High functionalization of 5-nitro-1h-imidazole derivatives: The TDAE approach

Article abstract of DOI:10.3390/molecules16086883

We report herein the synthesis of substituted 2-[4-(1,2-dimethyl-5-nitro- 1Himidazol- 4-yl)phenyl]-1-arylethanols, ethyl 3-[4-(1,2-dimethyl-5-nitro-1H- imidazol-4-yl)- phenyl]-2-hydroxypropanoate and 2-[4-(1,2-dimethyl-5-nitro-1H- imidazol-4-yl)benzyl]-2-

Full text of DOI:10.3390/molecules16086883

Molecules 2011, 16, 6883-6893; doi:10.3390/molecules16086883
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
High Functionalization of 5-Nitro-1H-imidazole Derivatives:
The TDAE Approach
Thierry Juspin, Laura Zink, Maxime D. Crozet, Thierry Terme and Patrice Vanelle *
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d’Aix-Marseille I, II
et III – CNRS, UMR 6264: Laboratoire Chimie Provence, 27 Bd Jean Moulin, 13385 Marseille Cedex
05, France
* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univmed.fr;
Tel.: +33-4-91835573; Fax: +33-4-86136822.
Received: 20 July 2011; in revised form: 5 August 2011 / Accepted: 8 August 2011 /
Published: 12 August 2011
Abstract: We report herein the synthesis of substituted 2-[4-(1,2-dimethyl-5-nitro-1H-
imidazol-4-yl)phenyl]-1-arylethanols, ethyl 3-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)-
phenyl]-2-hydroxypropanoate and 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)benzyl]-2-
hydroxy-acenaphthylen-1(2H)-one from the reactions of 4-[4-(chloromethyl)phenyl]-1,2-
dimethyl-5-nitro-1H-imidazole with various aromatic carbonyl and α-carbonyl ester
derivatives using tetrakis(dimethylamino)ethylene (TDAE) methodology.
Keywords: TDAE; 5-nitro-1H-imidazole; arylethanol; carbonyl derivatives
1. Introduction
The 5-nitroimidazole scaffold is well-known for displaying major anti-infectious activities [1-6].
Several 5-nitroimidazole-containing active principles such as metronidazole, secnidazole and
ornidazole are commonly used in medecine. These chemotherapeutic agents inhibit the growth of both
anaerobic bacteria and some anaerobic protozoa [7]. Nowadays, the most clinically used
drug-compounds for the treatment of both infections caused by protozoa such as Trichomonas
vaginalis, Entamœba histolytica, Giardia intestinalis and infections induced by anaerobic bacteria is
metronidazole. However, the 5-nitroimidazoles have been found to possess a high mutagenic activity
in prokaryotic micro-organisms. A nitroimidazole possessing good pharmacological activities with no

Molecules 2011, 16
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mutagenicity [8] would be of great interest, not only from a safety point of view, but would also
provide a basis for further investigations on the mechanism(s) involved in their mutagenicity.
Moreover, emergence of metronidazole-resistant Trichomonas vaginalis has resulted in decreased
success of current therapies [9,10]. These refractory cases are usually treated with higher doses of
metronidazole, which leads in turn to an increase in the occurrence of side effects [10,11], so
alternative curative therapies are needed.
In continuation of our program directed towards the study of electron transfer reactions in heterocyclic
series [12-14], we recently investigated SRN1 (unimolecular radical nucleophilic substitution) reactions
of 4(5)-[4-(chloromethyl)phenyl]-1,2-dimethyl-5(4)-nitro-1H-imidazoles, involving long distance (six
bonds) between the electron-withdrawing and leaving groups (LD-SRN1). The nitronate anions reacted
by the substitution at the chloromethyl group and the reaction was very probably mediated by a SRN1
mechanism [15].
Tetrakis(dimethylamino)ethylene (TDAE) is a reducing agent which reacts with halogenated
derivatives to generate an anion under mild conditions via two sequential transfers of one electron [16-18].
We have shown that from o- or p-nitrobenzyl chloride, TDAE could generate a nitrobenzyl carbanion
which is able to react with various electrophiles [19]. Since 2003, and using this strategy, we have
developed several reactions between nitrobenzylic, heterocyclic or quinonic substrates and a series
of carbonylated electrophiles such as aldehydes [19-22], ketones [19-22], α-ketoesters [23-25],
α-ketolactams [26], α-diketones [27,28] and diethyl ketomalonate [23-25] leading to the corresponding
alcohol adducts. In continuation of our program directed toward the study of electron transfer reactions
of bioreductive alkylating agents and the preparation of new and potentially safer nitroimidazoles, we
report herein the synthesis of some highly functionalized 5-nitro-1H-imidazoles from the reaction of
4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole with various aromatic carbonyl and
α-carbonyl ester derivatives using TDAE methodology.
2. Results and Discussion
4-[4-(Chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole (1) was prepared from the
previously described [4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]methanol [29], according to a
classical chlorination reaction with SOCl2 [20] (Scheme 1).
Scheme 1. Preparation of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole (1).
Cl
HO
HO
OH
OH
Br
O2N
B
N
N
SOCl2
rt, 16h
N
O2N
O2N
N
N
N
Pd(PPh3)4
DME, EtOH
Na2CO3
MW 150 W, 1 h
1 100%
The reaction of 1 with 3 equivalents of various aromatic aldehydes 2a-j in the presence of TDAE at
–20 °C for 1 h, followed by 24 h at rt (Scheme 2), led to the corresponding alcohol derivatives 3a-j in
moderate to good yields (24–78%) as shown in Table 1.

Molecules 2011, 16
Scheme 2. Reaction of 1 with various carbonyl compounds using TDAE strategy.
6885
R1
HO
R2
Cl
O
N
N
TDAE
+
O2N
O2N
R1
R2
N
N
DMF, -20°C
3a-m
1
2a-m
Table 1. Products’ yields from the reaction of 1 with various carbonyl compounds using
TDAE strategy.
Carbonyl compound
Product a
Product number Yield (%) b
HO
NO2
O
NO2
H
2a
3a
3b
69
46
N
O2N
N
NO2
HO
NO2
O
H
2b
N
O2N
N
O2N
HO
O2N
O
H
2c
3c
37
N
O2N
N
HO
Cl
O
Cl
2d
2e
3d
3e
24
60
H
N
N
O2N
HO
Br
O
H
Br
N
N
O2N

Molecules 2011, 16
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Table 1. Cont.
Carbonyl compound
Product a
Product number Yield (%) b
Br
HO
Br
O
H
2f
2g
2h
3f
3g
3h
68
78
30
N
O2N
N
HO
CN
O
H
CN
N
O2N
O2N
N
HO
OCH3
O2N
OCH3
O
H
OCH3
N
OCH3
O2N
N
HO
CF3
O
2i
2j
3i
3j
45
25
42
CF3
N
H
O2N
N
HO
CH3
O
H
CH3
N
O2N
N
HO
CO2CH2CH3
O
H
O
O CH2CH3
2k
3k
N
O2N
N
O
O
O
OH
2l
3l
45
N
O2N
N

Molecules 2011, 16
6887
Table 1. Cont.
Product a
NO2
Carbonyl compound
Product number Yield (%) b
HO
O
2mc
3m
64
NO2
N
O2N
N
a
All the reactions are performed using 3 equivalents of carbonyl compounds 2a-l, 1 equivalent of
chloride 1 and 1 equivalent of TDAE in anhydrous DMF stirred at –20 °C for 1 h and then warmed
up to rt for 24 h. b % Yield relative to chloride 1. c The reaction is performed using 3 equivalents of
carbonyl compounds 2m, 1 equivalent of chloride 1 and 1 equivalent of TDAE in anhydrous DMF
stirred at –20 °C for 1 h and then warmed up to 80 °C for 24 h.
High yields were obtained with p-nitrobenzaldehyde (2a), o-bromobenzaldehyde (2f) and
p-cyanobenzaldehyde (2g), whereas p-chlorobenzaldehyde (2d), p-methylbenzaldehyde (2j) and
6-nitroveratraldehyde (2h) produced low yields. In summary, the difference of yields seems explained
by the electronic effects, whereby the electron-withdrawing groups furnished the best yields, the
electron-donating groups furnished the lowest yields and the halogen groups led to varied yields. The
different yields with halobenzaldehydes could be explained by some purification problems
encountered with the compound 3d. With nitrobenzaldehydes, steric hindrance could explain the
difference between the o- and m-nitrobenzaldehyde (37% versus 46%). Moreover, after the reaction
with aromatic aldehydes, we have investigated the reaction of 1 with α-keto-ester derivatives such as
ethyl glyoxylate (2k), with an α-diketone such as acenaphthenedione (2l) and with a ketone like
p-nitroacetophenone (2m). The reaction of 1 in the presence of TDAE with these electrophiles
furnished the corresponding hydroxyl derivatives 3k-m in moderate to good yields (42–64%),
as shown in Table 1. As observed in the p-nitrobenzyl series [19], due to its poor reactivity,
p-nitroacetophenone (2l) needed heating for 24 h at 80 °C to drive the reaction to completion.
3. Experimental
Melting points were determined on Büchi B-540 and are uncorrected. Elemental analyses were
1
carried out at the Spectropole, Faculté des Sciences et Techniques de Saint-Jérome. Both H- and
1
13C-NMR spectra were determined on Bruker ARX 200 spectrometer. The H chemical shifts were
13
reported as parts per million downfield from tetramethylsilane (Me4Si), and the C chemical shifts
were referenced to the solvent peak of CDCl3 (76.9 ppm). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, 230–400 mesh). Thin-layer chromatography was
performed with silica gel Merck 60F-254 (0.25 mm layer thickness).
4-[4-(Chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole (1): This compound was prepared
from [4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]methanol [29], according to a classical
chlorination reaction with SOCl2 [20]. Yellow solid; mp 120 °C (isopropyl alcohol); 1H-NMR (CDCl3)
δ: 2.51 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.62 (s, 2H, CH2), 7.45 (d, J = 8.1 Hz, 2H, 2xCH), 7.76 (d,

Molecules 2011, 16
6888
13
J = 8.1 Hz, 2H, 2xCH); C-NMR (CDCl3) δ: 14.0 (CH3), 34.2 (CH3), 45.8 (CH2), 128.2 (2xCH),
129.9 (2xCH), 131.6 (C), 138.6 (C), 142.5 (C), 148.3 (C). The C-nitro was not observed in this
experiment; Anal. Calcd for C12H12N3O2Cl: C, 54.25; H, 4.55; N, 15.82. Found: C, 54.31; H, 4.61;
N, 15.97.
General Procedure for the Reaction of Chloride 1 and Aromatic Carbonyl Derivatives 2a-m Using
TDAE
A solution of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole (1, 0.15 g, 0.56 mmol,
1 equiv.) in anhydrous DMF (6 mL) and the corresponding carbonyl derivative 2a-m (1.68 mmol,
3 equiv.) were placed under nitrogen at −20 °C in a two-necked flask equipped with a silica-gel drying
tube and a nitrogen inlet. The solution was stirred and kept at this temperature for 30 min and then the
TDAE (0.11 g, 0.56 mmol, 1 equiv.) was added dropwise via a syringe. The solution was vigorously
stirred at −20 °C for 1 h and then warmed up to room temperature for 24 h [heating for 24 h at 80 °C in
the case of p-nitroacetophenone (2m)]. After this time TLC analysis (CH2Cl2/EtOAc (7/3) as eluent)
clearly showed that 1 was totally consumed. The orange-red turbid solution was filtered and
rinsed with toluene. The organic layer was washed with H2O (3 × 40 mL) and dried over MgSO4.
Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica
gel chromatography [CH2Cl2/EtOAc (7:3)] gave the corresponding arylethanol or α-hydroxyester
derivatives.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-(4-nitrophenyl)ethanol (3a): Beige solid; mp
1
200 °C (isopropyl alcohol); H-NMR (CDCl3) δ: 2.60 (s, 3H, CH3), 3.02–3.10 (m, 2H, CH2), 3.95 (s,
3H, CH3), 5.04 (dd, J = 5.3 Hz et J = 7.9 Hz, 1H, CH), 7.26 (d, J = 8.0 Hz, 2H, 2xCH), 7.52 (d,
13
J = 8.7 Hz, 2H, 2xCH), 7.73 (d, J = 8.0 Hz, 2H, 2xCH), 8.20 (d, J = 8.7 Hz, 2H, 2xCH); C-NMR
(CDCl3) δ: 13.9 (CH3), 34.1 (CH3), 45.1 (CH2), 72.7 (CH), 123.3 (2xCH), 127.3 (2xCH), 128.9
(2xCH), 129.3 (2xCH), 129.9 (C), 139.7 (C), 142.3 (C), 146.6 (C), 149.2 (C), 153.7 (C). The C-nitro
was not observed in this experiment; Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found:
C, 59.68; H, 4.92; N, 14.41.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-(3-nitrophenyl)ethanol (3b): Yellow solid; mp
1
225 °C (ethyl alcohol); H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 2.94–2.99 (m, 2H, CH2), 3.81 (s,
3H, CH3), 4.96–5.04 (m, 1H, CH), 5.67–5.69 (m, 1H, OH), 7.27 (d, J = 8.2 Hz, 2H, 2xCH), 7.58 (d,
J = 8.2 Hz, 2H, 2xCH), 7.64 (s, 1H, CH), 7.79 (d, J = 7.7 Hz, 1H, CH), 8.09 (d, J = 8.2 Hz, 1H, CH),
13
8.22 (s, 1H, CH); C-NMR (DMSO-d6) δ: 13.9 (CH3), 34.1 (CH3), 45.2 (CH2), 72.5 (CH), 120.7
(CH), 121.9 (CH), 128.9 (2xCH), 129.3 (2xCH), 129.6 (CH), 130.1 (C), 132.9 (CH), 134.6 (C), 139.8
(C), 142.4 (C), 147.8 (C), 148.2 (C), 149.2 (C); Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N,
14.65. Found: C, 59.25; H, 4.78; N, 14.36.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-(2-nitrophenyl)ethanol (3c): Orange solid; mp
216 °C (ethyl alcohol); 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 2.80 (dd, J = 8.1 Hz et J = 13.0 Hz,
1H, CH2), 3.04 (dd, J = 8.1 Hz and J = 13.0 Hz, 1H, CH2), 3.82 (s, 3H, CH3), 5.25 (m, 1H, CH), 5.66
(d, J = 4.9 Hz, 1H, OH), 7.31 (d, J = 8.1 Hz, 2H, 2xCH), 7.53 (t, J = 8.1 Hz, 1H, CH), 7.63 (d,

Molecules 2011, 16
6889
J = 8.1 Hz, 2H, 2xCH), 7.75 (t, J = 8.1 Hz, 1H, CH), 7.86 (d, J = 8.1 Hz, 1H, CH), 7.94 (d, J = 8.1 Hz,
1H, CH); 13C-NMR (DMSO-d6) δ: 14.0 (CH3), 34.1 (CH3), 44.7 (CH2), 69.2 (CH), 124.0 (CH), 128.4
(CH), 128.5 (CH), 129.1 (4xCH), 130.2 (C), 133.6 (CH), 134.7 (C), 140.2 (C), 140.8 (C), 142.5 (C),
147.5 (C), 149.3 (C); Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C, 58.83; H,
4.82; N, 14.01.
1-(4-Chlorophenyl)-2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]ethanol (3d): Pink solid; mp
1
199 °C (isopropyl alcohol); H-NMR (DMSO-d6): 2.45 (s, 3H, CH3), 2.90 (d, J = 6.6 Hz, 2H, CH2),
3.81 (s, 3H, CH3), 4.77–4.85 (m, 1H, CH), 5.44 (d, J = 4.8 Hz, 1H, OH), 7.23 (d, J = 8.1 Hz, 2H,
13
2xCH), 7.35 (bs, 4H, 4xCH), 7.57 (d, J = 8.1 Hz, 2H, 2xCH); C-NMR (DMSO-d6) δ: 13.9 (CH3),
34.1 (CH3), 45.4 (CH2), 72.9 (CH), 128.0 (4xCH), 128.9 (2xCH), 129.2 (2xCH), 130.0 (C), 131.3 (C),
134.6 (C), 140.2 (C), 142.5 (C), 144.8 (C), 149.3 (C); Anal. Calcd for C19H18ClN3O3: C, 61.38; H,
4.88; N, 11.30. Found: C, 60.85; H, 4.94; N, 11.03.
1-(4-Bromophenyl)-2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]ethanol (3e): White solid; mp
211 °C (isopropyl alcohol); 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 2.90 (d, J = 6.5 Hz, 2H, CH2),
3.81 (s, 3H, CH3), 4.80 (q, J = 5.3 Hz, 1H, CH), 5.42 (d, J = 4.8 Hz, 1H, OH), 7.23 (d, J = 8.2 Hz, 2H,
2xCH), 7.29 (d, J = 8.4 Hz, 2H, 2xCH), 7.49 (d, J = 8.4 Hz, 2H, 2xCH), 7.57 (d, J = 8.2 Hz, 2H,
13
2xCH); C-NMR (DMSO-d6) δ: 13.9 (CH3), 34.1 (CH3), 45.3 (CH2), 72.9 (CH), 119.8 (C), 128.4
(2xCH), 128.9 (2xCH), 129.2 (2xCH), 130.0 (C), 130.9 (2xCH), 134.6 (C), 140.2 (C), 142.5 (C), 145.2
(C), 149.3 (C); Anal. Calcd for C19H18BrN3O3: C, 54.82; H, 4.36; N, 10.09. Found: C, 54.78; H, 4.42;
N, 9.97.
1-(2-Bromophenyl)-2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]ethanol (3f): Yellow solid;
1
mp 228 °C (isopropyl alcohol); H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 2.59 (dd, J = 9.0 Hz et
J = 13.7 Hz, 1H, CH2), 2.98 (dd, J = 9.0 Hz and J = 13.7 Hz, 1H, CH2), 3.82 (s, 3H, CH3), 5.00–5.09
(m, 1H, CH), 5.56 (d, J = 4.9 Hz, 1H, OH), 7.20 (t, J = 7.7 Hz, 1H, CH), 7.32 (d, J = 8.0 Hz, 2H,
13
2xCH), 7.41 (t, J = 7.7 Hz, 1H, CH), 7.56 (s, 1H, CH), 7.62 (d, J = 8.0 Hz, 3H, 3xCH); C-NMR
(DMSO-d6) δ: 13.9 (CH3), 34.1 (CH3), 43.9 (CH2), 72.6 (CH), 121.3 (C), 127.9 (CH), 128.0 (CH),
129.0 (5xCH), 130.1 (C), 132.3 (CH), 134.7 (C), 140.4 (C), 142.5 (C), 144.7 (C), 149.3 (C); Anal.
Calcd for C19H18BrN3O3: C, 54.82; H, 4.36; N, 10.09. Found: C, 54.70; H, 4.44; N, 9.95.
4-{2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-hydroxyethyl}benzonitrile (3g): Yellow
1
solid; mp 208 °C (isopropyl alcohol); H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 2.91-2.92 (m, 2H,
CH2), 3.81 (s, 3H, CH3), 4.87–4.96 (m, 1H, CH), 5.60 (d, J = 4.9 Hz, 1H, OH), 7.24 (d, J = 8.1 Hz, 2H,
2xCH), 7.56 (t, J = 8.1 Hz, 4H, 4xCH), 7.77 (d, J = 8.1 Hz, 2H, 2xCH); 13C-NMR (DMSO-d6) δ: 13.9
(CH3), 34.1 (CH3), 45.1 (CH2), 73.0 (CH), 109.6 (C), 119.2 (C), 127.1 (2xCH), 128.9 (2xCH), 129.2
(2xCH), 130.1 (C), 132.1 (2xCH), 134.6 (C), 139.8 (C), 142.5 (C), 149.3 (C), 151.6 (C); Anal. Calcd
for C20H18N4O3: C, 66.29; H, 5.01; N, 15.46. Found: C, 66.17; H, 5.07; N, 15.22.
1-(4,5-Dimethoxy-2-nitrophenyl)-2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]ethanol (3h): Black
1
solid; mp 234 °C (acetonitrile); H-NMR (DMSO-d6) δ: 2.46 (s, 3H, CH3), 2.81 (dd, J = 7.9 Hz et
J = 13.4 Hz, 1H, CH2), 3.05 (dd, J = 2.1 Hz and J = 13.4 Hz, 1H, CH2), 3.83 (s, 3H, CH3), 3.84 (s, 3H,

Molecules 2011, 16
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CH3), 3.86 (s, 3H, CH3), 5.37–5.45 (m, 1H, CH), 5.61 (d, J = 4.9 Hz, 1H, OH), 7.29–7.34 (m, 3H,
3xCH), 7.59–7.65 (m, 3H, 3xCH); 13C-NMR (DMSO-d6) δ: 14.0 (CH3), 34.1 (CH3), 44.5 (CH2), 56.2
(2xCH3), 69.1 (CH), 107.5 (CH), 109.9 (CH), 129.0 (2xCH), 129.2 (2xCH), 130.2 (C), 134.7 (C),
136.8 (C), 139.1 (C), 140.3 (C), 142.6 (C), 147.4 (C), 149.3 (C), 153.3 (C); Anal. Calcd for
C21H22N4O7: C, 57.01; H, 5.01; N, 12.66. Found: C, 56.81; H, 4.95; N, 12.50.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]ethanol (3i): Yellow
solid; mp 195 °C (isopropyl alcohol); 1H-NMR (CDCl3) δ: 2.51 (s, 3H, CH3), 3.01–3.06 (m, 2H, CH2),
3.91 (s, 3H, CH3), 4.96 (dd, J = 5.5 Hz and J = 7.8 Hz, 1H, CH), 7.24 (d, J = 7.8 Hz, 2H, 2xCH), 7.46
(d, J = 8.2 Hz, 2H, 2xCH), 7.60 (d, J = 8.2 Hz, 2H, 2xCH), 7.70 (d, J = 8.2 Hz, 2H, 2xCH); 13C-NMR
(CDCl3) δ: 13.9 (CH3), 34.1 (CH3), 45.3 (CH2), 73.0 (CH), 124.6 (q, J = 272 Hz, C), 124.9 (q,
J = 3.5 Hz, CH), 125.0 (CH), 126.9 (2xCH), 127.6 (q, J = 31.5 Hz, C), 129.0 (2xCH), 129.2 (2xCH),
130.0 (C), 134.7 (C), 140.1 (C), 142.5 (C), 149.3 (C), 150.6 (C); Anal. Calcd for C20H18F3N3O3: C,
59.26; H, 4.48; N, 10.37. Found: C, 59.26; H, 4.81; N, 10.30.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-1-p-tolylethanol (3j): Yellow solid; mp 155 °C
(isopropyl alcohol); 1H-NMR (CDCl3) δ: 2.16 (bs, 1H, OH), 2.34 (s, 3H, CH3), 2.50 (s, 3H, CH3), 3.05
(d, J = 6.7 Hz, 2H, CH2), 3.89 (s, 3H, CH3), 4.88 (t, J = 6.7 Hz, 1H, CH), 7.14 (d, J = 8.0 Hz, 2H,
13
2xCH), 7.25 (d, J = 8.0 Hz, 4H, 4xCH), 7.69 (d, J = 8.0 Hz, 2H, 2xCH); C-NMR (CDCl3) δ: 14.1
(CH3), 21.1 (CH3), 34.1 (CH3), 45.9 (CH2), 75.0 (CH), 125.8 (2xCH), 129.1 (2xCH), 129.2 (2xCH),
129.6 (2xCH), 130.0 (C), 134.7 (C), 137.2 (C), 139.7 (C), 140.8 (C), 143.5 (C), 148.3 (C); Anal. Calcd
for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C, 68.36; H, 6.16; N, 11.90.
Ethyl 3-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-2-hydroxypropanoate (3k): Yellow solid;
1
mp 99 °C (isopropyl alcohol); H-NMR (CDCl3) δ: 1.28 (t, J = 7.1 Hz, 3H, CH3), 2.55 (s, 3H, CH3),
3.02 (dd, J = 6.7 Hz and J = 13.9 Hz, 1H, CH2), 3.17 (dd, J = 4.6 Hz and J = 13.9 Hz, 1H, CH2), 3.91
(s, 3H, CH3), 4.22 (q, J = 7.1 Hz, 2H, CH2), 4.46 (dd, J = 4.6 Hz and J = 6.7 Hz, 1H, CH), 7.31 (d,
J = 7.9 Hz, 2H, 2xCH), 7.72 (d, J = 8.2 Hz, 2H, 2xCH); 13C-NMR (CDCl3) δ: 14.2 (CH3), 34.5 (CH3),
40.4 (CH2), 61.9 (CH2), 70.9 (CH3), 77.2 (CH), 126.8 (C), 129.6 (2xCH), 129.8 (2xCH), 134.1 (C),
139.4 (C), 139.8 (C), 147.7 (C), 173.9 (C); Anal. Calcd for C16H19N3O5: C, 57.65; H, 5.75; N, 12.61.
Found: C, 57.74; H, 5.87; N, 12.65.
2-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)benzyl]-2-hydroxyacenaphthylen-1(2H)-one (3l): Yellow
solid; mp 211 °C (isopropyl alcohol); 1H-NMR (DMSO-d6) δ: 2.41 (s, 3H, CH3), 3.17 (d, J = 13.2 Hz,
1H, CH2), 3.41 (d, J = 13.2 Hz, 1H, CH2), 3.77 (s, 3H, CH3), 6.99 (d, J = 7.5 Hz, 2H, 2xCH), 7.12 (bs,
1H, OH), 7.33–7.40 (m, 3H, 3xCH), 7.63–7.77 (m, 2H, 2xCH), 7.84 (d, J = 8.4 Hz, 1H, CH), 7.94 (d,
13
J = 7.0 Hz, 1H, CH), 8.19 (d, J = 8.1 Hz, 1H, CH); C-NMR (DMSO-d6) δ: 13.7 (CH3), 34.2 (CH3),
42.9 (CH2), 79.8 (C), 121.3 (2xCH), 125.1 (CH), 128.5 (2xCH), 128.7 (2xCH), 129.9 (CH), 130.0
(2xCH), 130.2 (C), 131.0 (C), 132.0 (C), 134.6 (C), 137.0 (C), 140.4 (C), 140.8 (C), 141.7 (C), 149.1
(C), 205.3 (C); Anal. Calcd for C24H19N3O4: C, 69.72; H, 4.63; N, 10.16. Found: C, 69.41; H, 4.73;
N, 10.13.

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1-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-2-(4-nitrophenyl)propan-2-ol (3m): Orange solid;
1
mp 179 °C (acetonitrile); H-NMR (CDCl3) δ: 1.60 (s, 3H, CH3), 2.51 (s, 3H, CH3), 3.12 (dd,
J = 13.2 Hz and J = 18.3 Hz, 2H, CH2), 3.90 (s, 3H, CH3), 7.06 (d, J = 8.3 Hz, 2H, 2xCH), 7.57 (d,
13
J = 9.0 Hz, 2H, 2xCH), 7,63 (d, J = 8.3 Hz, 2H, 2xCH), 8.16 (d, J = 9.0 Hz, 2H, 2xCH); C-NMR
(CDCl3) δ: 14.0 (CH3), 29.4 (CH3), 34.1 (CH3), 50.0 (CH2), 74.4 (C), 123.3 (2xCH), 126.1 (2xCH),
129.4 (2xCH), 130.2 (2xCH), 130.4 (C), 134.7 (C), 137.2 (C), 142.9 (C), 146.7 (C), 148.3 (C), 154.8
(C); Anal. Calcd for C20H20N4O5: C, 60.60; H, 5.09; N, 14.13. Found: C, 60.60; H, 5.15; N, 13.97.
4. Conclusions
We have reported the synthesis of substituted 2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-
1-arylethanols, ethyl 3-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-2-hydroxypropanoate and
2-[4-(1,2-dimethyl-5-nitro-1H-imidazol-4-yl)benzyl]-2-hydroxy-acenaphthylen-1(2H)-one from the
reaction of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole with various aromatic
carbonyl and α-carbonyl ester derivatives using TDAE methodology. We have shown a new application
of TDAE methodology in a heterocyclic series. The pharmacological evaluation, against metronidazole-
resistant lines of Blastocystis sp., of all synthesized compounds is under active investigation.
Acknowledgments
This work was supported by the Centre National de la Recherche Scientifique. We express our
thanks to V. Remusat for recording the 1H- and 13C-NMR spectra.
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3a-m are available from the authors.
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