Regioselective nitro group substitution. synthesis of isomeric 4-amino-5-nitro- and 5-amino-4-nitroimidazoles

Article abstract of DOI:10.3987/COM-12-12502

On the basis of the reactions between 4,5-dinitroimidazole derivatives (1-methyl-4,5-dinitroimidazole, 1,2-dimethyl-4,5-dinitroimidazole and ethyl 2- (4,5-dinitroimidazol-1-yl)acetate) and cyclic amines (morpholine, piperidine or pyrrolidine) in mild cond

Full text of DOI:10.3987/COM-12-12502

HETEROCYCLES, Vol. 85, No. 9, 2012
2197
HETEROCYCLES, Vol. 85, No. 9, 2012, pp. 2197 - 2211. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 6th May, 2012, Accepted, 2nd July, 2012, Published online, 9th July, 2012
DOI: 10.3987/COM-12-12502
REGIOSELECTIVE NITRO GROUP SUBSTITUTION. SYNTHESIS OF
ISOMERIC 4-AMINO-5-NITRO- AND 5-AMINO-4-NITROIMIDAZOLES
Lucjusz Zaprutko,* Justyna Żwawiak, Dorota Olender, and Andrzej Gzella
Department of Organic Chemistry, Pharmaceutical Faculty, Poznan University of
Medical Sciences, 60-780 Poznan, Grunwaldzka 6, Poland
Abstract – On the basis of the reactions between 4,5-dinitroimidazole derivatives
(1-methyl-4,5-dinitroimidazole, 1,2-dimethyl-4,5-dinitroimidazole and ethyl 2-
(4,5-dinitroimidazol-1-yl)acetate) and cyclic amines (morpholine, piperidine or
pyrrolidine) in mild conditions (THF or ethanolic solution), the order of nitro
group substitution has been discovered for the first time. The influence of the
solvent, steric effects and possibility of hydrogen bonds formation on the reaction
direction has been discussed. Also, the way of formation of diamino-substitution
product and interesting isomerization process is presented.
INTRODUCTION
Nitro-bearing imidazoles show a wide spectrum of pharmacological activity. The compounds with a nitro
group at position 5 are usually more active than the corresponding 4-nitro-derivatives. On the other hand,
4-nitroimidazoles show less toxicity than 5-nitro-derivatives. These effects are particularly pronounced
for 2,4- and 2,5-dinitroimidazoles. Introduction of an electron accepting substituent at position 5 in the 4-
nitroimidazole ring causes increase in cytotoxic and radiosensibiliting activity.1 These compounds are
essential especially in the treatment of diseases caused by bacteria and protozoa. The best known –
Metronidazole, is effective against Bacteroides, Fusobacterium, Megasphaera, Clostridium, sometimes
Peptococcus and Helicobacter pylorii. Tinidazole was found to be active against Gardnella vaginalis,
Propionibacterium, Eubacterium, Campylobacter, Actinomyces and Spirochetes. Nimorazole and
ornidazole have demonstrated activity against trichomoniasis.1-4 Besides, nitroimidazoles are good
radiation enhancers of hypoxic cells. From among nitroazoles, Misonidazole seems to be the best known

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HETEROCYCLES, Vol. 85, No. 9, 2012
radiosensitizer.5 Moreover, some bicyclic nitroimidazooxazoles show considerable activity against
tuberculosis.6,7
A number of azole derivatives with a nitro and amino group in the same molecule are known to show
antifungal,8 anti-HIV9 and antioxidant activity.10 One of the methods of obtaining aminonitroimidazoles
is the substitution of one nitro group with amine in 4,5-dinitroimidazoles. Some examples of these
reactions have been described earlier,11-14 but in each of these cases only respective 5-amino-4-
nitroimidazole derivatives were obtained. The substitution of C-4 nitro group with amines in some 4,5-
dinitroimidazole derivatives leading to the respective 4-amino-5-nitroimidazole derivatives has also been
described.15-17
There have been some reports on simultaneous substitution of both the nitro groups with amines.15,16
Suwinski et al.11 as well as Koehler and Dockner12 reported that the treatment of 1-methyl- or 1,2-
dimethyl-4,5-dinitroimidazole (1, 5) with amines in water or alcoholic (mainly ethanolic) solutions, with
or without addition of the base, led to the nucleophilic substitution of C(5) nitro group. According to
these methods only respective 5-amino-4-nitroimidazoles can be obtained.
In continuation of our earlier studies on nitroimidazoles,16 in this paper it is shown that the nucleophilic
substitution of nitro group takes place both in positions 4 and 5 as result of the treatment of 1-methyl-4,5-
dinitroimidazole (1), 1,2-dimethyl-4,5-dinitroimidazole (5), as well as ethyl 2-(4,5-dinitroimidazol-1-yl)-
acetate (9) with cyclic amines, especially with morpholine, piperidine or pyrrolidine in THF solution
(method A) or in ethanolic solution (method B). The influence of the solvent, steric effects and possibility
of hydrogen bond formation on the reaction direction is being discussed. For the first time, the order of
nitro groups substitution in N-alkyl-4,5-dinitroimidazoles has been determined. What is more, interesting
observations of isomers transformation has been made. It is proved that the isomeric 4-amino-5-nitro- and
1
5-amino-4-nitroimidazole derivatives can be distinguished on the basis of the H-NMR spectral analysis
of the substrates and reaction products. Moreover, the order of nitro group substitution is discovered and a
mechanism of formation of diamino-substitution product manners is presented.
RESULTS AND DISCUSSION
The target compounds were synthesized by the procedure illustrated in Scheme 1. These reactions were
carried out most effectively only in some selected solvents such as THF (method A) or ethanol (method
B). The use of other reaction media e.g. methylene chloride, acetonitrile, DMF or DMSO caused
formation of complex mixtures from which it was difficult to isolate stable single products in pure state.
However, the presence of desired compounds in comparable concentrations in these mixtures was
confirmed by TLC as well as spectroscopic methods.

HETEROCYCLES, Vol. 85, No. 9, 2012
2199
R1
N
R1
R1
N
R
NH
R
N
R2
O2N
O2N
R2
N
R2
O2N
R
+
N
N
N
Meth. A: THF, r.t.
or
Meth. A: EtOH, r.t.
O2N
N
2b, 3b, 4b,
6b, 7b, 8b,
2a, 3a, 4a,
6a, 7a, 8a,
1, 5, 9, 13
10b, 11b, 12b
10a, 11a, 12a
Compd.
No.
R1
R2
R
1
Me
-H
-----
-CH2-O-CH2-
2a, 2b
3a, 3b
4a, 4b
5
Me
-H
Me
-H
-CH2-CH2-CH2-
-CH2-CH2-
-----
Me
-H
Me
Me
Me
Me
Me
-H
6a, 6b
7a, 7b
8a, 8b
9
Me
-CH2-O-CH2-
-CH2-CH2-CH2-
-CH2-CH2-
-----
Me
Me
-CH2CO2Et
-CH2CO2Et
-CH2CO2Et
-CH2CO2Et
-CH2CO2Et
10a, 10b
11a, 11b
12a, 12b
13
-H
-CH2-O-CH2-
-CH2-CH2-CH2-
-CH2-CH2-
-----
-H
-H
Me
Scheme 1. Synthesis of 4-amino-5-nitroimidazoles and 5-amino-4-nitroimidazoles in the nitro group
substitution reaction.
The appropriate 4,5–dinitroimidazole derivatives 1, 5, 9, and 13 were treated with morpholine, piperidine
or pyrrolidine in THF solution, at room temperature and at the 1:2 molar ratio. In these conditions the
respective 4-amino-5-nitroimidazoles 2a, 3a, 4a, 6a, 10a, 11a and 12a (Scheme 1) were formed as major
products, which could be isolated in crystalline form. Most of them were obtained with a satisfactory
yield not less than 70%. The only exceptions were the piperidine derivatives 3a (yield 46%) and 11a
(yield 42%). The attempts of obtaining of the compounds with methyl groups at 1 and 2 position and with
piperidine or pyrrolidine group connected with C(4) atom (7a, 8a) in the state enabling full
characterisation were not successful. These compounds were partially decomposed during isolation and
purification processes, but the presence of the expected products in the mixtures formed was confirmed

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HETEROCYCLES, Vol. 85, No. 9, 2012
by TLC and 1H NMR methods. The TLC plate shows an intensive yellow spot with Rf higher than for the
opposite isomer. The proton magnetic resonance spectrum reveals a distinct signal at  = 3.83 ppm, near
the signal at  = 3.45 ppm, which are characteristic of N-methyl groups in the differently substituted
nitroimidazole ring. The isomeric 5-amino-4-nitroimidazole derivatives 2b, 3b, 4b, 6b, 7b, 8b, 10b, 11b
and 12b in these conditions were formed in the yield below 10%.
We have found that a substituent with significant steric and electronic effect at the N-1 position of
imidazole ring affects the reactivity of the nitro group in the nucleophilic substitution reactions. The ester
group in compounds 13 and 9 prevents or obstructs separation of products. Only in compounds 9, it is
possible to isolate 5-nitro isomers labelled with a letter a. The b type isomer was formed in small
amounts but it can be detected only by 1H NMR spectroscopy.
The nitro group bonded to C(4) atom of the imidazole ring seems to be privileged in the substitution
reactions in aprotic solvents (e.g. THF) because of the steric effects. Besides, it is expected that in the
formed sigma-complex, dihedral angle between C(5) nitro group and imidazole ring will be significantly
diminished because of nitro group participation in conjugated 4-amino-5-nitroimidazole system. It causes
significant shortening of exocyclic C(5)-NO2 bond. This effect is observed in different 4-amino-5-
nitroimidazoles with refcodes: ELUBIW, QIKDUJ, QIKFAR, SATBIZ, SATQIO, WOCWAM,
WOCWAM01 deposited in CSD data base, Cambridge, version 5.32.18 In the found seven structures,
C(5) nitro group is approximately placed in the imidazole ring plane, and mean bond distance between
C(5) and NO2 group is 1.391(6) Å. It is shorter by 13than normal single Csp2 – NO2 bond distance
(1.468(1) Å).19
Besides, a stabilization of C(5) nitro group is possible through the intramolecular hydrogen bond between
the oxygen atom of that group and the hydrogen atom of amine.
If ethanol is used as solvent instead of THF and the remaining reaction conditions are similar to those
given above, the products of treatment on 1, 5 and 9 with morpholine, piperidine or pyrrolidine are again
a mixture of both isomeric 4-amino-5-nitro- and 5-amino-4-nitroimidazole derivatives. But then the yields
of 5-amino-4-nitroimidazole 2b – 4b and 6b – 8b are three to five times higher than reaction was run in
THF. In contrast the yields of 4-amino-5-nitroimidazoles 2a – 4a and 6a are significantly decreased
(Table 1). The isomeric ratios of the reaction products 10a and 10b, i.e. compounds with ester group at
N(1) atom, are in both methods comparable and independent of the nature of solvent used. This ratio was
1
found on the basis of H NMR signals intensity. In spite of much effort, the attempts to isolate the 5-
amino-4-nitroimidazole derivatives 10b – 12b failed, though they were visible on TLC plates. This failure
was probably due to unstability of these compounds. The majority of aminonitroimidazole derivatives
isolated in pure form undergo decomposition process when stored for a few months.

HETEROCYCLES, Vol. 85, No. 9, 2012
2201
Table 1. Amino-nitroimidazoles synthesized by a nitro group substitution with cyclic amine in
dinitroimidazoles.
Yield (%)
in method
Analysis,
Appearance
No. Solvent
crystallization (°C)a
Mp (°C)
Formula,
Molecular
mass
Time
(h)
calcd./found
for Lit.
mp.
A
B
C(%) H(%) N(%)
yellow needles
cyclohexane
132-134
---
C8H12N4O3 45.28 5.70 26.40
212.21 45.55 5.88 26.13
24
24
2
72
18
2a
pale
yellow
220-221
114-1155
C8H12N4O3 45.28 5.70 26.40
212.21 45.50 5.80 26.04
9
34
32
2b prisms
EtOAc
yellow needles
n-hexane
75-76
C9H14N4O2 51.41 6.71 26.65
210.24 51.60 6.78 26.54
46
3a
3b
71-725
pale
plates
n-hexane
yellow
+
180-182
184-1855
C9H14N4O2 51.41 6.71 26.65
210.24 51.57 6.80 26.49
2
8
38
EtOAc (2:1)
orange plates
n-hexane
105-106
---
C8H12N4O2 48.96 6.18 28.56
196.21 49.05 6.29 28.45
2
2
70
9
33
39
4a
4b
yellow plates
CCl4
89-90
C8H12N4O2 48.96 6.18 28.56
196.21 49.12 6.36 28.37
90-915
yellow plates
6a n-hexane
EtOAc (2:1)
130-131
---
C9H14N4O3 47.78 6.24 24.76
226.24 47.98 6.48 24.77
24
70
3
35
16
+
pale
yellow
plates
n-hexane
EtOAc (2:1)
158-159
140-1415
C9H14N4O3 47.78 6.24 24.76
24
2
6b
+
226.24
48.00 6.50 24.46
C10H16N4O2
224.26
7a unstable dark
yellow oil

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HETEROCYCLES, Vol. 85, No. 9, 2012
yellow prisms
n-hexane
EtOAc (2:1)
+
172-174
166-1675
2
6
21 C10H16N4O2 53.56 7.19 24.98
7b
8a
8b
224.26
53.80 7.22 24.79
unstable dark
yellow oil
C9H14N4O2
210.24
2
2
1
yellow plates
CCl4
87-88
C9H14N4O2 51.41 6.71 26.65
210.24 52.29 6.88 26.52
7
15
73
85-865
yellow needles
aqua
112-114
---
C11H16N4O5 46.55 5.56 19.88
72
10a
284.27
46.48 5.67 19.71
not isolated
C11H16N4O5
284.27
1
1
1
1
1
7
42
4
6
43
4
xxx
xxx
xxx
10b
11a
xxx
identified with
1H NMR only
orange needles
diluted EtOH
79-81
---
C12H18N4O4 51.28 6.35 19.77
282.30
51.06 6.43 19.85
not isolated
C12H18N4O4
282.30
xxx
xxx
xxx
11b identified with
xxx
1H NMR only
yellow needles
12a
97-98
---
C11H16N4O4 49.27 6.22 21.20
79
7
77
7
diluted EtOH
268.27
49.25 6.01 20.88
not isolated
C11H16N4O4
268.27
12b
xxx
xxx
xxx
identified with
xxx
1H NMR only
In alcoholic, and especially in ethanolic solutions, the C(4) nitro group of 4,5-dinitro-compounds 1 and 5
with relatively small substituent at N(1) position easily interacted with the solvent with formation of
intermolecular hydrogen bonds –N=O···HO–C2H5. Probably for this reason, substitution reactivity of C(4)
nitro group is slightly reduced in comparison with that of the same group in C(5) position, which becomes
more preferable and susceptible to substitution in these conditions. The possibility of C(5) nitro group

HETEROCYCLES, Vol. 85, No. 9, 2012
2203
substitution in dinitroimidazole derivatives with a bulkier group at N(1) atom, e.g. in compounds 9 and 13,
is essentially decreased. The ability of this group to form hydrogen bonds significantly influences its
substitution possibility. In this situation, the intramolecular hydrogen bonds –N=O···H–CH= between
oxygen atom of nitro group and hydrogen atom of C(6) methylene fragment are formed. This hydrogen
atom C(6)-H6B is activated by carbonyl group from neighbouring ester moiety in the chain. Presence of
the weak hydrogen bond in 9 was established with X-ray diffraction methods. The molecular structures of
compounds 9 and 7b and the atom-labelling schemes are illustrated in Figures 1 and 2, respectively.
Results of the X-ray analysis of 9 show that the C4- and C5-nitro groups are significantly twisted out of
the imidazole plane, the dihedral angles between the appropriate planes being 27.14(11) and 36.00(13)°
(Figure 1). Besides, the exocyclic C4–N12 [1.4453(13) Å] and C5–N15 [1.4524(15) Å] are similar and
only slightly shortened with respect to the normal length of the Csp2–NO2 bond of 1.468(1) Å [18]. These
observations are in consistence with that reported for 3-chloro-1-(4,5-dinitroimidazol-1-yl)propan-2-ol.15
It should be noticed that in this compound both nitro groups are exchanged for a piperidine or morpholine
residues.
Figure 1. A perspective view of the molecule of 9. Displacement ellipsoids are drawn at the 30%
probability level and H atoms are shown as spheres of arbitrary radii.
In compound 7b, the nitro group and the piperidine moiety are connected with C4 and C5 atoms,
respectively. The two substituents subtent very different interplanar angles of 6.90(6)° (nitro group) and
63.51(7)° (mean plane of the piperidine residue) to the imidazole ring (Figure 2).
The nitro group takes part in the conjugation system of the imidazole ring. In consequence, the bond
distance C4–N8 [1.4201(18) Å] is significantly shorter (about 23 δ) than the normal single Csp2–NO2

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HETEROCYCLES, Vol. 85, No. 9, 2012
bond and the nitro group shows an extraordinary stability on treatment with piperidine and
morpholine.15,16
Figure 2. A view of the molecule of 7b. Displacement ellipsoids are drawn at the 30% probability level
and H atoms are depicted as spheres of arbitrary radii.
For confirmation of the positions of nitro group and substituted amino group in compounds obtained from
dinitroimidazoles, their basic properties were compared with appropriate literature data for amino-
nitroimidazoles obtained from respective halonitroimidazoles with the known earlier determined structure.
Synthesis of 5-amino-4-nitroimidazoles 2b – 4b and 6b – 8b from appropriate 5-bromo- or 5-iodo-4-
nitroimidazole was described also by Kulkarni et al.20 The conformity of melting points proves the
location of amino group at position C(5) in the imidazole derivatives 3b, 4b, 7b and 8b. The compounds
of 5-aminoimidazole 2b and 6b are the exceptions (see Table 1). It is doubtlessly possible to distinguish
5-amino-4-nitroimidazoles 2b – 4b, 6b – 8b and 10b – 12b from 4-amino-5-nitroimidazoles 2a – 4a, 6a –
8a and 10a – 12a on the basis of their 1H NMR spectra analysis. The signal assigned to hydrogen atoms
of methyl or methylene aliphatic substituent directly bonded with N(1) atom of the imidazole ring,
therefore present in direct vicinity of substituent at C(5) imidazole atom, is used to distinguish these two
isomeric kinds of compounds. According to the data in Table 2, the substitution of C(4) nitro group in
dinitroimidazoles of with amines causes a very narrow (0.01-0.14 ppm) diamagnetic shift, but substitution
of C(5) nitro group causes a significantly greater (0.35-0.46 ppm) diamagnetic shift of proton signals
assigned to N(1)-CH3 or N(1)-CH2 – group. This difference in the position of these signals to enables a
simple distinction of the isomers obtained.

HETEROCYCLES, Vol. 85, No. 9, 2012
2205
Table 2. Differentiated magnetic shifts of 4-amino-5-nitro- and 5-amino-4-nitroimidazole derivativesa.
Magnetic Diamagnetic shift
shift of relatively
to
Compd.
No
protons
N-CH2-
[ppm]
4.01
3.94
3.61
3.92
3.56
3.90
3.58
3.86
3.85
3.51
3.83
3.45
3.83
3.46
5.08
4.97
4.62
4.95
4.64
4.94
4.64
respective
dinitrocompound
[ppm]
---
1
a
0.07
2
3
b
a
b
a
b
0.40
0.09
0.45
0.11
4
5
6
0.43
---
a
b
a
b
a
b
0.01
0.35
0.03
7
0.41
0.03
8
0.40
9
---
a
b
a
b
a
b
0.11
10
0.46
0.13
11
12
0.44
0.14
0.44
a 1H NMR chemical shifts for compounds 10b – 12b were determined from spectra recorded for crude
reaction mixtures containing both isomers
The isomers of aminonitroimidazoles with a nitro group in the C(5) position were found less stable than
the other isomers. Therefore, an attempt was made to synthesize this type of compound according to the
synthetic method for 7a. We had to use the method described by Kulkarni20 based on the treatment of
piperidine on 4-bromo-1,2-dimethyl-5-nitroimidazole (15a) because compound 7a was not isolated in

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HETEROCYCLES, Vol. 85, No. 9, 2012
pure state. It was proved that the known methods of syntheses of 15a15 and 7a20 are not fully reproducible.
We succeeded to develop a very selective methylation method of 4(5)-bromo-2-methyl-5(4)-
nitroimidazole to 15a. If diazomethane is used instead of dimethyl sulphate,21 the yield of 15a is 70% but
the isomeric 5-bromo-1,2-dimethyl-4-nitroimidazole 15b is formed with the yield of about 3% only.
Compound 7a in the form yellow needles should be obtained with a melting point at 107 – 108 °C
through excess of piperidine treatment on 15a in the reaction conditions described in.21 In the same
conditions we obtained only a colorless product with melting point 109 – 111 °C not identical with 7a,
but having the structure of 1,2-dimethyl-4,5-dipiperidineimidazole 16. The same compound was obtained
with the use of 5 as a substrate instead of 15a and at least fivefold excess of piperidine. Compound 7b,
which is a 4-nitro-5-piperidine- derivative, isomeric to compound 7a, is obtainable with use of an
appropriate halonitroimidazole, i.e. 5-bromo-1,2-dimethyl-4-nitroimidazole 15b by substitution of
bromine atom as well as using of respective dinitroimidazole derivative 5. The latter reaction gives a
mixture of isomers 7a and 7b. Only 4-nitro-isomer 7b could be isolated by a chromatographic method.
Attempts at 7a isomer isolation led to its systematic conversion into the more stable isomer 7b. However,
the treatment of the crude compound 7a with piperidine in at least double excess led to formation of 4,5-
dipiperidine derivative 16. In compound 7b it is not possible to substitute the C(4) nitro group with
piperidine in any reaction conditions used for compound 16 synthesis. Similar isomerization of 4-bromo-
2-methyl-5-nitro-1-phenacylimidazoles into 5-bromo-2-methyl-4-nitro-1-phenacylimidazoles upon
heating under reflux was described by Sobiak.22 Isomerization of 7a into 7b proceeding probably
according to the same reaction mechanism. The reaction in the reverse direction from 7b to 7a is
impossible (Scheme 2).
Me
N
piperidine
excess
N
Me
piperidine
Me
N
Me
N
O2N
7b
piperidine
Me
Br
a
b
Me
N
N
H
N
O2N
N
piperidine
N
15b
O2N
Me
Me
Br
Me
excess
N
N
N
Me
N
O2N
N
O2N
5
16
14
O2N
Me
N
piperidine
piperidine
Br
Me
N
15a
O2N
Me
piperidine
excess
N
N
7a
Scheme 2. Synthesis of piperidine-nitroimidazoles in the bromine or nitro group substitution reaction.a
a Reagents and conditions: (a) Me2SO4, NaOH, 60 °C; (b) Me2SO4, 30 °C or CH2N2.

HETEROCYCLES, Vol. 85, No. 9, 2012
2207
CONCLUSION
In conclusion, we have developed a synthetic approach to formation of isomeric substitution products
amino-nitroimidazoles. The substituent at the N-1 position of the imidazole ring was found to influence
the reactivity of the nitro group in nucleophilic substitution reactions. Moreover, the nitro group
connected with C(4) atom of the imidazole ring was found privileged in the substitution reactions in
aprotic solvents (e.g. THF) because of the steric effect.
EXPERIMENTAL
The substrates were obtained according to literature methods23,24 and 14 was obtained by the alkaline
bromination of a commercial 2-methyl-4-nitroimidazole. Reactions of dinitroimidazoles with amines
were performed with use of two methods (A and B). Progress of the reaction was monitored by TLC
method on plates covered with Kieselgel 60, which were developed with a mixture of n-hexane and
EtOAc (2:1). The spots were observed in the UV-light (254 nm) as well as in the daylight without
additional visualisation or after I2 vapour action. The products were purified by flash column
chromatography on neutral alumina I° acc. Brockmann. Melting points were determined on a Boetius
apparatus and are uncorrected. IR spectra were recorded in KBr tablets (0.5%) using a Carl Zeiss Jena
1
Specord 71-IR apparatus. H NMR spectra were recorded in CDCl3 solutions using a Varian Gemini
300VT (300 MHz) spectrometer. Chemical shifts (δ) are given in ppm relative to TMS as internal
standard. The mass spectrum of 16 was obtained on a Jeol JMS D-100 instrument. Elemental analyses for
C, H and N contents were performed on the Elementar Vario EL III apparatus.
Crystal structures of 1,2-dimethylo-4-nitro-5-piperidineimidazole 7b and ethyl 2-(4,5-dinitroimidazol-1-
yl)acetate 9 were determined by the X-ray diffraction studies. The diffraction intensity data for crystals
7b and 9 were collected at 130(2) K with an Oxford Diffraction Xcalibur A diffractometer processed
with the Oxford Diffraction CrysAlis Pro Software.25 Intensity data collection employed the ω- scans
with graphite monochromatized Mo Kα radiation. Both structures were solved by direct methods and
refined by full matrix least-squares on F2 (SHELXS-97 and SHELXL-97).26
General procedures for the reactions of N-substituted 4,5-dinitroimidazole derivatives 1, 5 and 9
with cyclic amines.
Method A (in THF solution). Into a solution of appropriate dinitroimidazole derivative (2.5 mmol, 1 –
0.43 g, 5 – 0.47 g, 9 – 0.61 g or 13 – 0.64 g) in THF (5.0 mL), a solution of a respective cyclic amine (5.0
mmol; 0.44 mL morpholine or 0.49 mL piperidine or 0.42 mL pyrrolidine) also in THF (5.0 mL), was
added dropwise. The mixture was stirred at room temperature until the spot of the substrate on TLC plate
disappeared. The times are given in Table 1. Subsequently Al2O3 (4.0 g) was added and the solvent was

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HETEROCYCLES, Vol. 85, No. 9, 2012
evaporated at a slightly increased temperature. The residue was dried in vacuum. Then it was purified by
chromatographic technique on the Al2O3 (30.0 g) column with a mixture of n-hexane and EtOAc (2:1).
The volumes of fractions were determined on the basis of TLC control and maintained in the range of 70
and 200 mL. The 4-amino-5-nitroimidazoles, i.e. compounds labelled with a letter a, were isolated from
the second fraction, but the isomeric 5-amino-4-nitroimidazoles, labelled with a letter b, were isolated
from the fourth fraction. Compounds 10b, 11b and 12b were not isolated but were identified in the fourth
fraction, as well as in the mother liquors after crystallization of compounds 10a, 11a and 12a.
Method B (in ethanolic solution). The reactions were performed in the same way as in the method A, with
the only difference in the use of EtOH as a solvent instead of THF. After the specified reaction times the
reaction mixtures were diluted with water (80 mL) and extracted many times with CH2Cl2. The combined
organic layers were dried with MgSO4 and concentrated at only slightly increased temperature, to a
volume of about 10 mL. Subsequently Al2O3 (4.0 g) was added and the isolation of products was
performed in the same manner as in method A.
Alternatively, it is possible to change a chromatographic eluent after isolation of the first isomer. The
mixture of n-hexane and EtOAc (2:1) can be replaced by this ester alone. In this way the volume of the
fraction with the second isomer can be significantly decreased.
In methods A or B the pure products or their mixtures were isolated as presented in Table 1.
Methylation of 4(5)-bromo-2-methyl-5(4)-nitroimidazole (14) with diazomethane: An excess of
diazomethane ethereal solution was added dropwise into a suspension of 4(5)-bromo-2-methyl-5(4)-
nitroimidazole (14) (4.12 g, 20.0 mmol) in Et2O (200 mL). The reaction mixture was left standing for
about 6 h at room temperature, during which the substrate was almost completely dissolved. The filtered
ethereal solution was concentrated and the solid residue was chromatographed on basic alumina with the
use of a mixture of n-hexane and EtOAc (2:1) as a developing solvent. The second fraction contained
3.02 g (68.6%) of 4-bromo-1,2-dimethyl-5-nitroimidazole (15a) but from the fourth fraction 0.13 g
(2.9%) of 5-bromo-1,2-dimethyl-4-nitroimidazole (15b) was obtained. The products were recrystallized
from diluted EtOH.
4-Bromo-1,2-dimethyl-5-nitroimidazole (15a). This compound was obtained as light cream prisms, mp
112-113 °C (lit.20: 107-108 °C, lit.21: 108-109 °C). IR (KBr, cm-1): 2920 (C-CH3), 2800 (N-CH3), 1560,
1310 (NO2); 1H NMR (CDCl3, δ ppm): 3.92 (s, 3H, N-CH3), 2.50 (s, 3H, 2-CH3).
5-Bromo-1,2-dimethyl-4-nitroimidazole (15b). This compound was obtained as light greenish-yellow
small prisms, mp 163-165 °C (lit.20: 158-159 °C, lit.21: 161-162 °C). IR (KBr, cm-1): 2925 (C-CH3), 2810
(N-CH3), 1540, 1320 (NO2); 1H NMR (CDCl3, δ ppm): 3.67 (s, 3H, N-CH3), 2.50 (s, 3H, 2-CH3).
The same compounds can be obtained with use of dimethyl sulfate in basic conditions, but in this manner

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there are formed in the reversed ratio.5,6
Reactions of 4(5)-bromo-5(4)-nitroderivatives of 1,2-dimethylimidazole (15a and 15b) with
piperidine.
Reaction of 5-bromo-1,2-dimethyl-4-nitroimidazole (15b) with piperidine. Into a solution of 5-bromo-
1,2-dimethyl-4-nitroimidazole (15b) (0.70 g, 3.0 mmol) in EtOH (20 mL), a solution of piperidine (1.47
mL, 15.0 mmol) in EtOH (20 mL) was added successively and intensely orange mixture was heated under
reflux for 4 h. After cooling, water (200 mL) was added and the mixture obtained was extracted many
times with CH2Cl2. Organic layer was dried with MgSO4 and concentrated. The oily residue was
crystallized with use of EtOH and water (1:3) mixture. The amount of 0.60 g (84%) of yellow needles of
1,2-dimethyl-4-nitro-5-piperidineimidazole (7b) with mp 166-167 °C was obtained. Subsequent
recrystallization from n-hexane and EtOAc (2:1) mixture gave yellow prisms with mp 172-174 °C, which
means that the product was the same as that obtained from 1,2-dimethyl-4,5-dinitroimidazole (5). (7b) IR
(KBr, cm-1): 2925 (C-CH3), 2810 (N-CH3), 1540, 1320 (NO2).
Reaction of 4-bromo-1,2-dimethyl-5-nitroimidazole (15a) with piperidine. Into a solution of 4-bromo-
1,2-dimethyl-5-nitroimidazole (15a) (0.70 g, 3.0 mmol) in EtOH (20 mL), a solution of piperidine (1.47
mL, 15.0 mmol) in EtOH (20 mL) was added successively and intensive orange mixture obtained was
heated under reflux for 4 h. Then nearly whole solvent was removed in distillation. The brown, thick
residue was extracted three times with small quantities of Et2O. Ethereal solution was concentrated and
light brown oily substance was crystallized from a mixture of EtOH and water (1:1) with charcoal. There
was obtained 0.32 g of 1,2-dimethyl-4,5-dipiperidineimidazole (16) (yield 39%) as fine white needles, mp
109-111 °C, Rf = 0.67 (on Al2O3, in 2:1 mixture of n-hexane and ethyl acetate); IR (KBr, cm-1): 2925 (C-
CH3), 2810 (N-CH3); 1H NMR (CDCl3, δ ppm): 2.25 (s, 3H, 2-CH3), 3.28 (s, 3H, N-CH3), 1.51 (m, 4H),
1.61 (m, 8H), 2.93 (m, 8H); 13C NMR (CDCl3, δ ppm): 13.89, 28.43, 24.26 and 24.34, 26.75, 26.95,
52.91, 53.86, 123.12, 126.36, 152.53; Ms m/z (% relative intensity): 262 (100), 219 (13), 205 (28), 193
(15), 191 (11), 69 (11); Anal. Calcd for C15H26N4: C, 68.66; H, 9.99; N, 21.35. Found: C, 68.40; H, 10.03;
N, 21.17.
The same product was obtained in the reaction of 1,2-dimethyl-4,5-dinitroimidazole (5) with fivefold
excess of piperidine in boiling ethanolic solution. The yields of the products from these above two
syntheses were comparable.
SUPPORTING INFORMATION
The supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data
Centre (CCDC), 12 Union ROAD, Cambridge CB2 1EZ (UK), Tel.: (+44) 1223/336-408, Fax: (+44)

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HETEROCYCLES, Vol. 85, No. 9, 2012
1223/336-033, E-mail: deposit@ccdc.cam.ac.uk, World Wide Web: http://www.ccdc.cam.ac.uk
(deposition No. for 7b: CCDC 836419, for 9: CCDC 836418).
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