JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
1491
hydrochloric acid (5 mL) over 1 h with vigorous stirring at the tem- 113.3, 113.0, 102.0. 62.1. 53.3. 48.7. 47.2 30.0 20.0. HRMS (ESI)
ꢂ
þ
perature between 70 and 80 C. The reaction mixture was stirred calcd for C22
H
23
N
O
[M þ H] : 439.1612; found: 439.1606.
4
6
ꢂ
for a further 3 h at 70 C. After removal of the solvent, the crude
intermediate 16 was obtained as a yellow oil .
18
2.1.10.3.
3-hydroxy-2,6-dimethyl-1–(2-(4-(((2-oxo-2H-chromen-7-
(27c).
white solid, yield: 93%; m.p.: 256–249 C; H NMR (600MHz, DMSO-
) d 8.34 (s, 1H), 8.02 (d, J ¼ 9.5 Hz, 1H), 7.66 (d, J ¼ 8.6 Hz, 1H),
.14 (s, 1H), 7.03 (s, 1H), 7.01 (dd, J ¼ 8.6, 2.5 Hz, 1H), 6.32 (d,
yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-4(1H)-one
ꢂ
1
2
.1.9. General procedure for the synthesis of intermediates 22, 24,
d
7
6
and 26
Propargyl bromide (2.4 mmol) was added to a suspension of the
coumarin (2.0 mmol) and potassium carbonate (4.0 mmol) in acet-
one (15 mL). The suspension was heated under reflux for 2 h. The
reaction was allowed to cool and then concentrated under
reduced pressure. Water (30 mL) was added and extracted with
EtOAc (3 ꢁ 30 mL). The organic extracts were combined and
washed with water (20 mL) and brine (20 mL) dried over anhyd-
rous sodium sulphate, then filtered and concentrated in vacuo.
J ¼ 9.5 Hz, 1H), 5.30 (s, 2H), 4.93 (t, J ¼ 6.3 Hz, 2H), 4.80 (t, J ¼ 6.2 Hz,
13
2
1
1
6
H), 2.41 (s, 3H), 2.34 (s, 3H). C NMR (150 MHz, DMSO-d ) d 161.4,
60.7, 159.1, 155.7, 148.4, 144.8, 143.1, 142.9, 141.9, 130.0, 126.4,
13.4, 113.2, 113.1, 112.6, 102.1, 61.9, 51.1, 47.7, 20.3, 13.6. HRMS
ESI) calcd for C H N O [Mþ H] : 409.1518; found: 409.1506.
þ
(
21 21 4 5
2.1.10.4.
3-hydroxy-2,6-dimethyl-1–(3-(4-(((2-oxo-2H-chromen-7-
yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)pyridin-4(1H)-one (27d).
white solid, yield: 87%; m.p.: 263–265 C; H NMR (600 MHz,
1
8
The crude product was purified by column chromatography .
1
ꢂ
DMSO-d ) d 8.43 (s, 1H), 8.01 (d, J ¼ 9.4 Hz, 1H), 7.66 (d, J ¼ 8.5 Hz,
6
1
H), 7.15 (s, 1H), 7.06 (s, 1H), 7.02 (d, J ¼ 8.7 Hz, 1H), 6.30 (d,
2
2
.1.10. General procedures for the synthesis of target compounds
7a-k
J ¼ 9.4 Hz, 1H), 5.30 (s, 2H), 4.62 (t, J ¼ 6.7 Hz, 2H), 4.28 (t,
1
3
J ¼ 6.7 Hz, 2H), 2.51 (s, J ¼ 7.0 Hz, 5H), 2.47 (s, 3H).
150 MHz, DMSO-d ) d 161.5, 160.7, 158.6, 155.7, 147.6, 144.7,
42.6, 142.5, 141.8, 130.0, 125.6, 113.4, 113.1, 113.1, 112.6, 102.1,
2.2, 49.1, 47.1, 28.8, 20.3, 13.4. HRMS (ESI) calcd for C H N O
C NMR
To a stirred solution of intermediate 13 (2.0 mmol) and alkyne 24
2.2 mmol) in MeOH/H O (3:3, V/V), CuSO .5H O (2.2 mmol) and
(
6
(
2
4
2
1
6
sodium ascorbate (0.5 mmol) were added. The reaction mixture
was stirred at room temperature for 2 h and then concentrated
under reduced pressure. Water (10 mL) was added and the mix-
ture was extracted with dichloromethane (3 ꢁ 20 mL). The com-
bined organic phases were washed over water (20 mL), dried over
anhydrous sodium sulphate, and evaporated to dryness. The crude
was purified by column chromatography with dichloromethane
and methanol (150:1, v/v) to yield the products as white solids.
Then, BBr3 (1.5 mmol) was added dropwise to a solution of this
2
2
23
4
5
þ
[M þ H] : 423.1663; found: 423.1676.
2.1.10.5. 2-ethyl-3-hydroxy-1–(3-(4-(((2-oxo-2H-chromen-7-yl)oxy)-
methyl)-1H-1,2,3-triazol-1-yl)propyl)pyridin-4(1H)-one (27e). white
ꢂ
1
solid, yield: 91%; m.p.: 204–206 C; H NMR (600 MHz, DMSO-d ) d
6
8
.29 (s, 1H), 8.02 (d, J ¼ 9.5 Hz, 1H), 7.88 (d, J ¼ 7.1 Hz, 1H), 7.66 (d,
J ¼ 8.6 Hz, 1H), 7.13 (d, J ¼ 2.4 Hz, 1H), 7.05 (d, J ¼ 6.6 Hz, 1H), 7.00
(dd, J ¼ 8.6, 2.4 Hz, 1H), 6.32 (d, J ¼ 9.5 Hz, 1H), 5.27 (s, 2H), 4.47 (s,
ꢂ
white solid (0.5 mmol) in dichloromethane (10 mL) at 0 C under
13
2
H), 3.95 (s, 2H), 2.58 (s, 2H), 2.24 (s, 2H), 1.02 (s, 3H). C NMR
N2 atmosphere. The reaction mixture was then warmed up to
room temperature and the stirring continued for 12 h. After the
reaction, methanol (10 mL) was added to the mixture and was
stirred for another 0.5 h. Concentration and recrystallization from
(
150 MHz, DMSO-d ) d 169.7, 161.5, 160.7, 155.8, 144.8, 142.6,
6
1
5
37.8, 137.7, 134.1, 129.9, 125.5, 113.4, 113.3, 113.0, 102.0, 62.1,
5.1, 49.8, 47.1, 31.9, 18.9, 13.0.HRMS (ESI) calcd for C21
H
21 4
N O
5
þ
[M þ H] : 409.1506; found: 409.1512.
19,20
.
2.1.10.6. 2-ethyl-3-hydroxy-1–(2-(4-(((2-oxo-2H-chromen-4-yl)oxy)-
methyl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-4(1H)-one (27f). White
2
2
4
.1.10.1.
H-chromen-7-yl)
(1H)-one (27a). yellow solid, yield: 81%; m.p.: 212–215 C;
) d 8.34 (s, 1H), 8.02 (d, J ¼ 9.5 Hz, 1H),
.01 (d, J ¼ 8.7 Hz, 1H), 7.66 (d, J ¼ 2.5 Hz, 1H), 7.25 (s, 1H), 7.01
3-hydroxy-2-(hydroxymethyl)-6-methyl-1–(2-(4-(((2-oxo-
ꢂ
1
solid, yield: 90%; m.p.: 253–256 C H NMR (600 MHz, DMSO-d
6
) d
oxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-
8
.28 (s, 1H), 8.01 (d, J ¼ 7.0 Hz, 1H), 7.87 (d, J ¼ 7.8 Hz, 1H), 7.65 (d,
ꢂ
1
H
J ¼ 8.4, 7.2, Hz, 1H), 7.12 (d, J ¼ 8.4 Hz, 1H), 7.00 (d, J ¼ 7.2 Hz, 1H),
NMR (600 MHz, DMSO-d
8
6
6
2
.99 (d, J ¼ 7.2 Hz, 1H), 6.31 (d, H), 5.27 (s, 2H), 4.91 (t, J ¼ 6.9 Hz,
H), 4.85 (t, J ¼ 6.9 Hz, 2H), 2.68 (q, J ¼ 6.0 Hz, 2H), 1.08 (t,
(
dd, J ¼ 8.6, 2.4 Hz, 1H), 6.30 (d, J ¼ 9.5 Hz, 1H), 5.29 (s, 2H), 4.99 (d,
13
J ¼ 6.0 Hz, 3H). C NMR (150 MHz, DMSO-d
6
) d 161.4, 160.7, 159.3,
1
3
J ¼ 5.9 Hz, 2H), 4.93 (s, J ¼ 5.9 Hz, 2H), 4.62 (s, 2H), 2.37 (s, 3H).
C
1
1
55.7, 146.9, 144.8, 143.2, 142.8, 138.8, 130.1, 126.3, 113.3, 113.2,
NMR (150 MHz, DMSO-d ) d 161.5, 161.4, 160.7, 155.7, 149.2, 144.7,
6
13.1, 111.3, 102.1, 61.9, 55.1, 49.8, 19.8, 12.1. HRMS (ESI) calcd for
1
6
42.9, 142.1, 142.0, 130.0, 126.3, 113.5, 113.3, 113.2, 113.1, 102.1,
1.9, 53.2, 50.3, 48.5, 20.1. HRMS (ESI) calcd for C H N O
þ
C H N O [M þ H] : 409.1506; found: 409.1500.
2
1 21 4 5
2
1 21 4 6
þ
[M þ H] : 425.1456; found: 425.1439.
2.1.10.7. 2-ethyl-3-hydroxy-1–(3-(4-(((2-oxo-2H-chromen-4-yl)oxy)-
methyl)-1H-1,2,3-triazol-1-yl)propyl)pyridin-4(1H)-one (27g). White
2
2
4
.1.10.2.
3-hydroxy-2-(hydroxymethyl)-6-methyl-1–(3-(4-(((2-oxo-
ꢂ
1
solid, yield: 92%; m.p.: 195–198 C; H NMR (600 MHz, DMSO-d ) d
6
H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)pyridin-
(1H)-one (27b). yellow solid, yield: 84%; m.p.: 189–192 C;
8
.48 (s, 1H), 8.29 (d, J ¼ 7.0 Hz, 1H), 7.74 (d, J ¼ 7.8 Hz, 1H), 7.66 (t,
ꢂ
1
H
J ¼ 8.0 Hz, 1H), 7.41 (d, J ¼ 8.4 Hz, 1H), 7.33 (t, J ¼ 7.2 Hz, 1H), 7.20
NMR (600 MHz, DMSO-d ) d 8.41 (s, 1H), 8.01 (d, J ¼ 9.5 Hz, 1H), (d, J ¼ 7.2 Hz, 1H), 6.17 (s, 1H), 5.45 (s, 2H), 4.59 (t, J ¼ 6.6 Hz, 2H),
6
7
.66 (d, J ¼ 8.6 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 7.02 (dd, 4.43 (t, J ¼ 6.6 Hz, 2H), 2.87 (q, J ¼ 7.5 Hz, 2H), 2.41 (m, 2H), 1.12 (t,
1
3
J ¼ 8.5 Hz, 1H), 6.30 (d, J ¼ 9.4, 1.7 Hz, 1H), 5.29 (s, 2H), 4.76 (s, 2H), J ¼ 7.2 Hz, 3H). C NMR (150 MHz, DMSO-d ) d 164.7, 161.9, 159.1,
6
4
6
1
.61 (t, J ¼ 6.7 Hz, 2H), 4.45 (t, J ¼ 8.5 Hz, 2H), 2.38 (s, 3H), 2.37 (m, 153.2, 146.5, 143.3, 141.6, 138.8, 133.2, 125.7, 124.6, 123.3, 117.1,
13
.9 Hz, 2H). C NMR (150 MHz, DMSO-d
6
) d 163.5, 161.5, 160.7, 115.6, 111.7, 91.8, 63.2, 53.2, 47.0, 31.5, 20.2, 12.2. HRMS (ESI) calcd
þ
60.0, 155.7, 148.8, 144.7, 142.7, 142.5, 142.3, 130.0, 125.5, 113.5, for C22
H
23
N O
4 5
[M þ H] : 423.1815; found: 423.1826.