), 3.26 (1.8H, s), 3.85 colorless crystals. H-NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 3.10 (1.5H,
(3H, s), 3.92 (3H, s), 4.36 (1.2H, s), 4.39 (0.8H, s), 4.62 (1H, septet, s), 3.20 (1.5H, s), 3.50—3.65 (2H, m), 3.85 (3H, s), 3.80—3.90 (2H, m),
Jꢄ6.1 Hz), 5.85 (1H, s), 6.58 (1H, s), 7.24 (2H, d, Jꢄ8.7 Hz), 7.61 (2H, d,
3.92 (3H, s), 4.62 (1H, septet, Jꢄ6.1 Hz), 5.83 (1H, s), 6.59 (1H, s), 7.24
Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1736, 1638, 1608, 1582. EI-MS m/z: 484 (Mꢃ). (2H, d, Jꢄ8.7 Hz), 7.58 (2H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1726, 1612. EI-
Anal. Calcd for C24H24N2O7S: C, 59.49; H, 4.99; N, 5.78. Found: C, 59.54; MS m/z: 489 (Mꢃ). Anal. Calcd for C24H27NO8S: C, 58.88; H, 5.56; N, 2.86.
H, 5.01; N, 5.85.
Found: C, 58.77; H, 5.56; N, 2.89.
{{{4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-yl)thio]phe-
2-{{4-{[(4-Hydroxypiperidino)carbonyl]oxy}phenyl}thio}-7-iso-
noxy}carbonyl}imino}diacetonitrile (2r) Yield from 1: 88%. 1H-NMR propoxy-5,6-dimethoxy-4H-chromen-4-one (2w) Yield from 1: 57%. 1H-
(acetone-d6) d: 1.40 (6H, d, Jꢄ6.0 Hz), 3.79 (3H, s), 3.82 (3H, s), 4.60— NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.0 Hz), 1.53—1.76 (2H, m), 1.94—2.05
4.90 (5H, m), 5.75 (1H, s), 6.84 (1H, s), 7.47 (2H, d, Jꢄ8.7 Hz), 7.79 (2H, d, (2H, m), 3.34—3.55 (2H, m), 3.85 (3H, s), 3.92 (3H, s), 3.93—4.02 (3H,
Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1742, 1636, 1610. EI-MS m/z: 509 (Mꢃ). Anal.
m), 4.62 (1H, septet, Jꢄ6.0 Hz), 5.82 (1H, s), 6.59 (1H, s), 7.22 (2H, d,
Calcd for C25H23N3O7S: C, 58.93; H, 4.55; N, 8.25. Found: C, 58.79; H, Jꢄ8.7 Hz), 7.58 (2H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1730, 1610. EI-MS m/z:
4.61; N, 8.32.
515 (Mꢃ).
Diethyl {{{4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2-
2-{{4-{{[(S)-2-(Hydroxymethyl)-1-pyrolidinyl]carbonyl}oxy}-
yl)thio]phenoxy}carbonyl}imino}diacetate (2s) Yield from 1: 100%. 1H- phenyl}thio}-7-isopropoxy-5,6-dimethoxy-4H-chromen-4-one
(2x)
Yield from 1: 89%. 1H-NMR (CDCl3) d: 1.43 (6H, d, Jꢄ6.0 Hz), 2.17—
d, Jꢄ6.1 Hz), 3.84 (3H, s), 3.92 (3H, s), 4.20—4.32 (8H, m), 4.62 (1H, 1.86 (4H, m), 3.57—3.75 (4H, m), 3.85 (3H, s), 3.92 (3H, s), 3.99—4.30
NMR (CDCl3) d: 1.30 (3H, t, Jꢄ7.1 Hz), 1.32 (3H, t, Jꢄ7.1 Hz), 1.42 (6H,
septet, Jꢄ6.1 Hz), 5.84 (1H, s), 6.58 (1H, s), 7.22 (2H, d, Jꢄ8.7 Hz), 7.58
(2H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1: 1754, 1728, 1632, 1610. Anal. Calcd for
C29H33NO11S: C, 57.70; H, 5.51; N, 2.32. Found: C, 57.60; H, 5.60; N, 2.36.
Typical Procedure for the Preparation of the Carbamates 2t—u
(1H, m), 4.62 (1H, septet, Jꢄ6.0 Hz), 5.83 (1H, s), 6.59 (1H, s), 7.26 (2H, d,
Jꢄ8.6 Hz), 7.59 (2H, d, Jꢄ8.6 Hz). IR (KBr) cmꢁ1: 1724, 1622. EI-MS m/z:
515 (Mꢃ).
2-{{4-{[Bis(2-hydroxyethyl)carbamoyl]oxy}phenyl}thio}-7-isopropoxy-
(Method F). {{{4-[(7-Isopropoxy-5,6-dimethoxy-4-oxo-4H-chromen-2- 5,6-dimethoxy-4H-chromen-4-one (2y) Yield from 1: 67%. 1H-NMR
yl)thio]phenoxy}carbonyl}methylamino}acetic Acid (2t) 1) A mixture
of 1 (518.2 mg, 1.34 mmol) and 3t (1.00 g) in pyridine (6 ml) was stirred at (3H, s), 3.90—3.96 (4H, m), 4.62 (1H, septet, Jꢄ6.1 Hz), 5.80 (1H, s), 6.60
room temperature for 20 h. After adding 3 N-HCl (20 ml), the mixture was
extracted with EtOAc (30 mlꢀ2), dried over Na2SO4 and concentrated. The
(CDCl3) d: 1.43 (6H, d, Jꢄ6.1 Hz), 3.58—3.70 (4H, m), 3.84 (3H, m), 3.91
(1H, s), 7.24 (2H, d, Jꢄ8.7 Hz), 7.59 (2H, d, Jꢄ8.7 Hz). IR (KBr) cmꢁ1
:
1720, 1702, 1630, 1612. FAB-MS m/z: 520 (MHꢃ). Anal. Calcd for
residue was purified by flash chromatography on silica gel (hexane/ C25H29NO9S: C, 57.79; H, 5.63; N, 2.70. Found: C, 57.63; H, 5.70; N, 2.69.
EtOAcꢄ10/7) to give tert-butyl {{{4-[(7-isopropoxy-5,6-dimethoxy-4-oxo-
2-{{4-{[(3-Hydroxypropyl)methylcarbamoyl]oxy}phenyl}thio}-7-iso-
4H-chromen-2-yl)thio]phenoxy}carbonyl}methylamino}acetate (776.7 mg, propoxy-5,6-dimethoxy-4H-chromen-4-one (2z) Yield from 1: 79%. H-
1