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. 2011 Aug 12;16(8):6883–6893. doi: 10.3390/molecules16086883

High Functionalization of 5-Nitro-1H-imidazole Derivatives: The TDAE Approach

Thierry Juspin 1, Laura Zink 1, Maxime D Crozet 1, Thierry Terme 1, Patrice Vanelle 1,*
PMCID: PMC6264209  PMID: 21841727

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 [1,2,3,4,5,6]. 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 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 [12,13,14], 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 [16,17,18]. 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 [19,20,21,22], ketones [19,20,21,22], α-ketoesters [23,24,25], α-ketolactams [26], α-diketones [27,28] and diethyl ketomalonate [23,24,25] 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.

Scheme 1

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Preparation of 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole (1).

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.

Scheme 2.

Scheme 2

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Reaction of 1 with various carbonyl compounds using TDAE strategy.

Table 1.

Products’ yields from the reaction of 1 with various carbonyl compounds using TDAE strategy.

Carbonyl compound Product a Product number Yield (%) b
2a graphic file with name molecules-16-06883-i001.jpg graphic file with name molecules-16-06883-i002.jpg 3a 69
2b graphic file with name molecules-16-06883-i003.jpg graphic file with name molecules-16-06883-i004.jpg 3b 46
2c graphic file with name molecules-16-06883-i005.jpg graphic file with name molecules-16-06883-i006.jpg 3c 37
2d graphic file with name molecules-16-06883-i007.jpg graphic file with name molecules-16-06883-i008.jpg 3d 24
2e graphic file with name molecules-16-06883-i009.jpg graphic file with name molecules-16-06883-i010.jpg 3e 60
2f graphic file with name molecules-16-06883-i011.jpg graphic file with name molecules-16-06883-i012.jpg 3f 68
2g graphic file with name molecules-16-06883-i013.jpg graphic file with name molecules-16-06883-i014.jpg 3g 78
2h graphic file with name molecules-16-06883-i015.jpg graphic file with name molecules-16-06883-i016.jpg 3h 30
2i graphic file with name molecules-16-06883-i017.jpg graphic file with name molecules-16-06883-i018.jpg 3i 45
2j graphic file with name molecules-16-06883-i019.jpg graphic file with name molecules-16-06883-i020.jpg 3j 25
2k graphic file with name molecules-16-06883-i021.jpg graphic file with name molecules-16-06883-i022.jpg 3k 42
2l graphic file with name molecules-16-06883-i023.jpg graphic file with name molecules-16-06883-i024.jpg 3l 45
2mc graphic file with name molecules-16-06883-i025.jpg graphic file with name molecules-16-06883-i026.jpg 3m 64
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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 carried out at the Spectropole, Faculté des Sciences et Techniques de Saint-Jérome. Both 1H- and 13C-NMR spectra were determined on Bruker ARX 200 spectrometer. The 1H chemical shifts were reported as parts per million downfield from tetramethylsilane (Me4Si), and the 13C 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, J = 8.1 Hz, 2H, 2xCH); 13C-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 200 °C (isopropyl alcohol); 1H-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, J = 8.7 Hz, 2H, 2xCH), 7.73 (d, J = 8.0 Hz, 2H, 2xCH), 8.20 (d, J = 8.7 Hz, 2H, 2xCH); 13C-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 225 °C (ethyl alcohol); 1H-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), 8.22 (s, 1H, CH); 13C-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, 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 199 °C (isopropyl alcohol); 1H-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, 2xCH), 7.35 (bs, 4H, 4xCH), 7.57 (d, J = 8.1 Hz, 2H, 2xCH); 13C-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, 2xCH); 13C-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; mp 228 °C (isopropyl alcohol); 1H-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, 2xCH), 7.41 (t, J = 7.7 Hz, 1H, CH), 7.56 (s, 1H, CH), 7.62 (d, J = 8.0 Hz, 3H, 3xCH); 13C-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 solid; mp 208 °C (isopropyl alcohol); 1H-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 solid; mp 234 °C (acetonitrile); 1H-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, 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, 2xCH), 7.25 (d, J = 8.0 Hz, 4H, 4xCH), 7.69 (d, J = 8.0 Hz, 2H, 2xCH); 13C-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; mp 99 °C (isopropyl alcohol); 1H-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, J = 7.0 Hz, 1H, CH), 8.19 (d, J = 8.1 Hz, 1H, CH); 13C-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.

1-[4-(1,2-Dimethyl-5-nitro-1H-imidazol-4-yl)phenyl]-2-(4-nitrophenyl)propan-2-ol (3m): Orange solid; mp 179 °C (acetonitrile); 1H-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, J = 9.0 Hz, 2H, 2xCH), 7,63 (d, J = 8.3 Hz, 2H, 2xCH), 8.16 (d, J = 9.0 Hz, 2H, 2xCH); 13C-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.

Footnotes

Sample Availability: Samples of the compounds 3a-m are available from the authors.

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