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147.2, 142.7, 134.2, 129.8, 128.4, 126.7, 123.2, 121.9, 121.0, 120.6,
118.1, 113.3, 55.8, 52.3, 31.1, 24.6, 21.6, 13.6 ppm; HPLC purity
87.6%; MS (ESI+) m/z 406 [M+H+, 35Cl2].
d=152.2, 149.0, 146.6, 141.7, 133.9, 130.6, 129.6, 128.9 (2C), 128.2,
127.9, 126.2, 125.1 (2C), 123.0, 121.7, 121.6, 119.2, 117.8, 116.5,
52.5 ppm; HPLC purity 98.4%; MS (ESI+) m/z 412 [M+H+, 35Cl2];
HRMS (ESI+) calcd for C21H16Cl2N3O2 412.0614 [M+H+, 35Cl2],
found 412.0596.
1-[4-(2,4-Dichlorophenoxy)-3-methoxybenzyl]-4-phenyl-1H-1,2,3-
triazole (8b): The title compound was prepared by following Gen-
eral Procedure A with phenylacetylene as the alkyne (pale-yellow
solid, 213 mg, 100%). 1H NMR ([D6]DMSO): d=8.66 (s, 1H), 7.86
(dd, J=8.3, 1.7 Hz, 2H), 7.69 (d, J=2.5 Hz, 1H), 7.44 (t, J=7.6 Hz,
2H), 7.35–7.27 (m, 3H), 7.05 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.2,
1.9 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.65 (s, 2H), 3.77 ppm (s, 3H);
13C NMR ([D6]DMSO): d=151.9, 150.6, 146.6, 142.8, 133.8, 130.6,
129.7, 128.9 (2C), 128.4, 127.9, 126.7, 125.2 (2C), 123.2, 121.5, 121.1,
120.9, 118.1, 113.6, 55.9, 52.7 ppm; HPLC purity 90%; MS (ESI+) m/
z 426 [M+H+, 35Cl2].
2-(2,4-Dichlorophenoxy)-5-(1H-1,2,3-triazol-1-ylmethyl)phenol
(9c): 1-[4-(2,4-Dichlorophenoxy)-3-methoxybenzyl]-1H-1,2,3-triazole
was prepared according to a published procedure.[46] To a stirred
solution of 8c (0.5 mmol) in dry THF (3.0 mL) was added dropwise
at room temperature nBu4NF (1.50 mL of a 1.0m solution in THF,
1.50 mmol, 3.0 equiv) and stirring was continued at room tempera-
ture for 23 h. After this time, MeOH (3.0 mL) was added, and the
solvents were evaporated in vacuo. The residue was purified by
flash chromatography on silica gel (hexanes, then hexanes/EtOAc
3:1) to give the pure product as a colorless oil (100 mg, 57%).
1H NMR ([D6]DMSO): d=8.23 (d, J=1.0 Hz, 1H), 7.76 (d, J=0.9 Hz,
1H), 7.69 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.8, 2.6 Hz, 1H), 7.23 (d,
J=1.9 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.87 (dd, J=8.2, 2.0 Hz, 1H),
6.68 (d, J=8.8 Hz, 1H), 5.62 (s, 2H), 3.74 ppm (s, 3H); 13C NMR
([D6]DMSO): d=152.0, 150.6, 142.7, 134.1, 133.6, 129.8, 128.4,
126.7, 125.0, 123.1, 121.1, 120.7, 118.1, 113.4, 55.8, 52.2 ppm; HPLC
purity 98.4%; MS (ESI+) m/z 350 [M+H+, 35Cl2]. Compound 9c
was then prepared by following General Procedure B with 1-[4-
(2,4-dichlorophenoxy)-3-methoxybenzyl]-1H-1,2,3-triazole as the
starting material. Purification by preparative HPLC provided the
pure product as a white solid (32 mg, 33% on a 0.29 mmol scale).
1H NMR (DMSO): d=9.90 (s, 1H), 8.19 (d, J=0.8 Hz, 1H), 7.77 (d,
J=0.7 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.9, 2.6 Hz, 1H),
6.98 (d, J=8.2 Hz, 1H), 6.86 (d, J=1.9 Hz, 1H), 6.77 (dd, J=8.2,
2.0 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 5.57 ppm (brs, 2H); 13C NMR
(DMSO): d=152.2, 148.9, 141.6, 134.1, 133.6, 129.6, 128.2, 126.2,
125.1, 123.0, 121.6, 119.1, 117.9, 116.5, 52.0 ppm; HPLC purity
99.7%; MS (ESI+) m/z 336 [M+H+, 35Cl2]; HRMS (ESI+) calcd for
C15H12Cl2N3O2 336.0301 [M+H]+, found 336.0297.
1-[4-(2,4-Dichlorophenoxy)-3-methoxybenzyl]-4-(trimethylsilyl)-
1H-1,2,3-triazole (8c): The title compound was prepared by fol-
lowing General Procedure A with trimethylsilylacetylene as the
alkyne (pale-yellow solid, 571 mg, 97% on a 1.5 mmol scale).
1H NMR ([D6]DMSO): d=8.24 (s, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.29
(dd, J=8.9, 2.6 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.02 (d, J=8.2 Hz,
1H), 6.89 (dd, J=8.2, 2.0 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.60 (s,
2H), 3.75 (s, 3H), 0.26 ppm (s, 9H); 13C NMR ([D6]DMSO): d=151.9,
150.6, 145.1, 142.7, 134.1, 130.6, 129.8, 128.4, 126.7, 123.2, 121.0,
120.8, 118.2, 113.6, 55.8, 51.9, ꢀ1.0 ppm (3C); HPLC purity 86.1%;
MS (ESI+) m/z 422 [M+H+, 35Cl2].
2-[1-[4-(2,4-Dichlorophenoxy)-3-methoxybenzyl]-1H-1,2,3-triazol-
4-yl]ethanol (8d): The title compound was prepared by following
General Procedure A with 4-butyn-1-ol as the alkyne (yellow oil,
395 mg, 100%). Purification by preparative HPLC provided the
pure material as pale-yellow oil (318 mg, 81% on a 1.0 mmol
1
scale). H NMR ([D6]DMSO): d=7.95 (s, 1H), 7.68 (d, J=2.7 Hz, 1H),
7.29 (dd, J=8.8, 2.5 Hz, 1H), 7.23 (d, J=1.9 Hz, 1H), 7.02 (d, J=
8.1 Hz, 1H), 6.88 (dd, J=8.2, 1.9 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H),
5.54 (s, 2H), 4.44 (s, 1H), 3.74 (s, 3H), 3.63 (t, J=6.9 Hz, 2H),
2.77 ppm (t, J=6.9 Hz, 2H); 13C NMR ([D6]DMSO): d=152.0, 150.6,
144.8, 142.7, 134.1, 129.8, 128.4, 126.7, 123.2, 122.6, 121.0, 120.8,
118.1, 113.5, 60.3, 55.9, 52.3, 29.2 ppm; HPLC purity 97.0%; MS
(ESI+) m/z 394 [M+H+, 35Cl2].
3-Chloro-4-(4-chloro-2-methoxyphenoxy)benzaldehyde (11): The
title compound was prepared by following a published proce-
dure.[48] To a stirred solution of 4-chloro-2-methoxyphenol (2.38 g,
15.0 mmol) in dry DMF (40 mL) was added 3-chloro-4-fluorobenzal-
dehyde (2.38 g, 15.0 mmol, 1.0 equiv) followed by Cs2CO3 (8.31 g,
25.5 mmol, 1.70 equiv). The mixture was stirred at 1008C for 16 h
under an Ar atmosphere, cooled to room temperature, diluted
with EtOAc, and poured into H2O. The phases were separated, and
the aqueous phase was extracted with EtOAc (3ꢂ100 mL). The
combined organic phases were washed with H2O (3ꢂ100 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to give the
crude material as a dark-green solid, which was subsequently puri-
fied by flash chromatography on silica gel (hexanes, then hexanes/
EtOAc 3:1–3:2) to obtain the title compound as a pale-yellow solid
(4.10 g, 92%). 1H NMR ([D6]DMSO): d=9.88 (s, 1H), 8.07 (d, J=
1.9 Hz, 1H), 7.77 (dd, J=8.5, 2.0 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H),
7.25 (d, J=8.6 Hz, 1H), 7.10 (dd, J=8.5, 2.4 Hz, 1H), 6.81 (d, J=
8.5 Hz, 1H), 3.76 ppm (s, 3H); 13C NMR ([D6]DMSO): d=190.7, 157.6,
151.8, 140.7, 131.6 (2C), 130.9, 130.0, 123.4, 122.2, 121.1, 115.8,
114.2, 56.4 ppm; HPLC purity 93.0%.
5-[(4-Butyl-1H-1,2,3-triazol-1-yl)methyl]-2-(2,4-dichlorophenoxy)-
phenol (9a): The title compound was prepared by following Gen-
eral Procedure B with 8a as the starting material. Purification by
preparative HPLC provided the pure material as a white crystalline
1
solid (84 mg, 43% on a 0.4 mmol scale). H NMR ([D6]DMSO): d=
9.89 (s, 1H), 7.89 (s, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.9,
2.6 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.76
(dd, J=8.2, 2.0 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.72 (s, 2H), 2.61 (t,
J=7.7 Hz, 2H), 1.57 (quin, J=7.6 Hz, 2H), 1.32 (sxt, J=7.3 Hz, 2H),
0.89 ppm (t, J=7.3 Hz, 3H); 13C NMR ([D6]DMSO): d=152.2, 148.9,
147.2, 141.6, 134.2, 129.6, 128.2, 126.2, 123.0, 122.0, 121.6, 119.1,
117.9, 116.5, 52.1, 31.1, 24.7, 21.7, 13.7 ppm; HPLC purity 99.7%;
MS (ESI+) m/z 392 [M+H+, 35Cl2]; HRMS (ESI+) calcd for
C19H20Cl2N3O2 392.0927 [M+H+, 35Cl2], found 392.0924.
2-(2,4-Dichlorophenoxy)-5-[(4-phenyl-1H-1,2,3-triazol-1-yl)me-
thyl]phenol (9b): The title compound was prepared by following
General Procedure B with 8b as the starting material. Purification
by preparative HPLC provided the pure material as a white crystal-
[3-Chloro-4-(4-chloro-2-methoxyphenoxy)phenyl]methanol (12):
The same procedure was applied as described for the synthesis of
compound 5 to give the title compound as pale-yellow oil (2.9 g,
100% on a 9.7 mmol scale). 1H NMR ([D6]DMSO): d=7.46 (s, 1H),
7.25 (d, J=2.3 Hz, 1H), 7.19 (dd, J=8.5, 1.9 Hz, 1H), 6.99 (dd, J=
8.6, 2.4 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.27
(t, J=5.7 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.79 ppm (s, 3H);
13C NMR ([D6]DMSO): d=151.3, 151.0, 142.9, 138.9, 129.0, 128.3,
1
line solid (53 mg, 26%). H NMR ([D6]DMSO): d=9.91 (s, 1H), 8.65
(s, 1H), 7.87–7.85 (m, 2H), 7.67 (d, J=2.6 Hz, 1H), 7.47–7.43 (m,
2H), 7.33 (tt, J=7.4, 1.2 Hz, 1H), 7.29 (dd, J=8.9, 2.6 Hz, 1H), 7.01
(d, J=8.2 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 6.84 (dd, J=8.2, 2.1 Hz,
1H), 6.67 (d, J=8.9 Hz, 1H), 5.60 ppm (s, 2H); 13C NMR ([D6]DMSO):
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ChemMedChem 2013, 8, 1138 – 1160 1152