2204 J . Org. Chem., Vol. 67, No. 7, 2002
Kelly and Lebedev
NMR (100 MHz, CDCl3) δ 116.2, 118.0, 129.0, 131.7, 132.0,
132.5, 140.4, 189.6; IR (CDCl3) ν 2230, 1672 cm-1. Anal. Calcd
for C10H7NO: C, 76.42; H, 4.49; N, 8.91. Found: C, 76.36; H,
4.61; N, 8.85.
starting material as judged by TLC on silica eluting with
80:20 hexanes/EtOAc). The reaction was then purged with
argon for ∼10 min and quenched with 10 mL of anhydrous
dimethyl sulfide. The reaction was then allowed to warm
slowly to room temperature and left to stir overnight under
argon. Most of the solvent was then removed on a rotary
evaporator and the insoluble white powder was collected,
affording 0.930 g of quinolone 31. The filtrate was concentrated
in vacuo, affording 3.58 g of yellow oil, to which 10 mL of 80:
20 hexanes/EtOAc and 2-3 mL of MeOH were added. A second
crop was collected, affording 0.170 g of quinolone 31 as a white
powder. The combined product (1.10 g, 60%) was used for the
next reaction without further purification: mp 192-194 °C;
1H NMR (400 MHz, CDCl3) δ 2.20 (p, 2H, J ) 6.4 Hz), 2.81 (t,
2H, J ) 6.4 Hz), 3.06 (t, 2H, J ) 6.4 Hz), 7.70 (d, 2H, J ) 8.8
Hz), 7.76 (d, 1H, J ) 8.0 Hz), 7.83 (d, 1H, J ) 8.0 Hz), 8.14 (d,
2H, J ) 8.8 Hz); 13C NMR (100 MHz, CDCl3) δ 22.8, 29.2, 40.1,
112.6, 118.7, 124.1, 127.7, 132.5, 138.9, 140.4, 142.5, 148.1,
154.2, 196.2; IR (CDCl3) ν 2229, 1705 cm-1. Anal. Calcd for
C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found: C, 77.72; H,
4.87; N, 11.27.
4-[3-(2-O x o c y c lo h e x y l)p r o p a n o y l]b e n ze n e c a r b o -
n itr ile (29). R,â-Unsaturated ketone 28 (4.38 g, 27.9 mmol),
50 mL of anhydrous CH2Cl2, and 1-cyclohexenyloxytrimeth-
ylsilane (6.78 mL, 34.8 mmol, Aldrich) were placed together
under argon into a 100 mL round-bottomed flask in the above
order. The resulting solution was then added through a
cannula to a stirred suspension of SnCl2 (6.86 g, 36.2 mmol)
in 10 mL of anhydrous CH2Cl2 cooled to -78 °C (after the
addition, the flask that contained 28 was washed with 20 mL
of anhydrous CH2Cl2 and the wash was added to the reaction
flask; small amounts of insoluble “polymeric” starting material
are usually left in the original flask). Trimethylsilyl chloride
(8.55 mL, 66.9 mmol) was then added all at once and the
reaction was stirred at -78 °C for ∼30 min and then at room
temperature for ∼1.5 h. The reaction was then quenched with
10% citric acid (∼30 mL), the layers were separated, and the
aqueous layer was extracted with EtOAc twice. The organic
layer and extracts might have small amounts of insoluble
“polymeric” starting material, which is filtered off after drying
over Na2SO4. The combined organic layer and extracts were
adsorbed on silica (∼25 g) and, after removal of volatiles,
loaded onto a 6 × 20 cm silica column. Elution with 75:25
hexanes/EtOAc afforded diketone 29 (5.30 g, 75%) as a light
yellow oil, which was immediately used for the next reaction.
An analytical sample was prepared using preparative TLC
(1000 µm 20 × 20 cm plate, 80:20 EtOAc/hexanes) as a white
solid: mp 58-59 °C; 1H NMR (400 MHz, CDCl3) δ 1.35-1.45
(m, 1H), 1.58-1.70 (m, 3H), 1.82-1.84 (m, 1H), 1.97-2.11 (m,
3H), 2.23-2.42 (m, 3H), 2.87-2.95 (m, 1H), 3.07-3.14 (m, 1H),
7.71 (d, 2H, J ) 8.4 Hz), 8.02 (d, 2H, J ) 8.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 24.6, 25.3, 28.2, 34.8, 36.9, 42.4, 49.9,
116.1, 117.9, 128.5, 132.4, 139.6, 198.6, 212.8; IR (CDCl3) ν
2229, 1699 cm-1. Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71;
N, 5.49. Found: C, 75.05; H, 6.64; N, 5.40.
4-[2-(5,6-Dih yd r o-8-oxo-7-{[4-(p h en ylm eth oxy)p h en yl]-
m eth ylen e}qu in olyl)]ben zen eca r bon itr ile (32). Quinolone
31 (1.10 g, 4.43 mmol), 4-benzyloxybenzaldehyde (1.22 g, 5.76
mmol, Aldrich, 97%), and 85% KOH pellets (1.14 g, 20 mmol)
were placed together into a 100 mL round-bottomed flask; 70
mL of anhydrous MeOH was added and then the reaction was
heated at reflux with stirring under argon for ∼3 h. The
reaction was then cooled on ice and the solid was collected by
vacuum filtration and washed with anhydrous MeOH (3 × 5
mL), affording compound 32 (1.63 g, 83%) as a bright yellow
solid. The compound is somewhat unstable and was im-
mediately used for the next reaction without further purifica-
1
tion: mp 228-230 °C; H NMR (400 MHz, CDCl3) δ 3.01 (t,
2H, J ) 6.0 Hz), 3.20 (t, 2H, J ) 6.0 Hz), 5.11 (s, 2H), 7.03 (d,
2H, J ) 8.8 Hz), 7.32-7.46 (m, 7H), 7.75 (d, 2H, J ) 8.4 Hz),
7.76 (d, 1H, J ) 7.8 Hz), 7.85 (d, 1H, J ) 7.8 Hz), 7.95 (s, 1H),
8,21 (d, 2H, J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 26.6,
27.8, 70.2, 112.8, 115.1, 119.0, 123.9, 127.6, 127.9, 128.3, 128.4,
128.9, 132.2, 132.7, 133.3, 136.6, 138.3, 138.7, 138.9, 142.9,
149.7, 154.9, 159.7, 186.3; IR (CDCl3) ν 2229, 1666, 1578, 1511,
1173 cm-1. HRMS (FAB) calcd for C30H23N2O2 (MH+) 443.1760,
found 443.1758.
4-[2-(5,6,7,8-T e t r a h y d r o q u in o ly l)]b e n ze n e c a r b o -
n itr ile (30). Diketone 29 (3.94 g, 15.4 mmol), ammonium
acetate (3.57 g, 46.3 mmol, Aldrich, 99.99+%), and 50 mL of
glacial acetic acid were placed together into a 100 mL round-
bottomed flask. The reaction was refluxed with stirring under
argon overnight. The reaction was then cooled on ice, made
strongly basic with a 20% NaOH solution, and extracted with
EtOAc (3 × 100 mL). The combined extracts were dried over
Na2SO4 and adsorbed on silica (∼15 g). Purification by flash
column chromatography using a 5 × 20 cm silica column and
eluting with 90:10 hexanes/EtOAc afforded compound 30 (1.52
4-{7-[4-(P h en ylm et h oxy)p h en yl]-5,6,8,9-t et r a h yd r o-
pyridino[3,2-h]quinolino[8,7-b]quinolin-2-yl}benzenecarbo-
n itr ile (33). Compound 32 (793 mg, 1.77 mmol) and quinolone
410 (264 mg, 1.77 mmol) were placed together in a 25 mL
round-bottomed flask under argon. BF3·Et2O (8 mL) was added
and the resulting blood-red solution was vigorously stirred
overnight. The reaction was then diluted with 50 mL of CH2-
Cl2, washed with saturated NaHCO3 solution twice (CAU-
TION: violent gas evolution!), dried over Na2SO4, and con-
centrated in vacuo, affording the intermediate diketone (1.09
g, 1.85 mmol) as a yellow foam. The diketone was placed into
a 100 mL round-bottomed flask, ammonium acetate (427 mg,
5.55 mmol, Aldrich, 99.99+%) and 30 mL of glacial acetic acid
were added, and the reaction was refluxed with stirring under
argon for ∼8 h or overnight. The reaction was then cooled on
ice, made strongly basic with a 20% NaOH solution, and
extracted with CH2Cl2 (3 × 50 mL). The combined extracts
were dried over Na2SO4 and concentrated in vacuo, affording
1.08 g of crude 2 as a purple solid. Flash column chromatog-
raphy using a 5 × 20 cm basic alumina column and eluting
starting with 80:20 CH2Cl2/EtOAc (until all dark purple
impurities elute), then with a small amount of 99:1 CH2Cl2/
MeOH, and then with 98:2 CH2Cl2/MeOH (until the product
elutes) afforded compound 33 (554 mg, 54%) as a pink-beige
foam: mp 210 °C slow dec; 1H NMR (500 MHz, CDCl3) δ 2.71-
2.86 (m, 4H), 2.88-2.95 (m, 4H), 5.14 (s, 2H), 7.11-7.15 (m,
4H), 7.22-7.26 (m, 1H), 7.35-7-38 (m, 1H), 7.43 (t, 2H, J )
7.5 Hz), 7.49 (d, 2H, J ) 7.5 Hz), 7.54 (d, 1H, J ) 7.5 Hz),
7.66 (s, 2H), 7.77 (d, 2H, J ) 8.5 Hz), 8.26 (d, 2H, J ) 8.5 Hz),
8.72 (d, 1H, J ) 4.0 Hz); 13C NMR (125 MHz, CDCl3) δ 25.6,
27.6, 70.3, 112.2, 115.2, 119.3, 121.5, 123.8, 127.7, 128.3, 128.4,
128.9, 129.5, 130.0, 132.5, 132.6, 133.4, 133.5, 133.7, 133.8,
1
g, 42%) as a white solid: mp 96-98 °C; H NMR (400 MHz,
CDCl3) δ 1.77-1.83 (m, 2H), 1.87-1.93 (m, 2H), 2.77 (t, 2H, J
) 6.4 Hz), 2.95 (t, 2H, J ) 6.4 Hz), 7.41 (d, 1H, J ) 8.0 Hz),
7.43 (d, 1H, J ) 8.0 Hz), 7.65 (d, 2H, J ) 8.4 Hz), 8.03 (d, 2H,
J ) 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 22.8, 23.2, 28.7,
32.9, 111.6, 118.1, 118.9, 127.1, 132.2, 137.5, 143.7, 151.8,
157.6; IR (CDCl3)
16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C, 81.72; H,
6.01; N, 11.79.
ν . Anal. Calcd for
2227, 1460 cm-1
C
4-[2-(8-Oxo-5,6,7-t r ih yd r oq u in olyl)]b e n ze n e ca r b o-
n itr ile (31). Compound 30 (1.75 g, 7.45 mmol), benzaldehyde
(2.27 mL, 22.4 mmol), and acetic anhydride (2.82 mL, 29.8
mmol) were placed together into a 25 mL round-bottomed flask
fitted with a condenser, and the reaction was refluxed with
stirring under argon overnight (temperature of oil bath is ∼160
°C). The reaction was then diluted with 30 mL of CH2Cl2 and
30 mL of water and made strongly basic with 2 M NaOH, and
the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 × 15 mL), and the combined organic layer and
extracts were dried over Na2SO4 and concentrated in vacuo,
affording crude olefin (4.00 g) as a yellow oil, which contains
some benzaldehyde. The crude oil was then dissolved in 15
mL of anhydrous CH2Cl2 and 30 mL of anhydrous MeOH.
Ozone generated using the Osmonics system set at 1 amp with
an oxygen flow rate of 2 L/min was bubbled through at ca.
-40 °C with stirring for ∼20 min (until disappearance of the