1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1573
solvent afforded a crude product that was purified on a silica
gel column chromatography (chloroform as eluent) to give 5
(0.35 g, 37%), mp 98-99 °C (ligroin). 1H NMR (CDCl3): δ 2.23
(s, 3H), 2.55 (s, 3H), 3.76 (u, 2H), 4.54 (u, 2H), 5.21 (s, 1H),
6.89-7.32 (m, 9H), 7.94 (s, 1H). Anal. (C20H21N3O3 (351.40))
C, H, N.
1-{2-[r-(3-Flu or oph en yl)ph en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (6). Yield 54%, mp 121-123 °C (ligroin).
1H NMR (CDCl3): δ 2.55 (s, 3H), 3.77 (t, J ) 4.9 Hz, 2H), 4.54
(t, J ) 4.9 Hz, 2H), 5.23 (s, 1H), 6.80-6.97 (m, 3H), 7.06-7.15
(m, 2H), 7.17-7.31 (m, 4H), 7.94 (s, 1H). Anal. (C19H18FN3O3
(355.37)) C, H, N, F.
binding conformations of 1, it is suggested that novel
DAMNI derivatives bearing two hydrogen bond accep-
tors on the flexible tail could lead to more potent
derivatives.
Exp er im en ta l Section
Ch em istr y. Melting points (mp) were determined on a
Bu¨chi 510 apparatus and are uncorrected. Infrared spectra (IR)
were run on a Perkin-Elmer 1310 spectrophotometer. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded
on a Bruker AM-200 (200 MHz) FT spectrometer in the
indicated solvent. Chemical shifts are expressed in δ units
(ppm) from tetramethylsilane. Standard abbreviations were
used (s, d, t, q, dd, m, broad, u ) unresolved). Column chro-
matographies were packed with silica gel Merck 60 (70-230
mesh). Fluka aluminum oxide/TLC cards (aluminum oxide
precoated aluminum cards with fluorescent indicator at 254
nm), Fluka silica gel/TLC cards and Macherey-Nagel Alugram
Sil G/UV254 (silica gel precoated aluminum cards with fluo-
rescent indicator at 254 nm) were used for thin-layer chro-
matography (TLC). Developed plates were visualized by a
spectroline ENF 260C/F UV apparatus. Organic solutions were
dried over anhydrous sodium sulfate. Concentration and
evaporation of the solvent after reaction or extraction were
carried out on a rotary evaporator (Bu¨chi Rotavapor) operating
at reduced pressure. Elemental analyses were performed by
the laboratory of Dr. M. Zancato, Dipartimento di Scienze
Farmaceutiche, University of Padova (Italy). Analytical results
were within (0.4% of the theoretical values.
1-{2-[r-(3-Ch lor oph en yl)ph en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (7). Yield 67%, mp 99-101 °C (toluene/
1
ligroin). H NMR (CDCl3): δ 2.54 (s, 3H), 3.75 (t, J ) 5.0 Hz,
2H), 4.52 (t, J ) 5.0 Hz, 2H), 5.21 (s, 1H), 6.92-7.35 (m, 9H),
7.93 (s, 1H). Anal. (C19H18ClN3O3 (371.82)) C, H, N, Cl.
1-{2-[r-(3-Nitr op h en yl)p h en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (8). Yield 50%, thick oil. 1H NMR
(CDCl3): δ 2.57 (s, 3H), 3.80 (t, J ) 5.0 Hz, 2H), 4.58 (t, J )
5.0 Hz, 2H), 5.34 (s, 1H), 7.08-7.20 (m, 2H), 7.27-7.35 (m,
3H), 7.41-7.48 (m, 2H), 7.94 (s, 1H), 8.10 (m, 2H). Anal.
(C19H18N4O5 (382.38)) C, H, N.
1-{2-{r-[3-(1H -P yr r ol-1-yl)p h e n yl]p h e n ylm e t h oxy}-
eth yl}-2-m e th yl-5-n itr oim id a zole (9). Yield 28%, thick oil.
1H NMR (CDCl3): δ 2.56 (s, 3H), 3.80 (t, J ) 4.9 Hz, 2H), 4.56
(t, J ) 4.9 Hz, 2H), 5.28 (s, 1H), 6.33 (t, J ) 2.0 Hz, 2H), 6.98-
7.04 (m, 3H), 7.11-7.18 (m, 3H), 7.22-7.34 (m, 5H), 7.89 (s,
1H). Anal. (C23H22N4O3 (402.45)) C, H, N.
1-{2-[r-(4-Nitr op h en yl)p h en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim idazole (10). Yield 36%, mp 115-118 °C (toluene/
cyclohexane). 1H NMR (CDCl3): δ 2.54 (s, 3H), 3.80 (t, J )
5.0 Hz, 2H), 4.57 (t, J ) 5.0 Hz, 2H), 5.34 (s, 1H), 7.04-7.14
(m, 2H), 7.23-7.38 (m, 5H), 7.93 (s, 1H), 8.14 (m, 2H). Anal.
(C19H18N4O5 (382.38)) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of DAMNIs 2-4.
Exam ple. 1-{2-[r-(2-Meth ylph en yl)ph en ylm eth oxy]eth yl}-
2-m eth yl-5-n itr oim id a zole (2). A solution of phosphorus
tribromide (3.12 g, 0.012 mol) in anhydrous diethyl ether (15
mL) was dropped into a well-stirred solution of 2-methylben-
zhydrol (2.38 g, 0.012 mol) in the same solvent (60 mL). After
being stirred at room temperature for 4 h, reaction mixture
was quenched with 5% sodium acetate aqueous solution. The
organic layer was separated, washed with brine, and dried.
Removal of the solvent gave an oily residue that was used
without further purification. A mixture of bromide (0.004 mol),
1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (0.68 g, 0.004
mol), K2CO3 (1.66 g, 0.012 mol), and acetone (40 mL) was
refluxed for 7 days. After 24 and 48 h, 0.004 mol of bromide
and 0.012 mol of K2CO3 were added. The mixture was diluted
with water and extracted with ethyl acetate. Organic extracts
were washed with brine and dried. Removal of the solvent gave
a residue that was purified by silica gel column chromatog-
raphy (chloroform as eluent) to give 2 (0.38 g, 27%), mp 97-
1-{2-[r-(4-Aceta m id op h en yl)p h en ylm eth oxy]eth yl}-2-
m eth yl-5-n itr oim id a zole (11). Yield 36%, mp 115-118 °C
1
(toluene/cyclohexane). H NMR (CDCl3): δ 2.14 (s, 3H), 2.54
(s, 3H), 3.75 (t, J ) 4.9 Hz, 2H), 4.53 (t, J ) 4.9 Hz, 2H), 5.22
(s, 1H), 7.02-7.14 (m, 4H), 7.17-7.30 (m, 4H, 3H after D2O
exchange), 7.33-7.44 (m, 2H), 7.94 (s, 1H). IR (Nujol): ν 1630,
3200 cm-1. Anal. (C21H22N4O4 (394.43)) C, H, N.
1-{2-[r-(4-Met h oxyp h en yl)p h en ylm et h oxy]et h yl}-2-
m eth yl-5-n itr oim id a zole (12). Yield 76%, thick oil. 1H NMR
(CDCl3): δ 2.54 (s, 3H), 3.68-3.80 (m, 5H), 4.52 (t, J ) 4.9
Hz, 2H), 5.20 (s, 1H), 6.79 (d, J ) 8.6 Hz, 2H), 6.98-7.15 (m,
4H), 7.18-7.28 (m, 3H), 7.93 (s, 1H). Anal. (C20H21N3O4
(367.40)) C, H, N.
1-{2-[r-(3,5-Dim eth ylp h en yl)p h en ylm eth oxy]eth yl}-2-
m eth yl-5-n itr oim id a zole (13). Yield 32%, mp 112-113 °C
(ligroin). 1H NMR (CDCl3): δ 2.24 (s, 6H), 2.55 (s, 3H), 3.75
(t, J ) 4.9 Hz, 2H), 4.54 (t, J ) 4.9 Hz, 2H), 5.17 (s, 1H), 6.70
(u, 2H), 6.84 (u, 1H), 7.06-7.16 (m, 2H), 7.20-7.32 (m, 3H),
7.94 (s, 1H). Anal. (C21H23N3O3 (365.43)) C, H, N.
1
99 °C (ligroin). H NMR (CDCl3): δ 2.28 (s, 3H), 2.57 (s, 3H),
3.75 (t, J ) 4.9 Hz, 2H), 4.54 (t, J ) 4.9 Hz, 2H), 5.22 (s, 1H),
6.88-7.30 (m, 9H), 7.96 (s, 1H). Anal. (C20H21N3O3 (351.40))
C, H, N.
1-{2-[r-(2-Flu or oph en yl)ph en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (3). Yield 9%, mp 73-75 °C (ligroin). 1H
NMR (CDCl3): δ 2.54 (s, 3H), 3.80 (m, 2H), 4.54 (m, 2H), 5.62
(s, 1H), 6.90-7.32 (9H), 7.94 ppm (s, 1H). Anal. C19H18FN3O3
(355.37)) C, H, N, F.
1-{2-[r-(2-Ch lor oph en yl)ph en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (4). Yield 13%, mp 78 °C (ligroin). 1H
NMR (CDCl3): δ 2.51 (s, 3H), 3.79 (u, 2H), 4.54 (u, 2H), 5.72
(s, 1H), 7.09-7.40 (m, 9H), 7.94 (s, 1H). Anal. (C19H18ClN3O3
(371.82)) C, H, N, Cl.
1-{2-[r-(3,5-Diflu or op h en yl)p h en ylm et h oxy]et h yl}-2-
m eth yl-5-n itr oim id a zole (14). Yield 54%, mp 110-112 °C
1
(ligroin). H NMR (CDCl3): δ 2.55 (s, 3H), 3.78 (m, 2H), 4.55
(t, J ) 5.0 Hz, 2H), 5.20 (s, 1H), 6.60-6.70 (m, 3H), 7.02-7.16
(m, 2H), 7.22-7.33 (m, 3H), 7.95 (s, 1H). Anal. (C19H17F2N3O3
(373.36)) C, H, N, F.
1-{2-[r-(3,5-Dich lor op h en yl)p h en ylm eth oxy]eth yl}-2-
m eth yl-5-n itr oim id a zole (15). Yield 54%, mp 112-114 °C
1
(diethyl ether). H NMR (CDCl3): δ 2.55 (s, 3H), 3.76 (t, J )
5.0 Hz, 2H), 4.55 (t, J ) 5.0 Hz, 2H), 5.17 (s, 1H), 7.01 (m,
1H), 7.04-7.13 (m, 2H), 7.19-7.32 (m, 5H), 7.95 (s, 1H). Anal.
(C19H17Cl2N3O3 (406.27)) C, H, N, Cl.
1-{2-[r-(3,4-Dich lor op h en yl)p h en ylm eth oxy]eth yl}-2-
m eth yl-5-n itr oim id a zole (16). Yield 18%, thick oil. 1H NMR
(CDCl3): δ 2.54 (s, 3H), 3.76 (t, J ) 5.1 Hz, 2H), 4.55 (t, J )
5.1 Hz, 2H), 5.20 (s, 1H), 6.95 (m, 1H), 7.03-7.13 (m, 2H),
7.21-7.38 (m, 5H), 7.95 (s, 1H). Anal. (C19H17Cl2N3O3 (406.27))
C, H, N, Cl.
Gen er a l P r oced u r e for th e Syn th esis of 5-18. Ex-
a m p le. 1-{2-[r-(3-Meth ylp h en yl)p h en ylm eth oxy]eth yl}-
2-m eth yl-5-n itr oim id a zole (5). A mixture of the 3-methyl-
benzhydrol (1.98 g, 0.01 mol), 1-(2-hydroxyethyl)-2-methyl-5-
nitroimidazole (0.46 g, 0.0027 mol), p-toluenesulfonic acid
monohydrate (PTSA, 0.65 g, 0.0034 mol), and benzene (65 mL)
was refluxed for 4 h. Water that formed during reaction was
removed by azeotropic distillation by a Dean-Stark trap. After
cooling, the reaction mixture was concentrated to a small
volume and extracted with ethyl acetate. Combined organic
extracts were washed with brine and dried. Evaporation of the
1-{2-[r-(Naph th alen -2-yl)ph en ylm eth oxy]eth yl}-2-m eth -
yl-5-n itr oim id a zole (17). Yield 57%, thick oil. 1H NMR