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D. Secci et al. / European Journal of Medicinal Chemistry 46 (2011) 4846e4852
monitored by TLC on 0.2 mm thick silica gel plates (60 F254 Merck).
Preparative flash column chromatography was carried out on silica
gel (230e400 mesh, G60 Merck). Organic solutions were dried over
anhydrous sodium sulphate. Concentration and evaporation of the
solvent after reaction or extraction was carried out on a rotary
evaporator (Büchi Rotavapor) operating at reduced pressure.
(m, 2H, ArH), 7.51e7.53 (m, 4H, ArH), 7.95 (s, 1H, ArH), 8.52 (s, 1H,
CH]). IR cmꢁ1 (KBr): 3023, 1708, 1612.
6.1.6. ethyl 7-(3,4-chlorobenzyloxy)-2-oxo-2H-chromene-3-carbox
ylate (39)
89% yield; mp 169e170 ꢃC; 1H NMR (DMSO-d6) 1.26e1.29 (m,
3H, CH3), 4.22e4.29 (m, 2H, CH2), 5.26 (s, 2H, ArCH2), 7.06e7.08 (m,
2H, ArH), 7.41 (s, 1H, ArH), 7.66e7.68 (m, 1H, ArH), 7.75 (s, 1H, ArH),
7.82e7.84 (m, 1H, ArH), 8.70 (s, 1H, CH]). IR cmꢁ1 (KBr): 3046,
1716, 1620.
6.1. General procedure for the synthesis of derivatives 1e58
3-Carbonyl coumarins were obtained by Knoevenagel cycliza-
tion between substituted salicylaldehydes (1 mmol) and methyl
acetoacetate (1 mmol) or ethyl benzoylacetate (1 mmol) in
ethanol (25 mL) with catalytic amounts of piperidine. The ethyl
ester of coumarin-3-carboxylic acid was prepared by Knoevenagel
reaction between diethyl malonate (1 mmol) and the appropriate
salicylaldehyde (1 mmol) with catalytic amounts of piperidine in
ethanol (50 mL). Then, if there was an hydroxyl group at position
7, etherification was performed by adding a suitable benzyl
bromide (1 mmol) or cycloheptyl bromide (1 mmol), and potas-
sium carbonate (1 mmol) in anhydrous acetone (100 mL), using
6.1.7. ethyl 7-(cycloheptyloxy)-2-oxo-2H-chromene-3-carboxylate
(40)
82% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 1/3); mp 79e80 ꢃC; 1H NMR (DMSO-d6) 1.39e1.42 (m, 3H,
CH3), 1.78e1.81 (m, 8H, 4 x CH2), 2.02e2.05 (m, 4H, 2 x CH2),
4.37e4.43 (m, 2H, CH2), 4.49 (s, 1H, CH), 6.75e6.76 (m, 1H, ArH),
6.84e6.85 (m, 1H, ArH), 7.46e7.49 (m, 1H, ArH), 8.50 (s, 1H, CH]).
IR cmꢁ1 (KBr): 2998, 1722, 1614.
N,N0-dicyclohexyl-18-crown-6-ether (1 mmol) as
a
chelating
6.1.8. 7-(3-chlorobenzyloxy)-2-oxo-2H-chromene-3-carboxylic
acid (49)
agent. Final products were purified by chromatography. Ethyl
ester derivatives (1 mmol) were dissolved and stirred at room
temperature in a solution of LiOH.H2O (6 mmol) in H2O/MeOH
(1:5, v/v; 50 mL); then HCl 3 N (50 mL) was added. The suspen-
sion was filtered and the solid was dried under vacuum.
3-Carboxyhydrazido derivatives were obtained by dissolving at
reflux 3-coumarin carboxylic acid (1 mmol) in thionyl chloride
(20 mL). After solvent evaporation under vacuum, the reactive
acyl chloride (1 mmol) was reacted with a suitable hydrazine
hydrochloride (2 mmol) in the presence of sodium acetate
(2 mmol) in H2O/CH3CN (1/4, v/v).
99% yield; mp 186e187 ꢃC; 1H NMR (DMSO-d6) 5.27e5.29 (m, 2H,
ArCH2), 7.09e7.12 (m, 2H, ArH), 7.43e7.44 (m, 2H, ArH), 7.55e7.56
(m, 2H, ArH), 7.85 (s,1H, ArH), 8.72 (s,1H, CH]),13.02 (bs,1H, COOH,
D2O exch.). IR cmꢁ1 (KBr): 3303, 3012, 1706, 1644, 1612.
6.1.9. 7-(4-tert-butylbenzyloxy)-2-oxo-2H-chromene-3-carboxylic
acid (50)
87% yield; mp 173e174 ꢃC; 1H NMR (DMSO-d6) 1.27e1.28 (m,
9H, 3 x CH3), 5.32 (s, 2H, ArCH2), 7.01e7.03 (m, 2H, ArH), 7.53e7.54
(m, 4H, ArH), 7.95 (s, 1H, ArH), 8.54 (s, 1H, CH]), 13.06 (bs, 1H,
COOH, D2O exch.). IR cmꢁ1 (KBr): 3344, 3036, 1722, 1614, 1599.
6.1.1. 3-acetyl-8-bromo-6-chloro-2H-chromen-2-one (11)
99% yield; mp 184e185 ꢃC; 1H NMR (CDCl3) 2.74 (s, 3H, CH3C]
O), 7.60 (s, 1H, ArH), 7.87 (s, 1H, ArH), 8.37 (s, 1H, CH]). IR cmꢁ1
(KBr): 3024, 1713, 1205, 850.
6.1.10. 7-(3,4-chlorobenzyloxy)-2-oxo-2H-chromene-3-carboxylic
acid (51)
90% yield; mp 232e233 ꢃC; 1H NMR (DMSO-d6) 5.25 (s, 2H,
ArCH2), 7.06e7.10 (m, 2H, ArH), 7.45e7.47 (m, 1H, ArH), 7.65e7.67
(d, Jo ¼ 8.4 Hz, 1H, ArH), 7.75 (s, 1H, ArH), 7.82e7.84 (d, Jo ¼ 8.4 Hz,
1H, ArH), 8.72 (s, 1H, ArH), 13.05 (bs, 1H, COOH, D2O exch.). IR cmꢁ1
(KBr): 3324, 3052, 1702, 1639, 1604.
6.1.2. 3-benzoyl-6-hydroxy-2H-chromen-2-one (17)
91% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 2/1); mp 224e225 ꢃC; 1H NMR (DMSO-d6) 7.13e7.15 (m, 1H,
ArH), 7.51e7.53 (m, 1H, ArH), 7.32e7.34 (m, 1H, ArH), 7.55 (s, 1H,
ArH), 7.68e7.70 (d, Jo ¼ 7.5 Hz, 2H, ArH), 7.89e7.91 (d, Jo ¼ 7.8 Hz,
2H, ArH), 8.34 (s, 1H, CH]) 9.90 (bs, 1H, OH, D2O exch.). IR cmꢁ1
(KBr): 3230, 1721, 1212.
6.1.11. 7-(cycloheptyloxy)-2-oxo-2H-chromene-3-carboxylic acid
(52)
84% yield; mp 160e161 ꢃC; 1H NMR (DMSO-d6) 1.47e1.63 (m,
12H, 6 x CH2), 4.74 (s, 1H, CH), 6.96e6.96 (m, 2H, ArH), 7.76e7.78
(m, 1H, ArH), 8.66 (s, 1H, CH]), 13.09 (bs, 1H, COOH, D2O exch.). IR
cmꢁ1 (KBr): 3339, 3051, 2959, 1710, 1646, 1619.
6.1.3. 3-benzoyl-8-bromo-6-chloro-2H-chromen-2-one (24)
89% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 1/3); mp 187e188 ꢃC; 1H NMR (CDCl3) 7.48e7.50 (m, 2H,
ArH), 7.54e7.55 (m, 3H, ArH), 7.66 (s, 1H, ArH), 7.89 (s, 1H, ArH), 7.94
(s, 1H, CH]). IR cmꢁ1 (KBr): 3019, 1728, 1270.
6.1.12. 2-oxo-2H-chromene-3-carboxylic acid N’-(2-nitro-phenyl)-
hydrazide (55)
84% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 1/1); mp 252e253 ꢃC; 1H NMR (DMSO-d6) 6.86e6.90 (s, 1H,
ArH), 7.19e7.21 (m, 1H, ArH), 7.37e7.43 (m, 1H, ArH), 7.49e7.58 (m,
2H, ArH), 7.69e7.77 (s, 1H, ArH), 8.08e8.10 (s, 1H, ArH), 8.79 (s, 1H,
ArCH]), 9.39 (bs, 1H, NH, D2O exch.), 10.52 (bs, 1H, NH, D2O exch.).
IR cmꢁ1 (KBr): 3309, 3029, 1706, 1624.
6.1.4. ethyl 7-(3-chlorobenzyloxy)-2-oxo-2H-chromene-3-carboxy
late (37)
80% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 1/1); mp 149e150 ꢃC; 1H NMR (DMSO-d6) 1.39e1.42 (m,
3H, CH3), 4.38e4.43 (m, 2H, CH2), 5.13 (s, 2H, ArCH2), 6.86e6.87 (m,
1H, ArH), 7.96e7.98 (d, Jo ¼ 8.6 Hz, 1H, ArH), 7.27 (s, 1H, ArH),
7.34e7.36 (m, 2H, ArH), 7.44 (s, 1H, ArH), 7.51e7.54 (d, Jo ¼ 8.6 Hz,
1H, ArH), 8.51 (s, 1H, CH]). IR cmꢁ1 (KBr): 3021, 1739, 1617.
6.1.13. 2-oxo-2H-chromene-3-carboxylic acid N’-p-tolyl-hydrazide
(56)
78% yield, purified by chromatography (SiO2, ethyl acetate/
hexane 1/1); mp 152e153 ꢃC; 1H NMR (DMSO-d6) 2.27 (s, 3H,
ArCH3), 7.22 (m, 2H, ArH), 7.27e7.34 (m, 4H, ArH), 7.57e7.64 (m, 2H,
ArH), 8.26 (s, 1H, ArCH]), 8.60 (s, 1H, NH, D2O exch.), 11.36 (s, 1H,
NH, D2O exch.). IR cmꢁ1 (KBr): 3312, 3017, 1713, 1615.
6.1.5. ethyl 7-(4-tert-butylbenzyloxy)-2-oxo-2H-chromene-3-carbo
xylate (38)
87% yield; mp 144e145 ꢃC; 1H NMR (DMSO-d6) 1.26e1.28 (m,
12H, 4 x CH3), 4.21e4.22 (m, 2H, CH2), 5.30 (s, 2H, ArCH2), 7.01e7.02