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C.-C. Peng et al. / Bioorg. Med. Chem. 16 (2008) 4064–4074
5.6.7. 3-(4-Hydroxy-3,5-diiodobenzoyl)-2-propyl-4H-chro-
men-4-one (3). Mp 198–200 ꢁC. 1H NMR (DMSO) d
8.11 (s, 2H), 8.02 (dd, J = 0.9, 7.8 Hz, 1H), 7.85 (m,
1H), 7.70 (d, J = 8.7 Hz, 1H), 7.51 (m, 1H), 2.50 (t,
J = 7.2 Hz, 2H), 1.70 (hex, J = 7.2 Hz, 2H), 0.882 (t,
J = 7.2 Hz, 3H); 13C NMR (DMSO) d 188.07, 175.93,
167.47, 165.23, 156.34, 141.08, 135.14, 128.20, 126.25,
125.69, 123.47, 123.11, 119.02, 89.03, 34.60, 20.74, 14.16.
(10.42 mL, 0.167 mmol) was added. The reaction mixture
was refluxed overnight and the cooled mixture was filtered
through a bed of Celite. The solvent was evaporated by ro-
tary evaporator to give clean white product in 99% yield.
1H NMR (CDCl3) d 8.25 (s, 2H), 8.18 (dd, J = 1.8,
8.1 Hz, 1H), 7.74 (m, 1H), 7.52 (dd, J = 0.6, 8.4 Hz, 1H),
7.45 (m, 1H), 3.90 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 1.80
(hex, J = 7.8 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3) d 190.63, 176.15, 169.52, 163.25, 156.25, 141.10,
136.70, 134.53, 126.28, 125.91, 123.55, 122.09., 118.21,
91.11, 61.02, 34.88, 21.22, 14.07. ESI-MS m/z 574.9
(M+1), 233.0 (Mꢀ341.9), 215.2 (Mꢀ359.7).
5.6.8. 3-(3,5-Dibromo-4-hydroxybenzoyl)-2-ethyl-4H-chro-
men-4-one (4). Mp 197–200 ꢁC. 1H NMR (CDCl3) d 8.19
(dd, J = 1.5, 8.1 Hz, 1H), 7.99 (s, 2H), 7.74 (m, 1H), 7.52
(dd, J = 0.9, 7.8 Hz, 1H), 7.45 (m, 1H), 2.64 (q,
J = 7.8 Hz, 2H), 1.32 (t, J = 7.8 Hz, 3H); 13C NMR
(CDCl3) d 190.39, 176.22, 170.17, 156.32, 154.42,
134.52, 133.76, 132.13, 126.30, 125.89, 123.55, 121.65,
118.20, 110.69, 26.66, 12.09.
5.6.14. 2-Ethyl-3-isonicotinoyl-4H-chromen-4-one (12).26,27
To a round-bottom flask equipped with a stirrer and con-
denser were combined isonicotinic acid (1.27 g,
10.36 mmol) and thionyl chloride (30 mL). The reaction
was heated to 70 ꢁC for 1 h with stirring. After this, the
condenser was removed and an argon stream was used
to remove excess thionyl chloride (15 min). The resulting
residue was cooled to room temperature and residual thio-
nyl chloride was removed using a rotary evaporator. The
solid was dissolved in two portions of ethyl acetate (2·
30 mL) and the resulting solution was evaporated to solid.
The crude isonicotinyl chloride was slowly added to a
100 mL round-bottom flask containing 2-hydroxyl aceto-
phenone (1.4 g 10.28 mmol) and pyridine (10 mL) at
0 ꢁC (ice bath). This reaction mixture was stirred at room
temperature for 3 h then was poured into a 200 mL beaker
containing 15 g of ice. This aqueous solution was adjusted
to pH ꢃ 6 using aq HCl (3 N). The resulting solid was col-
lected by vacuum filtration and washed with ice cold water
(20 mL) and dried under high vacuum. This crude com-
pound was purified by chromatography (60 g, silica gel
60, 0.063–0.200 mm) using a 1:1 mixture of hexane/ethyl
acetate. Crystallization from methanol gave pure 2-acetyl-
phenyl isonicotinate in 92% yield. From this stock, 482 mg
(2 mmol) was added to a 100 mL round-bottom flask fit-
ted with a stir bar and containing pyridine (5 mL) and
powered potassium hydroxide (112.2 mg, 2 mmol). This
mixture was stirred vigorously at room temperature over-
night. The solution was adjusted to pH ꢃ 6 with 1 M cold
aqueous acetic acid. The resulting solid was collected by
vacuum filtration and washed with ice cold water (2·
10 mL). The resulting solid was purified by crystallization
from methanol to give 41.5% yield of 1-(2-hydroxy-
5.6.9. 3-(4-Hydroxybenzoyl)-2-methyl-4H-chromen-4-one
1
(5). Mp 270–272 ꢁC. H NMR (DMSO) d 10.54 (s, 1H)
7.99 (dd, J = 1.8, 8.1 Hz, 1H), 7.82 (m, 1H), 7.76 (d,
J = 8.7 Hz, 2H), 7.67 (dd, J = 0.6, 8.4 Hz, 1H), 7.49
(m, 1H), 6.83 (d, J = 8.7 Hz, 2H), 2.24 (s, 3H); 13C
NMR (DMSO) d 191.92, 175.71, 164.80, 163.71,
156.29, 135.21, 132.77, 128.85, 126.28, 125.70, 123.38,
118.92, 116.25, 19.40.
5.6.10. 3-(4-Hydroxybenzoyl)-2-propyl-4H-chromen-4-one
(7). Mp 206–209 ꢁC. 1H NMR (CDCl3) d 8.24 (dd,
J = 1.5, 8.1 Hz, 1H), 7.96 (s, 1H), 7.76 (m, 1H), 7.64 (d,
J = 8.4 Hz, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.47 (m, 1H),
6.59 (d, J = 8.7 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.78
(hex, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H); 13C
NMR (DMSO) d 191.92, 175.97, 167.27, 163.72, 156.34,
135.26, 132.77, 128.97, 126.32, 125.66, 123.44, 123.38,
118.99, 116.24, 34.55, 20.71, 14.12.
5.6.11. 3-(4-Methoxybenzoyl)-2-methyl-4H-chromen-4-one
(8). Mp 135–136 ꢁC. 1H NMR (CDCl3) d 8.18 (dd,
J = 1.5, 7.8 Hz, 1H), 7.90 (d, J = 9 Hz, 2H), 7.69 (m,
1H), 7.47 (dd, J = 0.6, 8.4 Hz, 1H), 7.41 (m, 1H), 6.92
(d, J = 9 Hz, 2H), 3.85 (s, 3H), 2.36 (s, 3H); 13C NMR
(CDCl3) d 192.31, 176.07, 165.15, 164.45, 156.19,
134.22, 132.15, 130.29, 126.24, 125.60, 123.66, 123.53,
118.08, 114.24, 55.78, 19.33.
5.6.12. 3-(4-Methoxybenzoyl)-2-propyl-4H-chromen-4-one
(10). Mp 92–94 ꢁC. 1H NMR (CDCl3) d 8.19 (dd, J = 1.5,
7.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.70 (m, 1H), 7.48
(dd, J = 0.6, 8.7 Hz, 1H), 7.41 (m, 1H), 6.93 (d,
J = 9 Hz, 2H), 3.86 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H),
1.77 (hex, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3) d 192.32, 176.34, 168.19, 164.39, 156.27,
134.16, 132.14, 130.52, 126.28, 125.55, 123.70, 123.39,
118.09, 114.20, 55.77, 34.81, 21.07, 14.06.
phenyl)-3-(pyridin-4-yl)propane-1,3-dione.
Cyclization
was performed as for 2-ethyl-3-(4-methoxybenzoyl)-4H-
chromen-4-one (9) to give a 43.2% yield of 2-ethyl-3-isoni-
cotinoyl-4 H-chromen-4-one (12). 1H NMR (CDCl3) d
8.80 (d, J = 5.4 Hz, 2H), 8.15 (dd, J = 1.5, 8.1 Hz, 1H),
7.74 (m, 1H), 7.67 (d, J = 5.7 Hz, 2H), 7.53 (dd, J = 1.5,
10.2 Hz, 1H), 7.44 (m, 1H), 2.70 (q, J = 7.8 Hz, 2H),
1.35 (t, J = 7.8 Hz, 3H); 13C NMR (CDCl3) d 193.97,
176.34, 171.66, 156.23, 151.08, 143.56, 134.67, 126.09,
126.03, 123.54, 122.04, 121.39, 118.23, 26.56, 12.23. ESI-
MS m/z 280.5 (M+1).
5.6.13. 3-(3,5-Diiodo-4-methoxybenzoyl)-2-propyl-4H-chro-
men-4-one (11). Methylated from compound 3. To a
50 mL round-bottom flask equipped with a stir bar and a
water condenser were combined potassium carbonate
(15.42 mg, 0.112 mmol), 10 mL acetone, and compound 3
(25 mg, 0.0556 mmol). The reaction mixture was stirred
for 30 min at room temperature during which iodomethane
5.6.15. Alignment and comparative molecular field anal-
ysis (CoMFA) modeling. Ligands were constructed in
SYBYL version 6.6 (Tripos Inc., St. Louis) and mini-
mized using the AM1 semiempirical method in MO-
PAC. The partial charges of each ligand were