6836
T. H. V. Huynh et al. / Bioorg. Med. Chem. 20 (2012) 6831–6839
mixture was stirred at rt for 20 h. The precipitated solid was fil-
tered off and washed four times with ice-cold abs EtOH to afford
(26) (50 mg, 175
ononitrile (23 mg, 350
l
mol), acetaldehyde (20
lL, 350 lmol) and mal-
l
mol) in abs EtOH (4 mL) at rt and stirred
the titled compound as a pale-yellow solid (38 mg, 72
l
mol, 57%
for 5 h. After concentration in vacuo the crude product was puri-
yield); mp 264–266 °C; 1H NMR (300 MHz, CDCl3) (ꢁ1:3 ratio of
diastereomers) d 1.21 (t, J = 7.2 Hz, 6H), 2.72–3.10 (m, 4H), 3.41
(q, J = 7.2 Hz, 4H), 4.24–4.36 (m, 1H), 4.86 (s, 1H), 4.69 (s, 2H),
5.90 (s, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 9.0, 2.4 Hz, 1H),
7.29–7.60 (m, 4H), 7.75–8.07 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 12.0, 12.5, 29.4, 33.1, 34.2, 41.2, 43.2, 44.7, 61.3, 96.3, 97.7,
106.9, 107.3, 108.9, 113.6, 122.5, 122.6, 125.3, 125.7, 126.0,
126.8, 128.1, 129.2, 130.8, 134.0, 137.1, 151.0, 156.5, 158.4,
158.6, 163.2, 164.3, 195.0; LC–MS [M+H]+ calcd for C33H29N3O4:
532.2, found: 532.2; Anal. calcd for C33H29N3O4: C, 74.56; H,
5.50; N, 7.90, found: C, 74.12; H, 5.28; N, 7.84.
fied by column chromatography on silica gel. This afforded the
titled compound as a yellow solid (53 mg, 140 lmol, 80% yield):
Rf = 0.12 (EtOAc/heptane 1:1); mp 193–195 °C (decomposed); 1H
NMR (300 MHz, CDCl3) (ꢁ1:1 ratio of diastereomers) d 1.25 (d,
J = 6.9 Hz, 1.46H), 1.30 (d, J = 6.9 Hz, 1.54H), 2.48–2.89 (m, 4H),
3.39 (q, J = 6.6 Hz, 1H), 3.68–3.84 (m, 1H), 3.89 (s, 3H), 4.54 (s,
2H), 6.13 (s, 0.43H), 6.16 (s, 0.57H), 6.84–6.91 (m, 2H), 7.48 (d,
J = 8.7 Hz, 0.45H), 7.53 (d, J = 8.7 Hz, 0.55H); 13C NMR (100 MHz,
CDCl3) d 22.3, 22.9, 24.8, 24.9, 31.5, 31.6, 32.3, 32.8, 41.3, 55.9,
56.0, 57.5, 57.8, 101.1, 101.2, 109.3, 111.1, 111.2, 112.3, 114.7,
114.8, 119.9, 126.0, 126.1, 155.1, 156.5, 156.7, 158.6, 158.7,
160.2, 160.3, 162.4, 162.5, 162.8, 194.7, 194.9; LC–MS [M+H]+ calcd
for C21H18N2O5: 379.1, found: 379.1. Anal. calcd C, 66.66; H, 4.79; N
7.40, for C21H18N2O5: found: C, 66.23; H, 4.90; N, 7.03.
5.1.3. 2-Amino-4-(4-(7-methoxy-4-methyl-2-oxo-2H-chromen-
3-yl)phenyl)-5-oxo-7-phenyl-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (13)
4-(7-Methoxy-4-methyl-2-oxo-2H-chromen-3-yl)benzalde-
hyde (22) (55 mg, 0.19 mmol), 5-phenylcyclohexane-1,3-dione
(35 mg, 0.19 mmol) and malononitrile (12 mg, 0.19 mmol) were
5.1.6. 7-Methoxy-2-oxo-2H-chromene-4-carbaldehyde (18)
7-Methoxy-4-methyl-2H-chromen-2-one (17) (1 g, 5.26 mmol)
and selenium dioxide (875 mg, 7.89 mmol) were stirred in p-xylene
(50 mL) at 145 °C for 18 h. The reaction mixture was cooled to rt and
the white precipitate was filtered and purified by column chroma-
tography on silica gel. This afforded the titled compound as a yellow
solid (902 mg, 4.42 mmol, 84% yield): Rf = 0.59 (100% EtOAc); mp
200–202 °C (decomposed); 1H NMR (300 MHz, CDCl3) d 3.89 (s,
3H), 6.69 (s, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 9.0, 2.4 Hz,
1H), 8.47 (d, J = 9.0 Hz, 1H), 10.05 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 55.8, 101.1, 108.1, 113.3, 122.2, 127.3, 143.7, 156.5, 160.7, 163.3,
191.7; LC–MS [M+H]+ calcd for C11H8O4: 205.1, found: 205.1.
stirred in abs EtOH (5 mL) at rt. Piperidine (4 lL, 37 lmol) was
added and the reaction mixture was stirred for 16 h at rt. The white
precipitate was filtered off and washed three times with cold abs
EtOH. This afforded the titled compound as a pale-yellow solid
(60 mg, 0.11 mmol, 61% yield): mp 241–243 °C (decomposed); 1H
NMR (300 MHz, CDCl3) (ꢁ1:1 ratio of diastereomers) d 2.27 (s,
1.5H), 2.29 (s, 1.5H), 2.53–2.95 (m, 4H), 3.35–3.55 (m, 1H), 3.87
(s, 3H), 4.53 (s, 0.5H), 4.55 (s, 0.5H), 4.63 (s, 1H), 4.65 (s, 1H),
6.83–6.89 (m, 2H), 7.15–7.38 (m, 9H), 7.56 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 16.8, 16.9, 34.5, 34.6, 35.0, 35.2, 37.9,
38.8, 43.7, 43.9, 55.8, 62.9, 63.1, 100.6, 112.3, 112.4, 114.2, 115.2,
115.3, 118.7, 118.7, 123.9, 126.2, 126.6, 126.7, 127.4, 127.6,
128.9, 128.9, 130.5, 130.6, 133.4, 133.5, 141.7, 141.8, 142.5,
142.7, 148.1, 148.2, 154.3, 157.9, 158.1, 161.3, 161.4, 161.9,
162.3, 162.4, 162.8, 194.9, 195.2; LC–MS [M+H]+ calcd for
5.1.7. 7-(Diethylamino)-2-oxo-2H-chromene-4-carbaldehyde
(19)
Selenium dioxide (720 mg, 6.48 mmol) was added to a solution
of 7-(diethylamino)-4-methylcoumarine (3) (1 g, 4.32 mmol) in
p-xylene (50 mL) at rt under a N2 atmosphere. The reaction mix-
ture was stirred at 145 °C for 21 h and cooled to rt. The dark sus-
pension was filtered through celite and concentrated in vacuo.
The crude product was purified by column chromatography on
silica gel to afford the titled compound as a dark red solid
(320 mg, 1.38 mmol, 32% yield): Rf = 0.20 (100% dichloromethane);
1H NMR (300 MHz, CDCl3) d 1.22 (t, J = 7.2 Hz, 6H), 3.42 (q,
J = 7.2 Hz, 4H), 6.42 (s, 1H), 6.49 (d, J = 2.7 Hz, 1H), 6.60 (dd,
J = 9.0, 2.7 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 9.99 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 12.4, 44.8, 97.5, 103.7, 109.5, 117.2, 126.9,
143.8, 150.9, 157.3, 161.8, 192.5; LC–MS [M+H]+ calcd for
C33H26N2O5: 531.2, found: 531.3; Anal. calcd for C33H26N2O5: C,
74.7; H, 4.94; N, 5.28, found: C, 74.29; H, 4.62; N, 5.57
5.1.4. 5,6,7,8-Tetrahydro-4H-chromene-3-carbonitrile (14)
4-(7-(Diethylamino)-4-methyl-2-oxo-2H-chromen-3-yl)benz-
aldehyde (23) (100 mg, 0.30 mmol), 5-phenylcyclohexane-1,3-
dione (57 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol)
were stirred in abs EtOH (7 mL) at rt. Piperidine (6 lL, 60 lmol)
was added and the reaction mixture was stirred for 19 h at rt.
The white precipitate was filtered off and washed three times with
cold abs EtOH. This afforded the titled compound as a yellow solid
(139 mg, 0.25 mmol, 82% yield): mp 241–243 °C (decomposed); 1H
NMR (300 MHz, CDCl3) (ꢁ1:1 ratio of diastereomers) d 1.21 (t,
J = 7.2 Hz, 6H), 2.21 (s, 1.5H), 2.23 (s, 1.5H), 2.52–2.92 (m, 4H),
3.32–3.48 (m, 5H), 4.51 (s, 0.5H), 4.53 (s, 0.5H), 4.68 (s, 1H), 4.69
(s, 1H), 6.51 (t, J = 2.1 Hz, 1H), 6.60 (dd, J = 9.0, 2.1 Hz, 1H), 7.35–
7.13 (m, 9H), 7.42 (dd, J = 6.9, 2.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 12.9, 17.0, 35.0, 35.4, 35.7, 38.3, 39.2, 44.2, 45.2, 63.0,
63.2, 97.8, 109.0, 109.9, 115.5, 115.7, 119.4, 121.0, 126.6, 127.0,
127.1, 127.7, 127.9, 129.2, 129.3, 131.2, 131.3, 134.3, 134.4,
142.1, 142.2, 142.5, 142.7, 149.0, 149.1, 150.6, 155.4, 158.3,
158.5, 162.3, 162.6, 163.2, 195.4, 195.6; LC–MS [M+H]+ calcd for
C14H15NO3: 246.1, found: 246.1.
5.1.8. 3-Bromo-7-methoxy-4-methyl-2H-chromen-2-one (20)
N-Bromosuccinimide (224 mg, 1.26 mmol) was added slowly to
a
suspension of 7-methoxy-4-methyl-2H-chromen-2-one (17)
(200 mg, 1.05 mmol) in PEG-400 (6 mL). The reaction mixture
was stirred at rt for 2 h. The reaction mixture was extracted with
H2O (25 mL) and EtOAc (3 ꢂ 25 mL) and the combined organic
phases were washed with brine (30 mL). The organic phase was
dried over Na2SO4. After concentration in vacuo the crude product
was purified by column chromatography on silica gel. This afforded
the titled compound as a white solid (130 mg, 0.48 mmol, 46%
yield); Rf = 0.35 (EtOAc/heptane 1:2); mp 144–146 °C (decom-
posed); 1H NMR (300 MHz, CDCl3) d 2.60 (s, 3H), 3.88 (s, 3H),
6.81 (d, J = 2.7 Hz, 1H), 6.88 (dd, J = 9.0, 2.7 Hz, 1H), 7.54 (d,
J = 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 19.5, 55.8, 100.7,
109.7, 112.9, 113.4, 126.0, 151.1, 153.6, 157.3, 162.7; LC–MS
[M+H]+ calcd for C11H9BrO3: 269.0, found: 269.0; Anal. calcd for
C36H33N3O4: 572.2, found: 572.2; Anal. calcd for C36H33N3O4: C,
75.64; H, 5.82; N, 7.35, found: C, 75.44, H, 5.59; N, 7.12.
5.1.5. 20-Amino-7-methoxy-40-methyl-2,50-dioxo-50,60,70,80-
tetrahydro-2H,40H-4,70-bichromene-30-carbonitrile (15)
N-Methylmorpholine (10
lL, 88 lmol) was added to a solution
of 5-(7-methoxy-2-oxo-2H-chromen-4-yl)cyclohexane-1,3-dione
C11H9BrO3: C, 49.10, H, 3.37, found: C, 48.76; H, 3.13.