350
L.J. Legoabe et al. / European Journal of Medicinal Chemistry 49 (2012) 343e353
4.2. Synthesis of the C6-substituted chromone derivatives (3aeo)
155.07, 151.52, 134.66, 134.01, 128.92, 128.81, 125.44, 124.26, 119.78,
112.15, 106.03, 69.75. HRMS m/z: calcd for C16H11ClO3, 286.0397,
found 286.0395; Purity (HPLC): 98%.
To a solution of 6-hydroxy-4-chromone (3 mmol) in 20 mL of
acetone, were added anhydrous potassium carbonate (6 mmol) and
the appropriate alkyl bromide (6 mmol). The mixture was stirred
and heated at reflux for 24 h. The mixture was filtered through
a pad of celite and the solvent was removed in vacuo to yield
a reddish residue. This crude product was triturated with 50 mL
diethyl ether, filtered and dried overnight at 60 ꢂC. For 3b and 3o,
the residue obtained after removal of the reaction solvent was
purified via neutral alumina column chromatography using
CH2Cl2eethylacetate (4:1) as an eluent. The target chromones were
purified by recrystallization from ethanol.
4.2.6. 6-[(3-Bromobenzyl)oxy]-4H-chromen-4-one (3f)
The title compound (brown powder) was prepared by reacting
6-hydroxychromone, K2CO3 and 3-bromobenzyl bromide in
acetone with yield of 48%: mp 106.7e107.0 ꢂC. 1H NMR (CDCl3)
d
7.74 (d, J ¼ 5.9 Hz, 1H), 7.54e7.49 (m, 2H), 7.38e7.29 (m, 2H),
7.29e7.19 (m, 2H), 7.19e7.12 (m, 1H), 6.22 (d, J ¼ 6.0 Hz, 1H), 4.99 (s,
2H). 13C NMR (CDCl3)
177.36, 155.69, 155.08, 151.56, 138.45, 131.24,
d
130.42, 130.17, 125.97, 125.45, 124.24, 122.72, 119.83, 112.16, 105.98,
69.58. HRMS m/z: calcd for C16H11BrO3, 329.9892, found 329.9889;
Purity (HPLC): 99%.
4.2.1. 6-(Benzyloxy)-4H-chromen-4-one (3a)
The title compound (dark brown powder) was prepared by
reacting 6-hydroxychromone, K2CO3 and benzyl bromide in
acetone with yield of 67%: mp 115.9e116.0 ꢂC. 1H NMR (Bruker
4.2.7. 6-[(4-Bromobenzyl)oxy]-4H-chromen-4-one (3g)
The title compound (brown powder) was prepared by reacting
6-hydroxychromone, K2CO3 and 4-bromobenzyl bromide in
acetone, with yield of 21%: mp 179.6e180.2 ꢂC. 1H NMR (CDCl3)
Avance III 600 MHz, CDCl3)
d
7.82 (d, J ¼ 5.9 Hz, 1H), 7.66 (d,
J ¼ 3.1 Hz, 1H), 7.44 (dd, J ¼ 7.9, 1.5 Hz, 2H), 7.41e7.36 (m, 3H),
d
7.82 (d, J ¼ 6.0 Hz, 1H), 7.61 (d, J ¼ 3.1 Hz, 1H), 7.54e7.45 (m, 2H),
7.39 (d, J ¼ 9.1 Hz, 1H), 7.34e7.26 (m, 3H), 6.30 (d, J ¼ 5.9 Hz, 1H),
5.07 (s, 2H). 13C NMR (CDCl3)
177.35, 155.72, 155.07, 151.52, 135.17,
7.36e7.29 (m, 2H), 6.31 (d, J ¼ 5.9 Hz, 1H), 5.12 (s, 2H). 13C NMR
(Bruker Avance III 600 MHz, CDCl3)
d
177.46, 156.03, 155.04, 151.45,
d
136.15, 128.63, 128.20, 127.66, 125.44, 124.33, 119.68, 112.12, 106.01,
70.58. HRMS m/z: calcd for C16H12O3, 252.0786, found 252.0793;
Purity (HPLC): 99%.
131.75, 129.20, 125.44, 124.23, 122.13, 119.78, 112.14, 106.03, 69.76.
HRMS m/z: calcd for C16H11BrO3, 329.9892, found 329.9885; Purity
(HPLC): 99%.
4.2.2. 6-(2-Phenylethoxy)-4H-chromen-4-one (3b)
4.2.8. 6-[(3-Fluorobenzyl)oxy]-4H-chromen-4-one (3h)
The title compound (dark brown powder) was prepared by
reacting 6-hydroxychromone, K2CO3 and 2-phenylethyl bromide in
acetone with yield of 73%: mp 118.3e119.4 ꢂC. 1H NMR (CDCl3)
The title compound (white powder) was prepared by reacting 6-
hydroxychromone, K2CO3 and 3-fluorobenzyl bromide in acetone,
with yield of 53%: mp 91.3e91.4 ꢂC. 1H NMR (CDCl3)
d 7.73 (d,
d
7.80 (d, J ¼ 5.9 Hz, 1H), 7.54 (d, J ¼ 3.1 Hz, 1H), 7.36 (d, J ¼ 9.1 Hz,
J ¼ 6.0 Hz, 1H), 7.53 (t, J ¼ 2.2 Hz, 1H), 7.37e7.21 (m, 3H), 7.12e6.99
1H), 7.33e7.26 (m, 4H), 7.23 (m, 2H), 6.29 (d, J ¼ 5.9 Hz, 1H), 4.25 (t,
(m, 2H), 6.92 (t, J ¼ 8.6 Hz, 1H), 6.21 (d, J ¼ 5.6 Hz, 1H), 5.02 (s, 2H).
J ¼ 7.0 Hz, 2H), 3.11 (t, J ¼ 6.9 Hz, 2H). 13C NMR (CDCl3)
d
177.41,
13C NMR (CDCl3)
d 177.34, 163.74, 162.11, 155.69, 155.06, 151.53,
138.74, 138.69, 130.19, 130.14, 125.43, 124.22, 122.85, 122.83, 119.79,
115.08, 114.94, 114.35, 114.21, 112.13, 106.00, 69.65. HRMS m/z: calcd
for C16H11FO3, 270.0692, found 270.0681; Purity (HPLC): 99%.
156.09, 154.97, 151.28, 137.88, 128.91, 128.47, 126.53, 125.39, 124.06,
119.53, 112.05, 105.60, 69.20, 35.53. HRMS m/z: calcd for C17H14O3,
266.0942, found 266.0934; Purity (HPLC): 99%.
4.2.3. 6-(3-Phenylpropoxy)-4H-chromen-4-one (3c)
4.2.9. 6-[(4-Fluorobenzyl)oxy]-4H-chromen-4-one (3i)
The title compound (off-white powder) was prepared by
reacting 6-hydroxychromone, K2CO3 and 3-phenylpropyl bromide
in acetone with yield of 51%: mp 177.7e177.8 ꢂC. 1H NMR (CDCl3)
The title compound (white powder) was prepared by reacting 6-
hydroxychromone, K2CO3 and 4-fluorobenzyl bromide in acetone,
with yield of 27%: mp 138.1e138.9 ꢂC. 1H NMR (CDCl3)
d 7.83 (d,
d
7.86 (d, J ¼ 5.9 Hz, 1H), 7.56 (d, J ¼ 3.0 Hz, 1H), 7.42 (d, J ¼ 9.1 Hz,
J ¼ 5.9 Hz, 1H), 7.67e7.59 (m, 1H), 7.46e7.37 (m, 3H), 7.30 (dt,
1H), 7.34e7.27 (m, 3H), 7.27e7.19 (m, 3H), 6.34 (d, J ¼ 6.0 Hz, 1H),
J ¼ 9.2, 2.2 Hz, 1H), 7.07 (t, J ¼ 8.4 Hz, 2H), 6.31 (d, J ¼ 6.0 Hz, 1H),
4.08 (t, J ¼ 6.3 Hz, 2H), 2.85 (t, J ¼ 7.5 Hz, 2H), 2.22e2.13 (m, 2H). 13C
5.08 (s, 2H). 13C NMR (CDCl3)
d 177.41, 163.42, 161.79, 155.84, 155.06,
151.51, 131.95, 131.93, 129.55, 129.50, 125.45, 124.31, 119.76, 115.64,
115.50, 112.16, 105.99, 69.90. HRMS m/z: calcd for C16H11FO3,
270.0692, found 270.0694; Purity (HPLC): 99%.
NMR (CDCl3)
d
177.54, 156.34, 155.00, 151.29, 141.24, 128.45, 125.99,
125.45,124.10,119.55,112.08, 105.56, 67.61, 32.07, 30.64. HRMS m/z:
calcd for C18H16O3, 280.1099, found 280.1099; Purity (HPLC): 99%.
4.2.4. 6-[(3-Chlorobenzyl)oxy]-4H-chromen-4-one (3d)
4.2.10. 6-[(3-Methylbenzyl)oxy]-4H-chromen-4-one (3j)
The title compound (off-white powder) was prepared by
reacting 6-hydroxychromone, K2CO3 and 3-chlorobenzyl bromide
in acetone with yield of 47%: mp 117.0e117.4 ꢂC. 1H NMR (CDCl3)
The title compound (white powder) was prepared by reacting 6-
hydroxychromone, K2CO3 and 3-methylbenzyl bromide in acetone,
with yield of 29%: mp 95.2e96.1 ꢂC. 1H NMR (CDCl3)
d 7.82 (d,
d
7.82 (d, J ¼ 6.0 Hz, 1H), 7.62 (d, J ¼ 3.1 Hz, 1H), 7.46e7.37 (m, 2H),
J ¼ 5.9 Hz, 1H), 7.66 (d, J ¼ 3.0 Hz, 1H), 7.39 (d, J ¼ 9.1 Hz, 1H),
7.36e7.27 (m, 4H), 6.31 (d, J ¼ 5.9 Hz, 1H), 5.09 (s, 2H). 13C NMR
7.35e7.21 (m, 4H), 7.14 (d, J ¼ 7.3 Hz, 1H), 6.31 (d, J ¼ 5.9 Hz, 1H),
(CDCl3)
d
177.35, 155.69, 155.07, 151.55, 138.20, 134.55, 129.89,
5.08 (s, 2H), 2.36 (s, 3H). 13C NMR (CDCl3)
d 177.43, 156.06, 155.00,
128.29, 127.50, 125.48, 125.46, 124.23, 119.82, 112.15, 105.98, 69.64.
HRMS m/z: calcd for C16H11ClO3, 286.0397, found 286.0395; Purity
(HPLC): 99%.
151.40, 138.33, 136.02, 128.96, 128.51, 128.41, 125.42, 124.76, 124.29,
119.63, 112.10, 105.95, 70.64, 21.37. HRMS m/z: calcd for C17H14O3,
266.0943, found 266.0937; Purity (HPLC): 99%.
4.2.5. 6-[(4-Chlorobenzyl)oxy]-4H-chromen-4-one (3e)
4.2.11. 6-[(4-Methylbenzyl)oxy]-4H-chromen-4-one (3k)
The title compound (off-white powder) was prepared by
reacting 6-hydroxychromone, K2CO3 and 4-chlorobenzyl bromide
in acetone with yield of 41%: mp 169.5e171.1 ꢂC. 1H NMR (CDCl3)
The title compound (white powder) was prepared by reacting 6-
hydroxychromone, K2CO3 and 4-methylbenzyl bromide in acetone,
with yield of 46%: mp 116.5e116.7 ꢂC. 1H NMR (CDCl3)
d 7.82 (d,
d
7.82 (d, J ¼ 5.9 Hz, 1H), 7.68e7.59 (m, 1H), 7.48e7.26 (m, 6H),
J ¼ 5.9 Hz, 1H), 7.65 (d, J ¼ 2.9 Hz, 1H), 7.38 (d, J ¼ 9.2 Hz, 1H),
6.35e6.24 (m, 1H), 5.08 (s, 2H). 13C NMR (CDCl3)
d
177.37, 155.75,
7.35e7.26 (m, 3H), 7.19 (d, J ¼ 7.6 Hz, 2H), 6.30 (d, J ¼ 5.9 Hz, 1H),