Journal of Medicinal Chemistry
ARTICLE
substituent at C6, both kind and position of substituents included
in the 3-aryl group play a crucial role in activity and selectivity.
Meta and para substituents were the most favorable positions for
the desired activity. Currently, further research is going to be
conducted on the 3-arylcoumarin scaffold as potential agents for
the treatment of Parkinson’s disease.
128.3, 129.2, 129.5, 132.3, 134.1, 134.8, 138.0, 139.5, 139.8, 151.6, 160.8.
MS m/z 251 ([M + 1]+, 27), 250 (M+, 100), 222 (72), 221 (39), 178
(32), 150 (10), 136 (10), 124 (10). Anal. Calcd for C17H14O2: C, 81.58;
H, 5.64. Found: C, 81.56; H, 5.62.
General Procedure for the Preparation of 3-(Bromometh-
oxyphenyl)coumarins (15ꢀ18). A solution of 3-(methoxyphenyl)-
coumarins (3.76 mmol), NBS (4.51 mmol), and AIBN (cat.) in CCl4
(5 mL) was stirred under reflux for 18 h. The resulting solution was filtered
to remove the succinimide. The solvent was evaporated under vacuum
and purified by flash chromatography (hexane/ethyl acetate 95:5).
3-(3-Bromo-4-methoxyphenyl)-6-methylcoumarin (15). Yield: 41%;
mp 206ꢀ207 °C. 1H NMR (CDCl3) 2.42 (s, 3H, ꢀCH3), 3.94 (s, 3H,
ꢀOCH3), 6.97 (d, 1H, H-50 J = 8.7), 7.23ꢀ7.35 (m, 3H, H-20, H-60,
H-5), 7.69ꢀ7.74 (m, 2H, H-7, H-8), 7.89 (s, 1H, H-4). 13C NMR
(CDCl3) 20.8, 56.3, 111.5, 111.6, 116.1, 119.3, 126.3, 127.6, 128.5,
129.0, 132.5, 133.1, 134.2, 139.1, 151.5, 156.2, 160.6. MS m/z (%) 347
(18), 346 (98), 345 ([M + 1]+, 19), 344 (M+, 100), 303 (45), 301 (45),
275 (11), 250 (17), 222 (13), 194 (11), 178 (13), 165 (58), 163 (11),
139 (15), 132 (42), 82 (18), 76 (14), 63 (19), 50 (14). Anal. Calcd for
C17H13BrO3: C, 59.15; H, 3.80. Found: C, 59.10; H, 3.72.
3-(4-Bromo-3-methoxyphenyl)-6-methylcoumarin (16). Yield: 51%;
mp 139ꢀ140 °C. 1H NMR (CDCl3) 2.49 (s, 3H, ꢀCH3), 3.89 (s, 3H,
ꢀOCH3), 6.49 (dd, 1H, H-7, J = 7.4, J = 1.3), 7.08ꢀ7.12 (m, 3H, H-20,
H-60, H-8), 7.32ꢀ7.42 (m, 2H, H-5, H-50), 7.74 (s, 1H, H-4). 13C NMR
(CDCl3) 33.1, 55.4, 114.2, 114.7, 117.1, 119.7, 120.9, 126.8, 128.2,
128.7, 129.6, 132.2, 134.3, 135.7, 139.4, 153.2, 159.5. MS m/z (%) 346
(45), 345 ([M + 1]+, 10), 344 (M+, 100), 266 (49), 265 (45), 238 (24),
237 (67), 194 (42), 165 (29), 133 (28). Anal. Calcd for C17H14O2: C,
59.15; H, 3.80. Found: C, 59.17; H, 3.83.
3-(2-Bromo-3,5-dimethoxyphenyl)-6-methylcoumarin (17). Yield:
46%; mp 178ꢀ179 °C. 1H NMR (CDCl3) 2.40 (s, 3H, ꢀCH3), 3.79 (s,
3H, ꢀOCH3), 3.87 (s, 3H, ꢀOCH3), 6.51 (s, 2H, H-40, H-60),
7.26ꢀ7.33 (m, 3H, H-5, H-7, H-8), 7.60 (s, 1H, H-4). 13C NMR
(CDCl3) 20.8, 55.6, 56.4, 100.1, 104.3, 107.4, 116.4, 118.7, 127.9, 129.0,
132.8, 134.2, 137.6, 142.3, 152.1, 157.0, 159.7. MS m/z (%) 377 (42),
376 ([M + 1]+, 18), 375 (M+, 100), 282 (59), 279 (14), 239 (11) 208
(9), 152 (10), 118 (9), 58 (12). Anal. Calcd for C18H15BrO4: C, 57.62;
H, 4.03. Found: C, 57.61; H, 4.08.
3-(2-Bromo-3,4,5-trimethoxyphenyl)-6-methylcoumarin (18). Yield:
50%; mp 167ꢀ168 °C. 1H NMR (CDCl3) 2.40 (s, 3H, ꢀCH3), 3.83 (s,
3H, ꢀOCH3), 3.90 (s, 6H, ꢀ(OCH3)2), 6.72 (s, 1H, H-60), 7.25 (d, 1H,
H-8, J = 8.4), 7.29 (d, 1H, H-5, J = 1.9), 7.34 (dd, 1H, H-7, J = 8.4, J =
2.0), 7.63 (s, 1H, H-4). 13C NMR (CDCl3) 20.8, 55.6, 61.1, 61.1, 110.1,
110.4, 116.4, 118.7, 127.8, 128.4, 131.2, 132.9, 134.3, 142.7, 143.4, 151.2,
152.0, 152.7, 160.1. MS m/z (%) 408 (32), 407 ([M + 1]+, 12), 406 (M+,
68), 404 (5) 326 (22), 325 (59), 282 (15), 264 (15) 169 (9), 139 (10).
Anal. Calcd for C19H17BrO5: C, 56.31; H, 4.23. Found: C, 56.38;
H, 4.28.
’ EXPERIMENTAL SECTION
Chemistry. Melting points were determined using a Reichert Kofler
thermopan or in capillary tubes on a B€uchi 510 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 1640FT
spectrophotometer. 1H and 13C NMR spectra were recorded on a
Bruker AMX spectrometer at 300 and 75.47 MHz, respectively, using
TMS as internal standard (chemical shifts in δ values, J in Hz). Mass
spectra were obtained using a Hewlett-Packard 5988A spectrometer.
Elemental analyses were performed using a Perkin-Elmer 240B micro-
analyser and were within (0.4% of calculated values in all cases. Silica gel
(Merck 60, 230ꢀ00 mesh) was used for flash chromatography (FC).
Analytical thin layer chromatography (TLC) was performed on plates
precoated with silica gel (Merck 60 F254, 0.25 mm). The purity of
compounds 1ꢀ22 was assessed by HPLC and was found to be higher
than 95%.
General Procedure for the Preparation of 3-Phenylcou-
marins (1, 2, 6ꢀ14). A solution of 2-hydroxy-6-methylbenzaldehyde/
2-hydroxy-6-methoxybenzaldehyde (7.34 mmol) and the corresponding
phenylacetic acid (9.18 mmol) in dimethyl sulfoxide (15 mL) was
prepared. N,N0-Dicyclohexylcarbodiimide (11.46 mmol) was added,
and the mixture was heated in an oil bath at 110 °C for 24 h. Ice
(100 mL) and acetic acid (10 mL) were added to the reaction mixture.
After keeping it at room temperature for 2 h, the mixture was extracted
with ether (3 ꢁ 25 mL). The organic layer was extracted with sodium
bicarbonate solution (50 mL, 5%) and then water (20 mL). The solvent
was evaporated under vacuum, and the dry residue was purified by FC
(hexane/ethyl acetate 9:1).
6-Methoxy-3-(3-methylphenyl)coumarin (1). Yield 79%; mp 98ꢀ
99 °C. 1H NMR (CDCl3) 2.46 (s, 3H, ꢀCH3), 3.90 (s, 3H, ꢀOCH3),
7.01 (d, 1H, H-5, J = 2.8), 7.14 (dd, 1H, H-7, J = 9.0, J = 2.9), 7.25ꢀ7.41
(m, 3H, H-50, H-40, H-8), 7.50ꢀ7.54 (m, 2H, H-20, H-60), 7.79 (s, 1H,
H-4). 13C NMR (CDCl3) 21.5, 55.8, 109.9, 117.4, 119.0, 120.0, 125.7,
128.3, 128.8, 129.2, 129.6, 134.7, 138.0, 139.6, 147.9, 156.1, 160.7. MS
m/z 267 ([M + 1]+, 30), 266 (M+, 100), 238 (38), 195 (25), 167 (14),
165 (17), 152 (24). Anal. Calcd for C17H14O3: C, 76.68; H, 5.30. Found:
C, 76.72; H, 5.38.
6-Methoxy-3-(4-methylphenyl)coumarin (2). Yield 76%; mp 130ꢀ
131 °C. 1H NMR (CDCl3) 2.40 (s, 3H, ꢀCH3), 3.86 (s, 3H, ꢀOCH3),
7.01 (d, 1H, H-7, J = 3.9), 7.13ꢀ7.17 (m, 2H, H-5, H-8), 7.30ꢀ7.35 (m,
2H, H-30, H-50), 7.65 (d, 2H, H-20, H-60, J = 8.1), 7.78 (s, 1H, H-4). 13C
NMR (CDCl3) 21.3, 55.8, 109.8, 117.4, 118.9, 120.1, 128.4, 128.6,
129.2, 131.9, 138.9, 139.0, 147.9, 156.1, 160.8. MS m/z 267 ([M + 1]+,
20), 266 (M+, 100), 238 (25), 195 (18), 165 (9), 152 (16). Anal. Calcd
for C17H14O3: C, 76.68; H, 5.30. Found: C, 76.67; H, 5.23.
General Procedure for the Preparation of Hydroxy-3-
phenylcoumarins (3, 20ꢀ21). A solution of substituted 6-meth-
oxy-3-phenylcoumarin (0.50 mmol) in acetic acid (5 mL) and acetic
anhydride (5 mL), at 0 °C, was prepared. Hydriodic acid 57% (10 mL)
was added dropwise. The mixture was stirred, under reflux temperature,
for 3 h. The solvent was evaporated under vacuum, and the dry residue
was purified by CH3CN crystallization.
6-Hydroxy-3-(4-methylphenyl)coumarin (3). Yield 61%; mp 214ꢀ
215 °C. 1H NMR (DMSO-d6) 2.32 (s, 3H, ꢀCH3), 7.01 (d, 1H, H-7, J =
8.8, J = 2.9), 7.07 (d, 1H, H-5, J = 2.8), 7.21ꢀ7.26 (m, 3H, H-30, H-50,
H-8), 7.59 (d, 2H, H-20, H-60, J = 8.1), 8.08 (s, 1H, H-4), 9.77 (s, 1H,
ꢀOH). 13C NMR (DMSO-d6) 21.3, 113.0, 117.1, 120.0, 120.5, 127.2,
128.8, 129.2, 132.3, 138.5, 140.4, 146.7, 154.2, 160.5. MS m/z (%) 253
([M + 1]+, 51), 252 (M+, 100), 225 (35), 224 (96), 223 (62) 195 (13),
181 (17), 165 (19), 152 (31), 139 (10), 125 (15), 115 (15). Anal. Calcd
for C16H12O3: C, 76.18; H, 4.79. Found: C, 76.11; H, 4.77.
6-Methyl-3-(4-methylphenyl)coumarin (7). Yield 72%; mp: 139ꢀ
140 °C. 1H NMR (CDCl3) 2.40 (s, 6H, (ꢀCH3)2), 7.21ꢀ7.30 (m, 5H,
H-5, H-7, H-8, H-30, H-50), 7.60 (d, 2H, H-20, H-60, J = 8.2), 7.72 (s, 1H,
H-4). 13C NMR (CDCl3) 21.1, 21.6, 116.4, 119.7, 127.9, 128.4, 128.7,
129.4, 132.2, 132.5, 134.3, 139.0, 139.4, 139.5, 151.8, 161.2. MS m/z 251
([M + 1]+, 32), 250 (M+, 100), 222 (56), 221 (24), 178 (27), 150 (12),
136 (12), 124 (19). Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found:
C, 81.52; H, 5.60.
6-Methyl-3-(3-methylphenyl)coumarin (8). Yield 75%; mp 84ꢀ
1
85 °C. H NMR (CDCl3) 2.39 (s, 6H, ꢀ(CH3)2), 6.98ꢀ7.02 (m,
3H, H-40, H-7, H-8), 7.13ꢀ7.24 (m, 4H, H-20, H-5, H-50, H-60), 7.72 (s,
1H, H-4). 13C NMR (CDCl3) 20.8, 21.5, 116.1, 119.4, 125.6, 127.6,
7133
dx.doi.org/10.1021/jm200716y |J. Med. Chem. 2011, 54, 7127–7137