1750 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 4
Li et al.
157.888, 154.525, 150.054, 141.505, 135.158, 129.474, 128.715,
128.015, 118.268, 102.219, 99.318, 94.102, 49.817, 49.087,
45.895, 42.451, 17.004. HRMS calcd for C23H23N2O5 (M þ
Hþ) 407.1607; found 407.1594.
1H, J = 2.1 Hz), 6.110 (d, 1H, J = 2.1 Hz), 3.000 (m, 2H, J = 6.0
Hz), 2.638-4.000 (br, 8H), 2.638 (s, 3H), 1.162-1.412 (m, 10H,
J = 6.0 Hz), 0.845 (t, 3H, J = 6.0 Hz). HRMS calcd for
C22H32N3O5 (M þ Hþ) 418.2342; found 418.2342.
3-(4-Acryloylpiperazin-1-yl)-5,7-dihydroxy-4-methyl-2H-chro-
men-2-one (25). Off-white solid in 62.7% yield. Mp 225-228 °C.
1H NMR (300 MHz, DMSO-d6): 1H NMR (300 MHz, DMSO-
d6): δ 10.422 (s, 1H), 10.186 (s, 1H), 6.825 (dd, 1H, J = 12.6 Hz,
J = 7.8 Hz), 6.256 (d, 1H, J = 1.2 Hz), 6.121 (dd, 1H, J = 12.6 Hz,
J = 1.5 Hz), 6.118 (d, 1H, J = 1.2 Hz), 5.680 (d, 1H, J = 7.8 Hz,
J = 1.2 Hz), 2.720-4.501 (br, 8H), 2.660 (s, 3H). HRMS calcd for
C17H19N2O5 (M þ Hþ) 331.1294; found 331.1280.
4-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(2-phe-
noxyphenyl)piperazine-1-carboxamide (32). White powder in
1
32.6% yield. Mp 198-200 °C. H NMR (300 MHz, DMSO-
d6): δ 10.424 (s, 1H), 10.194 (s, 1H), 7.975 (s, 1H), 7.665 (d, 1H,
J = 7.5 Hz), 7.340 (t, 2H, J = 7.5 Hz), 7.079 (m, 3H), 6.930 (m,
3H), 6.251 (s, 1H), 6.117 (s, 1H), 2.000-4.000 (br, 8H), 2.623 (s,
3H). HRMS calcd for C27H26N3O6 (M þ Hþ) 488.1822; found
488.1810.
3-(4-(2-Chloroacetyl)piperazin-1-yl)-5,7-dihydroxy-4-methyl-
2H-chromen-2-one (26).White solid in 58.4% yield. Mp 262-264 °C.
1H NMR (300 MHz, DMSO-d6): δ 10.428 (s, 1H), 10.193 (s, 1H),
6.260 (d, 1H, J = 2.4 Hz), 6.120 (d, 1H, J = 2.4 Hz), 4.401 (s, 2H),
2.654-4.401 (br, 8H), 2.654 (s, 3H). HRMS calcd for C16H18ClN2O5
(M þ Hþ) 353.0904; found 353.0900.
4-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(4-(t-
rifluoromethoxy)phenyl)piperazine-1-carboxamide (33). White
powder in 41.2% yield. Mp 254-256 °C. 1H NMR (300 MHz,
DMSO-d6, 80 °C): δ 10.202 (s, 1H), 9.952 (s, 1H), 8.741 (s, 1H),
7.570 (d, 2H, J = 4.5 Hz), 7.200 (d, 2H, J = 4.5 Hz), 6.272 (d,
1H, J = 1.2 Hz), 6.132 (d, 1H, J=1.2 Hz), 3.524 (br, 4H), 2.961
(br, 4H), 2.685 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ
160.082, 157.855, 154.677, 154.452, 149.791, 142.460, 139.836,
128.153, 120.467, 120.012, 102.204, 99.204, 94.041, 48.994,
44.455, 16.858. HRMS calcd for C22H21F3N3O6 (M þ Hþ)
480.1382; found 480.1387.
N-Benzyl-4-(5,7-dihydroxy-4-methyl-2-oxo-2H-chromen-3-
yl)piperazine-1-carboxamide (34). Yellow powder in 41.8%
yield. Mp 277-280 °C. 1H NMR (300 MHz, DMSO-d6): δ
10.409 (s, 1H), 10.177 (s, 1H), 7.168-7.355(m, 5H), 7.096 (t, 1H,
J = 6.0 Hz), 6.250 (d, 1H, J = 2.4 Hz), 6.120 (d, 1H, J = 2.4 Hz),
4.250 (d, 2H, J = 6.0 Hz), 3.322-4.100 (m, 4H), 2.925 (br, 4H),
2.878 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 160.098,
157.900, 157.450, 154.502, 149.780, 141.007, 128.339, 128.046,
126.940, 126.345, 102.299, 99.351, 94.094, 59.708, 49.001,
44.264, 16.889. HRMS calcd for C22H24N3O5 (M þ Hþ)
410.1716; found 410.1711.
3-(4-benzoylpiperazin-1-yl)-5,7-dihydroxy-4-methyl-2H-chro-
men-2-one (27). White solid in 50.2% yield. Mp 260-262 °C. 1H
NMR (300 MHz, DMSO-d6): δ 10.421 (s, 1H), 10.187 (s, 1H),
7.396-7.458 (m, 5H), 6.254 (d, 1H, J = 1.8 Hz), 6.125 (d, 1H,
J = 1.8 Hz), 2.658-4.500 (br, 8H), 2.658 (s, 3H). HRMS calcd
for C21H21N2O5 (M þ Hþ) 381.1450; found 381.1449.
General Procedure B for Synthesis of Compounds 28 and 29.
To a solution of 1 (27.6 mg, 0.1 mmol) in 5 mL of dried DCM
were added pyridine (23.7 mg, 0.3 mmol) and sulfonyl chloride
(0.3 mmol). The reaction mixture was stirred at 45 °C. Chemical
conversion was monitored by LC-MS analysis. After the
reaction was completed, the solvent was evaporated in vacuo.
Water was added and then extracted twice using ethyl acetate
(30 mL ꢀ 2). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, and concentrated in
vacuo to give crude products. The final 28 and 29 were char-
acterized after purification by silica gel column chromatogra-
phy.
General Procedure D for Synthesis of Compounds 41-46. To a
mixture of various substitutional piperazines (1 mmol) and
anhydrous K2CO3 (165.8 mg,1.2 mmol) in acetonitrile (20
mL) was added dropwise 2-chloro-β-ketoethyl acetate (164.6
mg, 1 mmol) at room temperature. The mixture was stirred for 3
h. The solvent was evaporated in vacuo, and water was added.
The resulting mixture was extracted with EtOAc (3 ꢀ 30 mL).
The organic layers were combined, dried completely over anhy-
drous Na2SO4, and evaporated in vacuo to give a yellow oil
(35-40). Then the resulting oil and pholoroglucinol (126.1 mg, 1
5,7-Dihydroxy-4-methyl-3-(4-(phenylsulfonyl)piperazin-1-yl)-
2H-chromen-2-one (28). White solid in 13.6% yield. Mp
231-234 °C. 1H NMR (300 MHz, DMSO-d6, 80 °C): δ 10.400
(s, 1H), 10.201 (s, 1H), 7.710 (m, 5H), 6.226 (d, 1H, J = 2.4 Hz),
6.105 (d, 1H, J = 2.4 Hz), 3.855 (br, 1H), 3.187 (br, 3H), 2.997
(br, 4H), 2.487 (s, 3H). HRMS calcd for C20H20N2NaO6S (M þ
Naþ) 439.0940; found. 439.0932.
N-(4-(4-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-
piperazin-1-ylsulfonyl)phenyl)acetamide (29). White solid in
20.5% yield. Mp 258-260 °C. 1H NMR (300 MHz, DMSO-d6):
10.399 (s, 1H), 10.194 (s, 1H), 7.941 (s, 1H), 7.817 (m, 2H), 7.489
(m, 2H), 6.230 (d, 1H, J = 2.4 Hz), 6.108 (d, 1H, J = 2.4 Hz),
2.522-3.551 (br, 8H), 2.878 (s, 3H), 2.720 (s, 3H). HRMS calcd for
C22H24N3O7S (M þ Hþ) 474.1335; found. 474.1308.
mmol) were dissolved in absolute ethanol (10 mL). BF3 Et2O
3
(617 μL, 5 mmol) was added at room temperature, and the
mixture was refluxed until the reaction was completed as
monitored by fast LC-MS analysis. The solvent was evapo-
rated in vacuo and the resulting residue was eluted using
dichloromethane to give the final products.
General Procedure C for Synthesis of Compounds 30-34. To a
solution of 1 (55.2 mg, 0.2 mmol) in 5 mL of dry THF and a little
DMF, various isocyanates (0.24 mmol) were added, and the
reaction mixture was stirred at 50 °C. After the reaction was
completed, the solvent was evaporated in vacuo. The final
products were characterized after purification by silica gel
column chromatography.
5,7-Dihydroxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chro-
men-2-one (41). Off-white powder in 87.5% yield. Mp 208-210 °C.
1H NMR (500 MHz, DMSO-d6, 75 °C): δ 6.259 (d, 1H, J =
2.5 Hz), 6.114 (d, 1H, J = 2.5 Hz), 2.935-2.955 (br, 4H), 2.624
(s, 3H), 2.400-2.482 (br, 4H), 2.235 (s, 3H). HRMS calcd for
C15H19N2O4 (M þ Hþ) 291.1345; found 291.1344.
3-(4-Ethylpiperazin-1-yl)-5,7-dihydroxy-4-methyl-2H-chro-
men-2-one (42). Light-yellow powder in 85.4% yield. Mp
210-212 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.535 (s,
1H), 10.288 (s, 1H), 9.542 (s, 1H), 6.317 (d, 1H, J = 2.4 Hz),
6.135 (d, 1H, J = 2.4 Hz), 3.428-3.539 (br, 4H), 3.058-3.149
(br, 4H), 2.850 (br, 2H), 2.637 (s, 3H), 1.229 (t, 3H, J = 7.5 Hz).
HRMS calcd for C16H21N2O4 (M þ Hþ) 305.1501; found
305.1505.
4-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(4-iso-
propylphenyl)piperazine-1-carboxamide (30). Off-white solid in
25.3% yield. Mp 262-265 °C. 1H NMR (300 MHz, DMSO-d6):
δ 10.421 (s, 1H), 10.186 (s, 1H), 8.441 (s, 1H), 7.348 (dd, 2H, J =
8.7 Hz, J = 1.5 Hz), 7.082 (dd, 2H, J = 8.7 Hz, J = 1.5 Hz),
6.258 (d, 1H, J = 2.4 Hz), 6.124 (d, 1H, J = 2.4 Hz), 3.459 (s,
1H), 2.779-4.400 (br, 8H), 2.668 (s, 3H), 1.174 (s, 3H), 1.151 (s,
3H). HRMS calcd for C24H28N3O5 (M þ Hþ) 438.2029; found
438.2007.
4-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-hep-
tylpiperazine-1-carboxamide (31). Off-white powder in 56.0%
yield. Mp 282-284 °C. 1H NMR (400 MHz, DMSO-d6): δ
10.400 (s, 1H), 10.170 (s, 1H), 6.450 (t, 1H, J = 5.1 Hz), 6.249 (d,
5,7-Dihydroxy-4-methyl-3-(4-(3-(trifluoromethyl)phenyl)pip-
erazin-1-yl)-2H-chromen-2-one (43). Yellow powder in 52.5%
yield. Mp 235-238 °C. 1H NMR (300 MHz, DMSO-d6): δ
10.426 (s, 1H), 10.190 (s, 1H), 7.418, t, 1H, J = 7.8 Hz), 7.245 (d,
1H, J = 7.8 Hz), 7.188 (s, 1H), 7.065 (d, 1H, J = 7.8 Hz), 6.260
(d, 1H, J = 2.4 Hz), 6.128 (d, 1H, J = 2.4 Hz), 2.879-4.231 (br,