7152 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22
Nolan et al.
compound as a colorless solid (2.55 g, 65%): νmax/cm-1 2947 w,
2920 w, 2899 w, 1652 s (CdO), 1620 s, 1561 s; δH (300 MHz;
DMSO-d6) 7.86 (2H, d, J=7.9, 2 ꢀ CH), 7.56 (2H, t, J=8.8, 2 ꢀ
CH), 7.34-7.26 (4H, m, CH), 7.19-7.11 (5H, m, CH), 6.32 (1H,
s, CH); δC (125 MHz; DMSO-d6) some signals coincident: 166.0
(C), 165.3 (C), 165.0 (C), 164.8 (C), 152.6 (C), 150.6 (C), 141.9
(C), 140.6 (C), 132.5 (C), 131.7 (CH), 128.2 (CH), 128.0 (CH),
126.7 (CH), 126.6 (CH), 125.7 (CH), 125.4 (CH), 124.0 (CH),
123.8 (CH), 123.6 (CH), 118.5 (C), 116.5 (CH), 115.9 (CH),
114.9 (CH), 103.9 (C), 35.9 (CH); -ES m/z 412 (25%, [M]-),
411.4 (100, [M - H]-); found by -ES 411.0863, C25H15O6 ([M -
H]-) requires 411.0869, error 1.5 ppm.
3,30-(3,4-Dimethyl-phenylmethanediyl)bis(4-hydroxy-2H-chro-
men-2-one) 46. Using method A, 4-hydroxy-2H-chromen-2-one
30a (484 mg, 2.98 mmol) and 3,4-dimethylbenzaldehyde (200
mg, 1.49 mmol) gave the title compound as a colorless solid (264
mg, 40%): mp 268-270 ꢀC; νmax/cm-1 2919 w, 1673 s (CdO),
1631 m, 1608 m, 1566 m; δH (300 MHz; DMSO-d6) 7.88 (2H, d,
J=9.2, 2 ꢀ CH), 7.60-7.50 (2H, m 2 ꢀ CH), 7.36-7.24 (4H, m,
4 ꢀ CH), 6.96 (1H, d, J=8.2, CH), 6.85 (1H, s, CH), 6.84 (1H, d,
J=8.2, CH), 6.26 (1H, s, CH), 2.14 (3H, s, CH3), 2.10 (3H, s,
CH3); δC (75 MHz; DMSO-d6) some signals coincident: 165.3
(C), 164.7 (C), 152.3 (C), 150.5 (C), 141.9 (C), 136.6 (C), 135.7
(C), 133.4 (C), 132.5 (C), 129.3 (CH), 127.7 (CH), 124.0 (CH),
123.7 (CH), 116.4 (CH), 114.8 (C), 103.7 (C), 35.3 (CH), 19.7
(CH3), 18.9 (CH3); -ES m/z 440 (35%, [M]-), 439 (100, [M -
H]-); found by -ES 439.1197, C27H19O6 ([M - H]-) requires
439.1182, error 3.4 ppm.
3,30-(3,4-Dimethyl-phenylmethanediyl)bis(4-hydroxy-6,7-di-
methyl-2H-chromen-2-one) 47. Using method A, 4-hydroxy-6,
7-dimethyl-2H-chromen-2-one 30j (285 mg, 1.50 mmol) and 3,
4-dimethylbenzaldehyde (100 mg, 0.75 mmol) gave the title
compound as a colorless solid (258 mg, 69%): mp 283-284
ꢀC; νmax/cm-1 2937 b, 2916 b, 1668 s (CdO), 1603 s, 1560 m; δH
(300 MHz; DMSO-d6) 7.62 (2H, s, 2 ꢀ CH), 7.16 (2H, s, 2 ꢀ
CH), 6.95 (1H, d, J=8.0, CH), 6.84 (1H, s, CH), 6.80 (1H, d, J=
8.0, CH), 6.22 (1H, s, CH), 2.31 (6H, s, 2 ꢀ CH3), 2.26 (6H, s, 2 ꢀ
CH3), 2.14 (3H, s, CH3), 2.09 (3H, s, CH3); δC (75 MHz; DMSO-
d6) some signals coincident: 165.9 (C), 165.1 (C), 164.8 (C), 152.2
(C), 138.5 (C), 137.1 (C), 135.6 (C), 133.5 (C), 133.3 (C), 131.9
(CH), 129.2 (CH), 127.8 (CH), 124.2 (CH), 123.9 (CH), 123.8
(CH), 117.9 (C), 116.0 (CH), 104.3 (C), 35.6 (CH), 19.6 (CH3),
18.9 (CH3); -ES m/z 495 (100%, [M - H]-); found by
-ES 495.1823, C31H27O6 ([M - H]-) requires 495.1808 error
3.0 ppm.
[M - H]-); found by þES 330.1252, C22H18O3 ([M]þ) requires
330.1256, error 1.2 ppm.
4-Hydroxy-6,7-dimethyl-3-(2-naphthylmethyl)-2H-chromen-
2-one 17. Using method B, 3,30-(2-naphthylmethanediyl)bis-
(4-hydroxy-6,7-dimethyl-2H-chromen-2-one) 35 (500 mg, 0.96
mmol) and NaCNBH3 (182 mg, 2.89 mmol) gave the title
compound (139 mg, 43%) as a colorless solid after purification
by flash column chromatography: mp 246-247 ꢀC (decomp.);
ν
max/cm-1 3084 bw (O-H), 3053 b, 3010 b, 2966 b, 1677 w, 1652
m (CdO), 1619 s, 1561 m; δH (500 MHz; DMSO-d6) 7.84 (1H, d,
J=8.2, CH), 7.81 (2H, d, J=8.2, 2 ꢀ CH), 7.75 (1H, s, CH), 7.67
(1H, s, CH), 7.46-7.41 (3H, m, 3 ꢀ CH), 7.20 (1H, s, CH), 4.03
(2H, s, CH2), 2.32 (3H, s, CH3), 2.29 (3H, s, CH3); δC (125 MHz;
DMSO-d6) 163.3 (C), 161.1 (C), 150.6 (C), 141.7 (C), 137.8 (C),
133.1 (C), 132.4 (C), 131.7 (C), 127.5 (CH), 127.5 (CH), 127.4
(CH), 126.1 (CH), 125.8 (CH), 125.4 (CH), 123.4 (CH), 123.3
(CH), 116.7 (CH), 113.8 (C), 103.1 (C), 29.4 (CH2), 19.7 (CH3),
19.1 (CH3); -ES m/z 330 (18%, [M]-), 329 (100, [M - H]-);
found by þEI 330.1262, C22H18O3 ([M]þ) requires 330.1256,
error 1.8 ppm; Anal. Calcd for C22H18O3): C, 79.98; H, 5.49.
Found: H, 79.46; C, 5.18.
3-Benzyl-4-hydroxy-6,7-dimethyl-2H-chromen-2-one 18.
Using method B, 3,30-(phenylmethanediyl)bis(4-hydroxy-6,
7-dimethyl-2H-chromen-2-one) 36 (500 mg, 1.07 mmol) and
NaCNBH3 (201 mg, 3.20 mmol) gave the title compound (120
mg, 40%) as a colorless solid after purification by flash column
chromatography: mp 242-245 ꢀC (decomp.); νmax/cm-1 3130
bw (O-H), 3064 w, 2969 w, 2921 w, 1666 s (CdO), 1624 s, 1605
s, 1563 s; δH (300 MHz; DMSO-d6) 11.47 (1H, broad s, OH),
7.70 (1H, s, CH), 7.22-7.27 (4H, m, 4 ꢀ CH), 7.12-7.17 (2H, m,
2 ꢀ CH), 3.86 (2H, s, CH2), 2.27 (3H, s, CH3), 2.25 (3H, s, CH3);
δC (75 MHz; DMSO-d6) 163.1 (C), 160.7 (C), 150.4 (C), 141.4
(C), 140.0 (C), 132.2 (C), 128.2 (CH), 128.1 (CH), 125.8 (CH),
123.2 (CH), 116.6 (CH), 113.7 (C), 103.3 (C), 29.1 (CH2), 19.6
(CH3), 18.9 (CH3); -ES m/z 280 (14%, [M]-), 279 (100, [M -
H]-); found by þES 280.1094, C18H16O3 ([M]þ) requires
280.1099, error 1.8 ppm.
4-Hydroxy-3-(1-naphthylmethyl)-2H-benzo[h]chromen-2-one
19. Using method B, 3,30-(1-naphthylmethanediyl)bis(4-hydro-
xy-2H-benzo[h]chromen-2-one) 37 (106 mg, 0.19 mmol) and
NaCNBH3 (59 mg, 0.95 mmol) gave (15 mg, 22%) after
chromatography: mp 258-260 ꢀC (decomp.); νmax/cm-1 3203
bw (O-H), 3056 w, 1646 s (CdO), 1609 s, 1566 m; δH (500 MHz;
DMSO-d6) 8.40-8.38 (1 H, m, CH), 8.27 (1 H, d, J=8.2 CH),
8.07-8.05 (1H, m, CH), 8.01 (1H, d, J=8.2 CH), 7.95 (1H, d, J=
8.2 CH), 7.88 (1H, d, J=8.2 CH), 7.77 (1H, d, J=8.2 CH),
7.74-7.72 (2H, m, 2 ꢀ CH), 7.63-7.54 (2H, m, 2 ꢀ CH),
7.38-7.34 (1H, m, CH), 7.15 (1H, d, J=6.9, CH), 4.38 (2H, s,
CH2); δC (75 MHz; DMSO-d6) some signals coincident: 162.9
(C), 162.4 (C), 149.1 (C), 134.8 (C), 134.4 (C), 133.4 (C), 131.8
(C), 128.6 (CH), 128.5 (CH), 128.0 (CH), 126.4 (CH), 126.0
(CH), 125.7 (CH), 125.6 (CH), 123.7 (CH), 123.7 (CH), 122.2
(C), 121.6 (CH), 119.4 (CH), 111.6 (C), 102.1 (C), 26.6 (CH2);
-ES m/z 352 (22%, [M]-), 351 (100, [M - H]-); found by -ES
352.1094, C24H16O3 ([M]-) requires 352.1099, error 1.4 ppm.
4-Hydroxy-3-(2-naphthylmethyl)-2H-benzo[h]chromen-2-one
20. Using method B, 3,30-(2-naphthylmethanediyl)bis(4-hydro-
xy-2H-benzo[h]chromen-2-one) 38 (220 mg, 0.39 mmol) and
NaCNBH3 (123 mg, 1.95 mmol) gave (35 mg, 25%) as a color-
less solid after chromatography: mp 260-263 ꢀC (decomp.);
3-Substituted 4-Hydroxy-2H-chromen-2-ones. Method B.
The preparation of 3-substituted 4-hydroxy-2H-chromen-2-
ones was carried out according to the procedure described by
Appendino and co-workers: please note the caution;27 in the
majority of cases, purification was achieved by flash column
chromatography on silica using CH2Cl2/MeOH 95:5 as the
eluent.
4-Hydroxy-6,7-dimethyl-3-(1-naphthylmethyl)-2H-chromen-
2-one 16. Using method B, 3,30-(1-naphthylmethanediyl)bis(4-
hydroxy-6,7-dimethyl-2H-chromen-2-one) 34 (500 mg, 0.96
mmol) and NaCNBH3 (182 mg, 2.89 mmol) gave the title
compound (167 mg, 53%) after purification by flash column
chromatography as a colorless solid: mp 253-255 ꢀC (decomp.);
ν
max/cm-1 3048 bw (O-H), 2970 w, 2920 w, 1737 w, 1653 m
ν
max/cm-1 3166 bw (O-H), 3051 b, 1651 s (CdO), 1608 s, 1563
(CdO), 1619 s, 1561 m; δH (500 MHz; DMSO-d6) 8.27 (1H, d,
J=8.2, CH), 7.94 (1H, d, J=8.2, CH), 7.77 (1H, d, J=8.2, CH),
7.75 (1H, s, CH), 7.62-7.53 (2H, m, 2 ꢀ CH), 7.38-7.32 (1H, m,
CH), 7.23 (1H, s, CH), 7.09 (1H, d, J=6.3, CH), 4.31 (2H, s,
CH2), 2.34 (3H, s, CH3), 2.30 (3H, s, CH3); δC (125 MHz;
DMSO-d6) 164.4 (C), 163.2 (C), 150.6 (C), 141.6 (C), 134.9 (C),
133.3 (C), 132.3 (C), 131.8 (C), 128.4 (CH), 126.4 (CH),
125.9 (CH), 125.6 (CH), 125.5 (CH), 123.9 (C), 123.7 (CH),
123.6 (CH), 123.2 (CH), 116.6 (CH), 101.5 (C), 26.4 (CH2),
19.6 (CH3), 18.9 (CH3); -ES m/z 330 (18%, [M]-), 329 (100,
m; δH (500 MHz; DMSO-d6) 8.40-8.32 (1H, m, CH), 8.10-8.00
(1H, m, CH), 8.02 (1H, d, J=8.8, CH), 7.86 (1H, d, J=8.8, CH),
7.86-7.85 (3H, m, 3 ꢀ CH), 7.82 (1H, d, J=8.2, CH), 7.73-7.69
(2H, m, 2 ꢀ CH), 7.49 (1H, d, J=10.1, CH), 7.45-7.41 (2H, m, 2
ꢀ CH), 4.12 (2H, s, CH2); δC (75 MHz; DMSO-d6) some CH
signals coincident: 162.6 (C), 161.7 (C), 149.0 (C), 137.4 (C),
134.3 (C), 133.1 (C), 131.7 (C), 128.5 (CH), 127.7 (CH), 127.4
(CH), 127.3 (CH), 126.0 (CH), 125.8 (CH), 125.2 (CH), 123.6
(CH), 122.1 (C), 121.6 (CH), 119.4 (CH), 111.6 (C), 103.7 (C),