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EtOAc. The combined organic layers were washed with H2O and
brine. After being dried over anhydrous Na2SO4, the solvent was re-
moved in vacuo. The crude products were purified by CombiFlashÒ
column chromatography or preparative-TLC eluting with n-hex-
ane–EtOAc.
4.3.7. N-(4-Nitro-3-(trifluoromethyl)phenyl)pivalamide-
methylcurcumin (10)
Yield: 3%; amorphous solid; 1H NMR (300 MHz, acetone-d6): d
8.55 (s, 1H), 8.32 (s, br, 1H), 8.18–8.20 (m, 1H), 7.66–7.61 (m,
2H), 7.46 (br s, 1H), 7.39–7.14 (m, 4H), 7.00–7.03 (m, 1H), 6.86–
6.73 (m, 2H), 6.03 (s, 1H), 3.98 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
3.87 (s, 3H, OCH3), 1.57 (s, 6H, CH3); ESI MS m/z 657.3 (M+H)+.
4.3.2. N-(4-Nitro-3-(trifluoromethyl)phenyl)pivalamide-
curcumin (5)
Yield: 10%; amorphous solid; 1H NMR (300 MHz, DMSO-d6): d
8.49 (s, 1H), 8.36–8.32 (m 1H), 8.24–8.21 (m, 1H), 7.58–7.53 (m,
2H), 7.42 (br s, 1H), 7.32 (br s, 1H), 7.26–7.14 (m, 2H), 6.96–6.89
(m, 2H), 6.84–6.56 (m, 2H), 6.09 (s, 1H), 3.84 (s, 3H, OCH3), 3.81
(s, 3H, OCH3), 1.53 (s, 6H, CH3); ESI MS m/z 643.13 (M+H)+.
4.3.8. N-(4-Cyano-3-(trifluoromethyl)phenyl)pivalamide-
methylcurcumin (11)
Yield: 5% (starting with 0.13 mmol of methylcurcumin), amor-
phous solid; 1H NMR (400 MHz, CDCl3): d 1.79 (6H, s, CH3), 3.80,
3.93 and 3.94 (each 3H, s, OCH3), 4.96 (1H, s), 5.84 (1H, s, C@CH),
6.51 and 6.55 (each 1H, d, J = 16.0 Hz, CH@CH), 6.79 (1H, dd,
J = 8.4, 2.3 Hz, Ar-H0), 6.89 (1H, d, J = 8.4 Hz, Ar-H), 6.90 (1H, d,
J = 8.0 Hz, Ar-H), 6.96 (1H, d, J = 2.3 Hz, Ar-H0), 7.08 (1H, d,
J = 1.7 Hz, Ar-H), 7.10 (1H, s, Ar-H), 7.14 (1H, dd, J = 8.0, 1.7 Hz,
Ar-H), 7.15 (1H, dd, J = 8.2, 1.7 Hz, Ar-H), 7.59 and 7.63 (each 1H,
d, J = 15.8 Hz, CH@CH), 7.61 (1H, d, J = 8.6 Hz, Ar-H0). ESI-MS (posi-
tive, m/z): 637.30 [M+H]+.
4.3.3. N-(4-Cyano-3-(trifluoromethyl)phenyl)pivalamide-
curcumin (6)
Yield: 5% (starting with 0.26 mmol of curcumin), amorphous
solid; 1H NMR (400 MHz, CDCl3): d 1.58 (6H, s, CH3), 3.95 and
3.96 (each 3H, s, OCH3), 5.83 (1H, s, C@CH), 6.50 and 6.56 (each
1H, d, J = 15.8 Hz, CH@CH), 6.94 (1H, d, J = 8.2 Hz, Ar-H), 7.06
(1H, d, J = 1.7 Hz, Ar-H), 7.08 (1H, d, J = 8.0 Hz, Ar-H), 7.136 (1H,
dd, J = 8.2, 1.7 Hz, Ar-H), 7.141 (1H, d, J = 1.9 Hz, Ar-H), 7.17
(1H, dd, J = 8.4, 1.9 Hz, Ar-H), 7.61 and 7.62 (each 1H, d,
J = 15.8 Hz, CH@CH), 7.83 (1H, d, J = 8.4 Hz, Ar-H0), 8.03 (1H, dd,
J = 8.4, 2.1 Hz, Ar-H0), 8.09 (1H, d, J = 1.9 Hz, Ar-H0), 10.02 (1H,
s). ESI-MS (positive or negative, m/z): 623.50 [M+H]+, 621.30
[MꢀH]ꢀ.
4.3.9. N-(4-Chloro-3-(trifluoromethyl)phenyl)pivalamide-
methylcurcumin (12)
Yield: 3% (starting with 0.26 mmol of methylcurcumin), amor-
phous solid; 1H NMR (400 MHz, CDCl3): d 1.72 (6H, s, CH3), 3.78,
3.91 and 3.92 (each 3H, s, OCH3), 4.36 (1H, s), 5.82 (1H, s, C@CH),
6.49 and 6.53 (each 1H, d, J = 15.6 Hz, CH@CH), 6.75 (1H, dd,
J = 8.7, 2.7 Hz, Ar-H0), 6.87 (2H, d, J = 8.2 Hz, Ar-H), 6.98 (1H, d,
J = 2.7 Hz, Ar-H0), 7.067 (1H, s, Ar-H), 7.074 (1H, s, Ar-H0), 7.11
(1H, dd, J = 8.0, 1.7 Hz, Ar-H), 7.13 (1H, dd, J = 8.0, 1.7 Hz, Ar-H0),
7.27 (1H, d, J = 8.7 Hz, Ar-H0), 7.57 and 7.61 (each 1H, d,
J = 15.6 Hz, CH@CH). ESI-MS (positive, m/z): 646.15 [M+H]+.
4.3.4. N-(4-Fluoro-3-(trifluoromethyl)phenyl)pivalamide-
curcumin (7)
Yield: 6% (starting with 0.27 mmol of curcumin), amorphous so-
lid; 1H NMR (400 MHz, CDCl3): d 1.58 (6H, s, CH3), 3.95 (6H, s,
OCH3), 5.83 (1H, s, C@CH), 6.49 and 6.55 (each 1H, d, J = 15.8 Hz,
CH@CH), 6.94 (1H, d, J = 8.2 Hz, Ar-H), 7.05 (1H, s, Ar-H), 7.07
(1H, d, J = 8.6 Hz, Ar-H), 7.13 (1H, s, Ar-H), 7.16 (2H, d, J = 8.2 Hz,
Ar-H), 7.61 and 7.62 (each 1H, d, J = 15.8 Hz, CH@CH), 7.75 (1H,
d, J = 8.6 Hz, Ar-H0), 7.87 (1H, d, J = 8.6 Hz, Ar-H0), 7.90 (1H, s, Ar-
H0), 9.68 (1H, s). ESI-MS (positive or negative, m/z): 616.25
[M+H]+, 614.40 [MꢀH]ꢀ.
4.4. Synthesis of N-(4-substituted-3-(trifluoromethyl)phenyl)
methacrylamide (14a,b): N-(4-substituted-3-(trifluoromethyl)
phenyl)-2-hydroxy-2-methylpropanamide-methylcurcumin
(15–16)
4.4.1. General procedure
Methacryloyl chloride (1.2–3.0 equiv) was added dropwise to a
solution of 4-nitro-3-trifluoromethylphenylamine (3a) or 4-cyano-
3-trifluoromethylphenylamine (3b) in CH2Cl2 containing triethyl-
amine (1.2–3.0 equiv) at 0 °C. After stirring at room temperature
for 4–12 h with TLC monitoring, the reaction mixture was diluted
with CH2Cl2 and washed with H2O. The CH2Cl2 extract was then
dried over Na2SO4, concentrated, and purified by flash column
chromatography to afford the desired compounds.
4.3.5. N-(4-Chloro-3-(trifluoromethyl)phenyl)pivalamide-
curcumin (8)
Yield: 6% (starting with 0.33 mmol of curcumin), yellow solid;
mp 268–270 °C, 1H NMR (400 MHz, CDCl3): d 1.58 (6H, s, CH3),
3.95 and 3.96 (each 3H, s, OCH3), 5.83 (1H, s, C@CH), 6.50 and
6.55 (each 1H, d, J = 15.8 Hz, CH@CH), 6.94 (1H, d, J = 8.2 Hz, Ar-
H), 7.06 (1H, d, J = 1.9 Hz, Ar-H), 7.07 (1H, d, J = 8.2 Hz, Ar-H),
7.13 (1H, d, J = 1.9 Hz, Ar-H), 7.14 (1H, dd, J = 8.6, 1.9 Hz, Ar-H),
7.16 (1H, dd, J = 8.4 1.9 Hz, Ar-H), 7.49 (1H, d, J = 8.7 Hz, Ar-H0),
7.61 and 7.62 (1H, d, J = 15.8 Hz, CH@CH), 7.88 (1H, dd, J = 8.6,
2.5 Hz, Ar-H0), 7.96 (1H, d, J = 2.5 Hz, Ar-H0), 9.74 (1H, s). ESI-MS
(positive or negative, m/z): 632.10 [M+H]+, 634.25 [M+2+H]+,
630.35 [MꢀH]ꢀ, 632.35 [M+2ꢀH]ꢀ.
4.4.2. N-(4-Nitro-3-trifluoromethylphenyl)methacrylamide
(13a)
Yield: 41%; amorphous solid; 1H NMR (300 MHz, CDCl3): d 1.98
(s, 3H, CH3), 5.70 (s, 1H, ethylene-H), 5.79 (s, 1H, ethylene-H),
8.38–8.17 (m, 3H, aromatic-H); ESI MS m/z 274.2 (M+H)+.
4.3.6. N-(4-Methyl-3-(trifluoromethyl)phenyl)pivalamide-
curcumin (9)
4.4.3. N-(4-Cyano-3-trifluoromethylphenyl)methacrylamide
(13b)
Yield: 2% (starting with 0.27 mmol of 1), amorphous solid; 1H
NMR (400 MHz, CDCl3): d 1.58 (6H, s, CH3), 2.46 (3H, s, Ar-CH3),
3.80 and 3.95 (each 3H, s, OCH3), 5.85 (1H, s, C@CH), 6.56 and
6.57 (each 1H, d, J = 15.8 Hz, CH@CH), 6.77 (1H, dd, J = 8.4,
2.5 Hz, Ar-H), 6.88 (1H, d, J = 8.0 Hz, Ar-H), 6.97 (1H, d, J = 2.3 Hz,
Ar-H), 7.07 (1H, d, J = 8.2 Hz, Ar-H), 7.08 (1H, s, Ar-H), 7.15 (1H,
d, J = 8.0 Hz, Ar-H), 7.28 (1H, d, J = 8.7 Hz, Ar-H0), 7.61 and 7.63
(each 1H, d, J = 15.8 Hz, CH@CH), 7.80 (1H, d, J = 8.4 Hz, Ar-H0),
7.83 (1H, s, Ar-H0), 9.61 (1H, s). ESI-MS (positive or negative, m/
z): 612.25 [M+H]+, 610.15 [MꢀH]ꢀ.
Yield: 20%; amorphous solid; 1H NMR (300 MHz, CDCl3): d 2.08
(s, 3H, CH3), 5.60 (s, 1H, ethylene-H), 5.86 (s, 1H, ethylene-H),
8.05–7.78 (m, 3H, aromatic-H); ESI MS m/z 254.2 [M+H]+.
4.5. Synthesis of N-(4-substituted-3-(trifluoromethyl)phenyl)-
2-methyloxirane-2-carboxamide (14a,b)
4.5.1. General procedure
To a solution of N-arylmethacrylamides (13a or 13b, 1.7 mmol)
in CH2Cl2 (25 mL) was added 0.31 mL of hydrogen peroxide (30%,