Synthesis, spectroscopic and structural studies of new 2-substituted 4-nitroimidazoles

Article abstract of DOI:10.2174/15701786113106660090

This study describes the synthesis of novel 4-nitro-2-substitutedimidazole derivatives via a transposition reaction of nitro group. Conversion of 5-nitro-2-phenylethanol (styryl) imidazole derivatives into the corresponding 4- nitroisomers was achieved in good yields in nitrobenzene using a catalytic amount of methyl iodide. Spectroscopic study and single crystal X-ray structures are reported for five compounds to understand the conformational structures of these compounds.

Full text of DOI:10.2174/15701786113106660090

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174
Letters in Organic Chemistry, 2014, 11, 174-179
Synthesis, Spectroscopic and Structural Studies of New 2-Substituted 4-
Nitroimidazoles
Hayette Alliouchea, Abdelmalek Bouraioua, Sofiane Bouacidab, Mebarek Bahnousa,
Thierry Roisnelc and Ali Belfaitah*a
aLaboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Faculté des Sciences Exactes, Cam-
pus de Chaabat Ersas, Université Constantine1, 25000, Algérie; bUnité de Recherche de Chimie de l’Environnement et
Moléculaire Structurale, Université Constantine1, 25000, Algérie; cCentre de Diffractométrie X, Sciences Chimiques de
Rennes, UMR 6226 CNRS, Université de Rennes I, 35042 Rennes CEDEX, France
Received July 09, 2013: Revised October 19, 2013: Accepted October 29, 2013
Abstract: This study describes the synthesis of novel 4-nitro-2-substitutedimidazole derivatives via a transposition reac-
tion of nitro group. Conversion of 5-nitro-2-phenylethanol (styryl) imidazole derivatives into the corresponding 4-
nitroisomers was achieved in good yields in nitrobenzene using a catalytic amount of methyl iodide. Spectroscopic study
and single crystal X-ray structures are reported for five compounds to understand the conformational structures of these
compounds.
Keywords: Transposition reaction, 4-nitroimidazole, 5-nitroimidazole, crystal structure.
INTRODUCTION
by a transposition reaction. The structures of prepared com-
pounds were established and examined by NMR spectros-
copy and by X-ray diffraction.
Nitroimidazoles and their derivatives have drawn a con-
tinuing interest over the years due to their varied biological
activities. 5-Nitroimidazoles are commonly used in medi-
cine, and some of them have been extensively investigated
for hypoxia-selective cytotoxicity and hypoxic cell radiosen-
sitization in in vitro and in vivo studies [1].
Initially, 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-1-phenyl
ethanol 2a was prepared by reacting 1,2-dimethyl-5-nitro-
1H-imidazole 1 with benzaldehyde, as preferred aromatic
aldehyde in condensation reaction, in the presence of potas-
sium hydroxide in ethanol at room temperature. The (E)-1-
methyl-5-nitro-2-styryl-1H-imidazole 3a was easily obtained
by acid catalyzed dehydration of the corresponding com-
pound 2a, in glacial acetic acid (Scheme 1) [9].
The 5-nitroimidazole derivatives generally possess a sig-
nificant biological activity. However, only few properties of
4-nitroimidazole derivatives have been reported [2]. This
could be the result of the few available synthetic methods of
4-nitroimidazole derivatives.
The transposition reaction of 2-(phenylethanol)-5-
nitroimidazole 2a and 2-styryl-5-nitroimidazole 3a, realized
in nitrobenzene in the presence of catalytic amount of methyl
iodide, was selected as a model reaction for catalyst evalua-
tion (Scheme 1).
Nitration of 1, 2-disubstitutedimidazoles leads to a mix-
ture of 4-nitro and 5-nitro derivatives, [3] and the presence
of various substituents at second position does not change
the direction of nitration [4]. For example, the nitration of 2-
ethylimidazole, [5] 2-isopropylimidazole, [6] and 2-
styrylimidazole [7] takes place similarly.
The results showed that no reaction took place at room
temperature. However, after 24h at 160 °C, in minimum vol-
ume of nitrobenzene, the starting material 2a or 3a had been
consumed (TLC) and quantitative yields of products 4a or 5a
were obtained without the need of chromatographic separa-
tion. The 4-nitroimidazoles 4a and 5a are isolated, by simple
filtration after addition of hexane/Et2O mixture, in 89 and
94%, respectively.
The transposition of nitro group in 5-nitroimidazoles is
described in the literature and represents an efficient syn-
thetic procedure of 4-nitroisomer [8]. However, only few
examples of this reaction are described using methyl iodide
[8b].
In order to enlarge the known transposition reaction of
nitro group to other substituted 5-nitroimidazole derivatives,
we describe herein an efficient and selective procedure for
the preparation of 4-nitro-2-phenylethanol (styryl) imidazole
Note that this method furnishes compound 5a in high
yield compared to the previously reported reaction involving
the addition of ꢀBr3 radical as catalyst (65%) [8b].
The proposed mechanism is similar to the previously re-
ported one for the transposition of 1,2-dimethyl-5-nitroimi-
dazole using methyl iodide as catalyst. It is clear that the
thermal decomposition of the 1,2,3-trimethyl-5-nitroimida-
zolium entity during the transformation with elimination of a
*Address correspondence to this author at the Laboratoire des Produits
Naturels d’Origine Végétale et de Synthèse Organique, Faculté des Sciences
Exactes, Campus de Chaabat Ersas, Université Constantine1, 25000,
Algérie; Tel: +213 31818862; Fax: +213 31818862;
E-mail: abelbelfaitah@yahoo.fr
1875-6255/14 $58.00+.00
© 2014 Bentham Science Publishers

Synthesis, Spectroscopic and Structural Studies of New 2-Substituted 4-Nitroimidazoles
Letters in Organic Chemistry, 2014, Vol. 11, No. 3 175
HO
N
N
N
i
ii
N
N
O2N
N
O2N
O2N
3a
iii
2a
1
iii
HO
O2N
O2N
N
N
N
N
4a
5a
Scheme 1. Reagents and conditions: (i) benzaldehyde (3 equiv), KOH, EtOH, rt, 48h; (ii) AcOH, H2SO4, 110 °C, 18h; (iii) methyl iodide
(0.1 equiv), nitrobenzene, 160 °C, 24h.
O2N
i
N
N
N
N
R
R
O2N
3b-h
Scheme 2. Reagents and conditions: (i) methyl iodide (0.1 equiv), nitrobenzene, 160 °C, 24h.
5b-h
methyl group leads to the formation of the 4-nitroimidazole
structure [8b].
pared with 4-position. However, in 13C NMR, no significant
differences were observed in the chemical shifts of the
methyl carbon atom for the two isomers.
Encouraged by these results, and to demonstrate the effi-
ciency and the scope of the present method, we performed
the intramolecular transposition reaction using various sub-
stitutions on the aromatic phenyl ring.
Chemical shifts of carbon C5 are about 124 ppm for the 4-
nitro derivatives (compounds 4a and 5a) and 139 ppm for
the 5-nitro isomers (2a and 3a), whereas chemical shifts for
carbon C4 are around 146 ppm for the 4-nitro and 133 ppm
for the corresponding 5-nitro isomer. The chemical shift of
C2 atom is also dependent on the location of the nitro sub-
stituent. Thus in 5-nitroimidazole series (Table 2), it is at
some 5-7 ppm more downfield than that in the corresponding
4-nitroimidazole (Table 3).
X-ray crystallographic analyses of compounds 2a, 3a, 4a
and 5a were carried out to examine the influence of the nitro
substituent on the molecular structure of the imidazole ring.
Moreover, the structures of nitroimidazoles have been stud-
ied more thoroughly and can explain wide applications of
these compounds, especially in medicine.
As shown in (Table 1), substrates 3b-h containing aro-
matic nucleus with electron-withdrawing groups (such as
halide) or electron-donating groups (such as methoxy or
methyl), gave the corresponding products 5 in good to high
yields under the same reaction conditions. No obvious ef-
fects resulting from the electronic or steric nature of the
aromatic ring substituents were observed.
Most studies of nitroimidazoles are focused on the syn-
thesis and biological activity, but only a few studies are con-
centrated to understand the conformational structures of
these compounds.
Structures of products 2a, 3a, 4a, and 5a were confirmed
by means 1H, 13C-NMR spectroscopy and X-ray single
crystal diffraction. Spectroscopic results were in full
agreement with literature report [10] and chemical shifts data
of selected atoms in 1-methyl-2-substituted-4- and 5-
nitroimidazoles are summarized in (Tables 2 and 3).
Suitable crystals for X-ray experiments of compounds 1,
2a, 3a, 4a and 5a were obtained by slow evaporation from a
water/methanol or isopropanol solution at room temperature.
X-ray single-crystal structures of compounds 1 have been
shown in (Fig. 1), those of compounds 2a and 3a, in (Fig. 2)
and those of 4a and 5a in (Fig. 3) [11].
The analysis shows that the values for the ring carbon at-
oms and protons are definitive for the groups of compounds
and can be used to assign unambiguously the position of the
nitro group.
Selected geometry details of compounds 1, 2a, 3a, 4a
and 5a are presented in (Table 4). Compound 1 is composed
of 1-methylimidazole bearing at C2 a methyl group and a
nitro group at C5 atom.
1
In H NMR spectroscopy, the 1-methyl group protons
The bond lengths of 1,2-dimethyl-5-nitroimidazole 1
have been compared with the corresponding ones of Bis(2-
methylimidazol-1-yl)methane[12]. This examination shows
that the bond lengths of N1-C2, N3-C4 and N1-C1 in the
appeared, for 5-nitroimidazole derivatives 2a and 3a at low
field (Table 2) relative to the corresponding 4-nitroimidazole
4a and 5a respectively (Table 3). This can be explained by
the greater de-shielding effect of the 5-nitro group as com-

176 Letters in Organic Chemistry, 2014, Vol. 11, No. 3
Alliouche et al.
Table 1. Methyl Iodide Catalyzed Transposition of Nitro Group
Table 2. 13C (1H) NMR Chemical Shifts of 2-substituted-5-
nitroimidazole
N
R
Compounds
4a
Product
Yield (%)a
N
HO
O2N
O2N
O2N
CH3
N
89
N
Chemical Shifts (ꢀ) Values
Compound
R
1-CH3
C2
C4
C5
5a
5b
N
N
2a
3a
CH2CH(OH)Ph 33.7(3.75)
CH=CH-Ph 33.2(4.04)
152.3 132.9 139.1
150.2 134.6 139.5
94
Table 3. 13C (1H) NMR Chemical Shifts of 2-substituted-4-
nitroimidazole
O2N
N
N
94
96
97
83
95
O2N
N
R
N
CH3
5c
O2N
O2N
Br
N
N
Compound
Chemical shifts (ꢀ) values
1-CH3 C2 C4
R
C5
5d
Cl
N
N
4a
5a
CH2CH(OH)Ph 33.9(3.58) 147.0 145.6 123.5
CH=CH-Ph 33.9(3.86) 145.4 146.4 124.2
5e
5f
imidazole ring are practically unchanged when the nitro
group is introduced into position 5.
O2N
N
N
The incorporation of an NO2 group affects the valence
angles of the imidazole cycle [13]. This variation is caused
by electron-acceptor effect of the nitro group (see Table 4).
The examination of valence angles of compound 1 shows an
increasing of the angle C4-C5-N1 as well as a decreasing of
the adjacent angle N3-C4-C5 compared with Bis(2-
methylimidazol-1-yl)methane.
MeO
Cl
O2N
N
N
Series of compounds 2a (4a) and 3a (5a) are composed
of 1-methylimidazole bearing at C2 a phenylethanol or a
styryl fragment, and a nitro group at C5 (C4) atom. X-ray
analysis data of the compounds 2a, 3a, 4a and 5a given in
(Table 4) indicate that the five-membered ring of 4 or 5-
nitroimidazole is planar, while the nitro group is slightly
rotated by 2.15(1)°, 5.03(12)°, 6.06(1)° and 1.33(9)°, respec-
tively with respect to the imidazole cycle.
5g
5h
O2N
OMe
N
88
94
N
O2N
N
N
Cl
The bond lengths of 4 or 5-nitroimidazole unit have been
compared with the corresponding ones of Bis(2-
methylimidazol-1-yl)methane. The bond lengths of C4-C5,
C2-N3 of both 5-nitro-2-substitutedimidazoles (2a and 3a)
or their 4-isomers (4a and 5a), are longer than that in Bis(2-
methylimidazol-1-yl)methane. Similarly, the location of ni-
tro group influences the bond length of C5-N1. Indeed, the
C5-N1 bond length in the Bis(2-methylimidazol-1-
yl)methane is 1.374(3)Å, which is longer than the corre-
sponding one in 4-nitroimidazole derivatives (for 4a,
1.3559(16)Å and 1.3595(16)Å for 5a), but shorter than that
in 5-isomers (for 2a, 1.3848(16)Å and 1.376(2)Å for 3a).
a Yields of isolated pure products from transposition reaction of 2a and 3a-h
Fig. (1). ORTEP plot of the X-ray crystal structure of 1. Displace-
ment ellipsoids are drawn at the 50% probability level [11].

Synthesis, Spectroscopic and Structural Studies of New 2-Substituted 4-Nitroimidazoles
Letters in Organic Chemistry, 2014, Vol. 11, No. 3 177
2a
3a
Fig. (2). ORTEP plot of the X-ray crystal structure of 5-nitroimidazoles 2a and 3a. Displacement ellipsoids are drawn at the 50% probability
level [11].
4a
5a
Fig. (3). ORTEP plot of the X-ray crystal structure of 4-nitroimidazoles 4a and 5a. Displacement ellipsoids are drawn at the 50% probability
level [11].
Table 4. Selected Bonds and Angles for Characterized Compounds
Bonds Lengths
1
2a
3a
4a
5a
Bis(2-methylimidazol-1-yl)methane
N1-C2
C2-N3
1.3571(19)
1.3367(19)
1.361(2)
1.3524(15)
1.3409(16)
1.3545(17)
1.3647(18)
1.3848(16)
1.4724(16)
1.358(2)
1.345(2)
1.348(2)
1.370(2)
1.376(2)
1.466(2)
1.3680(17)
1.3225(16)
1.3649(16)
1.3561(18)
1.3559(16)
1.4656(16)
1.3752(15)
1.3272(16)
1.3570(15)
1.3736(17)
1.3595(16)
1.4631(15)
1.362(2)
1.309(3)
1.368(3)
1.341(3)
1.374(3)
1.445(2)
N3-C4
C4-C5
1.3679(19)
1.3824(18)
1.4712(18)
C5-N1
N1-C1
Bands Angles
N1-C2-N3
C2-N3-C4
N3-C4-C5
C4-C5-N1
C5-N1-C2
112.22(14)
105.68(12)
109.40(13)
107.51(13)
105.19(12)
111.97(10)
105.95(10)
109.29(11)
107.65(11)
105.14(10)
111.69(16)
105.67(14)
109.86(15)
107.28(15)
105.49(14)
111.08(11)
103.90(10)
112.59(11)
104.42(11)
108.01(11)
111.49(10)
103.81(10)
112.89(11)
104.11(11)
107.70(10)
110.62(16)
105.69(15)
111.0(2)
105.35(17)
107.29(15)
It is interesting to note that the bond lengths of both C4-
C5 and N1-C1 are practically equal in the two isomers
series. However, the N1-C2 and N3-C4 are longer in 4-nitro-
2-substitutedimidazoles than in 5-isomers, for the two
series.
An increase of the valence angle in the 4 or 5-
nitroimidazole ring of the carbon atom bearing the nitro
group (C4 or C5, respectively) as well as a decrease of the
adjacent angles (C5 or C4, respectively), were observed for
the 2-substituedimidazole derivatives 4a and 5a compared
with Bis(2-methylimidazol-1-yl)methane. Consequently, the
two adjacent angles to C4 and C5 (C5-N1-C2 and C4-N3-
C2) are affected. Similar effect was observed in others nitro-
imidazoles [14]. However, the valence angles N1-C2-N3 in 5
or 4-nitro-2-substitutedimidazole derivatives are not changed
and are similar to those observed in Bis(2-methylimidazol-1-
yl)methane. In summary, these spectroscopic data provide a
The others two C-N bond lengths in both for 5-
nitroimidazole, C2-N3 (1.3409(16)Å), and C5-N1
(1.3848(16)Å) for 2a, and for 3a, C2-N3 (1.345(2)Å), C5-
N1 (1.376(2)Å) are longer than the corresponding bonds in
4-nitroimidazoles (for 4a, C2-N3 1.3225(16)Å, C5-N1
1.3559(16)Å, and C2-N3 1.3272(16)Å, C5-N1 1.3595(16)Å
for 5a).

178 Letters in Organic Chemistry, 2014, Vol. 11, No. 3
Alliouche et al.
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direct indication of the location effect of the nitro group on
the structural features of the imidazole nucleus.
In conclusion, we have elaborated an effective synthetic
pathway toward unknown 4-nitro-2-phenylethanol or styryl
imidazole derivatives by reaction of methyl iodide with the
corresponding 5-nitroisomers, which could be prepared in-
[3]
1
dependently by simple methods in high yields. H, and 13C-
NMR and X-ray crystallographic analysis of the nitrated
compounds revealed that their molecular structures were
affected by the position of the nitro group. These routes may
contribute to the synthesis of novel 4-nitroisomer derivatives
and may open new ways for their utilization in bioorganic
science. The structural information is potentially useful for a
further derivatization of these compounds.
[4]
[5]
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
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ACKNOWLEDGEMENTS
We are grateful to all personnel at the PHYSYNOR
Laboratory, Université Constantine 1, for their assistance.
Financial support by MESRS (Ministère de l’Enseignement
Supérieur et de la Recherche Scientifique) and ATRST
(Agence Thématique pour la Recherche Scientifique et
Technologique)- Algeria has highly been acknowledged.
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Å, c = 10.8633(7) Å, ꢀ = 102.732(3)°, V = 643.76(8) Å3, Z = 4, ꢀc=
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Crystal structure analysis: for 2a: C12H13N3O3, Mr = 247.25 g.mol-1,
monoclinic, space group P 21/n, a = 7.5076(5) ꢁ, b = 10.1643(6) ꢁ,
c = 15.2589(9) ꢁ, ꢁ = 95.080(2)°, V = 1159.83(12) ꢁ3, Z = 4, ꢀc=
1.416 g.cm3, F(000) = 520, crystal size: 0.38 x 0.29 x 0.15 mm.
Crystal structure analysis for 3a: C12H11N3O2, Mr = 229.24 g.mol-1,
monoclinic, space group P 21/n, a = 6.4969(5) Å, b = 12.3713(10)
Å, c = 13.7871(8) Å, ꢁ = 102.732(3)°, V = 1080.89(14)Å3, Z = 4,
ꢀc= 1.409 g.cm3, F(000) = 480, crystal size: 0.38 x 0.16 x 0.11 mm.
Crystal structure analysis: for 4a: C12H13N3O3, Mr = 247.25 g mol-1,
monoclinic, space group P 21/c, a = 9.5950(9) Å, b = 12.0748(14)
Å, c = 10.5260(8) Å, ꢁ = 99.555(3)°, V = 1202.6(2) Å3, Z = 4,
ꢂc=1.366 g.cm3, F(000) = 520, crystal size: 0.33 x 0.3 x 0.3 mm.
Crystal structure analysis: for 5a: C12H11N3O2, Mr = 229.24 g mol-1,
triclinic, space group P -1, a = 6.7430(3) Å, b = 7.2223(3) Å, c =
11.6924(5) Å, ꢃ = 94.535(2)°, ꢁ = 104.866(2)°, ꢄ = 98.808(2)°,V =
539.68(4) Å3, Z = 2, ꢂc=1.411 g.cm3, F(000) = 240, crystal size:
0.34 x 0.19 x 0.07 mm. Crystallographic data (excluding structure
factors) for these compounds have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication num-
bers CCDC 920910 for 1, CCDC 901753 for 2a, CCDC 901751 for
3a, CCDC 901752 for 4a and CCDC 901754 for 5a. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif./cif.
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