Journal of Medicinal Chemistry
Article
to heat until 45 °C as well as stirred for 24 h. It was cooled, filtered,
and diluted with ethyl acetate (100 mL), and the resulting solution
was added to aqueous hydrochloric acid (1 M, 100 mL). The organic
layer was partitioned, washed with saturated NaCl (3 × 100 mL), and
then dried over anhydrous Na2SO4. After being concentrated under
reduced pressure, the rough sample was purified by silica gel column
chromatography (DCM/MeOH, from 99:1 to 95:5) to afford
product (1.66 g, 4.32 mmol, 1 equiv) in DMSO (30 mL) was added I2
(0.11 g, 0.43 mmol, 0.05 eq). The mixture was heated to 110 °C and
reacted for 8 h. Upon completion, the reaction mixture was poured
into a 10% solution of Na2S2O3. The residue was collected by
filtration and rinsed with water and n-hexane. Recrystallization of the
rough product with ethanol−water (1:1) yielded the known product 7
(0.91 g, 47% over two steps) as a yellow powder. ESI-MS m/z 381 [M
− H]−.
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compound 3e as a yellow powder (0.61 g, 87%); H NMR (300
MHz, CDCl3): δ 7.75 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H),
6.69 (s, 1H), 6.32 (d, J = 1.6 Hz, 1H), 6.09 (d, J = 1.6 Hz, 1H), 4.79−
4.68 (m, 1H), 4.68−4.56 (m, 1H), 2.38 (s, 3H), 1.43 (d, J = 6.1 Hz,
6H), 1.40 (d, J = 6.1 Hz, 6H); ESI-MS m/z 353 [M + H]+.
8-(3-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)phenyl)-5,7-dihy-
droxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one (8a). A mixture of
compounds 7 (0.29 g, 0.75 mmol, 1.5 equiv), 4a (0.22 g, 0.5 mmol, 1
equiv), Pd(IPr*) (cin)Cl (32.3 mg, 0.05 mmol, 0.1 equiv), and
NaOH (0.06 g, 1.5 mmol, 3 equiv) in DMF (20 mL) was heated to
100 °C and stirred for 12 h under nitrogen. After cooling to ambient
temperature, the reaction solution was poured into ice water (200
mL) and extracted with DCM (3 × 40 mL). The combined organic
layer was rinsed with brine (100 mL), dried over anhydrous sodium
sulfate, and concentrated in vacuum. The rough product was purified
using a flash column to give the title compound 8a, a yellow powder
(0.14 g, 43%); 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.90 (d,
J = 7.6 Hz, 1H), 7.63−7.54 (m, 2H), 7.46 (d, J = 8.9 Hz, 2H), 6.76
(d, J = 8.9 Hz, 2H), 6.63 (s, 1H), 6.60 (s, 1H), 6.54 (s, 1H), 6.41 (d, J
= 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 4.63−4.49 (m, 2H), 4.07 (s,
3H), 3.91 (s, 3H), 3.72 (s, 3H), 1.45 (d, J = 6.1 Hz, 6H), 1.34 (d, J =
6.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 178.0, 177.4, 162.4,
162.4, 162.2, 162.2, 161.0, 160.8, 160.6, 160.1, 159.6, 134.2, 133.4,
131.9, 129.0, 128.7, 127.7 (C × 2), 125.3, 123.6, 114.5 (C × 2),
109.4, 109.4, 106.9, 106.9, 100.9, 100.9, 94.6, 91.9, 72.6, 70.7, 56.7,
56.3, 55.5, 22.0 (C × 4); ESI-MS m/z 649 [M + H]+.
8-Iodo-5,7-dimethoxy-2-(4-methoxyphenyl)-4H-chromen-4-one
(4a). TFA (7.43 μL, 0.1 mmol, 0.1 equiv) was added to a solution of
3a (0.31 g, 1 mmol, 1 equiv) in acetonitrile (5 mL) at 0 °C. To the
string reaction mixture was gradually added N-iodosuccinimide (NIS)
(0.24 g, 1.05 mmol, 1.05 equiv) over a period of 15 min, during which
a yellow or white suspension was gradually formed. The solution was
warmed to room temperature and allowed to stand for additional 2 h
until the starting material disappeared, which was monitored by TLC.
Acetonitrile was evaporated under reduced pressure to yield a crude
product, to which 5% Na2CO3 solution (20 mL) was added. The
product was extracted with Et2O/H2O. The Et2O layer was collected
and dried with MgSO4. The solvent was evaporated under reduced
pressure to afford iodinated flavones 4a as a white powder (137.0 mg,
95%); 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J = 8.8 Hz, 2H), 7.02
(d, J = 8.8 Hz, 2H), 6.63 (s, 1H), 6.43 (s, 1H), 4.02 (s, 6H), 3.89 (s,
3H); 13C NMR (75 MHz, CDCl3): δ 177.6, 162.7, 162.5, 162.1,
161.4, 157.8, 128.4 (C × 2), 123.7, 114.7 (C × 2), 110.1, 107.0, 92.1,
65.2, 56.9, 56.8, 55.7; ESI-MS m/z 439 [M + H]+.
8-(3-(5,7-Diisopropoxy-4-oxo-4H-chromen-2-yl)phenyl)-5,7-dii-
sopropoxy-2-(p-tolyl)-4H-chromen-4-one (8e). 8e was prepared
according to the same Suzuki−Miyama coupling for 8a, starting
from compounds 7 (0.29 g, 0.75 mmol, 1.5 equiv), 4d (0.24 g, 0.5
mmol, 1 equiv), Pd(IPr*) (cin)Cl (32.3 mg, 0.05 mmol, 0.1 equiv),
and NaOH (0.06 g, 1.5 mmol, 3 equiv) in DMF (20 mL). Purification
of the raw material using a flash column yielded 8d (yellow powder,
8-Iodo-5,7-Diisopropoxy-2-(p-tolyl)-4H-chromen-4-one (4e). 4e
was prepared according to the same procedure for 4a, starting from 3e
(0.35 g, 1 mmol, 1 equiv), NIS (0.24 g, 1.05 mmol, 1.05 equiv), and
TFA (7.43 μL, 0.1 mmol, 0.1 equiv) in acetonitrile (5 mL). 4e was
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obtained as a white powder (0.45 g, 95%); H NMR (300 MHz,
CDCl3): δ 7.87 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.77 (s,
1H), 6.19 (s, 1H), 4.97−4.80 (m, 1H), 4.79−4.58 (m, 1H), 2.41 (s,
3H), 1.54−1.41 (m, 12H); 13C NMR (75 MHz, CDCl3): δ 180.8,
168.3, 165.1, 165.1, 158.9, 147.4, 140.1, 131.6 (C × 2), 129.8 (C ×
2), 111.6, 107.5, 96.1, 73.6, 73.1, 59.6, 22.2 (C × 4), 21.7; ESI-MS m/
z 479 [M + H]+.
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0.17 g, 50%); H NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 7.94−
7.79 (m, 1H), 7.63−7.53 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.06 (d, J
= 8.0 Hz, 2H), 6.63 (s, 1H), 6.58 (d, J = 6.0 Hz, 2H), 6.39 (d, J = 1.7
Hz, 1H), 6.37−6.29 (m, 1H), 4.73−4.46 (m, 4H), 2.26 (s, 3H), 1.50
(d, J = 6.0 Hz, 6H), 1.44 (d, J = 6.0 Hz, 6H), 1.33 (d, J = 6.0 Hz, 6H),
1.29 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 177.7,
177.3, 162.3, 160.8, 160.7, 160.1, 159.6, 159.2, 159.1, 156.4, 141.7,
134.3, 133.7, 131.6, 129.7 (C × 2), 129.1, 128.7, 128.4, 125.9 (C ×
2), 124.9, 112.6, 110.8, 110.4, 109.2, 107.7, 100.9, 99.8, 94.7, 73.6,
72.6, 71.7, 70.71, 22.2 (C × 2), 22.1 (C × 2), 22.0 (C × 2), 22.0 (C ×
2), 21.4; ESI-MS m/z 689 [M + H]+.
1-(2-Hydroxy-4,6-diisopropoxyphenyl)ethan-1-one (6). K2CO3
(5.39 g, 39 mmol, 3.9 equiv) and (CH3)2CHI (3.91 mL, 39 mmol,
3.9 equiv) were added to a stirred solution of 2′,4′,6′-trihydrox-
yacetophenone (5) (2.70 g, 10 mmol, 1 equiv) in a mixture solution
of acetone/acetonitrile (1:2, 100 mL). Afterward, the mixture was
heated to 60 °C and stirred for additional 24 h. The mixture was
cooled to room temperature, filtered, and then diluted with ethyl
acetate (100 mL). Then, aqueous hydrochloric acid solution (1 M,
100 mL) was added slowly. The organolayer was partitioned. After
washing with saturated NaCl (3 × 100 mL), the organolayer was then
dried over anhydrous Na2SO4. After concentration under vacuum, the
rough sample was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 40:1) to yield the known compound 6
(1.91 g, 76%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 13.99
(s, 1H), 6.00 (d, J = 2.2 Hz, 1H), 5.86 (d, J = 2.2 Hz, 1H), 4.73−4.42
(m, 2H), 2.62 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H), 1.34 (d, J = 6.1 Hz,
6H).
(3-(5,7-Diisopropoxy-4-oxo-4H-chromen-2-yl)phenyl)boronic
acid (7). To a suspension of 1-(2-hydroxy-4,6-diisopropoxyphen-
yl)ethan-1-one (6) (1.26 g, 5 mmol, 1 equiv) in ethanol (30 mL) was
added 60% KOH solution (2.33 mL, 5 equiv) at 0 °C in an ice bath.
The mixture was stirred for a few minutes, and then, the appropriate
aldehyde (0.82 g, 5.5 mmol, 1.1 equiv) was added. After a few
minutes, the color of the reaction mixture turned into red. Also, it was
stirred overnight under ambient conditions. Then, the solution was
acidified to pH 1 by adding 10% aqueous HCl; the yellow precipitate
was filtered and washed with cold ethanol and water. After drying
under reduced vacuum, the raw intermediates were used without
further purification; to a solution of the aforementioned condensation
8-(3-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)phenyl)-5,7-dihy-
droxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (9a). BBr3 (2M
solution in DCM) (0.70 mL, 1.4 mmol, 7 equiv) was added dropwise
to a stirred solution of intermediates 8a (87.6 mg, 0.2 mmol, 1 equiv)
in anhydrous DCM (5 mL) at 40 °C for 1 h. After addition, the
reaction mixture was warmed to ambient temperature for 3 h. Then,
excess ice water was added and stirred for 10 min. Then, the
suspension was filtrated, and the raw residue was purified using a flash
column to obtain compounds 9a as a yellow powder (79.3 mg, 76%);
1H NMR (500 MHz, DMSO−d6): δ 8.26 (s, 1H), 8.07 (d, J = 7.2 Hz,
1H), 7.73 (d, J = 7.2 Hz, 1H), 7.70−7.64 (m, 1H), 7.60 (d, J = 8.4
Hz, 2H), 6.99 (s, 1H), 6.77 (s, 1H), 6.68 (d, J = 8.3 Hz, 2H), 6.46 (s,
1H), 6.40 (s, 1H), 6.21 (s, 1H); 13C NMR (75 MHz, DMSO−d6): δ
182.3, 182.2, 165.4, 164.1, 163.7, 163.1, 161.8, 161.5, 161.0, 157.9,
154.6, 135.3, 133.8, 130.8, 129.5, 129.1, 128.6, 128.6, 125.4, 121.7,
116.1, 116.1, 107.4, 105.6, 104.2, 103.7, 103.0, 99.6, 99.5, 94.7; HR-
ESI-MS m/z calcd for C30H17O9 [M − H]−, 521.0878; found,
521.0872.
8-(3-(5,7-Dihydroxy-4-oxo-4H-chromen-2-yl)phenyl)-5,7-dihy-
droxy-2-(p-tolyl)-4H-chromen-4-one (9e). 9e was prepared accord-
ing to the same procedure for 9a, starting from compounds 8e (95.6
mg, 0.2 mmol, 1 equiv) and BBr3 (2M solution in DCM) (0.50 mL,
1.0 mmol, 5 equiv) in DCM (20 mL). The raw residue was purified
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J. Med. Chem. 2021, 64, 12089−12108