Journal of Medicinal Chemistry
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dried over Na2SO4. Flash column chromatography (1:2 hexane−ethyl
acetate) afforded 8 (106 mg, 65%) as a yellow solid. mp 94−96 °C. 1H
NMR (CDCl3) δ 3.29 (s, 6H), 3.95 (t, J = 5.0 Hz, 2H), 4.61 (t, J =
5.0 Hz, 2H), 4.62 (s, 2H), 7.24 (d, J = 17.5 Hz, 1H), 7.41 (d, J = 16.5 Hz,
1H), 7.62 (d, J = 5.0 Hz, 2H), 7.79 (s, 1H), 8.22 (d, J = 9.0 Hz, 2H).
MS (EI) m/z 304 (M+). HRMS calcd for C14H16N4O4, 304.1168;
found, 304.1171.
(t, J = 5.0 Hz, 2H), 3.80 (t, J = 5.0 Hz, 2H); MS (CI) m/z 88
(M+ + H). HRMS calcd for C2H6N3O, 88.0511; found, 88.0513.
4-(Diethoxymethyl)-1-(2-hydroxyethyl)-1H-1,2,3-triazole
(13). Sodium ascorbate (409 mg, 2.06 mmol) and CuSO4·5H2O (258
mg, 1.03 mmol) were added to a 1:1 t-butanol−water solution (19
mL) of 3,3-diethoxy-1-propyne (736 μL, 5.16 mmol) and 12 (450 mg,
5.16 mmol). The reaction mixture was stirred at room temperature for
4 h. At the end of the reaction, the mixture was diluted with water
(100 mL) and extracted with CH2Cl2 (200 mL); then, the combined
organic layer was washed with water (200 mL) and dried over Na2SO4.
Flash column chromatography (15:1 CH2Cl2−methanol) afforded 13
(E)-4-(4-Aminostyryl)-1-(2-hydroxyethyl)-1H-1,2,3-triazole
(9). SnCl2·2H2O (303 mg, 1.34 mmol) and conc. HCl (307 μL) were
added to a solution of 8 (100 mg, 0.328 mm0l) in EtOH (6.2 mL),
and the reaction mixture was stirred at 80 °C for 2 h. The mixture was
neutralized with a saturated NaHCO3 solution (aq, 50 mL) and
extracted twice with ethyl acetate (200 mL), and then the combined
organic layer was washed with brine (200 mL) and dried over Na2SO4.
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(840 mg, 76%) as a colorless oil. H NMR (CDCl3) δ 1.24 (t, J =
7.0 Hz, 6H), 3.72 (q, J = 7.0 Hz, 4H), 4.11 (t, J = 5.0 Hz, 2H), 4.58
(t, J = 4.0 Hz, 2H), 8.26 (s, 1H), 10.15 (s, 1H). MS (CI) m/z 216
(M+ + H). HRMS calcd for C9H18N3O3, 216.1348; found, 216.1346.
4-(Formyl)-1-(2-hydroxyethyl)-1H-1,2,3-triazole (14). Tri-
fluoroacetic acid (4.4 mL, aq, 50%) was added dropwise to a solution
of 13 (503 mg, 2.34 mmol) in CHCl3 (13 mL) at 0 °C and stirred for
2 h at the same temperature. At the end of the reaction, the reaction
mixture was concentrated in vacuo to remove CHCl3 and neutralized
with 1 N NaOH, extracted with ethyl acetate (100 mL); then, the
combined organic layer was washed with brine (100 mL) and dried
over Na2SO4. Compound 14 (300 mg, 91%) was obtained as a white
solid. 1H NMR (CDCl3) δ 4.12 (t, J = 5.0 Hz, 2H), 4.59 (t, J = 5.0 Hz,
2H), 8.27 (s, 1H), 10.14 (s, 1H); MS (EI) m/z 141 (M+). HRMS
calcd for C5H7N3O2, 141.0538; found, 141.0539.
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Compound 9 (50 mg, 76%) was obtained as a yellow solid. H NMR
(acetone-d6) δ 3.99 (t, J = 5.0 Hz, 2H), 4.51 (t, J = 5.0 Hz, 2H), 6.90
(d, J = 16.5 Hz, 1H), 7.12 (d, J = 16.0 Hz, 1H), 7.30 (d, J = 6.0 Hz,
2H), 7.53 (d, J = 8.0 Hz, 2H), 8.05 (s, 1H). MS (EI) m/z 230 (M+).
HRMS calcd for C12H14N4O, 230.1170; found, 230.1167.
(E)-1-(2-Hydroxyethyl)-4-(4-N,N-dimethylaminostyryl)-1H-
1,2,3-triazole (10). Sodium cyanoborohydride (36.8 mg, 0.58 mmol)
was added to a solution of 9 (45 mg, 0.19 mmol) and paraform-
aldehyde (58.6 mg, 1.95 mmol) in acetic acid (9 mL), which was
allowed to stir at room temperature for 20 h. The reaction mixture was
then neutralized with a saturated NaHCO3 solution (aq, 250 mL) and
extracted twice with ethyl acetate (200 mL); then, the combined
organic layer was washed with water (200 mL) and dried over Na2SO4.
Compound 10 (35 mg, 69%) was obtained as a yellow solid. 1H NMR
(CD3OD) δ 2.97 (s, 6H), 3.96 (t, J = 5 Hz, 2H), 4.49 (t, J = 5 Hz,
2H), 6.76 (d, J = 9 Hz, 2H), 6.88 (d, J = 16.5 Hz, 1H), 7.19 (d, J =
16.5 Hz, 1H), 7.40 (d, J = 9 Hz, 2H), 8.02 (s, 1H). MS (EI) m/z 258
(M+). HRMS calcd for C14H18N4O, 258.1480; found, 258.1480.
(E)-1-(2-Methanesulfonyloxyethyl)-4-(4-N,N-dimethylamino-
styryl)-1H-1,2,3-triazole (11). Triethylamine (161.9 μL, 1.16 mmol)
was slowly added to a solution of 10 (50 mg, 0.193 mmol) in CH2Cl2
(1.5 mL), which was stirred at room temperature for 1 h. Methane-
sulfonyl chloride (30 μL, 0.387 mmol) was added to the solution at
0 °C, and the mixture was stirred at room temperature for 2 h. At the
end of the reaction, the reaction mixture was diluted with water (50 mL)
and extracted twice with ethyl acetate (50 mL); then, the combined
organic layer was washed with brine (100 mL) and dried over Na2SO4.
Flash column chromatography (1:3 hexane−ethyl acetate) afforded 11
4-(Formyl)-1-(2-(methoxymethoxy)ethyl)-1H-1,2,3-triazole
(7). DIPEA (741 μL, 4.25 mmol) was slowly added to a solution of 14
(300 mg, 2.12 mmol) in THF (15 mL) at 0 °C. Subsequently,
chloromethylmethyl ether (323 μL, 4.251 mmol) was added dropwise
at the same temperature. The resulting mixture was warmed to room
temperature and stirred for 1 h and then at 65 °C for 16 h. At the end
of the reaction, the mixture was quenched with a saturated NH4Cl
solution (aq, 100 mL) and extracted with ethyl acetate (100 mL). The
combined organic layer was washed with brine (100 mL) and dried
over Na2SO4. Flash column chromatography (30:1 CH2Cl2−methanol)
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gave 7 (230 mg, 58%) as a colorless oil. H NMR (CDCl3) δ 3.27
(s, 3H), 3.94 (t, J = 5.0 Hz, 2H), 4.61 (s, 2H), 4.64 (t, J = 5.0 Hz, 2H),
8.25 (s, 1H), 10.15 (s, 1H); MS (CI) m/z 186 (M+ + H). HRMS calcd
for C7H12N3O3, 186.0879; found, 186.0874.
Diethyl 3,5-Dimethoxybenzylphosphonate (15). A solution of
3,5-dimethoxybenzyl bromide (1.0 g, 4.32 mmol) in triethyl phosphite
(750 μL, 4.37 mmol) was stirred at 160 °C for 4 h using a pressure
vial. The reaction mixture was transferred to a round-bottomed flask
using ethyl acetate (25 mL) and then concentrated in vacuo. Flash
column chromatography (CH2Cl2-methanol 20:1) gave 15 (1.23 g,
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(46 mg, 71%) as a light-yellow solid. mp 142−145 °C. H NMR
(CDCl3) δ 2.95 (s, 6H), 2.99 (s, 3H), 4.70 (t, J = 5.0 Hz, 2H), 4.75 (t,
J = 5.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 16.0 Hz, 1H),
7.40 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 15.0 Hz, 1H), 8.10 (s, 1H). MS
(EI) m/z 336 (M+). HRMS calcd for C15H20N4O3S, 336.1256; found,
336.1260.
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99%) as a light-yellow oil. H NMR (CDCl3) δ 1.26 (t, J = 7.0 Hz,
6H), 3.07 (s, 1H), 3.11 (s, 1H), 3.78 (s, 6H), 4.02−4.05 (m, 4H), 6.35
(d, J = 2.0 Hz, 1H), 6.46 (t, J = 2.5 Hz, 2H). MS (EI) m/z 288 (M+).
HRMS calcd for C13H21O5P, 288.1122; found, 288.1127.
(E)-1-(2-Fluoroethyl)-4-(4-N,N-dimethylaminostyryl)-1H-
1,2,3-triazole (1). Cesium fluoride (27 mg, 0.17 mmol) was added to
a solution of 11 (20 mg, 0.06 mmol) in CH3CN (1 mL), and the
reaction mixture was stirred at 100 °C for 10 h. At the end of the
reaction, the reaction mixture was diluted with water (20 mL) and
extracted twice with ethyl acetate (30 mL), and the combined organic
layer was then washed twice with water (20 mL) and dried over
Na2SO4. Flash column chromatography (2:1 hexane−ethyl acetate)
afforded 1 (7.2 mg, 47%) as a yellow solid. mp 126−127 °C. 1H NMR
(CDCl3) δ 2.98 (s, 6H), 4.67 (dt, J = 27.0 and 4.5 Hz, 2H), 4.80 (dt, J
= 47.0 and 4.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 16.5 Hz,
1H), 7.24 (d, J = 16.5 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 8.19 (s, 1H).
MS (EI) m/z 260 (M+). HRMS calcd for C14H17FN4, 260.1437;
found, 260.1440.
2-Azidoethanol (12). Sodium azide (3.146 g, 48.1 mmol) was
added to a solution of 2-bromoethanol (2.26 mL, 32.1 mmol) in water
(12 mL). The reaction mixture was stirred at 85 °C for 16 h.52 At the
end of the reaction, the mixture was diluted with water and extracted
with diethyl ether (50 mL); then, the combined organic layer was
washed with water (50 mL) and dried over Na2SO4. Compound 12
(1.97 g, 70%) was obtained as a colorless oil. 1H NMR (CDCl3) δ 3.47
(E)-1-(4-Fluorostyryl)-3,5-dimethoxybenzene (2). Potassium
t-butoxide (233 mg, 2.08 mmol) was added to a solution of 15 (300 mg,
1.04 mmol) and 4-fluorobenzaldehyde (129 mg, 1.04 mmol) in DMF
(5 mL) at 0 °C. The reaction mixture was warmed to room tempera-
ture and stirred for 1 h. At the end of the reaction, the mixture was
diluted with water (30 mL) and extracted twice with ethyl acetate
(50 mL); then, the combined organic layer was washed with brine
(150 mL) and dried over Na2SO4. Flash column chromatography
(10:1 hexane−ethyl acetate) afforded 2 (196 mg, 74%) as a white
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solid. mp 44−45 °C. H NMR (CDCl3) δ 3.83 (s, 6H), 6.40 (t, J =
2.0 Hz, 1H), 6.65 (d, J = 2.5 Hz, 2H), 6.94 (d, J = 16.0 Hz, 1H), 7.04 (d,
J = 16.5 Hz, 1H), 7.05 (t, J = 11.0 Hz, 2H), 7.45−7.48 (m, 2H). MS (EI)
m/z 258 (M+). HRMS calcd for C16H15O2F, 258.1075; found, 258.1056.
(E)-5-(4-Fluorostyryl)benzene-1,3-diol (3). BBr3 (1 M) in CH2Cl2
(2.32 mL) was added dropwise to a solution of 2 (100 mg) in CH2Cl2
(1.6 mL) with vigorous stirring at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 20 h. After the addition
of a saturated NaHCO3 solution (aq, 20 mL), the mixture was
extracted twice with CH2Cl2 (50 mL), and the combined organic layer
was washed with water (50 mL) and dried over Na2SO4. Flash column
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dx.doi.org/10.1021/jm201400q | J. Med. Chem. 2012, 55, 883−892