110
H.-H. Ko et al. / Bioorg. Med. Chem. 11 (2003) 105–111
cmÀ1. 1H NMR (CDCl3) d 3.81 (3H, s, OMe), 3.86 (3H,
s, OMe), 6.94 (1H, d, J=9.0 Hz, H-30), 7.04 (1H, dd,
J=9.0, 3.1 Hz, H-4), 7.19 (1H, d, J=3.1 Hz, H-60), 7.41
(1H, d, J=15.8 Hz, H-a), 7.42–7.52 (4H, m, H-2,-3,-5
and -6), 7.58 (1H, d, J=15.8 Hz, H-b). 13C NM R
(CDCl3) d 55.8 (OMe), 56.4 (OMe), 113.4 (C-60), 114.4
(C-30), 119.4 (C-a), 124.3 (C-10), 127.3 (C-40), 129.1 (C-
1), 129.7 (C-3,-5), 132.0 (C-2,-6), 134.1 (C-4), 141.5 (C-
b), 152.6 (C-50), 153.6 (C-20), 191.9 (CO). EIMS (70 eV)
m/z (% rel. int.): 348 [M+1]+ (11), 177 (20), 165 (100).
(–OCH2 CH2–), 25.4 (–OCH2CH2–), 30.4 (–CH2CH¼),
30.6 (–CH2CH¼), 62.1 (–OCH2–), 62.9 (–OCH2–), 94.6
(–CH2CH¼), 97.6 (–CH2CH¼), 116.5 (C-3), 119.2 (C-a),
119.4 (C-60), 121.7 (C-40), 127.6 (C-6), 130.0 (C-2), 130.9
(C-5), 133.3 (C-1), 134.0 (C-3), 134.7 (C-4), 142.5 (C-b),
149.1 (C-50), 158.6 (C-20), 192.7 (CO). EIMS (70 eV) m/z
(% rel. int.): 480 (0.02) [M+4]+, 478 (0.1), [M+2]+,
476 (0.2) [M]+, 394 (0.2), 392 (0.3), 310 (43), 308 (70),
136 (100). It failed to show a molecular ion peak under
high-resolution conditions. Crude 4b and P-toluene-
sulfonic acid (0.18 g, 1.05 mmol) were dissolved in
MeOH (100 mL). The reaction mixture was stirred for
4 h at room temperature, and then evaporated in vacuo.
Water (100 mL) was added to the mixture, neutralized
with 5% NaHCO3 (50 mL), and extracted with EtOAc.
The organic layer was separated, washed with water,
dried, and evaporated in vacuo. The residue was eluted
through a silica gel column with cyclohexane–EtOAc
(4:1) to give 4 (5.02 g, 16.3 mmol, 65%):IR (KBr) 3434,
3,4-Dichloro-20,50-dimethoxychalcone (3). 2,5-Dimethoxy-
acetophenone (4.5 g, 25 mmol), 3,4-dichlorobenz-
aldehyde (4.38 g, 25 mmol), and barium hydroxide
octahydrate (4.29 g, 25 mmol) were treated as in the
synthesis of 1b to give 3 (4.05 g, 12 mmol, 48%): IR
1
(KBr) 1669, 1605 cmÀ1. H NMR (CDCl3): d 3.81 (3H,
s, OMe), 3.88 (3H, s, OMe), 6.95 (1H, d, J=9.2 Hz, H-
30), 7.05 (1H, dd, J=9.2, 3.2 Hz, H-40), 7.20 (1H, d,
J=3.2 Hz, H-60), 7.41 (1H, d, J=16.0 Hz, H-a), 7.41
(1H, dd, J=8.4, 2.0 Hz, H-6), 7.47 (1H, d, J=8.4 Hz,
H-5), 7.54 (1H, d, J=16.0 Hz, H-b), 7.66 (1H, d, J=2.0
Hz, H-2). 13C NMR (CDCl3): d 55.9 (OMe), 56.2
(OMe), 113.6 (C-60), 114.5 (C-30), 119.8 (C-a), 127.3 (C-
40), 128.4 (C-6), 129.2 (C-10), 129.8 (C-2), 130.8 (C-5),
133.2 (C-1), 134.0 (C-3), 135.4 (C-4), 139.9 (C-b), 152.8
(C-50), 153.7 (C-20), 191.6 (CO). EIMS (70 eV) m/z
(%rel. int.): 336 [MÀ1]+ (11), 165 (100).
1
1636, 1600 cmÀ1. H NMR ((CD3)2CO): d 6.86 (1H, d,
J=8.0 Hz, H-30), 7.16 (1H, dd, J=8.0, 2.8 Hz, H-40),
7.63 (1H, d, J=2.8 Hz, H-60), 7.69 (1H, d, J=8.0 Hz,
H-5), 7.85 (1H, d, J=16.0 Hz, H-a), 7.88 (1H, dd,
J=8.0, 2.8 Hz, H-6), 8.06 (1H, d, J=16.0 Hz, H-b),
8.16 (1H, bs, OH-50), 8.19 (1H, d, J=2.8 Hz, H-2),
12.16 (1H, s, OH-20). 13C NMR ((CD3)2CO): d 116.5
(C-60), 120.2 (C-a), 121.3 (C-10), 124.6 (C-30), 126.9
(C-40), 130.4 (C-6), 131.8 (C-2), 132.6 (C-5), 134.2 (C-1),
135.3 (C-3), 137.2 (C-4), 143.6 (C-b), 151.0 (C-50), 158.6
(C-20), 195.1 (CO). EIMS (70 eV) m/z (% rel. int.): 308
[M]+ (8), 163 (21), 136 (100).
3,4-Dichloro-20,50-dihydroxychalcone (4). 2,5-Dihydroxy-
acetophenone (3.8 g, 25 mmol), and pyridinium P-
toluenesulfonate (0.15 g, 0.6 mmol) were stirred for 0.5
h in methylene chloride (80 mL), and then 3,4-dihydro-
a-pyran in methylene chloride (13 mL in 20 mL) was
added dropwise. The reaction mixture was stirred at
room temperature for 4 h. The reaction mixture was
washed twice with water, dried, and evaporated in
vacuo. The residue yielded crude 20,50-bis(tetrahy-
dropyran-2-yloxy) acetophenone (4a). A part of crude
4a was eluted through a silica-gel column with n-hex-
ane–CH2Cl2 (2:1) to give 4a: yellow oil. It was identified
with various spectral data and compared with those of
authentic sample.2 Crude 4a, 3,4-dichlorobenzaldehyde
(4.4 g, 25 mmol), and barium hydroxide octahydrate
(4.2 g, 25 mmol) were dissolved in MeOH (100 mL).
The reaction mixture was stirred for 12 h at 40 ꢀC and
then evaporated in vacuo. Water (100 mL) was added
and the mixture was neutralized with HCl (1M, 30 mL)
and extracted with EtOAc. The organic layer was sepa-
rated, washed with water, dried, and evaporated in
vacuo. The residue yielded crude 20,50-bis(tetrahy-
dropyran-2-yloxy)-3,4-dichlorochalcone (4b). A part of
crude 4b was eluted through a silica-gel column with n-
hexane–CH2Cl2 (2:1) to give 4b: yellow powder. 1H
NMR: d 1.65 (6H, m, –OCH(CH2)3CH¼), 1.95 (6H, m,
–OCH(CH2)3CH¼), 3.63 (2H, m, –OCH2–), 3.94 (2H,
m, –OCH2–), 5.34 (2H, t, J=2.8 Hz, –CH2CH¼Â2),
6.94 (1H, d, J=8.8 Hz, H-30), 7.09 (1H, d, J=2.8 Hz,
H-60), 7.29 (1H, dd, J=8.8, 2.8 Hz, H-40), 7.44 (1H, d,
J=9.0 Hz, H-3), 7.51 (1H, d, J=15.8 Hz, H-a), 7.53
(1H, dd, J=9.0, 3.0 Hz, H-2), 7.53 (1H, d, J=3.0 Hz,
H-6), 7.75 (1H, d, J=15.8, H-b). 13C NMR (CDCl3): d
18.7 (–CH2CH2CH2–), 19.7 (–CH2CH2CH2–), 25.1
3,4-Dichloro-20,50-diethoxychalcone (5). A mixture of
(7.7 g, 25 mmol), ethyliodide (8.1 g, 52 mmol), and
potassium carbonate (15 g, 25 mmol) in DMF (50 mL)
were stirred at room temperature for 18 h. The mixture
was diluted with water and washed three times with
water. The organic phase was dried over sodium sulfate,
filtered, and concentrated in vacuo to give the product.
Purification via silica-gel column chromatography yield
5 (5.3 g, 14.5 mmol, 58%): IR (KBr) 1657, 1596 cmÀ1
.
1H NMR (CDCl3): d 1.40 (6H, m, 2ÂMe), 4.06 (4H,
2ÂOCH2), 6.91 (1H, d, J=9.2 Hz, H-30), 7.03 (1H, dd,
J=9.2, 3.2 Hz, H-40), 7.24 (1H, d, J=3.2 Hz, H-60), 7.40
(1H, dd, J=8.4, 2.0 Hz, H-6), 7.46 (1H, d, J=8.4 Hz,
H-5), 7.51 (1H, d, J=16.0 Hz, H-a), 7.56 (1H, d,
J=16.0 Hz, H-b), 7.66 (1H, d, J=2.0 Hz, H-2). 13C
NMR (CDCl3): d 14.8 (Me), 15.0 (Me), 64.1 (OCH2),
65.2 (OCH2), 114.7 (C-60), 115.1 (C-30), 120.7 (C-a),
127.2 (C-40), 128.7 (C-6), 129.2 (C-10), 129.7 (C-2),
130.9 (C-5), 133.2 (C-1), 133.8 (C-3), 135.5 (C-4), 139.2
(C-b), 152.3 (C-50), 153.1 (C-20), 191.3 (CO). EIMS (70
eV) m/z (% rel. int.): 366 [M+1]+ (25), 164 (100), 136
(79).
3,4-Dichloro-20-hydroxy-50-propoxychalcone (6). A mix-
ture of 4 (7.7 g, 25 mmol), n-propyl iodide (8.84 g, 52
mmol), and potassium carbonate (15 g, 25 mmol) in
DMF (50 mL) were treated as in synthesis of 5 to give 6
(4.04 g, 11.5 mmol, 46%). IR (KBr): 1646, 1577 cmÀ1
.
1H NMR (CDCl3): d 1.07 (3H, t, Me), 1.83 (2H, m,
CH2), 3.94 (2H, t, OCH2), 6.97 (1H, d, J=9.0 Hz, H-
30), 7.16 (1H, dd, J=9.0, 2.9 Hz, H-40), 7.33 (1H,