Nitroimidazoles, part 4: Synthesis and anti-HIV activity of new 5-alkylsulfanyl and 5-(4′-arylsulfonyl)piperazinyl-4-nitroimidazole derivatives

Article abstract of DOI:10.1002/hc.20301

The development of new HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating structures of increased potency. On this basis, a series of 5-alkylsulfanyl and 5-(4′-arylsulfpnyl) piperazine derivatives of 1-phenyl-

Full text of DOI:10.1002/hc.20301

Heteroatom Chemistry
Volume 18, Number 4, 2007
Nitroimidazoles, Part 4: Synthesis and
Anti-HIV Activity of New 5-alkylsulfanyl and
ꢀ
5-(4 -arylsulfonyl)piperazinyl-4-nitroimidazole
Derivatives
Yaseen A. Al-Soud,1 Najim A. Al-Masoudi,2 Erik De Clercq,3
and Christoph Paneccoque3
1Department of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
2Formerly Fachbereich Chemie, Universita¨t Konstanz, Postfach 5560, D-78457 Konstanz, Germany
3Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received 20 June 2006; revised 14 July 2006
®
and in cancer chemotherapy [1–4]. Dacarbazine
(DTIC) [5] and misonidazole [1-methoxy-3-(4-
nitroimidazol-1-yl)propan-2-ol, 1] [6] are approved
drugs for inhibition of de novo purine synthe-
sis in addition to the potent anticancer activ-
ity. Some compounds of nitroimidazoles are re-
ported as potent whereas selective histamine H-3
receptor agonists [7–9], mitogen-activated protein
(MAP) kinases inhibitors [10–15], nitric-oxide syn-
thase inhibitors [16], and anti-inflammatory agents
[17]. 5-Nitro-substituted-haloimidazoles, the inter-
esting class of such compounds, showed an impor-
tant biological activity as potential radiosensitizers
[18].
ABSTRACT: The development of new HIV nonnucle-
oside reverse transcriptase inhibitors (NNRTIs) offers
the possibility of generating structures of increased po-
tency. On this basis, a series of 5-alkylsulfanyl and
5-(4ꢀ-arylsulfonyl)piperazine derivatives of 1-phenyl-
2-alkyl-4-nitroimidazoles 5–21 was synthesized with
the aim to develop new NNRTIs. The new synthesized
compounds were assayed against HIV-1 and HIV-2
in MT-4 cells. Compounds 9 and 13, with an alkyl-
sulfanyl group at C-5 of the 4-nitroimidazole back-
bone, showed inhibition of HIV-1 with EC50 4.04
µg/mL and 2.37 µg/mL, and therapeutic indexes (SI)
ꢁ
C
of 17 and 13, respectively.
2007 Wiley Periodicals,
Inc. Heteroatom Chem 18:333–340, 2007; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20301
Other imidazole derivatives having 5-alkylsul-
fanyl residues exhibited remarkable antitumor
activity [19]. Clotrinazole [1-(2-chlorotrityl)-1H-
®
imidazole] [20,21] and metronidazole (Flagyl
[2-(2-methyl-5-nitro-imidazol-1-yl)ethanol, 2] [22]
are considered as potent fungicides and antipro-
tozoal agents especially for treatment of Tri-
chomonas vaginalis, Entamoeba histolytica, and
Gardia lamblia. Capravirine S-1153 3 [23] is re-
ported as a new imidazole analogue with a high
anti-HIV inhibitory activity. Many laboratories [24–
32] have engaged in the development of new
INTRODUCTION
Nitro-substituted imidazoles have important ap-
plications, particularly as antibacterial agents
Correspondence to: Najim A. Al-Masoudi; e-mail: dr@al-masoudi.
de.
c
ꢀ
2007 Wiley Periodicals, Inc.
333

334 Al-Soud et al.
high-yielding routes leading to interesting imida-
zole derivatives bearing various alkylsulfanyl or
alkylamino groups via nucleophilic substitution
of the halogen by nitrogen or sulfur nucleo-
philes. We report here the synthesis of new
5-alkylsulfanyl and 5-(4ꢀ-arylsulfonyl)piperazinyl-4-
nitroimidazole derivatives with evaluation of their
anti-HIV activity.
23◦C afforded the amide 6 (90%), whereas a simi-
lar treatment of 7, prepared previously in our lab-
oratory [33] with NH3/MeOH, gave the thioammo-
nium salt 10 as a result of the β-elimination of the
ethyl ester group at C5–S group. When the acid 8 was
treated with SOCl2 at 23◦C, the acyl chloride 9 was
obtained, which, in turn, was used directly without
purification in the next step by treating it with the
piperazine in the presence of Et3N to give 11 (71%)
(Scheme 1).
RESULTS AND DISCUSSION
Chemistry
The structures of the newly synthesized products
5–11 were confirmed by the 1H, 13C NMR, and mass
spectra. In the 1H NMR spectra, the phenyl and ethyl
protons showed rather similar patterns, whereas the
singlets in the region δH 5.49–5.31 were attributed
to the methylene of benzyl group. The SCH2 pro-
tons of 5 and 6 appeared as singlets at δH 3.74 and
3.60, respectively, whereas the same protons of 8 and
11 appeared as triplets at δH 3.15 and 3.19 (J = 6.8
and 6.6 Hz), respectively. The triplet at δH 2.69 rep-
resent the methylene protons adjacent piperazine of
11, whereas the two broad singlets at δH 3.36 and 2.82
represent the piperazine protons. In the 13C NMR
spectra of 5–11, C-2 resonated between δC 146.6 and
δC 152, whereas C-4 appeared between δC 134.9 and δC
138.4. The resonances between δC 129.8 and δC 23.3
represent C-5 and the phenyl carbon atoms. SCH2
Recently, we have prepared some new 5-alkylamino
and 5-alkylsulfanyl derivatives of imidazoles [33] via
the nucleophilic displacements of the bromine group
activated by an adjacent nitro group. Our efforts
are continued in preparation of such compounds
carrying various potential groups and might lead
to biological active candidates. Benzyl-5-bromo-2-
ethyl-4-nitro-1H-imidazole 4 has been selected for
the synthesis of our targets by treatment with dif-
ferent alkylsulfanyl nucleophiles such as ethyl 2-
mercaptoacetate and 3-mercaptopropanoic acid in
the presence of K2CO3 in hot i-PrOH to give, af-
ter purification, 5 and 8 in 83% and 60% yield, re-
spectively. Treatment of 5 with 16% NH3/MeOH at
SCHEME 1 Reagents and conditions: (i) R(CH2)nSH, K2CO3, i-PrOH, 60–70◦C; 4h; (ii) NH3/MeOH, 23◦C, 10 h; (iii) SOCl2,
CHCl3, 23◦C, 18 h.
Heteroatom Chemistry DOI 10.1002/hc

Nitroimidazoles, Part 4 335
SCHEME 2 Reagents and conditions: (i) OH(CH2)2SH, KOH, iPrOH, 60–80◦C; (ii) SOCl2, CHCl3, 23◦C, 18 h; (iii) CI(CH2)2SH,
i
KOH, PrOH, 60–80◦C; 4 h; (iv) mCPBA, 1N NaOH, CH2Cl2, 23◦C, 6 h; (v) NHEt2, DMF, 80–90◦C, 4 h; (vi) HS(CH2)2NEt2,
KOH, iPrOH, 60–80◦C, 4 h.
of 5, 6, 8, and 11 resonated between δC 31.2 and δC
37.2.
pounds 5–11 and the previously reported data of 7
[33]. The structural assignment of 15 follows from
the mass spectrum and the 1H and 13C NMR spectra.
Irradiation at δH 6.18 produced an 18% NOE on the
signals at δH 5.33 and 5.14 assigned to SCH olefinic
proton.
Replacement of the bromo residue of 4 by piper-
azine in hot DMF furnished 17 (72%). When 17 was
treated with the arylsulfonyl chlorides in the pres-
ence of Et3N, the sulfonate derivatives 18–21 were
obtained in 53, 43, 49, and 43% yields, respectively
(Scheme 3).
The structures of 17–21 were assigned on the
basis of the 1H, 13C NMR, and mass spectra. The 1H
NMR spectra demonstrated broad singlets, triplets,
or multiplets in the region between δH 2.89 and 3.58,
attributed to the piperazine protons. The 13C NMR
spectra supported the proposed structures because
the carbons of the imidazole ring were deduced by
Other models of alkylsulfanyl groups at C-5 of
the imidazole backbone are prepared. Thus, treat-
ment of 4 with 2-mercaptoethanol in the presence
of KOH afforded 12 (65%). Chlorination of 12 by
treatment with SOCl2 afforded 13 at low yield (30%).
Oxidation of 13 with mCPBA in the presence of base
furnished, after purification, the sulfone 14 (71%).
Our attempt to prepare 16 from the chloro
compound 13 by treatment with diethyl amine
was unsuccessful, and instead, compound 15 was
obtained (76%) as a result of dehydrochlorina-
tion of 13. Alternatively, treatment of 4 with
2-(diethylamino)ethanethiol hydrochloride in hot
iPrOH and KOH furnished 16 in 55% yield
(Scheme 2).
The assignment of protons and carbons of the
imidazole ring was deduced in comparison to com-
SCHEME 3 Reagents and conditions: (i) piperazine, DMF, 70–80◦C, 6 h; (ii) ArSO2Cl, Et3N, CH2Cl2, 23◦C, 4 h.
Heteroatom Chemistry DOI 10.1002/hc

336 Al-Soud et al.
comparison with those of 5–11 and the structurally
proven 5-alkylamino imidazole derivatives [33].
pounds 9 and 13 showed EC50 of 4.04 µg/mL (CC50
of 57.9 7.8 µg/mL) and 2.37 µg/mL (CC50 of 2.85
0.4 µg/mL), and resulting in selectivity index of 17
and 13, respectively.
On the basis of the chemical structure and the
fact that compounds 9 and13 inhibits HIV-1, but not
HIV-2 replication, these molecule can be proposed
to act as an NNRTI.
In Vitro Anti-HIV Activity
Compounds 5–21 were evaluated for their in vitro
anti-HIV-1 activity by using the IIIB strain for HIV-1
and the ROD strain for the HIV-2, and monitored
by the inhibition of the virus-induced cytopathic ef-
fect in the human T-lymphocyte (MT-4) cells. The
results are summarized in Table 1, in which the data
for efavirenz [34] and capravirine [35] were included
for comparison purposes. Compound 9 and 13 were
found to be the only two compounds from the se-
ries inhibiting HIV-1 replication in cell culture. Com-
EXPERIMENTAL
General
Melting points were measured on a Bu¨chi melting
¨
point apparatus B-545 (BUCHI Labortechnik AG,
Switzerland) and are uncorrected. Microanalytical
TABLE 1 In Vitro Anti-HIV-1a and HIV-2b of Some New Nitroimidazoles
Virus strain
EC (µg/mL)c
CC (µg/mL)d
SI e
50
50
5
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
IIIB
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>44.3
>53.6
>12.4
>13.4
>11.8
>12.6
>64.5
>64.5
4.04
>57.9
>0.39
>0.37
>42.8
>48.7
>0.44
>0.48
2.37
>2.95
>4.43
>3.79
>0.39
>0.37
>34.4
>37.9
>36.0
>21.4
>68.5
>62.9
>91.2
>82.3
>68.5
>62.9
>91.2
82.3
48.2 4.8
48.2 4.8
13.0 0.6
13.0 0.6
12.4 0.5
12.4 0.5
64.5 5.3
64.5 5.3
57.9 7.8
57.9 7.8
0.41 0.1
0.41 0.1
46.2 3.1
46.2 3.1
0.46
<1
<1
<1
<1
<1
<1
<1
<1
17
<1
<1
<1
<1
<1
<1
<1
13
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
13,333
7,857
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
0.46
2.85 0.4
2.85 0.4
6.1 3.4
6.1 3.4
0.41 0.1
0.41 0.1
46.8 18.5
46.8 18.5
>or = 36.0
>or = 36.0
80.8 26.3
80.8. 26.3
90.0 7.2
90.0 7.2
80.8 26.3
80.8. 26.3
90.0 7.22
90.0 7.22
40
ROD
IIIB
Efavirenz [34]
Capravirine [35]
IIIB
IIIB
0.003
0.0014
11
aAnti-HIV-1 activity measured with strain IIIB.
bAnti-HIV-2 activity measured with strain ROD.
cCompound concentration required to achieve 50% protection of MT-4 cells from the HIV-1- and HIV-2-induced cytopathogenic effect.
dCompound concentration that reduces the viability of mock-infected MT-4 cells by 50%.
eSI: Selectivity index (CC50/EC50).
Heteroatom Chemistry DOI 10.1002/hc

Nitroimidazoles, Part 4 337
data were obtained with a Vario, Elementar appara-
tus (Shimadzu, Japan). NMR spectra were recorded
on 300 and 600 MHz (1H) and at 150.91 MHz (13C)
spectrometers (Bruker, Germany) with TMS as inter-
nal standard and on δ scale in ppm. Heteronuclear
propanoate (0.30 g, 2.50 mmol). Yield: 1.43 g, 82%;
mp 94–95◦C (from EtOH). MS: m/z (EI) 349 (M)+.
1
The H- and 13C NMR spectra were identical to the
authentic sample prepared previously.
1
assignments were verified by H-13C HMBC experi-
3-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)-
propanoic acid (8). To a solution of 4 (3.10 g,
10.0 mmol) in iPrOH (50 mL) was added 3-
mercapto-propanoic acid (1.06 g, 10.0 mmol) and
KOH (0.56 g, 10.0 mmol) and stirred at 60–70◦C
for 4 h. After cooling, the solution was neutralized
with 1N HCl to give 8 (2.0 g, 60%) as a powder;
ment. Mass spectra were recorded on 70 eV EI and
FAB MAT 8200 spectrometers (Finnigana MAT), us-
ing 3-nitrobenzyl alcohol (NBOH) or glycerol as ma-
trixes. Some molecular ions were detected by doping
the sample with Na+ ion.
1
Ethyl 2-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-
ylthio)acetate (5). A suspension of ethyl 2-
mecaptoacetate (1.44 g, 12.0 mmol) and K2CO3
(2.45 g, 25.0 mmol) was stirred in dry i-PrOH (40 mL)
under argon at 23◦C. To this suspension, 4 (3.10 g,
10 mmol) was added slowly and was stirred at 60–
70◦C for 4 h. The mixture was poured into ice
water, and the precipitate was filtered off and re-
crystallized from EtOH to give 5 (2.78 g, 83%); mp
mp 167–170◦C dec. H NMR (CDCl3): δ 10.8 (s, 1H,
CO2H); 7.35–7.26 (m, 3H, Ph-H); 6.99–6.95 (m, 2H,
Ph-H); 5.35 (s, 2H, PhCH2); 3.15 (t, 2H, J = 6.8 Hz,
SCH2CH2); 2.66 (t, 2H, J = 6.8 Hz, SCH2CH2); 2.58
(q, 2H, J = 6.8 Hz, CH2CH3); 1.26 (t, 3H, CH2CH3).
13C NMR (CDCl3): δ 174.8 (CO2H); 150.7 (C-2);
134.9 (C-4); 129.3, 129.2, 128.4, 126.0, 125.7 (C-5,
Ph-C); 48.6 (CH2Ph); 34.1 (SCH2CH2CO2H); 31.2
(SCH2CH2CO2H); 21.3 (CH2CH3); 11.6 (CH2CH3).
Anal. Calcd for C15H17N3O4S (335.38): C, 53.72; H,
5.11; N, 12.53. Found: C, 53.43; H, 5.00; N, 12.31;
m/z (FAB): 358 (M + Na)+.
1
80–81◦C. H NMR (DMSO-d6): δ 7.36–7.32 (m, 3H,
Ph-H); 7.00–6.96 (m, 2H, Ph-H); 5.49 (s, 2H, CH2Ph);
4.09 (q, 2H, J = 7.1 Hz, OCH2CH3); 3.74 (s, 2H,
SCH2); 2.68 (q, 2H, J = 7.2 Hz, CH2CH3); 1.28 (t, 3H,
OCH2CH3); 1.22 (t, 2H, CH2CH3). 13C NMR (DMSO-
d6): δ 168.7 (C O); 150.6 (C-2); 135.1 (C-4); 129.4,
129.1, 128.9, 128.2, 127.1, 126.0, 123.3 (C-5, Ph-C);
61.9 (OCH2CH3); 47.9 (CH2Ph); 37.2 (SCH2); 21.2
(CH2CH3); 13.9 (OCH2CH3); 11.2 (CH2CH3). Anal.
Calcd for C16H19N3O4S (349.4): C, 55.00; H, 5.48; N,
12.03. Found: C, 54.72; H, 5.31; N, 11.84. m/z (FAB):
350 (M + H)+.
Ammonium 1-benzyl-2-ethyl-4-nitro-1H-imidazol-
5-thiolate (10). A solution of 7 (1.67 g, 4.78 mmol)
in 16% NH3/MeOH (20 mL) was stirred at 23◦C
for 5 h. The solution was evaporated to dryness,
and the residue was recrystallized from EtOH to
give 10 (1.20 g, 90%), mp 170–171◦C. 1H NMR
(DMSO-d6): δ 7.30–7.15 (m, 5H, Ph-H); 5.31 (s, 2H,
CH2Ph); 2.36 (q, 2H, J = 7.5 Hz, CH2CH3); 1.01 (t,
3H, CH2CH3). 13C NMR (DMSO-d6): δ 146.6 (C-2);
138.4 (C-4); 128.6, 127.2, 127.0 (C-5, Ph-C); 45.1
(CH2Ph); 21.0 (CH2CH3); 11.2 (CH2CH3). Anal. Calcd
for C12H16N4O2S. (280.35): C, 51.41; H, 5.75; N, 19.98.
Found: C+, 51.22; H, 5.41; N, 19.84. m/z (FAB): 262
(M − NH4 )+.
2-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)-
acetamide (6). A solution of 5 (0.50 g, 1.43 mmol)
in 16% NH3/MeOH (20 mL) was stirred at 23◦C for
10 h. The solution was evaporated to dryness, and
the residue was recrystallized from EtOH to give
1
6 (90%), as orange crystals, mp 175–178◦C dec. H
NMR (DMSO-d6): δ 7.53 (m, 1H, Ph-H); 7.34 (m, 2H,
Ph-H); 7.09–7.02 (m, 2H, Ph-H); 5.49 (s, 2H, CH2Ph);
3.60 (s, 2H, SCH2); 2.63 (q, 2H, J = 7.2 Hz, CH2CH3);
1.10 (t, 3H, CH2CH3). 13C NMR (DMSO-d6): δ 170.1
(CONH2); 151.1 (C-2); 136.6 (C-4); 129.8, 128.6,
126.9, 125.5 (C-5, Ph-C); 48.0 (CH2Ph); 40.0 (SCH2);
21.2 (CH2CH3); 11.5 (CH2CH3). Anal. Calcd for
C14H16N4O3S (320.4): C, 52.49; H, 5.03; N, 17.49.
Found: C, 52.17; H, 4.96; N, 17.27; m/z (FAB): 321
(M + H)+.
3-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)-
1-(piperazin-1-yl)propan-1-one (11). SOCl2 (0.36 g,
3.0 mmol) was added stepwise to a solution of 8
(0.50 g, 1.50 mmol) in CHCl3 (10 mL), and the
reaction mixture was stirred at 23◦C for 18 h. The
solution was evaporated to dryness, and the residue
was washed with ether (3 × 30 mL) to give a crude 9
(0.34 g, 65%). This product was used directly for the
next step by dissolving in CH2Cl2 (15 mL), followed
by the addition of piperazine (0.15 g, 1.70 mmol)
and Et3N (1.0 mL), and the reaction mixture was
stirred at 23◦C for 18 h. The mixture was evaporated
to dryness, and the residue was recrystallized from
Methyl 3-(1-benzyl-2-ethyl-4-nitro-3H-imidazole-
5-ylsulfanyl)propanoate(7). This compound was pre-
pared according to reference [33]. Compound 4
(1.55 g, 5.0 mmol) and methyl 3-mercapto-
1
EtOH to give 11 (0.27 g, 71%), mp 149–152◦C. H
NMR (CDCl3): δ 7.37–7.26 (m, 3H, Ph-H); 7.01–6.97
Heteroatom Chemistry DOI 10.1002/hc

338 Al-Soud et al.
(m, 2H, Ph-H); 5.40 (s, 2H, PhCH2); 3.36 (br s.,
4H, piperazine); 3.19 (t, 2H, J = 6.6 Hz, SCH2CH2);
2.82 (br s., 4H, piperazine); 2.69 (t, 2H, J = 6.6 Hz,
SCH2CH2); 2.59 (q, 2H, J = 6.7 Hz, CH2CH3); 1.27
(t, 3H, CH2CH3). 13C NMR (CDCl3): δ 171.6 (CO-
piperazine)); 152.1 (C-2); 135.2 (C-4); 129.6, 129.7,
128.9, 126.3, 125.9 (C-5, Ph-C); 49.5 (piperazine);
48.4 (CH2Ph); 45.6 (piperazine); 34.8 (SCH2CH2CO);
31.3 (SCH2CH2CO); 21.2 (CH2CH3); 11.8 (CH2CH3).
Anal. Calcd for C19H25N5O3S. (403.50): C, 56.56; H,
6.25; N, 17.36. Found: C, 56.32; H, 6.12; N, 17.16.
m/z (FAB): 404 (M + H)+.
1.07 mmol) in CH2Cl2 (15 mL) was stirred with
mCPBA (0.47 g, 2.15 mmol) for 6 h at 23◦C. The
solution was partitioned with water (15 mL), the
organic layer was dried (Na2SO4), filtered, and
evaporated to dryness, and the residue was re-
crystallized from EtOH to give 14 (0.25 g, 71%),
1
mp 135–136◦C dec. H NMR (600 MHz, CDCl3): δ
7.40–7.34 (m, 3H, Ph-H); 7.07 (m, 2H, Ph-H); 5.59
(s, 2H, PhCH ); 3.78–3.75 (m, 2H, CH2Cl); 3.34–3.31
2
(m, 2H, SCH2); 2.76 (q, 2H, J = 7.4 Hz, CH2CH3);
1.36 (t, 3H, CH2CH3). 13C NMR (HMQC, CDCl3). δ
153.7 (C-2); 135.3, 129.128.5, 128.3, 126.2 (Ph-C);
47.9 (CH2Ph); 55.6 (SO2CH2); 47.9 (CH2Ph); 36.2
(SCH2); 20.4 (CH2CH3); 11.3 (CH2CH3). Anal. Calcd
for C14H16ClN3O4S (357.81): C, 46.99; H, 4.51; N,
11.74. Found: C, 46.72; H, 4.36; N, 11.52; m/z (FAB):
357/359 (M + H)+.
2-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)-
ethanol (12). This compound was prepared from 4
(0.93 g, 3.0 mmol) and 2-mercaptoethanol (0.24 g,
3.0 mmol) by following the same procedure as for 5.
Yield: 0.60 g (65%); oil. 1H NMR (CDCl3): δ 7.38–7.29
(m, 3H, Ph-H); 7.07–6.98 (m, 2H, Ph-H); 5.41 (s,
2H, PhCH2); 3.65 (t, 2H, J = 5.6 Hz, CH2OH); 3.00
(t, 2H, J = 5.6 Hz, SCH2); 2.64 (q, 2H, J = 7.5 Hz,
CH2CH3); 1.21 (t, 3H, CH2CH3). Anal. Calcd for
C14H17N3O3S (307.37): C, 54.71; H, 5.57; N, 13.67.
Found: C, 54.52; H, 5.39; N, 13.38; m/z (FAB): 330
(M + Na)+.
1-Benzyl-2-ethyl-4-nitro-5-(vinylthio)-1H-imidazole-
(15). Et2NH (73 mg, 1.0 mmol) was added to
a solution of 13 (330 mg, 1.0 mmol) in DMF
(10 mL) containing NaH (30 mg, 1.25 mmol).
The solution was stirred at 80–90◦C for 4 h and
evaporated to dryness. The residue was partitioned
between CHCl3 (2 × 15 mL) and water (15 mL),
and the combined organic extracts was dried
(Na2SO4), filtered, and evaporated to dryness. The
residue was poured onto SiO2 column (5.0 g),
using CH3Cl-MeOH (95–5%) as eluent to give 15
1-Benzyl-5-(2-chloroethylthio)-2-ethyl-4-nitro-1H-
imidazole (13).
Method a—SOCl2 (1.19 g, 10.08
mmol) was added stepwise to a solution of 12 (1.55
g, 5.04 mmol) in CHCl3 (20 mL) and the reaction
mixture was stirred at 23◦C for 18 h. The solution
was evaporated to dryness and the residue was
washed with ether (3 × 30 mL) and the residue
was recrystallized from EtOH to give 13 (0.47 g,
30%), as a light yellow crystal, mp 146–147◦C
1
(0.22 g, 76%); mp 58–61◦C dec. H NMR (CDCl3): δ
7.40–7.30 (m, 3H, Ph-H); 7.02–6.99 (m, 2H, Ph-H);
6.18 (dd, 1H, J = 9.4 Hz, 16.5 Hz, SCH CH2);
5.33 (dd, 1H, J = 9.4 Hz, 16.5 Hz; SCH CH );
2
5.14 (d, 1H, J = 16.5 Hz, SCH CH ); 5.30 (s, 2H,
2
CH2Ph); 2.66 (q, 2H, J = 7.5 Hz, CH2CH3); 1.25
(t, 2H, CH2CH3). 13C NMR (CDCl3): δ 150.9 (C-2);
134.5 (C-4); 129.3, 129.1, 128.3, 128.2, 127.1, 125.1
(C-5, Ph-C); 120.7 (SCH CH2); 116.5 (SCH CH2);
47.7 (CH2Ph); 21.2 (CH2CH3); 11.1 (CH2CH3). Anal.
Calcd for C14H15N3O2S (289.35): C, 58.11; H, 5.23;
N, 14.52. Found: C, 57.94; H, 5.14; N, 14.31; m/z
(FAB): 290 (M + H)+.
1
dec. H NMR (CDCl3): δ 7.39–7.26 (m, 3H, Ph-H);
6.99–6.96 (m, 2H, Ph-H); 5.39 (s, 2H, PhCH2); 3.50
(t, 2H, J = 6.9 Hz, CH2Cl); 3.22 (t, 2H, J = 6.9 Hz,
SCH2); 2.68 (q, 2H, J = 7.4 Hz, CH2CH3); 1.28 (t,
3H, CH2CH3). 13C NMR (CDCl3). δ 150.8 (C-2);
134.9 (C-4); 129.5, 129.3, 128.4, 126.0, 123.5 (C-5,
Ph-C); 47.9 (CH2Ph); 42.6 (CH2Cl); 38.4 (SCH2);
21.3 (CH2CH3); 11.3 (CH2CH3). Anal. Calcd for
C14H16ClN3O2S (325.81): C, 51.61; H, 4.95; N, 12.90.
Found: C, 51.29; H, 4.78; N, 12,70; m/z (FAB):
325/327 (M + H)+.
2-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-ylthio)-
N,N-diethylamine (16). This compound was
prepared from 4 (0.47 g, 1.5 mmol) and 2-
(diethylamino)ethanethiol hydrochloride (0.25 g,
1.5 mmol) by following the same procedure as for 5.
Yield 0.30 g (55%); oil. 1H NMR (DMSO-d6): δ 7.36–
7.33 (m, 3H, Ph-H); 7.00–6.97 (m, 2H, Ph-H); 5.40 (s,
2H, CH2Ph); 3.02 (t, 2H, J = 5.7 Hz, SCH2CH2); 2.67
(t, 2H, J = 5.7 Hz, SCH2CH2); 2.60 (q, 2H, J = 7.2 Hz,
CH2CH3); 2.46 (q, 4H, J = 7.4 Hz, 2 × NCH2CH3);
Method b—This compound was prepared from
4 (1.0 g, 3.22 mmol) and 2-chloroethanethiol (0.29 g,
3.0 mmol) by following the same procedure as for 5.
Yield: 0.30 g (29%); mp, mixed mp, and the NMR
spectra were identical to the authentic sample pre-
pared in Method a.
1-Benzyl-5-(2-chloroethylsulphonyl)-2-ethyl-4-nitro-
1H-imidazole (14). A solution of 13 (0.35 g,
1.29 (t, 3H, CH2CH3); 0.95 (t, 6H, 2 × NCH2CH3). 13
C
NMR (DMSO-d6): δ 150.0 (C-2); 135.1 (C-4); 129.1,
Heteroatom Chemistry DOI 10.1002/hc

Nitroimidazoles, Part 4 339
128.1, 125.9 (C-5, Ph-C); 51.7 (NCH2CH2S); 47.7
(CH2Ph); 46.7 (2 × NCH2CH3); 34.2 (NCH2CH2S);
21.2 (C2-CH2CH3); 11.3 (C2-CH2CH3, 2xNCH2CH3).
Anal. Calcd for C18H26N4O2S (362.5): C, 59.64; H,
7.23; N, 15.46. Found: C, 59.44; H, 7.09; N, 15.23;
m/z (FAB): 363 (M + H)+.
1-(Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-4-
chlorobenzenesulfonylpiperazine (19). From
4-
chlorobenzenesulfonyl chloride (0.19 g). Yield: 0.21
1
g (43%); mp 191–193◦C. H NMR (CDCl3): δ 7.60
(d, 2H, J = 8.5 Hz, ArSO2 H); 7.47 (d, 2H, J = 8.5
Hz, ArSO2 H); 7.22 (m, 3H, Ph-H); 6.83–6.78 (m,
2H, Ph-H), 4.94 (s, 2H, CH2Ph); 3.58 (t, 2H, J = 5.7
Hz, piperazine); 3.42 (t, 2H, J = 5.7 Hz, piperazine);
3.01–2.92 (m, 4H, piperazine); 2.56 (q, 2H, J = 7.5
Hz, CH2CH3); 1.18 (t, 3H, CH2CH3). 13C NMR
(CDCl3): δ 160.6 (C-2); 145.6 (ArSO2 C); 139.6 (C-4);
138.8, 137.8 (ArSO2 C); 135.0, 134.6, 129.5, 129.1,
129.2, 129.1, 128.3, 125.7 (C-5, Ar-C); 48.5, 46.0
(piperazine-C); 39.3 (CH2Ph); 20.8 (CH2CH3); 11.4
(CH2CH3). Anal. Calcd for C22H24ClN5O4S (489.98):
C, 53.93; H, 4.94; N, 14.29. Found: C, 53.72; H, 4.89;
N, 13.96; m/z (FAB): 490/492 (M + H)+.
1-(1-Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-
piperazine (17). Piperazine (1.03 g, 12.0 mmol)
was added to a stirred solution of 4 (3.10 g, 10
mmol) in DMF (25 mL) and heated at 70–80◦C
for 6 h. The solution was evaporated to dryness,
and the residue was recrystallized from EtOH to
1
give 17 (3.41 g, 72%); mp 228–231◦C dec. H NMR
(DMSO-d6): δ 10.6 (s, 1H, NH); 7.38–7.27 (m, 3H,
Ph-H); 7.15–7.08 (m, 2H, Ph-H); 5.25–5.21 (m, 2H,
CH2Ph); 3.02, 2.89 (2 × br s., 8H, piperazine); 2.56
(q, 2H, J = 7.8 Hz, CH2CH3); 1.09 (t, 3H, CH2CH3).
13C NMR (DMSO-d6): δ 145.8 (C-2); 139.4 (C-4);
137.0 (C-5); 129.6, 128.3, 127.0 (Ph-C); 46.6, 43.8
(piperazine-C); 41.0 (CH2Ph); 20.9 (CH2CH3); 11.3
(CH2CH3). Anal. Calcd for C16H21N5O2 (315.37): C,
60.94; H, 6.71; N, 22.21. Found: C, 60.79; H, 6.59; N,
21.97; m/z (FAB): 316 (M + H)+.
1-(Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-4-
nitrobenezenesulfonylpiperazine (20). From 4-nitro-
benzenesulfonyl chloride (0.22 g). Yield: 0.25 g
(49%); mp 246–247◦C dec. 1H NMR (CDCl3): δ
8.41 (d, 2H, J = 8.8 Hz, ArSO2 H); 7.94 (d, 2H,
J = 8.8 Hz, ArSO2 H); 7.31–7.27 (m, 3H, Ph-H);
6.88–6.82 (m, 2H, Ph-H), 5.00 (s, 2H, CH2Ph); 3.52
(br s., 8H, piperazine); 2.57 (q, 2H, J = 7.6 Hz,
CH2CH3); 1.25 (t, 3H, CH2CH3). 13C NMR (CDCl3):
δ 150.3 (C-2); 145.3 (ArSO2 C-NO2); 142.6 (C-4);
139.9 (ArSO2 Ca); 137.5, 135.2, 129.2, 128.8, 128.3,
125.5, 124.4 (C-5, Ar-C); 48.5, 46.2 (piperazine-C);
46.1 (CH2Ph); 21.1 (CH2CH3); 11.2 (CH2CH3). Anal.
Calcd for C22H24N6O6S (500.53): C, 52.79; H, 4.83;
N, 16.79. Found: C, 52.57; H, 4.77; N, 16.57; m/z
(FAB): 501 (M + H)+.
General Preparation of 4-Arylsulfonyl-1-(benzyl-2-
ethyl-4-nitro-1H-imidazol-5-yl)-piperazines (18–21).
Arylsulfonyl chloride (1.0 mmol) was added to a so-
lution of 17 (0.32 g, 1.0 mmol) in CH2Cl2 (20 mL)
containing Et3N (0.10 g, 1.0 mmol) and stirred at
23◦C for 4 h. Few drops of water were added, and
the solution was stirred for 1 h, and then partitioned
between CHCl3 (3 × 20 mL) and water (20 mL). The
combined organic layer was dried (Na2SO4), filtered,
and evaporated to dryness. The residue was coevapo-
rated with EtOH (3 × 20 mL) and then recrystallized
from EtOH to give the desired sulfonate derivatives.
1-(Benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)-4-
toluenesulfonylpiperazine (18). From 4-toluene-
sulfonyl chloride (0.19 g). Yield: 0.25 g (53%); mp
181–83◦C. 1H NMR (CDCl3): δ 7.53 (d, 2H, J = 8.6 Hz,
ArSO2 H); 7.28 (d, 2H, J = 8.6 Hz, ArSO2 H); 7.27–
721 (m, 3H, Ph-H); 6.81–6.72 (m, 2H, Ph-H), 4.94
(s, 2H, CH2Ph); 3.56 (t, 2H, J = 5.5 Hz, piperazine);
3.40 (t, 2H, J = 5.5 Hz, piperazine); 2.98–2.89 (m,
4H, piperazine); 2.58 (q, 2H, J = 7.6 Hz, CH2CH3);
2.37 (s, 3H, Ar-Me); 1.19 (t, 3H, CH2CH3). 13C NMR
(CDCl3): δ 160.6 (C-2); 145.2 (ArSO2-C-Me); 143.9
(C-4); 135.4, 129.8, 129.7, 129.1, 128.2, 127.7, 127.6,
126.1, 125.7 (C-5, Ar-C); 48.6, 46.0 (piperazine-C);
39.3 (CH2Ph); 21.0 (CH2CH3); 11.3 (CH2CH3). Anal.
Calcd for C23H27N5O4S (469.56): C, 58.83; H, 5.80;
N, 14.91. Found: C, 58.63; H, 5.68; N, 14.70; m/z
(FAB): 470 (M + H)+.
4-Acetamidobenzenesulfonyl-1-(benzyl-2-ethyl-4-
nitro-1H-imidazol-5-yl)piperazine (21). From 4-
acetamidobenzenesulfonyl chloride (0.22 g). Yield:
0.22 g (43%); mp 136–139◦C. 1H NMR (CDCl3): 9.12
(s, 1H, NH), δ 7.77 (d, 2H, J = 8.7 Hz, ArSO2 H);
7.51 (d, 2H, J = 8.7 Hz, ArSO2 H); 7.21–7.17 (m,
3H, Ph-H); 6.79–6.75 (m, 2H, Ph-H), 4.97–4.93 (m,
2H, CH2Ph); 3.00 (br s., 8H, piperazine); 2.53 (q, 2H,
J = 7.5 Hz, CH2CH3); 1.14 (t, 3H, CH2CH3). 13C NMR
(CDCl3): δ 169.7 (NHCO2Me); 145.8 (C-2); 143.2
(ArSO2 C-NHAc); 138.6 (C-4); 138.3, 134.8, 129.4,
129.1, 128.6, 128.3, 125.6, 119.6 (C-5, Ar-C); 48.4,
46.5 (piperazine-C); 46.0 (CH2Ph); 24.5 (NHCO2Me);
20.8 (CH2CH3); 11.2 (CH2CH3). Anal. Calcd for
C24H28N6O5S (512.58): C, 56.24; H, 5.51; N, 16.40.
Found: C, 56.06; H, 5.44; N, 16.20; m/z (FAB): 513
(M + H)+.
Heteroatom Chemistry DOI 10.1002/hc

340 Al-Soud et al.
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ACKNOWLEDGMENT
We thank Miss Friemel of Chemistry Department,
University of Konstanz, Germany, for the 2D NMR
experiments.
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Heteroatom Chemistry DOI 10.1002/hc