Y. M. Ahn et al. / Bioorg. Med. Chem. 15 (2007) 702–713
709
131.1, 130.8, 129.2, 128.7, 128.5, 127.7, 117.9, 111.6,
111.3, 110.4; HRMS (FAB) m/z calcd for C22H14O4NCl2
[M+H]+ 426.0300; found 426.0277.
(DMSO-d6, 100 MHz): d 183.3, 171.4, 163.5, 161.5,
157.2, 156.3, 147.2, 133.1, 132.8, 131.6, 131.5, 131.3,
131.2, 129.5, 128.5, 127.4, 111.0, 104.9, 104.5, 99.8;
MS (FAB) m/z calcd for C29H17Cl3NO6 [M+H]+
581.8; found 582.1.
4.7.3. 3,4-Dichloro-N-[2-(2-chlorophenyl)-5-hydroxy-4-
oxo-4H-chromen-8-yl]benzamide (17c). 15.8 mg (79%);
1
mp 222–223 ꢁC; Rf 0.91 (1:1 hexane/EtOAc); H NMR
4.9. General procedure for reactions with benzoyl
chlorides
(400 MHz): d 12.0 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H),
8.21 (br s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.74 (dd,
J = 2.1, 8.4 Hz, 1H), 7.64 (m, 3H), 7.56 (dt, J = 1.6,
7.5 Hz, 1H), 7.48 (dt, J = 1.2, 7.6 Hz, 1H), 6.92 (d,
J = 9.0 Hz, 1H), 6.63 (s, 1H); 13C NMR (100 MHz): d
182.7, 163.2, 162.9, 156.8, 148.3, 136.4, 133.9, 133.3,
132.6, 132.2, 131.2, 130.9, 130.8, 130.5, 129.1, 128.1,
127.6, 126.0, 117.4, 111.3, 111.1, 110.2; HRMS (FAB)
m/z calcd for C22H13O4NCl3 [M+H]+ 459.9910; found
459.9903.
The procedure for the synthesis of 19a was also used for
the preparation of 19b–19d.
4.9.1.
N-[2-(2-Chlorophenyl)-5,7-dihydroxy-4-oxo-4H-
chromen-8-yl]benzamide (19a). To a solution of 16
(30.0 mg, 0.099 mmol) in CH2Cl2 (2 mL) were added
DIEA (19 lL, 0.11 mmol) and benzoyl chloride
(13 lL, 0.11 mmol). The reaction mixture was stirred
at room temperature for 2 h and then quenched with
ice water (20 mL). The solution was extracted with
EtOAc and then the solvent was removed until the
volume of the solution was around 6 mL. To the solu-
tion was added 40% KOH (4 mL). The solution was
stirred at room temperature for 15 min. and then the
organic layer was washed with water, 3N-HCl, and
brine. The organic layer was dried over anhydrous
Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by silica gel column
chromatography (1:5 EtOAc/hexane) to yield 20 mg
(50%) of 19a as a yellow solid: mp 205–206 ꢁC; Rf
0.44 (1:1 hexane/EtOAc); 1H NMR (300 MHz): d
12.2 (s, 1H), 11.2 (br s, 1H), 8.50 (br s, 1H), 7.93
(dd, J = 1.3, 7.2 Hz, 2H), 7.62 (dt, J = 1.6, 7.6 Hz,
2H), 7.4–7.6 (m, 5H), 6.54 (s, 1H), 6.53 (s, 1H); 13C
NMR (100 MHz): d 181.7, 174.3, 164.8, 167.4, 162.7,
159.7, 157.1, 148.8, 133.0, 132.7, 131.2 (2), 131.1,
129.1, 127.8, 127.6, 111.6, 106.8, 104.8, 102.7; HRMS
(FAB) m/z calcd for C22H15O5NCl [M+H]+ 408.0639;
found 408.0638.
4.7.4. N-[2-(2-Chlorophenyl)-5-hydroxy-4-oxo-4H-chro-
men-8-yl]-4-methylbenzamide (17d). 16.9 mg (92%); mp
252.5–254 ꢁC; Rf 0.72 (1:1 hexane/EtOAc); 1H NMR
(400 MHz): d 12.1 (s, 1H), 8.61 (d, J = 8.9 Hz, 1H),
8.26 (br s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.64 (d,
J = 7.5 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.53 (t,
J = 7.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.31 (d,
J = 7.9 Hz, 2H), 6.91 (d, J = 9.0 Hz, 1H), 6.62 (s, 1H),
2.44 (s, 3H); 13C NMR (100 MHz): d 183.1, 165.5,
163.4, 156.7, 146.5, 142.8, 132.7, 131.6, 131.4, 131.2,
131.0, 129.6, 128.7, 127.7, 127.2, 118.4, 111.6, 111.4,
110.5, 21.6; HRMS (FAB) m/z calcd for C23H17O4NCl
[M+H]+ 426.0846; found 426.0842.
4.7.5. N-[2-(2-Chlorophenyl)-5-hydroxy-4-oxo-4H-chro-
men-8-yl]-4-methoxybenzamide (17e). 15.8 mg (86%);
mp 210–210.5 ꢁC; Rf 0.76 (1:1 hexane/EtOAc); 1H
NMR (400 MHz): d 12.0 (s, 1H), 8.56 (d, J = 9.0 Hz,
1H), 8.20 (br s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.64 (dd,
J = 1.3, 7.7 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 (dt,
J = 1.3, 7.9 Hz, 1H), 7.45 (t, J = 7.6 Hz, 3H), 6.98 (d,
J = 8.7 Hz, 2H), 6.89 (d, J = 9.0 Hz, 1H), 6.60 (s, 1H);
13C NMR (100 MHz): d 183.0, 165.0, 163.3, 162.6,
156.5, 146.4, 132.6, 131.2, 131.1, 130.9, 128.9, 128.7,
127.6, 126.5, 118.4, 114.1, 111.5, 111.2, 110.4, 55.5;
HRMS (FAB) m/z calcd for C23H17O5NCl [M+H]+
422.0795; found 422.0781.
4.9.2. 4-Chloro-N-[2-(2-chlorophenyl)-5,7-dihydroxy-4-
oxo-4H-chromen-8-yl]benzamide (19b). 20 mg (45%);
1
mp 234 ꢁC; Rf 0.38 (1:1 hexane/EtOAc); H NMR (ace-
tone-d6, 500 MHz): d 12.6 (s, 1H), 9.21 (br s, 1H), 8.04
(d, J = 8.4 Hz, 2H), 7.84 (dd, J = 1.6, 7.7 Hz, 1H), 7.54
(dt, J = 1.3, 8.0 Hz, 1H), 7.51 (dd, J = 1.6, 7.9 Hz,
2H), 7.49 (d, J = 8.4 Hz, 2H), 7.44 (dt, J = 1.3, 8.0 Hz,
1H), 6.61 (s, 1H), 6.39 (s, 1H); 13C NMR (acetone-d6,
125.5 MHz): d 182.6, 166.8, 163.0, 161.3, 153.6, 138.3,
133.4, 133.1, 132.9, 131.9, 131.8, 131.6, 130.3, 129.3,
128.3, 111.8, 105.8, 105.3, 100.6; HRMS (FAB) m/z
calcd for C22H14O5NCl2 [M+H]+ 442.0249; found
442.0250.
4.8. 2-(2-Chlorophenyl)-8-(4-chlorophenylamido)-5-hy-
droxy-4-oxo-4H-chromen-7-yl 4-chlorobenzoate (18b)
To a solution of 16 (30.0 mg, 0.099 mmol) in CH2Cl2
(3 mL) were added DIEA (34.5 lL, 0.20 mmol) and ben-
zoyl chloride (25.2 lL, 0.20 mmol). The reaction mix-
ture was stirred at room temperature for 40 min and
then quenched with ice water (20 mL). The solution
was extracted with EtOAc and the organic layer was
dried over anhydrous Na2SO4 and the removed solvent
under reduced pressure. The residue was purified by sil-
ica gel column chromatography (1:5 EtOAc/hexane) to
yield 20 mg (50%) of 18b as a yellow solid: mp 241 ꢁC;
Rf 0.57 (1:1 hexane/EtOAc); 1H NMR (DMSO-d6,
400 MHz): d 12.8 (s, 1H), 10.3 (s, 1H), 7.83 (d,
J = 1.2 Hz, 1H), 7.66 (m, 5H), 7.55 (d, J = 1.3, 2H),
7.40 (m, 4H), 7.09 (s, 1H), 6.87 (s, 1H); 13C NMR
4.9.3. N-[2-(2-Chlorophenyl)-5,7-dihydroxy-4-oxo-4H-
chromen-8-yl]-4-methylbenzamide (19c). 21 mg (49%);
1
mp 210–212 ꢁC; Rf 0.50 (1:1 hexane/EtOAc); H NMR
(DMSO-d6, 300 MHz): d 12.7 (s, 1H), 11.1 (br s, 1H),
9.52 (s, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.76 (d,
J = 7.5 Hz, 1H), 7.4–7.7 (m, 3H), 7.29 (d, J = 7.8 Hz,
2H), 6.69 (s, 1H), 6.42 (s, 1H), 2.36 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz): d 181.5, 166.0, 162.1, 161.2,
159.3, 153.4, 141.3, 132.7, 131.3, 131.1, 130.7, 130.4,
128.8, 127.7, 127.6, 110.5, 105.0, 103.7, 98.9, 20.9;