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4.7.2.7. General procedure for the synthesis of imidazole alcohols
(10ae10h). A mixture of the -bromoketone (8aeh, 1 mmol, 1 eq),
ethanone (8g) according to the general procedure to afford 10g as a
white solid in 65% yield, 1H NMR (400 MHz, CD3OD):
7.63 (bs, 1H),
a
d
imidazole (3 mmol, 3 eq), and anhydrous K2CO3 (3 mmol, 3 eq) in
DMF (3 mL) was stirred at room temperature for 2e3 h. The reac-
tion mixture was diluted with H2O (10 mL) and extracted with
EtOAc (15 mL, twice). The combined organic phase was washed
sequentially with H2O (10 mL) and brine (10 mL). The combined
organic extracts were dried over Na2SO4, and evaporated. High-
vacuum drying gave crude 9aeh. A solution of crude 9aeh
(1 mmol, 1 eq) in methanol (4 mL) was added to a suspension of
sodium borohydride (1 mmol,1 eq) in anhydrous methanol (20 mL)
maintaining the temperature below 5 ꢃC under atmospheric pres-
sure. The resulting mixture was stirred at room temperature for 1 h
and then heated to 50 ꢃC for 1 h. After cooling to room temperature
the reaction mixture was concentrated and water (8 mL) was
added. The product was extracted with ethyl acetate (10 mL, twice).
The organic phase was dried over Na2SO4 and purified by flash
chromatography on silica gel using MeOHeEtOAc (6:94) as the
eluent to afford the imidazole alcohol (10ae10h); overall yields up
to 77%.
7.41e7.36 (m, 2H), 7.29e7.23 (m, 1H), 7.08 (bs, 1H), 6.93 (s, 1H),
5.75e5.69 (m, 1H), 4.69e4.61 (m, 1H), 4.49e4.42 (m, 1H) ppm.
4.7.2.15. 2-(1-Hydroxy-2-(1H-imidazol-1-yl)ethyl)phenol
(10h).
Synthesized from 2-bromo-1-(2-hydroxyphenyl)ethanone (8h)
according to the general procedure to afford 10h as a white solid in
70% yield, m.p. 149e152 ꢃC, IR (film): nmax: 3360, 2938, 1594, 1511,
1454, 1282, 820, 752 cmꢂ1, 1H NMR (400 MHz, CDCl3):
d 7.42 (bs,
1H), 7.14 (td, 1H, J ¼ 7.6, J ¼ 1.5 Hz), 7.05e7.01 (m, 1H), 6.94 (bs, 1H),
6.90 (s, 1H), 6.84e6.77 (m, 2H), 5.03e4.97 (m, 1H), 4.23e4.11 (m,
2H) ppm. 13C NMR (100 MHz, CD3OD):
d 153.9, 137.5, 128.2, 127.2,
126.8, 126.3, 120.2, 119.2, 114.6, 68.7, 52.3 ppm. ESI-TOF-HRMS: m/z
calcd for (MþH) C11H12N2O2 205.0977 found 205.0984.
4.7.2.16. 1-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol
(10i) [115,116]. Synthesized from 2-bromo-1-(2,4-dichlorophenyl)
ethanone (8a) and 1H-1,2,4-triazole according to the general pro-
cedure to afford 10i as a white solid in 74% yield, 1H NMR (400 MHz,
4.7.2.8. 1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (10a)
[110]. Synthesized from 2-bromo-1-(2,4-dichlorophenyl)ethanone
(8a) according to the general procedure to afford 10a as a white
CD3OD):
d
8.43 (s, 1H), 7.96 (s, 1H), 7.56 (d, 1H, J ¼ 8.2 Hz), 7.47 (d,
1H, J ¼ 6.0 Hz) 7.36 (dd, 1H, J ¼ 8.3, J ¼ 2.1 Hz), 5.41e5.36 (m, 1H),
4.51e4.44 (m, 1H), 4.38e4.30 (m, 1H) ppm.
solid in 75% yield, 1H NMR (400 MHz, CDCl3):
d 7.61e7.57 (m, 1H),
7.44e7.39 (m, 2H), 7.34e7.30 (m, 1H), 6.93 (s, 1H), 6.92e6.87 (m,
1H), 5.30e5.25 (m, 1H), 4.28e4.20 (m, 1H), 3.94e3.85 (m, 1H) ppm.
4.7.2.17. 1-(2,4-Dichlorophenyl)-2-(1H-1,2,3-triazol-5-yl)ethanol
(13). Activated zinc powder (5.75 mmol, 1.15 eq) was placed in a
flame-dried round-bottom flask (50 mL) fitted with a magnetic stir
bar. 2,4-Dichlorobenzaldehyde (5 mmol, 1 eq) and propargyl-
bromide (5.75 mmol, 1.15 eq) were added. The resulting mixture
was vigorously stirred for 1 h at room temperature. After reaction
completion, sat. aq. soln of NH4Cl was poured into the mixture and
stirred for several minutes. Diethyl ether was added and the
organic layer was separated and dried over anhydrous MgSO4. The
residue was purified by flash chromatography on silica gel giving 1-
phenylpropargylalcohol (12). To a stirred solution of 12 (1 mmol,
1 eq) and CuI (0.05 mmol, 0.05 eq) in DMF/MeOH solution (2 mL
9:1) under an argon atmosphere was added trimethylsilyl azide
(1.5 mmol, 1.5 eq). The resulting solution was stirred at 100 ꢃC for
10e12 h. After consumption of ethynyl substrate, the mixture was
cooled to room temperature and the precipitate was filtered off and
the solution concentrated under reduced pressure. The crude res-
idue was purified by silica gel column chromatography to afford 13
as an oil in 60% yield. IR (film): nmax: 3142, 2932, 2828, 1588, 1560,
4.7.2.9. 2-(1H-imidazol-1-yl)-1-phenylethanol
(10b)
[111].
Synthesized from 2/bromo/1/phenylethanone (8b) according to the
general procedure to afford 10b as a white solid in 70% yield, 1H
NMR (400 MHz, CDCl3):
d 7.43e7.29 (m, 6H), 7.02 (bs, 1H), 6.92 (s,
1H), 4.98e4.93 (m, 1H), 4.20e4.08 (m, 2H) ppm.
4.7.2.10. 1-(2-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanol
(10c)
[112]. Synthesized from 2-bromo-1-(2-chlorophenyl)ethanone
(8c) according to the general procedure to afford 10c as a white
solid in 72% yield, 1H NMR (400 MHz, CDCl3):
d 7.60e7.54 (m, 2H),
7.40e7.37 (m, 1H), 7.35e7.27 (m, 2H), 7.02 (bs, 1H), 6.98 (s, 1H), 5.35
(dd, 1H, J ¼ 7.8, J ¼ 2.2 Hz), 4.34e4.27 (m, 1H), 4.03e3.96 (m, 1H)
ppm.
4.7.2.11. 1-(3,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (10d)
[113,114]. Synthesized from 2-bromo-1-(3,4-dichlorophenyl)etha-
none (8d) according to the general procedure to afford 10d as a
1467, 1069, 1043, 818, 789 cmꢂ1. 1H NMR (400 MHz, CD3OD):
d 8.20
white solid in 75% yield, 1H NMR (400 MHz, CDCl3):
d 7.49e7.41 (m,
(s, 1H), 7.54e7.47 (m, 2H), 7.38e7.33 (m, 1H), 5.37e5.30 (m, 1H),
3H), 7.14 (dd, 1H, J ¼ 8.3, J ¼ 2.0 Hz), 7.01 (bs, 1H), 6.91 (s, 1H), 4.95
3.39e3.33 (m, 1H), 3.20e3.12 (m, 1H) ppm. 13C NMR (100 MHz,
(m, 1H), 4.18e4.01 (m, 2H) ppm.
CD3OD):
d 140.5, 133.2, 132.1, 128.5, 128.4, 127.0, 68.5, 32.4 ppm.
ESI-TOF-HRMS: m/z calcd for (MþH) C10H9N3Cl2O 258.0201 found
4.7.2.12. 1-(3-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanol
(10e)
258.0191.
[113,114]. Synthesized from 2-bromo-1-(3-chlorophenyl)ethanone
(8e) according to the general procedure to afford 10a as a white
solid in 77% yield, 1H NMR (400 MHz, CDCl3):
d 7.42 (bs, 1H), 7.38 (s,
4.7.2.18. 1-(2,4-Dichlorophenyl)-1H-imidazole
(15)
[79].
1H), 7.34e7.28 (m, 2H), 7.22e7.16 (m, 1H), 6.99 (bs, 1H), 6.91 (s, 1H),
4.96e4.90 (m, 1H), 4.18e4.03 (m, 2H) ppm.
Synthesized from 2,4-dichloro-1-fluorobenze and 1-(trime-
thylsilyl)-1H-imidazole, according to reported procedure [79] to
afford 15 as a solid in 70% yield. 1H NMR (400 MHz, CDCl3):
d 7.70 (s,
4.7.2.13. 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol (10f) [76].
Synthesized from 2-bromo-1-(4-chlorophenyl)ethanone (8f) ac-
cording to the general procedure to afford 10f as a white solid in
1H), 7.60 (d, 1H, J ¼ 2.2 Hz), 7.40 (dd, 1H, J ¼ 8.3, J ¼ 2.2 Hz), 7.32 (d,
1H, J ¼ 8.4 Hz), 7.25 (bs, 1H), 7.16 (bs, 1H) ppm.
68% yield, 1H NMR (400 MHz, CD3OD):
d 7.50 (bs, 1H), 7.35e7.27 (m,
4H), 7.07 (bs, 1H), 6.90 (s, 1H), 4.95e4.90 (m, 1H), 4.26e4.12 (m, 2H)
Disclosure of potential conflict of interest
ppm.
B.J. Van den Eynde is a cofounder of and received consultancy
fees from iTeos Therapeutics. No potential conflicts of interest were
disclosed by the other authors.
4.7.2.14. 1-(2,6-Dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (10g)
[113,114]. Synthesized
from
2-bromo-1-(2,6-dichlorophenyl)