T. Rodrigues et al. / European Journal of Medicinal Chemistry 69 (2013) 872e880
877
[M þ H]þ (100); Anal. Calcd. (C22H15ClO3): C, 72.83; H, 4.17%. Found:
1.6 Hz, AreH); 7.80 (2H, d, J ¼ 8.8 Hz, AreH); 8.23 (1H, dd, J ¼ 8.0
and 1.6 Hz, AreH); 13C NMR (CDCl3, 101 MHz)
107.8; 118.2; 124.0;
C, 72.59; H, 4.16%.
d
125.5; 125.9; 126.4; 127.8; 130.8; 132.5; 134.1; 156.3; 162.4; 178.4;
IR (film): nmax 1640; 1468; 1406; 1130; 752 cmꢀ1; ESI-MS m/z
(abund.): 303 [M þ H]þ (100); Anal. Calcd. (C15H9BrO2$0.5H2O): C,
58.09; H, 3.26%. Found: C, 58.24; H, 3.12%.
4.1.3.5. 6-Chloro-2-(4-(4-chlorophenoxy)phenyl)-7-methyl-4H-chro-
men-4-one (6e). Yellow solid; 21%; mp 185e187 ꢁC; 1H NMR (CDCl3,
400 MHz)
d 2.54 (3H, s, CH3); 6.76 (1H, s, AreH3); 7.06 (2H, d,
J ¼ 7.2 Hz, AreH); 7.10 (2H, d, J ¼ 7.2 Hz, AreH); 7.39 (2H, d, J ¼ 7.2 Hz,
AreH); 7.48 (1H, s, AreH); 7.90 (2H, d, J ¼ 7.2 Hz, AreH); 8.20 (1H, s,
4.1.3.11. 2-([1,10-Biphenyl]-4-yl)-3-bromo-7-bromomethyl-6-chloro-
4H-chromen-4-one (6k). Compound 6i (1 M eq.), NBS (1.2 M eq.)
and benzoyl peroxide (0.1 M eq.) were suspended in CCl4 (5 mL/
mmol). The mixture was heated to reflux for 24 h and then cooled
to room temperature. The organic phase was washed with water
and evaporated to dryness in vacuum. The crude product was pu-
rified by flash chromatography, hexane : EtOAc (9:1). Yellow solid;
AreH); 13C NMR (CDCl3, 101 MHz)
d 20.9; 106.7; 118.3; 119.9; 121.3;
123.0; 125.4; 126.2; 128.2; 129.7; 130.1; 131.9; 143.00; 154.3; 154.5;
160.5; 162.9; 177.2; IR (film): nmax 1630; 1481; 1400; 1237; 1163;
827 cmꢀ1; ESI-MS m/z (abund.): 397 [M þ H]þ (100); Anal. Calcd.
(C22H14Cl2O3þ0.2H2O): C, 65.92; H, 3.62%. Found: C, 65.72; H, 3.50%.
4.1.3.6. 6-Chloro-7-methyl-2-(4-(4-trifluoromethoxy)phenoxy)
phenyl-4H-chromen-4-one (6f). Pinkish solid; 40%; mp 171e173 ꢁC;
27%; mp 262e265 ꢁC; 1H NMR (CDCl3, 400 MHz)
d 4.67 (2H, s, CH2);
7.45 (1H, t, J ¼ 7.0 Hz, AreH); 7.53 (2H, t, J ¼ 7.4 Hz, AreH); 7.69e
7.71 (3H, m, AreH); 7.79 (2H, d, J ¼ 8.6 Hz, AreH); 7.99 (2H, d,
J ¼ 8.6 Hz, AreH); 8.34 (1H, s, AreH); 13C NMR (CDCl3, 101 MHz)
1H NMR (CDCl3, 400 MHz)
d 2.55 (3H, s, CH3); 6.76 (1H, s, AreH3);
7.12e7.14 (4H, m, AreH); 7.28 (2H, d, J ¼ 8.0 Hz, AreH); 7.48 (1H, s,
AreH8); 7.91 (2H, d, J ¼ 7.2 Hz, AreH); 8.20 (1H, s, AreH5); 13C NMR
d
29.0; 109.1; 120.6; 122.4; 127.1; 127.3; 127.4; 128.3; 129.0; 129.9;
(CDCl3, 101 MHz)
d
20.9; 106.8; 118.5; 119.9; 120.9; 122.9; 122.9;
131.0; 131.5; 139.7; 141.8; 144.3; 153.9; 162.2; 171.9; IR (film): nmax
1651; 1613; 1549; 1453; 1409; 1332; 1076 cmꢀ1; ESI-MS m/z
(abund.): 503 [M þ H]þ (25); 505 [Mþ3]þ (100); Anal. Calcd.
(C22H13Br2ClO2): C, 52.37; H, 2.60%. Found: C, 52.01; H, 2.51%.
123.0; 123.0; 125.4; 126.4; 128.3; 132.0; 143.0; 145.5; 154.2; 160.3;
162.8; 177.2; IR (film): nmax 1630; 1503; 1251; 1163; 1037; 904;
830 cmꢀ1; ESI-MS m/z (abund.): 447 [M þ H]þ (100); Anal. Calcd.
(C23H14ClF3O4): C, 61.83; H, 3.16%. Found: C, 61.86; H, 3.10%.
4.1.3.12. 2-([1,10-Biphenyl]-4-yl)-3-bromo-6-chloro-7-methyl-4H-
chromen-4-one (6l). Compound 6i (1 M eq.), NBS (1.2 M eq.) and
ZrCl4 (0.1 M eq.) were suspended in CH2Cl2. The suspension was
stirred at room temperature for 24 h and water was added. The
aqueous phase was extracted with CH2Cl2 (4 ꢅ 50 mL), and the
combined extracts were evaporated to dryness under reduced
pressure. The crude product was purified by flash chromatography,
hexane : EtOAc (9:1). Yellow solid; 10%; mp 190e192 ꢁC; 1H NMR
4.1.3.7. 2-([1,10-Biphenyl]-4-yl)-6-chloro-7-methyl-4H-chromen-4-
one (6i). Yellow solid; 27%; mp 197e199 ꢁC; 1H NMR (CDCl3,
400 MHz)
d 2.56 (3H, s, CH3); 6.87 (1H, s, AreH3); 7.44 (1H, tt,
J ¼ 1.2 and 7.2 Hz, AreH); 7.50e7.54 (3H, m, AreH and AreH8); 7.68
(2H, d, J ¼ 8.0 Hz, AreH); 7.78 (2H, d, J ¼ 6.8 Hz, AreH); 8.01 (2H, d,
J ¼ 6.8 Hz, AreH); 8.22 (1H, s, AreH5); 13C NMR (CDCl3, 101 MHz)
d
20.9; 107.2; 120.0; 123.1; 125.4; 126.8; 127.2; 127.7; 128.3; 129.0;
129.1; 130.3; 132.0; 139.7; 143.1; 144.6; 154.5; 177.3; IR (film): nmax
1630; 1451; 1407; 1244; 1051; 908; 827 cmꢀ1; ESI-MS m/z (abund.):
347 [M þ H]þ (100); Anal. Calcd. (C22H15ClO2$0.2CH2Cl2): C, 73.29;
H, 4.27%. Found: C, 73.66; H, 4.31%.
(CDCl3, 400 MHz) d 2.55 (3H, s, CH3); 7.41e7.48 (2H, m, AreH); 7.52
(2H, t, J ¼ 7.6 Hz, AreH); 7.66e7.72 (2H, m, AreH); 7.78 (2H, d,
J ¼ 8.6 Hz, AreH); 7.97 (2H, d, J ¼ 8.6 Hz, AreH); 8.28 (1H, s, AreH);
13C NMR (CDCl3, 101 MHz)
d 21.0; 109.0; 119.7; 120.8; 126.0; 127.0;
127.3; 128.2; 129.0; 129.9; 131.4; 132.5; 139.8; 143.7; 144.1; 153.9;
161.7; 172.1; IR (film): nmax 1651; 1606; 1542; 1409 cmꢀ1; HRMS calc.
(C22H14BrClO2): 423.9866/425.9845. Found: 423.9861/425.9839.
4.1.3.8. 6-Chloro-7-methyl-2-(4-(4,4,4-trifluorobutoxy)phenyl)-4H-
chromen-4-one (6h). Yellow solid; 15%; mp 161e162 ꢁC; 1H NMR
(CDCl3, 400 MHz)
CH2CH2CF3); 2.54 (3H, s, CH3); 4.13 (2H, t,
d
2.13 (2H, m, CH2CH2CH2); 2.36 (2H, m,
6.0 Hz,
J
¼
4.1.4. General Suzuki coupling for the preparation of flavones 6mer
To a solution of compound 6i in dry 1,4-dioxane at room tem-
perature was consecutively added PdCl2(Ph3P)2 (0.1 equiv.), Na2CO3
1 N (3 equiv.), and boronic acid (1.2 equiv.). After degassing during
5 min, the resulting mixture was heated at 100 ꢁC, under N2 at-
mosphere, during 3e5 h. The mixture was then cooled to room
temperature, diluted with DCM and filtered through a pad of celite.
The filtrate was concentrated under reduce pressure and the crude
product was purified by flash chromatography (hexane:EtOAc, 8:2)
or thin layer chromatography (EtOAc:hexane:Et3N, 6:4:0.5).
CH2CH2CH2CF3); 6.74 (1H, s, AreH3); 7.03 (2H, d, J ¼ 8.6 Hz, AreH);
7.48 (1H, s, AreH8); 7.88 (2H, d, J ¼ 8.6 Hz, AreH); 8.19 (1H, s, Are
H5); 13C NMR (CDCl3, 101 MHz)
d 20.9; 22.1; 29.8; 30.5; 66.3; 106.1;
114.9; 119.9; 123.0; 124.2; 125.4; 128.1; 131.8; 142.8; 154.5; 161.4;
163.4; 177.2; IR (film): nmax 1638; 1504; 1408; 1243; 1019 cmꢀ1
ESI-MS m/z (abund.): 397 [M
H]þ (100); Anal. Calcd.
(C20H16ClF3O3): C, 60.54; H, 4.06%. Found: C, 60.49; H, 3.93%.
;
þ
4.1.3.9. 2-(4-(3-(Trifluoromethoxy)phenoxy)phenyl)-4H-chromen-4-
one (6g). Yellow solid; 37%; mp 86e87 ꢁC; 1H NMR (CDCl3,
400 MHz)
d
6.81 (1H, s, AreH3); 6.99e7.10 (3H, m, AreH); 7.18 (2H,
4.1.4.1. 2-([1,10-Biphenyl]-4-yl)-4H-chromen-4-one
(6m). White
6.88 (1H, s,
d, J ¼ 8.8, AreH); 7.41e7.48 (2H, m, AreH); 7.59 (1H, d, J ¼ 7.6 Hz,
AreH); 7.73 (1H, ddd, J ¼ 8.6, 7.2 and 1.6 Hz, AreH); 7.96 (2H, d,
J ¼ 8.8 Hz, AreH); 8.26 (1H, dd, J ¼ 7.6 and 1.6 Hz, AreH); 13C NMR
solid; 75%; mp 135e137 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
AreH3); 7.38e7.46 (2H, m, AreH); 7.49 (2H, t, J ¼ 7.5 Hz, AreH); 7.60
(1H, d, J ¼ 8.4 Hz, AreH); 7.66 (2H, d, J ¼ 7.5 Hz, AreH); 7.69e7.78
(3H, m, AreH); 8.02 (2H, d, J ¼ 8.5 Hz, AreH); 8.25 (1H, dd, J ¼ 7.9 and
(CDCl3, 101 MHz)
d 107.1; 112.6; 116.5; 117.7; 118.0; 118.4; 118.9;
123.9; 125.3; 125.8; 127.1; 128.3; 130.6; 130.9; 133.8; 156.2; 157.0;
159.6; 162.8; 178.4; IR (film): nmax 1632; 1587; 1478; 1370; 1262;
1172 cmꢀ1; ESI-MS m/z (abund.): 399 [M þ H]þ (100); Anal. Calcd.
(C22H13F3O4): C, 66.34; H, 3.29%. Found: C, 66.40; H, 3.22%.
1.3 Hz, AreH); 13C NMR (CDCl3,101 MHz)
d 107.6; 118.2; 124.1; 125.4;
125.9; 126.9; 127.3; 127.8; 128.4; 129.2; 130.6; 133.9; 139.9; 144.6;
156.4; 163.3; 178.6; IR (film): nmax 1645; 1574; 1464; 1409;
1243 cmꢀ1; ESI-MS m/z (abund.): 299 [M þ H]þ (100); Anal. Calcd.
(C21H14O2$1.9H2O): C, 75.84; H, 5.41%. Found: C, 75.94; H, 5.74%.
4.1.3.10. 3-(4-Bromophenyl)-4H-chromen-4-one (6j). white solid;
25%; mp 179e181 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
6.80 (1H, s, Are
4.1.4.2. 2-(40-Chloro-[1,10-biphenyl]-4-yl)-4H-chromen-4-one (6n).
H3); 7.43 (1H, td, J ¼ 8.0 and 1.0 Hz, AreH); 7.56 (1H, d, J ¼ 8.0 Hz,
White solid; 50%; mp 208e210 ꢁC; 1H NMR (CDCl3, 400 MHz)
d
6.88
AreH); 7.67 (2H, d, J ¼ 8.8 Hz, AreH); 7,71 (1H, ddd, J ¼ 8.4, 7.2 and
(1H, s, AreH3); 7.41e7.49 (3H, m, AreH); 7.56e7.63 (3H, m, AreH);