Selective reduction of 2,4-dinitro- and 4,5-dinitroimidazole derivatives using iron dust

Article abstract of DOI:10.1002/jhet.418

(Chemical Equation Presented) A series of N-substituted 2,4-dinitroimidazoles, 4,5-dinitroimidazoles, and 2-methyl-4,5-dinitroimidazoles have been selectively reduced to the corresponding aminonitroimidazole derivatives, using iron dust in glacial acetic acid at room temperature. 2,4-Dinitroimidazoles have been reduced to the 2-amino-4-nitro-derivatives only but 4,5-dinitroimidazoles have given 4-amino-5-nitro- or 5-amino-4- nitroderivatives depended on the structure of the N-substituent.

Full text of DOI:10.1002/jhet.418

September 2010
Selective Reduction of 2,4-Dinitro- and 4,5-Dinitroimidazole
Derivatives Using Iron Dust
1049
_
Dorota Olender, Justyna Zwawiak, and Lucjusz Zaprutko*
´
Department of Organic Chemistry, Poznan University of Medical Sciences, Poznan 60-780, Poland
*E-mail: zaprutko@ump.edu.pl
Received November 23, 2009
DOI 10.1002/jhet.418
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of N-substituted 2,4-dinitroimidazoles, 4,5-dinitroimidazoles, and 2-methyl-4,5-dinitroimida-
zoles have been selectively reduced to the corresponding aminonitroimidazole derivatives, using iron
dust in glacial acetic acid at room temperature. 2,4-Dinitroimidazoles have been reduced to the 2-
amino-4-nitro-derivatives only but 4,5-dinitroimidazoles have given 4-amino-5-nitro- or 5-amino-4-nitro-
derivatives depended on the structure of the N-substituent.
J. Heterocyclic Chem., 47, 1049 (2010).
INTRODUCTION
for instance iron in an acidic medium [11,12], hydrogen
in the presence of palladium [13,14], Raney nickel [15]
sodium borohydride [16]. Only limited number of all
reduction methods have described the selective reduction
of one nitro group in dinitro-compounds with remain
unchanged of other functional groups. For example, reduc-
tion of 2,4-dinitrophenol using sodium sulfide has led to
2-amino-4-nitrophenol [17], but 4-amino-2-nitro-carboxa-
mide mustard have been obtained by selective 4-nitro
group reduction of 2,4-dinitrobenzamide derivative with
SnCl2 in concentrated HCl [18]. Lin and Sun [17] have
found that using either Zn in HCOONH4 or tin (II) chlo-
ride dihydrate can deliver traceless synthesis of 2-quinoxa-
linone analogues, an o-nitroaniline intermediate without
further reduction of another nitro group under microwave
irradiation or by conventional heating.
Imidazoles and their derivatives are very important
group of compounds for their pharmacological properties
[1,2]. Particularly, the nitroimidazole class of medicines
mainly shows activity against bacteria [3,4]. Also, these
drugs have become the important agents for treatment of
serious infections caused by protozoa. Some of them have
been tested against HIV [5]. 2-Nitroimidazoles played a
major role as bioreductive markers for tumour hypoxia [6]
and as radiosensitizers [7,8]. Our earlier investigations
have been devoted to synthesis and antifungal as well as
antibacterial properties of N-phenacyl-4,5-dinitroimidazole
and 4-substituted amino-5-nitroimidazole derivatives,
which have been prepared by nucleophilic displacement
of the nitro group in 4,5-dinitroimidazole derivatives by
primary or secondary amines [9,10].
Products of reductions of nitroimidazole derivatives
exhibit potential biological significance and are inter-
mediates in syntheses of a variety of biologically active
imidazoles. The compounds containing amino group in
azoles ring can show good antimicrobial activity. In par-
ticular, the introduction of a bromine or two chlorine
atoms or one phenyl group to the phenyl ring, except
for the amino group in 2-amino-4(5)-arylimidazoles
Reduction of the nitro compounds has been one of the
most important reactions in organic chemistry used as a
routine method for the preparation of various nitrogen
derivatives such as amines, nitrosocompounds, or hydrox-
ylamines. The reported reduction methods of aromatic
nitro compounds to prepare amino derivatives are very
numerous. The reduction of the nitroazoles is readily
achieved by using of one of many possible reagents like
C
V
2010 HeteroCorporation

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D. Olender, J. Zwawiak, and L. Zaprutko
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Vol 47
Scheme 1
leads to compounds provided some antimicrobial activ-
ity [19]. Moreover, compound with the amino and the
nitro groups have played important role as potent inhibi-
tor of Coxackie virus B3 replication [20]. Synthetic 2-
aminoimidazole derivatives including 2-aminohistamine
have shown to have H1 and H2 receptor agonist and an-
tagonist activity. Other 2-aminoimidazole derivatives are
selective 5-HT3 receptor antagonists, which may be
potentially useful in the treatment of chemotherapy
induced emesis [21]. Imidazole alkaloids containing the
amino group at C-2 position in the heterocyclic ring
also show interesting biological property such as anthel-
minthic activity (dorimidazole A, preclathridine A) [1].
troimidazoles (4–17) were obtained in the reaction of 1
or 2 with (CH3)2SO4, epoxypropane, epichlorohydrin, or
phenacyl bromides in accordance with the method
described in the literature [9,23,24]. The N-(2-hydroxy-
propyl) and N-(3-chloro-2-hydroxypropyl) compounds
(6–8) were oxidized by Jones reagent to the desired car-
bonyl derivatives (10–12) [24]. Additionally, 2-methyl-
4,5-dinitroimidazole was alkylated with epibromohydrin
according to the method described for prepared epichlor-
ohydrin derivatives [9]. The treatment of 2 with an
excess of epibromohydrin (1:2) under reflux without sol-
vent for about 3 h led to new 1-(3-bromo-2-hydroxy-
propyl)-2-methyl-4,5-dinitroimidazole (9). This new de-
rivative was oxidized by Jones reagent to the 1-(3-
bromo-2-oxopropyl)-2-methyl-4,5-dinitroimidazole (13)
in accordance with the method described earlier [24].
Synthesis of N-substituted 4,5-dinitroimidazole deriva-
tives 4–17 is shown in the Scheme 1.
Also, the 2,4-dinitroimidazole (3) was put on the
reactions with (CH3)2SO4 and phenacyl bromides
according to the methods described in the literature
[9,23,25]. The reactions of 3 with appropriate reagents
resulted in the formation of N-substituted derivatives of
2,4-dinitroimidazole (18–20), as shown in the Scheme 2.
The N-methyl (18) and N-phenacyl derivatives of 2,4-
dinitroimidazole (19,20) in the reduction gave only re-
spective 2-amino-4-nitroimidazole with yield 54–82%
(Scheme 3). When the reaction was complete, the excess
of iron and its oxidation products were filtered off and the
reaction mixture was diluted with water. The 2-amino-1-
methyl-4-nitroimidazole (21) was isolated by extraction.
After removal of the solvent, the crude product was crys-
tallized. The precipitated crude reduction products (22,
23) were filtered off. A large, lipophilic phenacyl group
facilitated obtaining the aminonitroderivatives. Reduction
RESULTS AND DISCUSSION
The reduction of N-substituted 2,4-dinitroimidazole,
4,5-dinitroimidazole, and 2-methyl-4,5-dinitroimidazole
to the corresponding aminonitroderivatives by use of
iron dust in glacial acetic acid at room temperature
exhibits high selectivity. It is very surprising that iron
dust in an acidic medium is capable of reducing one
nitro group without further reduction of second nitro
group. It is known that iron in the presence of acid is
not selective agent [11]. In our experiments, treatment
of dinitroimidazole derivatives with iron dust afforded,
after purification, the crystalline aminonitro-compounds.
Stability of these compounds depended on the position
of the amino group, decreased in a series of 2-amino, 5-
amino and 4-amino compounds.
The starting 4,5-dinitroimidazole (1), 2-methyl-4,5-
dinitroimidazole (2), and 2,4-dinitroimidazole (3) were
prepared according to the methods described in the liter-
ature [22,23]. The N-substituted derivatives of 4,5-dini-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Selective Reduction of 2,4-Dinitro- and 4,5-Dinitroimidazole
Derivatives Using Iron Dust
1051
Scheme 2
of N-substituted 2,4-dinitroimidazole derivatives 18–20 is
shown in the Scheme 3.
position of the new formed amino group and yielding of
4-amino-compounds was the poorest. The low efficiency
in reduction reactions of 4,5-dinitroimidazole alkyl
derivatives probably is connected with structures and
stability of compounds obtained. Moreover, the isolation
of pure, definite, aminonitroderivatives was very incon-
venient. Some of them were obtained after complex
extraction, then purification by column chromatography
and additional crystallization.
The structures of 21–23 were confirmed by full spectral
data. The infrared spectra showed absorptions at about
3400 and 3265 cmꢀ1 and also 1560 and 1300 cmꢀ1 indic-
ative for the NAH and NO2 resonances, respectively. The
mass spectra exhibit strong molecular ions at 142, 246,
and 280, respectively. In addition to the molecular ions, in
spectra of compounds 22 and 23 strong signal (rel. int.
100%) corresponding to ion from phenacyl (m/z 105) or
p-chlorophenacyl group (m/z 139) was observed. In the
1H NMR spectra, the signals of the amino groups are as
singlets at about 6.30 ppm, CH2 protons of the phenacyl
groups resonated as singlet at 5.56 and 5.54 ppm. The ar-
omatic protons at C-5 position of the imidazole ring were
observed at about 7.84 ppm.
Reduction of N-substituted 4,5-dinitroimidazole deriv-
atives 4,5,7–17 is shown in the Scheme 4.
Reaction of the compounds containing N-methyl
group (4, 5) with iron dust afforded 4-amino-5-nitroim-
idazoles (24, 25) only that were separated after
extraction with chloroform. In the reduction of the
N-halohydroxypropyl derivatives (7–9) were formed
5-amino-4-nitro-compounds (26–28). These substances
were obtained as solid products. Other 4,5-dinitroimida-
zoles (10–17) containing the carbonyl group in the chain
Reduction of 4,5-dinitroimidazole alkyl derivatives
led to N-alkylaminonitroimidazoles, as well. The iron
dust in glacial acetic acid reduced with facility one nitro
group but the second remained unreactive. In the same
conditions, mixture of two isomers: 4-amino-5-nitro-
and 5-amino-4-nitro- with predomination of the latter
mentioned were formed (Scheme 4). The 4,5-diaminoi-
midazoles were not observed in the reaction mixtures.
Formation of the aminonitroimidazoles depended on the
Scheme 4
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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D. Olender, J. Zwawiak, and L. Zaprutko
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Vol 47
at N-1 position of the imidazole ring provided mainly
4-amino-5-nitro- derivatives, after extraction (29–34, 36,
37). Only in the reduction of 2-methyl-4,5-dinitro-1-phe-
nacylimidazole (15) and (17), the mixtures of two prod-
ucts were obtained. After reduction of 15, isomers: 4-
amino-2-methyl-5-nitro-1-phenacylimidazole (34) and 5-
amino-2-methyl-4-nitro-1-phenacylimidazole (35) were
obtained. Compound 35 was separated by the filtration
and purified by crystallization. Dominating product, 34,
was obtained after extraction and was purified by col-
umn chromatography. Similarly, the 4-amino-1-(p-chlor-
ophenacyl)-2-methyl-5-nitroimidazole (37) and 5-amino-
derivatives using iron dust in the acetic acid solution at
room temperature. This method provided the products
with the amino and the nitro group simultaneously. The
presence of an electron-donating amino group at a posi-
tion neighbouring to the nitro group can have influence
on the many biological properties, which depended on
the kind of substituents at positions N-1 and C-2 in the
heterocyclic ring, as well.
To recapitulate, the N-derivatives of 2,4-dinitroimida-
zoles were reduced only to the 2-amino-4-nitro com-
pounds. It was found that the reduction process among
the N-derivatives of 4,5-dinitroimidazoles is more compli-
cated, but it concerns mainly the 4-NO2 group. Nitro
group at C-5 position of imidazole ring is susceptible to
reduction when there is a hydroxy group in the N-1 alkyl
chain connected with tetrahedral carbon atom. Probably,
some specific trigonal arrangements have the influence on
the direction of nitro group reduction process.
1-(p-chlorophenacyl)-2-methyl-4-nitroimidazole
(38)
were obtained as products of the reduction of 1-(p-chlor-
ophenacyl)-2-methyl-4,5-dinitroimidazole (17). These
derivatives were separated by column chromatography.
In all cases, 4,5-diamino derivatives were not observed.
The infrared spectra of 24–38 showed absorptions at
about 3400 and 3260 cmꢀ1 and also 1560 and 1300
cmꢀ1 indicative for the NAH and NO2 resonances,
respectively. The mass spectra confirmed that only one
nitro group in the dinitroimidazoles was reduced. The
1H NMR spectra of new products provided evidence for
the presence of the amino group. The NH2 protons were
observed as a singlet at about 7.40 ppm (24, 25) or
within the range of 7.57–7.71 ppm (26–38). In the 13C
NMR spectra of 26–28, signal for the carbon jointed
with hydroxyl group was near 67 ppm. Moreover, the
signal corresponded to the C¼¼O group of 29–38 reson-
ated in the range of 190.88–201.22 ppm. The position of
the amino group in 26–38 was connected with the place
of a signal of a methylene group at N-1 position of the
heterocylic ring. In the 13C NMR of 26–28, the signal in
the range 46.29–47.09 ppm was assigned to the CH2
group. It is also observed that in the 13C NMR of 29–
32, the resonances due to CH2 occurred in the range
52.21–54.40 ppm. It is very interesting that the signals
of the methylene groups of the pairs 34, 35 and 37, 38
occurred at different values: 52.01 and 50.27 ppm or
51.96 and 49.65 ppm, respectively. In the spectra of 5-
amino-4-nitro-products, the signals of the carbons in the
imidazole ring appeared in lower values, too. Addition-
ally, the X-ray structures determination of the pair of
isomers (34,35) facilitated the interpretation of NMR
data and to determine the position of the amino group.
The geometry of the molecules confirmed that the com-
pound 35 is 5-amino-4-nitro- derivative but the second
is 4-amino-5-nitro-isomer (34). The results obtained
were in agreement with our interpretation of NMR spec-
tra. The signals of the methylene group and carbon
atoms of the imidazole ring of the all 5-amino-4-nitro
compounds were shifted toward the lower field.
EXPERIMENTAL
Melting points were determined on a Boetius apparatus and
1
were uncorrected. The H and 13C NMR spectra were recorded
on Varian Gemini 300 VT spectrometer (300 and 75 MHz
respectively). Chemical shifts (d) are expressed in ppm, rela-
tive to tetramethylsilane (TMS) as an internal standard, using
DMSO–d6 as solvents. Coupling constants (J values) are
expressed in Hertz (Hz). Splitting patterns are designated as
follows: s, singlet; d, doublet; t, triplet; m, multiplet. MS spec-
tra were recorded on a 402 AMD INTECTRA apparatus by
the electron impact technique, operating at 75 eV. The infrared
(IR) spectra were recorded in KBr tablets using a Specord 75–
IR spectrophotometer and were expressed in cmꢀ1 scale. Ele-
mental analysis was performed on a Vario EL III model of
elemental analyzer and data of C, H, and N were within
60.4% of calculated values. The progress of reactions and pu-
rity of products were controlled with thin-layer chromatogra-
phy method (TLC) on silica gel plates (60 F254 from Merck)
in a CHCl3/MeOH (9:1, v/v) as a developing system. The
spots on the plates were observed in the UV light (k ¼
254nm). Solid products of amino-nitro-derivatives were puri-
fied in the crystallization process using acetonitrile. Crude,
oily products were purified by column chromatography on
silica gel using the mixture of chloroform and methanol (50:0
! 50:5) as eluent. Among substances, which were used as
substrates, the epichlorohydrin, epoxypropane, epibromohydrin,
phenacyl bromides, and iron dust were commercial products.
Compounds 4–8, 10–12, and 14–18 were obtained according
to the literature method [9,23–25].
1-(3-Bromo-2-hydroxypropyl)-2-methyl-4,5-dinitroimidazole
(9). The 2-methyl-4,5-dinitroimidazole (3.44 g, 20 mmol) was
added to epibromohydrin (3.42 mL, 40 mmol). The mixture
was heated under reflux for about 3 h. Then, cooled and
poured into the water. The precipitate was filtered off, washed
with water, air-dried and crystallized from 40% EtOH as yel-
low needles; 5.40 g (87.5%); mp 103–105ꢁC; Rf ¼ 0.64; IR:
1
In conclusion, we have demonstrated very selective
nitro group reduction method in the dinitroimidazole
3380, 1520, 1340; H NMR (300 MHz, DMSO–d6): d ¼ 5.92
(m, 1H, OH), 4.49 (m, 1H, CH), 4.21 and 4.00 (2 m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Selective Reduction of 2,4-Dinitro- and 4,5-Dinitroimidazole
Derivatives Using Iron Dust
1053
CH2Br), 3.59 (m, 2H, N-CH2), 2.49 (s, 3H, CH3); 13C NMR
(75 MHz, DMSO–d6): d ¼ 145.42, 139.29, 130.68, 67.97,
50.09, 35.81, 13.72; ms: m/z 308 (2) and 310 (2) (Mþ), 182
(100.0); Anal. calc. for C7H9N4O5Br: C, 27.29; H, 2.94; N,
18.19; found: C, 27.25; H, 2.98; N, 18.22.
fied by column chromatography on silica gel. All new products
were crystallized from MeCN.
2-Amino-1-methyl-4-nitroimidazole (21). This compound
was obtained as yellow needles (MeCN), 0.15 g (53.6%); mp
1
216–218ꢁC; Rf ¼ 0.18; IR: 3425, 3265, 1627, 1554, 1300; H
1-(3-Bromo-2-oxopropyl)-2-methyl-4,5-dinitroimidazole
(13). To a solution of 9 (3.10 g, 10 mmol) in acetone
(50 mL), at room temperature was dropped Jones reagent (10
mL). After 24 h, i-PrOH (10 mL) was added. The dark green
precipitate was filtered and washed with a small volume of ac-
etone. The combined filtrates were poured into the water (200
mL) and the solution was held 2–3 days to afford the crystal-
line solid. The precipitate was filtered off, washed with water,
air-dried, and crystallized from MeOH as yellow needless;
2.32 g (76.0%); mp 117–119ꢁC; Rf ¼ 0.64; IR: 1720, 1510,
1380; 1H NMR (300 MHz, DMSO–d6): d ¼ 5.54 (s, 2H,
CH2), 4.59 (s, 2H, CH2Br), 2.43 (s, 3H, CH3); 13C NMR (75
MHz, DMSO–d6): d ¼ 193.95, 146.10, 140.06, 129.42, 53.28,
33.62, 13.31; ms: m/z 308 (15) and 306 (16) (Mþ), 156 (100);
Anal. calc. for C7H7N4O5Br: C, 27.47; H, 2.92; N, 18.31;
found: C, 27.52; H, 2.97; N, 18.28.
NMR (300 MHz, DMSO–d6): d ¼ 7.88 (s, H, 5-Im), 6.23 (s,
2H, NH2), 3.44 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6):
d ¼ 149.38, 143.29, 119.93, 32.30; ms: m/z 142 (68) (Mþ), 42
(100); Anal. calc. for C4H6N4O2: C, 33.82; H, 4.25; N, 39.44;
found: C, 33.86; H, 4.20; N, 39.42.
2-Amino-4-nitro-1-phenacylimidazole (22). This compound
was obtained as yellow needles (MeCN), 0.40 g (81.3%); mp
243–245ꢁC; Rf ¼ 0.41; IR: 3400, 3270, 1680, 1627, 1560,
1
1295; H NMR (300 MHz, DMSO–d6): d ¼ 8.03 (m, 2H, 2,6-
Ph), 7.84 (s, H, 5-Im), 7.73 (m, H, 4-Ph), 7.60 (m, 2H, 3,5-
Ph), 6.31 (s, 2H, NH2), 5.56 (s, 2H, CH2); 13C NMR (75
MHz, DMSO–d6):
d
¼
192.16, 149.51, 143.63, 134.34,
134.06, 128.92, 128.11, 119.67, 51.83; ms: m/z 246 (14) (Mþ),
105 (100); Anal. calc. for C11H10N4O3: C, 53.68; H, 4.09; N,
22.76; found: C, 53.73; H, 4.11; N, 22.81.
2-Amino-1-(p-chlorophenacyl)-4-nitroimidazole (23). This
compound was obtained as yellow needles (MeCN), 0.42 g
(75.0%); mp 260–262ꢁC; Rf ¼ 0.43; IR: 3375, 3265,1675,
General procedure for synthesis of N-phenacyl-2,4-dini-
troimidazole derivatives (19–20). The solution of Na (1.38 g,
60 mmol) in absolute EtOH (40 mL) was added dropwise
under stirring to a solution of 2,4-dinitroimidazole (3) (7.90 g,
50 mmol) in absolute ethanol (50 mL). Subsequently, a solu-
tion of phenacyl bromide or p-chlorophenacyl bromide
(50 mmol) in absolute ethanol (100 mL) was dropped and
heated under reflux for 4 h. The mixture was cooled and the pre-
cipitate was filtered off, air-dried, and crystallized from EtOH.
2,4-Dinitro-1-phenacylimidazole (19). This compound was
obtained as cream needles (EtOH), 12.50 g (90.6%); mp 123–
1
1634, 1565, 1285; H NMR (300 MHz, DMSO–d6): d ¼ 8.05
(m, 2H, 2,6-Ph), 7.82 (s, H, 5-Im), 7.70 (m, 2H, 3,5-Ph), 6.33
(s, 2H, NH2), 5.54 (s, 2H, CH2); 13C NMR (75 MHz, DMSO–
d6): d ¼ 191.33, 149.48, 143.64, 138.87, 133.03, 130.00,
129.05, 119.54, 51.83; ms: m/z 282 (6) and 280 (18) (Mþ),
139 (100); Anal. calc. for C11H9N4O3Cl: C, 47.17; H, 3.23; N,
20.00; found: C, 47.15; H, 3.26; N, 20.05.
4-Amino-1-methyl-5-nitroimidazole (24). This compound
was obtained as yellow needles (MeCN), 0.03 g (10.7%); mp
1
1
125ꢁC; Rf ¼ 0.64; IR: 1680, 1526, 1320; H NMR (300 MHz,
157–160ꢁC; Rf ¼ 0.18; IR: 3405, 3265, 1620, 1540, 1350; H
DMSO–d6): d ¼ 8.72 (s, 1H, 5-Im), 8.09 (m, 2H, 2,6-Ph),
7.76 (m, 1H, 4-Ph), 7.66 (m, 2H, 3,5-Ph), 6.27 (s, 2H, CH2);
13C NMR (75 MHz, DMSO–d6): d ¼ 190.84, 142.30, 141.69,
134.87, 133.34, 129.27, 128.27, 126.86, 57.24; ms: m/z 276
(28) (Mþ), 105 (100); Anal. calc. for C11H8N4O5: C, 47.86; H,
2.92; N, 20.29; found: C, 47.90; H, 2.94; N, 20.32.
NMR (300 MHz, DMSO–d6): d ¼ 7.72 (s, 1H, 2-Im), 7.40 (s,
2H, NH2), 3.76 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6):
d ¼ 153.23, 143.56, 121.09, 34.83; ms: m/z 142 (51) (Mþ), 42
(100); Anal. calc. for C4H6N4O2: C, 33.82; H, 4.25; N, 39.44;
found: C, 33.86; H, 4.26; N, 39.45.
4-Amino-1,2-dimetylo-5-nitroimidazole (25). This com-
pound was obtained as yellow needles (MeCN), 0.09 g
(29.0%); mp 265–268ꢁC; Rf ¼ 0.43; IR: 3405, 3265, 1625,
1-(p-Chlorophenacyl)-2,4-dinitroimidazole (20). This com-
pound was obtained as cream needles (EtOH), 11.20 g (72.2%);
mp 154–156ꢁC; Rf ¼ 0.62; IR: 1680, 1526, 1320; 1H NMR
(300 MHz, DMSO–d6): d ¼ 8.71 (s, 1H, 5-Im), 8.12 (m, 2H,
2,6-Ph), 7.74 (m, 2H, 3,5-Ph), 6.26 (s, 2H, CH2); 13C NMR (75
MHz, DMSO–d6): d ¼ 190.02, 142.29, 141.65, 139.80, 132.05,
130.18, 129.42, 126.85, 57.16; ms: m/z 312 (11), 310 (32)
(Mþ), 139 (100); Anal. calc. for C11H7N4O5Cl: C, 42.61; H,
2.27; N, 18.07; found: C, 42.58; H, 2.24; N, 18.10.
General procedure for synthesis of Aminonitroimidazoles
(21–38). Appropriate N-substituted 2,4-dinitro-, 4,5-dinitro-, or
2-methyl-4,5-dinitroimidazole derivatives (2 mmol) were dis-
solved in glacial AcOH (25 mL), and the excess of iron dust
(0.37 g, 6.60 mmol) was added. The resulting mixtures were
then left for about 3 days at room temperature shaking them
from time to time. Upon completion reaction, the excess of
iron and its oxidation products were filtered off, and the reac-
tion mixtures were diluted with water (75 mL). The precipi-
tated crude products were filtered off. If products not solidi-
fied, then the filtrate was extracted with CHCl3 (4 ꢂ 5 mL)
and the combined organic phases were dried (MgSO4), filtered
off. After removal of the solvents, the crude product was puri-
1
1555, 1380; H NMR (300 MHz, DMSO–d6): d ¼ 7.47 (s, 2H,
NH2), 3.70 (s, 3H, N-CH3), 2.27 (s, 3H, CH3); 13C NMR (75
MHz, DMSO–d6): d ¼ 153.20, 152.66, 120.32, 32.88, 13.84;
ms: m/z 156 (100) (Mþ); Anal. calc. for C5H8N4O2: C, 38.47;
H, 5.16; N, 35.89; found: C, 38.51; H, 5.21; N, 35.93.
5-Amino-1-(3-chloro-2-hydroxypropyl)-4-nitroimidazole
(26). This compound was obtained as dark yellow pales
(MeCN), 0.14 g (31.9%); mp 160–162ꢁC; Rf ¼ 0.05; IR: 3360,
3325, 3225, 1625, 1560, 1340; 1H NMR (300 MHz, DMSO–
d6): d ¼ 7.57 (s, 2H, NH2), 7.20 (s, 1H, 2-Im), 5.71 (s, 1H,
OH), 3.90 (m, 2H, N-CH2), 3.68 (m, 2H, CH2Cl), 3.58 (m,
1H, CH); 13C NMR (75 MHz, DMSO–d6): d ¼ 143.39,
132.56, 128.06, 67.80, 47.34, 47.19; ms: m/z 222 (19) and 220
(44) (Mþ), 70 (100); Anal. calc. for C6H9N4O3Cl: C, 32.75; H,
4.12; N, 25.46; found: C, 32.80; H, 4.15; N, 25.47.
5-Amino-1-(3-chloro-2-hydroxypropyl)-2-methyl-4-nitroimid-
azole (27). This compound was obtained as light yellow pales
(MeCN), 0.16 g (34.1%); mp 206–208ꢁC; Rf ¼ 0.25; IR: 3360,
3325, 3300, 1625, 1560, 1400; 1H NMR (300 MHz, DMSO–
d6): d ¼ 7.61 (s, 2H, NH2), 5.72 (s, 1H, OH), 3.91 (m, 2H, N-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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D. Olender, J. Zwawiak, and L. Zaprutko
1054
Vol 47
CH2), 3.78 (m, 2H, CH2Cl), 3.64 (m, 1H, CH), 2.23 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO–d6): d ¼ 144.61, 140.30,
126.80, 67.78. 47.56, 46.29, 13.44; ms: m/z 236 (16) and 234
(45) (Mþ), 55 (100); Anal. calc. for C7H11N4O3Cl: C, 35.91;
H, 4.73; N, 23.93; found: C, 35.92; H, 4.75; N, 23.96.
5-Amino-1-(3-bromo-2-hydroxypropyl)-2-methyl-4-nitroimid-
azole (28). This compound was obtained as yellow needles
(MeCN), 0.14 g (25.4%); mp 195–197ꢁC; Rf ¼ 0.19; IR: 3380,
3350, 3250, 1625, 1565, 1345; 1H NMR (300 MHz, DMSO–
d6): d ¼ 7.61 (s, 2H, NH2), 5.74 (m, 1H, OH), 3.70 (m, 5H,
CH2CH(OH)CH2Br), 2.23 (s, 3H, CH3); 13C NMR (75 MHz,
DMSO–d6): d ¼ 144.40, 140.09, 126.64, 67.34, 47.09, 37.23,
13.50; ms: m/z 280 (7) and 278 (7) (Mþ), 80 (100); Anal.
calc. for C7H11N4O3Br: C, 30.24; H, 3.98; N, 20.15; found: C,
30.22; H, 4.03; N, 20.18.
4-Amino-2-methyl-5-nitro-1-phenacylimidazole (34). This
compound was obtained as light yellow pales (MeCN), 0.16 g
(30.1%); mp 227–229ꢁC; Rf ¼ 0.45; IR: 3400, 3250, 1680,
1
1620, 1500, 1340; H NMR (300 MHz, DMSO–d6): d ¼ 8.06
(m, 2H, 2,6-Ph), 7.68 (m, 5H, 3,4,5-Ph, NH2), 5.84 (s, 2H,
CH2), 2.28 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6): d ¼
192.52, 153.66, 153.28, 134.06, 133.94, 128.80, 128.07,
120.42, 52.01, 13.70; ms: m/z 260 (27) (Mþ), 105 (100); Anal.
calc. for C12H12N4O3: C, 55.41; H, 4.65; N, 21.54; found: C,
55.42; H, 4.62; N, 21.54.
5-Amino-2-methyl-4-nitro-1-phenacylimidazole (35). This
compound was obtained as yellow needles (MeCN), 0.03 g
(5.8%); mp 265–267ꢁC; Rf ¼ 0.28; IR: 3495, 3265, 1665,
1
1625, 1555, 1355; H NMR (300 MHz, DMSO–d6): d ¼ 8.06
(m, 2H, 2,6-Ph), 7.69 (m, 5H, 3,4,5-Ph, NH2), 5.63 (s, 2H,
CH2), 2.10 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6): d ¼
192.80, 146.08, 142.11, 135.40, 134.40, 129.83, 129.06,
127.17, 50.27, 13.44; ms: m/z 260 (53) (Mþ), 105 (100); Anal.
calc. for C12H12N4O3: C, 55.41; H, 4.65; N, 21.54; found: C,
55.40; H, 4.67; N, 21.50.
4-Amino-2-methyl-5-nitro-1-(2-oxopropyl)-imidazole (29). This
compound was obtained as yellow pales (MeCN), 0.20 g
(51.3%); mp 232–234ꢁC; Rf ¼ 0.26; IR: 3420, 3350, 1720,
1
1620, 1520, 1340; H NMR (300 MHz, DMSO–d6): d ¼ 7.60
(s, 2H, NH2), 5.13 (s, 2H, CH2), 2.20 (s, 6H, 2xCH3); 13C
NMR (75 MHz, DMSO–d6): d ¼ 201.22, 153.16, 153.09,
120.29, 107.08, 54.40, 26.83, 13.59; ms: m/z 198 (100.0)
(Mþ); Anal. calc. for C7H10N4O3: C, 42.44; H, 5.08; N, 28.28;
found: C, 42.48; H, 5.05; N, 28.30.
4-Amino-1-(p-chlorophenacyl)-5-nitroimidazole (36). This
compound was obtained as yellow pales (MeCN), 0.12 g
(21.4%); mp 245–248ꢁC; Rf ¼ 0.23; IR: 3440, 3255, 1680,
1
1625, 1565, 1300; H NMR (300 MHz, DMSO–d6): d ¼ 8.06
4-Amino-1-(3-chloro-2-oxopropyl)-5-nitroimidazole (30). This
compound was obtained as yellow needles (MeCN), 0.08 g
(18.2%); mp 215ꢁC; Rf ¼ 0.23; IR: 3405, 3360, 1710, 1610,
(m, 2H, 2,6-Ph), 7.73 (s, 1H, 2-Im), 7.69 (m, 2H, 3,5-Ph), 7.61
(s, 2H, NH2), 5.85 (s, 2H, CH2); 13C NMR (75 MHz, DMSO–
d6): d ¼ 191.78, 153.16, 144.22, 138.90, 132.57, 129.79,
129.05, 120.33, 53.39; ms: m/z 282(3), 280 (10) (Mþ), 139
(100); Anal. calc. for C11H9N4O3Cl: C, 47.18; H, 3.24; N,
20.01; found: C, 47.20; H, 3.28; N, 19.98.
1
1500, 1300; H NMR (300 MHz, DMSO–d6): d ¼ 7.71 (s, 1H,
2-Im), 7.61 (s, 2H, NH2), 5.25 (s, 2H, NACH2), 4.68 (s, 2H,
CH2Cl); 13C NMR (75 MHz, DMSO–d6): d ¼ 195.94, 153.11,
144.29, 119.96, 53.57, 46.98; ms: m/z 220 (26) and 218 (75)
(Mþ), 68 (100); Anal. calc. for C6H7N4O3Cl: C, 33.05; H,
3.23; N, 25.69; found: C, 33.09; H, 3.26; N, 25.69.
4-Amino-1-(p-chlorophenacyl)-2-methyl-5-nitroimidazole
(37). This compound was obtained as dark yellow pales
(MeCN), 0.06 g (10.2%); mp 270–272ꢁC; Rf ¼ 0.43; IR: 3440,
3255, 1680, 1625, 1565, 1300; 1H NMR (300 MHz, DMSO–
d6): d ¼ 8.07 (m, 2H, 2,6-Ph), 7.70 (m, 4H, 3,5-Ph, NH2),
5.82 (s, 2H, CH2), 2.27 (s, 3H, CH3); 13C NMR (75 MHz,
DMSO–d6): d ¼ 191.70, 153.64, 153.24, 138.80, 132.76,
129.97, 128.92, 120.36, 51.96, 13.68; ms: m/z 296 (10), 294
(32) (Mþ), 139 (100); Anal. calc. for C12H11N4O3Cl: C, 49.01;
H, 3.77; N, 19.05; found: C, 49.04; H, 3.78; N, 19.09.
4-Amino-1-(3-chloro-2-oxopropyl)-2-methyl-5-nitroimidazole
(31). This compound was obtained as yellow needles (MeCN),
0.20 g (43.5%); mp 270ꢁC; Rf ¼ 0.20; IR: 3395, 3260, 1725,
1
1625, 1540, 1390; H NMR (300 MHz, DMSO–d6): d ¼ 7.65
(s, 2H, NH2), 5.24 (s, 2H, NACH2), 4.68 (s, 2H, CH2Cl), 2.23
(s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6): d ¼ 195.73,
153.44, 153.12, 120.12, 52.21 46.99, 13.62; ms: m/z 234 (18),
232 (50) (Mþ), 67 (100); Anal. calc. for C7H9N4O3Cl: C,
36.23; H, 3.90; N, 24.14; found: C, 36.20; H, 3.89; N, 24.15.
4-Amino-1-(3-bromo-2-oxopropyl)-2-methyl-5-nitroimidazole
(32). This compound was obtained as yellow crystals (MeCN),
0.21 g (38.5%); mp 186–189ꢁC; Rf ¼ 0.29; IR: 3395, 3260,
5-Amino-1-(p-chlorophenacyl)-2-methyl-4-nitroimidazole
(38). This compound was obtained as cream needles (MeCN),
0.08 g (13.5%); mp 220ꢁC; Rf ¼ 0.25; IR: 3420, 3250, 1680,
1
1625, 1540, 1320. H NMR (300 MHz, DMSO–d6): d ¼ 8.06
(m, 2H, 2,6-Ph), 7.71 (m, 4H, 3,5-Ph, NH2), 5.61 (s, 2H,
CH2), 2.10 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6): d ¼
190.88, 144.91, 139.65, 138.78, 132.75, 130.05, 128.76,
126.58, 49.65, 12.84; ms: m/z 296 (10), 294 (31) (Mþ), 139
(100); Anal. calc. for C12H11N4O3Cl: C, 49.01; H, 3.77; N,
19.05; found: C, 49.03; H, 3.75; N, 19.09.
1
1725, 1625, 1540, 1360; H NMR (300 MHz, DMSO–d6): d ¼
7.65 (s, 2H, NH2), 5.23 (s, 2H, NACH2), 4.68 (s, 2H, CH2Br),
2.24 (s, 3H, CH3); 13C NMR (75 MHz, DMSO–d6): d ¼
195.72, 153.44, 153.11, 120.11, 52.21, 46.98, 13.61; ms: m/z
278 (7), 276 (7) (Mþ), 67 (100); Anal. calc. for C7H9N4O3Br:
C, 30.46; H, 3.28; N, 20.30; found: C, 30.42; H, 3.26; N, 20.27.
4-Amino-5-nitro-1-phenacylimidazole (33). This compound
was obtained as dark yellow pales (MeCN), 0.10 g (20.4%);
mp 219–221ꢁC; Rf ¼ 0.30; IR: 3400, 3250, 1670, 1626, 1510,
Acknowledgment. This study was partially supported by Polish
State Committee for Scientific Research (Grant No. 2 PO5F
03927).
1
1350; H NMR (300 MHz, DMSO–d6): d ¼ 8.01 (m, 2H, 2,6-
Ph), 7.65 (m, 3H, 3,4,5-Ph), 7.69 (s, 2H, NH2), 7.23 (s, 1H, 2-
Im), 5.64 (s, 2H, CH2); 13C NMR NMR (75 MHz, DMSO–
d6): d ¼ 191.49, 153.65, 144.06, 134.18, 133.75, 129.01,
128.32, 120.42, 50.55; ms: m/z 246 (6) (Mþ), 105 (100); Anal.
calc. for C11H10N4O3: C, 53.69; H, 4.09; N, 22.77; found: C,
53.72; H, 4.10; N, 22.74.
REFERENCES AND NOTES
[1] De Luca, L. Curr Med Chem 2006, 13, 1.
[2] Mital, A. Sci Pharm 2009, 77, 497.
[3] Barry, C. E.; Boshoff, H. I. M.; Dowd, C. S. Curr Pharm
Des 2004, 10, 3239.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Selective Reduction of 2,4-Dinitro- and 4,5-Dinitroimidazole
Derivatives Using Iron Dust
1055
´
[15] Suwinski, J.; Walczak, K. Pol J Chem 1994, 68, 678.
´
[16] Suwinski, J.; Wagner, P. Tetrahedron 1996, 52, 9541.
[4] Edwards, D. I. J Antimicrob Chemother 1993, 31, 9.
[5] Silvestri, R.; Artico, M.; De Martino, G.; Ragno, R.; Massa,
S.; Loddo, R.; Murgioni, Ch.; Loi, A. G.; La Colla, P.; Pani, A. J Med
Chem 2002, 45, 1567.
[17] Lin, M.-J.; Sun, C.-M. J Comb Chem 2006, 8, 455.
[18] Cavalleri, B.; Volpe, G.; Arioli, V.; Perenti, F. Arzneim--
Forsch/Drug Res 1977, 27, 1889.
[6] Hodgkiss, R. J. Anti-Cancer Drug Des 1998, 13, 687.
[7] Kasai, S.; Nagasawa, H.; Yamashita, M.; Masui, M.; Kuwa-
saka, H.; Oshodani, T.; Uto, Y.; Inomata, T.; Oka, S.; Inayama, S.;
Hori, H. Bioorg Med Chem 2001, 9, 453.
[19] Makarov, V. A.; Riabova, O. B.; Granik, V. G.; Dahse, V.
M.; Stelzner, A.; Wutzler, P.; Schmidtke, M. Bioorg Med Chem Lett
2005, 15, 37.
[8] Hori, H.; Jin, C.-Z., Kiyono, M.; Kasai, S.; Shimamura, M.;
Inayama, S. Bioorg Med Chem 1997, 5, 591.
´
[9] Zaprutko, L.; Gajdzinski, M.; Michalska, W.; Pietkiewicz, K.;
[20] Little, T. L.; Webber, S. E. J Org Chem 1994, 59, 7299.
[21] Chen, B.-C.; Chao, S. T.; Sundeen, J. E.; Tellew, J.;
Ahmad, S. Tetrahedron Lett 2002, 43, 1595.
Lutomski, K.; Łukaszewski, Z.; Wrzeciono, U. Pharmazie 1989, 44, 817.
[10] Zaprutko, L.; Olender, D.; Gzella, A. Monatsch Chem
2003, 134, 1145.
[22] Bulusu, S.; Damavarapu, R.; Autera, J. R.; Behrens, R., Jr.;
Minier, L. M.; Villanueva, J.; Jayasuriya, K.; Axenrod, T. J Phys
Chem 1995, 99, 5009.
[11] Castera, C.; Crozet, M. D.; Crozet, M. P.; Vanelle, P. Het-
erocycles 2005, 65, 337.
[23] Novikov, S. S.; Khmel’nitskii, L. I.; Lebedev, O. V.; Sevas-
t’yanova, V. V.; Epishina, L. V. Khim Geterotsikl Soedin 1970, 6,
503.
[12] Grehn, L.; Ding, L.; Ragnarsson, U. Acta Chem Scand
1990, 44, 67.
_
[24] Olender, D.; Zwawiak, J.; Lukianchuk, V.; Lesyk, R.; Kro-
[13] Palmer, B. D.; Zijl, P.; Denny, W. A.; Wilson, W. R. J
Med Chem 1995, 38, 1229.
pacz, A.; Fojutowski, A.; Zaprutko, L. Eur J Med Chem 2009, 44,
645.
[14] Helal, C. J.; Kang, Z.; Lucas, J. C.; Bohall, B. R. Org Lett
2004, 6, 1853.
[25] Sehgal, R. K.; Webb, M. W.; Agrawal, K. C. J Med Chem
1981, 24, 601.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet