Tricyclic Pyridones Containing a Fused Seven-Membered Ring
followed by sodium hydride (60% in mineral oil) (0.71 g, 17.8
mmol) in portions over 20 min. The mixture was stirred at
-10 °C for 15 min and allowed to warm to room temperature
for 3 h before being slowly poured into NH4Cl solution (200
mL, saturated aqueous). The aqueous was extracted with
EtOAc (3 × 100 mL). The combined organics were washed with
water (3 × 50 mL) and brine (2 × 50 mL) and dried (Na2SO4)
and the solvent was removed in vacuo. The residue was
purified by flash chromatography (15% EtOAc/hexanes) to
afford the title compound as an oil (1.69 g, 75%). 1H NMR (400
MHz, CDCl3) mixture of ketone and enol tautomers, enol
reported, δ 0.00 (6H, s), 0.84 (9H, s), 1.80 (2H, pentet, J ) 6),
2.14 (3H, s), 2.60-2.70 (1H, m), 2.73-2.83 (1H, m), 3.61 (2H,
t, J ) 6), 3.70 (3H, s), 6.71-6.75 (1H, m), 6.80-6.86 (1H, m),
6.95-7.03 (3H, m), 7.97 (1H, s), 8.20 (1H, d, J ) 5), 13.17 (1H,
s); MS (ES+) m/z 442 (M + H+).
mide (2) (1.06 g, 6.76 mmol) was added to a solution of 12a
(2.3 g, 5.41 mmol) in dry DMF (75 mL). Sodium hydride (0.87
g, 60% in mineral oil, 21.6 mmol) was added in 4 portions
before the solution was stirred for 10 min at room temperature.
Dry MeOH (0.22 mL, 5.4 mmol) was added and the mixture
was heated at 50 °C for 2 h before being cooled to room
temperature. HCl (1 N) was added until the reaction mixture
was strongly acidic. After 5 min water (100 mL) was added
and the pH was adjusted to 5 with NaHCO3 solution (saturated
aqueous). The aqueous was extracted with EtOAc (4 × 100
mL) and the combined organics were washed with water (2 ×
50 mL) and brine (2 × 50 mL) and dried (MgSO4). The solvent
was removed in vacuo to 50 mL total volume during which
time a white precipitate formed. The solid was collected by
filtration and washed with cold EtOAc (10 mL) and Et2O (3 ×
10 mL) to afford the title compound (1.502 g; 69%). Melting
point 292-294 °C; 1H NMR (400 MHz, d6-DMSO) δ 1.39-1.44
(1H, m), 1.55-1.61 (1H, m), 2.27-2.34 (1H, m), 2.42-2.46 (1H,
m), 2.43 (3H, s), 3.28-3.31 (2H, m), 4.47 (1H, br), 7.11 (2H, d,
J ) 7), 7.20-7.27 (4H, m), 7.33 (1H, s), 8.45 (1H, s), 8.46 (1H,
d, J ) 7), 8.50 (1H, s), 12.7 (1H, br s); MS (ES+) m/z 404 (M +
H+).
4′-(3-Hyd r oxyp r op yl)-5-(4-m eth ylth ia zol-2-yl)-3-o-tolyl-
1H-[2,3′]bip yr id in yl-6-on e (13b). 4-Methylthiazole-2-acet-
mide (2) (178 mg, 1.14 mmol) was added to a solution of 12b
(0. 4 g, 0.91 mmol) in dry DMF (10 mL). Sodium hydride (60%
in oil) (146 mg, 3.65 mmol) was added in 4 portions. The
mixture was stirred for 10 min and then heated at 50 °C for
16 h before being cooled to room temperature. The mixture
was slowly poured into water (50 mL) and 1 N HCl was added
until it was strongly acidic. After 10 min the pH was adjusted
to 5 with NaHCO3 solution (saturated aqueous). The aqueous
was extracted with EtOAc (3 × 50 mL), the combined organics
were washed with water (2 × 25 mL) and brine (2 × 25 mL)
dried (Na2SO4), and the solvent was removed in vacuo. The
residue was purified by flash chromatography (EtOAc-5%
MeOH/EtOAc) to afford the title compound as a pale solid (140
mg, 37%). Melting point 263-265 °C; 1H NMR (400 MHz, d6-
DMSO) δ 1.40-1.83 (2H, br m), 2.16 (3H, br s), 2.20-2.30 (2H,
m), 2.41 (3H, s), 3.33-3.43 (2H, m), 4.55 (1H, t, J ) 5), 6.90-
7.05 (1H, br m), 7.02 (1H, t, J ) 7), 7.11-7.19 (2H, m), 7.21-
7.25 (1H, br m), 7.32 (1H, s), 8.32 (1H, s), 8.38 (1H, d, J ) 5),
8.4-8.6 (1H, br m), 12.68 (1H, s); MS (ES+) m/z 418 (M + H+).
9-(4-Me t h ylt h ia zol-2-yl)-11-p h e n yl-6,7-d ih yd r o-5H -
2,7a -d ia za d ib en zo[a ,c]cycloh ep t en -8-on e (5a ). Diethyl-
azodicarboxylate (0.72 mL, 4.57 mmol) was added to a suspen-
sion of 13a (1.47 g, 3.65 mmol) and triphenylphosphine (1.20
g, 4.57 mmol) in dry THF (500 mL). Dissolution occurred
within 5 min. After 10 min the solution was partitioned
between water (300 mL) and EtOAc (300 mL). The layers were
separated and the aqueous extracted with EtOAc (2 × 150
mL). The combined organics were washed with water (100 mL)
and brine (100 mL) and dried (MgSO4) and the solvent was
removed in vacuo. The residue was dissolved in MeOH (30 mL)
and CH2Cl2 (5 mL) before loading onto SCX resin (40 g). The
resin was washed with MeOH (800 mL) and then the product
was eluted with 10% NH3 in MeOH (300 mL) and concentrated
to 25-mL volume. The resultant crystalline solid was collected
by filtration and washed with Et2O to afford the title compound
as yellow needles (1.19 g, 84%). Melting point 238-240°C;
HPLC (70% MeCN/H2O) Rt ) 4.8 min, 99.6%; UV-vis (MeOH)
390 nm; 1H NMR (400 MHz, CDCl3) δ 2.01-2.07 (1H, m), 2.52
(3H, s), 2.55-2.61 (1H, m), 2.75-2.83 (2H, m), 2.89 (1H, dd, J
) 13, 7), 5.32 (1H, dd, J ) 13, 5), 6.99-7.02 (2H, m), 7.05 (1H,
s), 7.21-7.25 (4H, m), 8.02 (1H, s), 8.47 (1H, d, J ) 5), 8.74
(1H, s); MS (ES+) m/z 386 (M + H+); 13C NMR (100.6 MHz,
CDCl3) δ 17.3, 28.6, 29.4, 42.5, 116.5, 121.6, 122.3, 123.0, 127.4,
128.6, 129.3, 129.8, 137.4, 138.0, 142.9, 147.6, 150.6, 150.7,
152.5, 159.3, 159.9. Anal. Calcd for C23H19N3OS‚0.25H2O: C,
70.83; H, 5.04; N, 10.77. Found: C, 70.89; H, 4.98; N, 10.55.
1-{4-[3-(ter t-Bu tyld im eth ylsila n yloxy)p r op yl]p yr id in -
3-yl}-2-p h en yleth a n on e (11a ). Sodium chloride (7.36 g, 126
mmol) and water (3 mL, 172 mmol) were added to a solution
of 10a (49.0 g, 114 mmol) in DMSO (800 mL) and the solution
was heated at 150 °C. After 2 h the solution was allowed to
cool and poured into water (2 L). The aqueous was extracted
with 1:1 EtOAc/Et2O (5 × 800 mL). The combined organic
extracts were washed with water (4 × 800 mL) and brine (2
× 800 mL) and dried (Na2SO4). The solvent was removed in
vacuo and the residue was purified by flash chromatography
(30% EtOAc/hexanes) to afford the title compound as an oil
1
(29.6 g, 70%). H NMR (400 MHz, CDCl3) δ 0.01 (6H, s), 0.86
(9H, s), 1.60-1.69 (2H, m), 2.77-2.81 (2H, m), 3.54 (2H, t, J
) 6), 4.19 (2H, s), 7.16-7.28 (6H, m), 8.50 (1H, d, J ) 5), 8.90
(1H, s); MS (ES+) m/z 370 (M + H+).
1-{4-[3-(ter t-Bu tyld im eth ylsila n yloxy)p r op yl]p yr id in -
3-yl}-2-o-tolyleth a n on e (11b). Sodium chloride (0.1 g, 1.74
mmol) and water (0.06 mL, 3.2 mmol) were added to a solution
of 10b (0.7 g, 1.59 mmol) in DMSO (10 mL) and the solution
was heated at 150 °C. After 30 min the solution was allowed
to cool and poured into water (150 mL). The aqueous was
extracted with 1:1 Et2O:EtOAc (3 × 50 mL). The organics were
washed with water (2 × 50 mL) and brine (2 × 50 mL) and
dried (Na2SO4). The solvent was removed in vacuo and the
residue was purified by flash chromatography (20% EtOAc/
hexanes) to afford the title compound as an oil (0.465 g, 76%).
1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.86 (9H, s), 1.68-
1.73 (2H, m), 2.23 (3H, s), 2.77-2.81 (2H, m), 3.55 (2H, t, J )
6), 4.22 (2H, s), 7.07-7.20 (4H, m), 7.19 (1H, d, J ) 5), 8.53
(1H, d, J ) 5), 8.91 (1H, s); MS (ES+) m/z 384 (M + H+).
1-{4-[3-(ter t-Bu tyld im eth ylsila n yloxy)p r op yl]p yr id in -
3-yl}-3-(d im eth yla m in o)-2-p h en ylp r op en on e (12a ). 11a
(29.2 g, 79 mmol) was dissolved in N,N-dimethylformamide-
dimethyl acetal (400 mL) and stirred for 18 h at room
temperature. The N,N-dimethylformamide-dimethyl acetal
was removed in vacuo and the residue azeotroped with toluene
(2 × 200 mL) to afford an oil. The title compound thus produced
was used without purification in subsequent reactions (33.55
1
g; 100%). H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.85 (9H,
s), 1.77-1.81 (2H, m), 2.66 (6H, br s), 3.58 (2H, t, J ) 6), 7.07
(1H, d, J ) 5), 7.07 (1H, d, J ) 5), 7.11-7.22 (6H, m), 8.32
(1H, s), 8.34 (1H, d, J ) 5); MS (ES+) m/z 425 (M + H+).
1-{4-[3-(ter t-Bu tyld im eth ylsila n yloxy)p r op yl]p yr id in -
3-yl}-3-(d im eth yla m in o)-2-o-tolylp r op en on e (12b). 11b
(0.44 g, 1.15 mmol) was dissolved in N,N-dimethylformamide-
dimethyl acetal (15 mL, 105 mmol) and stirred for 8 h at 50
°C. The N,N-dimethylformamide-dimethyl acetal was re-
moved in vacuo and the residue was azeotroped with toluene
(2 × 20 mL) to afford an oil. The title compound thus produced
was used without purification in subsequent reactions (0.485
1
g, 96%). H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.86 (9H,
s), 1.79-1.85 (2H, m), 2.21 (3H, s), 2.60 (6H, br s), 2.68-2.75
(2H, m), 3.59 (2H, d, J ) 6), 6.9 (1H, br), 7.05-7.17 (5H, m),
8.35-8.41 (2H, m); MS (ES+) m/z 439 (M + H+).
4′-(3-Hyd r oxyp r op yl)-5-(4-m eth ylth ia zol-2-yl)-3-p h en -
yl-1H-[2,3′]bip yr id in yl-6-on e (13a ). 4-Methylthiazole-2-acet-
9-(4-Meth ylth ia zol-2-yl)-11-o-tolyl-6,7-d ih yd r o-5H-2,7a -
d ia za d ib en zo[a ,c]cycloh ep t en -8-on e (5b ). Diisopropyl-
J . Org. Chem, Vol. 67, No. 26, 2002 9359