Y. Shan et al. / European Journal of Medicinal Chemistry 164 (2019) 440e447
445
bath was removed, and the mixture was reacted at room temper-
ature overnight. The product was extracted with CH2Cl2
(30 mL ꢁ 3), washed twice with water and brine, and dried over
Na2SO4. After filtration and concentration in vacuo, the residues
was purified by silica gel flash chromatography (PE/ AcOEt ¼ 15:1)
afford (6h) as white solid (0.20 g, 83%). m.p. ¼ 210e212 ꢀC, MS (EI)
8.16e8.11 (m, 2H), 7.86 (s, 1H), 7.58 (d, J ¼ 8.2 Hz, 2H), 7.41 (d,
J ¼ 7.0 Hz, 1H), 7.37 (d, J ¼ 8.3 Hz, 2H), 7.35e7.30 (m, 2H), 5.67 (s,
2H), 3.85 (s, 3H). 13C NMR (101 MHz, DMSO)
d 160.19,157.74,140.42,
140.39, 136.61, 133.96, 133.13, 130.22, 130.14, 129.15, 128.44, 127.83,
127.80, 125.71, 125.49, 125.46, 124.44, 124.33, 121.82, 118.91, 118.78,
116.63, 116.42, 53.21, 39.16.
[M]þ: m/z ¼ 395. 1H NMR (400 MHz, DMSO‑d6)
d 10.32 (s, 1H), 9.20
(s, 1H), 9.15 (s, 2H), 8.65 (s, 1H), 8.17 (t, J ¼ 1.9 Hz, 1H), 7.85 (d,
J ¼ 8.3 Hz, 2H), 7.54 (d, J ¼ 8.2 Hz, 3H), 7.48 (d, J ¼ 7.8 Hz,1H), 7.35 (t,
J ¼ 7.9 Hz, 1H), 5.73 (s, 2H), 1.80 (s, 1H), 0.82 (s, 4H). 13C NMR
4.1.1.16. 1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-phenyl-1H-1,2,3-
triazole (7f). m.p. ¼195e197 ꢀC, MS (EI) [M]þ: m/z ¼ 315.1H NMR
(400 MHz, DMSO‑d6)
d 8.65 (s, 1H), 8.14 (s, 1H), 7.88e7.83 (m, 3H),
(101 MHz, DMSO)
d
172.29, 157.93, 155.31, 147.20, 140.42, 137.29,
7.58 (d, J ¼ 8.2 Hz, 2H), 7.44 (t, J ¼ 7.6 Hz, 2H), 7.39e7.31 (m, 3H),
134.20, 133.26, 131.56, 129.87, 129.44, 127.96, 122.18, 120.47, 118.99,
116.12, 53.13, 15.07, 7.75.
5.62 (s, 2H), 3.86 (s, 3H).13C NMR (101 MHz, DMSO)
d
147.16, 136.61,
133.93, 133.13, 131.19, 129.41, 129.11, 128.45, 128.40, 125.73, 125.66,
121.98, 121.83, 53.33, 39.17.
4.1.1.11. 4-(2-fluorophenyl)-1-[4-(1H-pyrazol-4-yl)benzyl]-1H-1,2,3-
triazole (7a). A flask charged with Pd(dppf)Cl2 (0.26 g, 0.36 mmol),
CS2CO3 (3.52 g, 10.81 mmol), and 1-(4-bromobenzyl)-4-(2-
fluorophenyl)-1H-1,2,3-triazole (4) (1.20 g 3.60 mmol) and 4-
4.1.1.17. 4-(4-methylphenyl)-1-[4-(1-methyl-1H-pyrazol-þ4-yl)
benzyl]-1H-1,2,3-triazole (7g). m.p. ¼ 213e215 ꢀC, MS (EI) [M] : m/
z ¼ 329. 1H NMR (400 MHz, DMSO‑d6)
d 8.59 (s, 1H), 8.14 (s, 1H),
7.86 (s, 1H), 7.74 (d, J ¼ 8.1 Hz, 2H), 7.58 (d, J ¼ 8.2 Hz, 2H), 7.35 (d,
J ¼ 8.2 Hz, 2H), 7.25 (d, J ¼ 8.0 Hz, 2H), 5.61 (s, 2H), 3.86 (s, 3H), 2.32
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(5)
(0.91 g, 4.68 mmol) were flushed with nitrogen and suspended in
1,4-dioxane (30 mL) and water (10 mL). The mixture was then
refluxed overnight under nitrogen. The hot suspension was filtered
and the filtrate distilled by rotary evaporation to remove 1,4-
dioxane. Water (50 mL) was added and the product was extracted
with AcOEt (60 mLꢁ3), washed with water, and dried over Na2SO4.
After filtration and concentration in vacuo, the residue was purified
by silica gel flash chromatography (PE/AcOEt ¼ 15:1) affording (7a)
as white solid (0.20 g, 17%). m.p. ¼ 232e234 ꢀC, MS (EI) [M]þ: m/
(s, 3H). 13C NMR (101 MHz, DMSO)
d 153.85, 147.24, 137.69, 136.62,
133.97, 133.12, 129.96, 129.13, 128.46, 125.73, 125.60, 121.83, 121.55,
53.30, 39.17, 21.34.
4.1.1.18. 4-(3-methylphenyl)-1-[4-(1-methyl-1H-pyrazol-þ4-yl)
benzyl]-1H-1,2,3-triazole (7h). m.p. ¼194e196 ꢀC, MS (EI) [M] : m/
z ¼ 329. 1H NMR (400 MHz, DMSO‑d6)
d 8.62 (s, 1H), 8.14 (s, 1H),
7.86 (s, 1H), 7.69 (s, 1H), 7.64 (d, J ¼ 7.8 Hz, 1H), 7.58 (d, J ¼ 8.2 Hz,
2H), 7.33 (dd, J ¼ 17.1, 8.0 Hz, 3H), 7.14 (d, J ¼ 7.5 Hz,1H), 5.61 (s, 2H),
z ¼ 319. 1H NMR (400 MHz, DMSO‑d6)
d 12.97 (s, 1H), 8.55 (d,
J ¼ 3.9 Hz, 1H), 8.17 (d, J ¼ 24.9 Hz, 2H), 7.92 (s, 1H), 7.63 (d,
3.85 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, DMSO)
d 147.26,
J ¼ 8.1 Hz, 2H), 7.36 (dd, J ¼ 17.6, 7.5 Hz, 5H), 5.67 (s, 2H). 13C NMR
138.56, 136.62, 133.93, 133.14, 131.10, 129.32, 129.15, 129.05, 128.46,
126.24, 125.73, 122.82, 121.91, 121.84, 53.34, 40.00, 39.18, 21.55.
(101 MHz, DMSO)
d 160.19, 157.74, 140.39, 133.84, 133.45, 129.12,
127.84, 127.80, 125.90, 125.50, 125.46, 124.42, 124.30, 121.11, 118.91,
118.78, 116.64, 116.42, 53.24.
The title compounds 7b-7k were prepared by using the General
Procedure described above.
4.1.1.19. 1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-[4-(tri-
fluoromethyl)phenyl]-1H-1,2,3-triazole (7i). m.p. ¼197e199 ꢀC, MS
(EI) [M]þ: m/z ¼ 383. 1H NMR (400 MHz, DMSO‑d6)
d 8.83 (s, 1H),
8.14 (s, 1H), 8.09 (d, J ¼ 8.1 Hz, 2H), 7.87 (s, 1H), 7.81 (d, J ¼ 8.3 Hz,
4.1.1.12. 4-(3-methylphenyl)-1-[4-(1H-pyrazol-4þ-yl)benzyl]-1H-
2H), 7.59 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.3 Hz, 2H), 5.66 (s, 2H), 3.86
1,2,3-triazole (7b). m.p. ¼190e192 ꢀC, MS (EI) [M] : m/z ¼ 315. 1H
(s, 3H). 13C NMR (101 MHz, DMSO)
d 145.80, 136.62, 135.16, 133.70,
NMR (400 MHz, DMSO‑d6)
d
12.97 (s, 1H), 8.61 (s, 1H), 8.20 (s, 1H),
133.22, 129.21, 128.46, 126.42, 126.38, 126.19, 125.76, 123.41, 123.26,
121.82, 53.47, 39.16.
7.93 (s, 1H), 7.75e7.57 (m, 4H), 7.34 (dd, J ¼ 18.9, 7.8 Hz, 3H), 7.14 (d,
J ¼ 7.3 Hz, 1H), 5.61 (s, 2H), 2.35 (s, 3H). 13C NMR (101 MHz, DMSO)
d
147.25, 138.54, 136.79, 133.80, 133.45, 131.11, 129.30, 129.11,
4.1.1.20. 1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-[3-(tri-
129.03, 126.23, 125.91, 122.81, 121.87, 121.11, 53.35, 21.54.
fluoromethyl)phenyl]-1H-1,2,3-triazole (7j). m.p. ¼136e138 ꢀC, MS
(EI) [M]þ: m/z ¼ 383. 1H NMR (400 MHz, DMSO‑d6)
d 8.85 (s, 1H),
4.1.1.13. 1-[4-(1H-pyrazol-4-yl)benzyl]-4-[4-(trifluoromeþthyl)
phenyl]-1H-1,2,3-triazole (7c). m.p. ¼ 282e284 ꢀC, MS (EI) [M] : m/
8.17 (d, J ¼ 20.1 Hz, 3H), 7.87 (s, 1H), 7.70 (d, J ¼ 5.1 Hz, 2H), 7.59 (d,
J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 5.65 (s, 2H), 3.86 (s, 3H). 13
C
z ¼ 369. 11H NMR (400 MHz, DMSO‑d6)
d
12.98 (s, 1H), 8.83 (s, 1H),
NMR (101 MHz, DMSO) d 145.80, 136.62, 133.68, 133.22, 132.26,
8.21 (s, 1H), 8.09 (d, J ¼ 8.1 Hz, 2H), 7.93 (s, 1H), 7.81 (d, J ¼ 8.3 Hz,
130.62, 129.44, 129.23, 128.46, 126.01, 125.76, 124.88, 124.84,
123.30, 122.96, 122.03, 121.99, 121.82, 53.50, 39.16.
2H), 7.64 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 5.65 (s, 2H).13
C
NMR (101 MHz, DMSO)
d 145.79, 135.16, 133.58, 129.18, 128.65,
128.34, 126.42, 126.39, 126.19, 125.94, 123.41, 123.23, 121.10, 53.49.
4.1.1.21. 3-{1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-1,2,3-
triazol-4-yl}aniline (7k). m.p. ¼194e196 ꢀC, MS (EI) [M]þ: m/
4.1.1.14. 3-{1-[4-(1H-pyrazol-4-yl)benzyl]-1H-1,2,3-triazol-4-yl}ani-
z ¼ 330. 1H NMR (400 MHz, DMSO‑d6)
d 12.98 (s, 1H), 8.46 (s, 1H),
line (7d). m.p. ¼ 233e235 ꢀC, MS (EI) [M]þ: m/z ¼ 316. 1H NMR
8.20 (s, 1H), 7.93 (s, 1H), 7.63 (d, J ¼ 8.2 Hz, 2H), 7.35 (d, J ¼ 8.2 Hz,
2H), 7.07 (dd, J ¼ 16.1, 8.4 Hz, 2H), 6.93 (d, J ¼ 7.6 Hz, 1H), 6.52 (d,
J ¼ 9.3 Hz, 1H), 5.59 (s, 2H), 5.18 (s, 2H). 13C NMR (101 MHz, DMSO)
(400 MHz, DMSO‑d6) d 12.99 (s, 1H), 8.48 (s, 1H), 8.22 (s,1H), 7.94 (s,
1H), 7.64 (d, J ¼ 8.3 Hz, 2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 7.08 (dd, J ¼ 16.1,
8.4 Hz, 2H), 6.95 (d, J ¼ 7.6 Hz, 1H), 6.53 (d, J ¼ 7.9 Hz, 1H), 5.61 (s,
d
149.56, 147.83, 136.60, 133.04, 133.08, 131.63, 129.85, 129.11,
2H), 5.19 (s, 2H).13C NMR (101 MHz, DMSO)
d
149.52, 147.78, 133.89,
128.44, 125.70, 121.84, 121.50, 114.09, 113.51, 110.93, 53.23, 39.16.
133.37, 131.60, 129.82, 129.05, 126.11, 125.86, 121.44, 121.09, 114.05,
113.46, 110.89, 53.22.
4.1.1.22. N-(3-{1-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-1,2,3-
triazol-4-yl}phenyl)cyclopropanecarboxamide (7l).
4.1.1.15. 4-(2-fluorophenyl)-1-[4-(1-methyl-1H-pyrazol-þ4-yl)
benzyl]-1H-1,2,3-triazole (7e). m.p. ¼147e149 ꢀC, MS (EI) [M] : m/
3-(1-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-1,2,3-triazol-4-yl)
aniline (7k) (0.20 g, 0.61 mmol) was dissolved in anhydrous CH2Cl2
(10 mL) and the mixture was stirred on the ice-bath.
z ¼ 333. 1H NMR (400 MHz, DMSO‑d6)
d
8.55 (d, J ¼ 3.8 Hz, 1H),