2-amino-X-nitrobenzimidazoles as precursors of food-borne carcinogens: A new approach to IQ synthesis

Article abstract of DOI:10.1002/jhet.786

Cyclization of (non)-methylated nitro-o-phenylenediamines with cyanogen bromide provided nitro-substituted 2-aminobenzimidazoles in good up to excellent yields. Catalytic hydrogenation of 2-amino-1-methyl-5-nitrobenzimidazole yielded 2,5-diamino-1-methylbenzimidazole, which on treatment with 1,1,3,3-tetramethoxypropane in methanol and subsequently after removal of methanol in polyphosphoric acid afforded food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in 20% yield. Copyright

Full text of DOI:10.1002/jhet.786

March 2012
2-Amino-X-Nitrobenzimidazoles as Precursors of Food-Borne
Carcinogens: A New Approach to IQ Synthesis
293
a
Maros Bella, Viktor Milata, * and Lyudmila I. Larina
a
b
ˇ
aDepartment of Organic Chemistry, Institute of Organic Chemistry, Catalysis and Petrochemistry,
´
Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho street
9, 812 37 Bratislava, Slovak Republic
bA.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1
Favorsky street, Irkutsk 664033, Russian Federation
*E-mail: viktor.milata@stuba.sk
Received August 24, 2010
DOI 10.1002/jhet.786
Published online 21 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
Cyclization of (non)-methylated nitro-o-phenylenediamines with cyanogen bromide provided nitro-
substituted 2-aminobenzimidazoles in good up to excellent yields. Catalytic hydrogenation of 2-amino-
1-methyl-5-nitrobenzimidazole yielded 2,5-diamino-1-methylbenzimidazole, which on treatment with
1,1,3,3-tetramethoxypropane in methanol and subsequently after removal of methanol in polyphosphoric
acid afforded food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in 20% yield.
J. Heterocyclic Chem., 49, 293 (2012).
INTRODUCTION
and cooked food (broiled sun-dried sardines and fishes,
fried beef, hamburgers, potatoes): pyrolysates of various
amino acids and proteins, with strong mutagenic and carci-
nogenic activity, even higher than that of aflatoxin B1.
The simplest synthetic route for accessing these can-
cerogens by heterocyclic synthesis is the construction of
the 2-aminoimidazole ring from corresponding precur-
sors. Thus, 5,6- or 7,8-diaminoquinolines became impor-
tant precursors for the preparation of carcerogens such
as IQ and MeIQ mostly after action of cyanogen bro-
mide [16]. Another possibility is the amination of appro-
priate N-methylbenzimidazole by sodium amide [17] or
phenylazide [18]. Futher approach uses methylation of
2-aminoimidazoquinoline [19].
There exist many reactions leading to fused substituted
pyridine ring such as Bischler–Napieralski, Camps,
Combes, Conrad–Limpach, Doebner, Knorr, Meth–Cohn,
Pfitzinger, and Riehm reactions [1]. 3-Substituted pyridines,
especially those of them which have fused benzene ring,
are suitable precursors for quinolone drugs of the nalidixic
acid type [2]. Some of the reactions also yielded unsubsti-
tuted parent heterocycles such as Skraup [3], Doebner–von
¨
Miller [4], Friedlander [5], extended Gould–Jacobs reaction
[6] or no-named protocols like exploitation of ynones such
as propynal [7] prepared by chromium trioxide oxidation
from propynol [8] enhanced by Veliev [9]; or 3-alkoxya-
crolein prepared by trihalogenmethane Sydnes’ method
[10], 3-alkoxy/aminoacrolein like in Breitmaier’s reaction
[11]; or their equivalent like 1,1,3,3-tetralkoxypropane–
malonodialdehyde method [12].
RESULTS AND DISCUSSION
Compounds containing
a
benzimidazole moiety
Till now, reversal synthetic approach, for example,
fusion of the pyridine ring to a 2-aminobenzimidazole ring
is unknown. Within this respect, we have decided to
explore the preparation of nitro-substituted 2-aminobenzi-
midazoles 2, as potential precursors for food-borne carcino-
gens or their analogs, by convenient cyclization of nitro-o-
phenylenediamines 1 with cyanogen bromide (Scheme 1).
Synthesis of nitro-o-phenylenediamines 1 as starting mate-
rials for the above mentioned cyclization is summarized in
this journal published by us [20]. Preparation of nonmethy-
lated 2-aminonitrobenzimidazoles 2a,b by treatment of
nitro-o-phenylenediamines 1a,b with cyanogen bromide
attached to a heterocyclic system are important chemical
substances having a number of significant biological
activities against several viruses such as HIV, herpes
(HSV-1), influenza, and Epstein-Barr [13].
Although chemistry of imidazoquinolines is relatively
old and due to this fact also well reviewed [14], special
attention has been paid after discovery of carcinogenic ac-
tivity of imidazoquinolines bearing aminogroup in position
2 of the imidazole ring found in thermally treated meat
food [15]. In the early 1980’s, a large group of heterocyclic
compounds was isolated from thermally processed meats
C
V
2011 HeteroCorporation

294
M. Bella, V. Milata, and L. I. Larina
Vol 49
Scheme 1
methylated analogs, aminobenzimidazoles 2a,b exist in
tautomeric equilibria. The introduction of the nitro and
amino groups into the benzimidazole ring leads to sig-
nificant changes of chemical shifts. The 1H- and 13C-
NMR spectra of 2a,b compounds show broadening of
some signals caused by prototropic exchange. The avail-
ability of the prototropic exchange in NH-benzimida-
zoles 2a,b did not allow detection of nitrogen signals N-
1 and N-3 in the 15N-NMR spectra (Table 3). In the
15N-NMR spectra of N-methyl-substituted benzimida-
zoles 2c–f (no tautomerism), it was possible to identify
all four 15N-NMR signals of the benzimidazole system
(Table 3).
To obtain the food-borne carcinogen 4 (IQ), we have
decided to apply malonodialdehyde dimethylacetal
(1,1,3,3-tetramethoxypropane) methodology to diamine
3. This construction of the pyridine ring exploits differ-
ent reactivity of two aminogroups of diamine 3: less re-
active 2-aminoimidazole versuss aniline-like type in
position 5 of the benzimidazole ring. The above men-
tioned diamine 3 was prepared from 5-nitro-1-methyl-2-
aminobenzimidazole (2d) by catalytic hydrogenation on
Raney-nickel in methanol. Resulted diamine 3 has not
been isolated but used directly into ring closure after fil-
tering off the catalyst. After the reflux of diamine 3
with 1,1,3,3-tetramethoxypropane in methanol, the sol-
vent was evaporated under reduced pressure and
replaced by PPA. Simple heating in PPA at 120ꢀC fur-
nished 2-aminoimidazo[4,5-f]quinoline 4 in 20% yield
(Scheme 2). Angular anelation of the pyridine ring was
confirmed by coupling constants of the benzene ring.
All spectral data and physical properties of amine 4 are
in accordance with previously obtained ones [16,17b].
Presented synthesis of the nitro-substituted 2-amino-
benzimidazoles 2 is direct, simple, and convenient
method for the preparation of compounds 2a–f from
corresponding 1,2-phenylenediamines 1. Also this syn-
thesis can be extended to the synthesis of typical food
carcinogen 2-aminoimidazo[4,5-f]quinoline 4 type of
compounds, exploiting pyridine ring fusion in last reac-
tion step using malondialdehyde method.
has already been reported [21]. Described ring closure is
conducted at room temperature in methanol, methanol/
water, or dioxan/water as solvents. However, to our sur-
prise, analogical synthesis of 1-methyl-2-aminobenzimida-
zoles 2c–f starting from N-methyl nitro-o-phenylenedi-
amines 1c–f has not been described in the literature so far.
In this article, we report the cyclization of appropriate com-
ponents (1a–f and BrCN) in refluxing methanol to afford
desired products 2a–f (Scheme 1). Compounds 2a,b were
isolated in about 50% yields after two crystallizations from
water, but derivative 2b was obtained as a monohydrate,
which was confirmed by elemental analysis and DTA-TGA
analysis, respectively. 1-Methyl-2-aminobenzimidazoles
2c–f were obtained in good yields and high purity so no
further purification was necessary.
All prepared 2-aminobenzimidazoles 2a–f are fully
1
characterized by multinuclear H-, 13C-, and 15N-NMR
spectroscopy and 2D experiments HSQC, HMBC and
NOESY (Tables 1–3). Prototropic rearrangements of
almost all NH-benzazoles in solutions proceed so
quickly on the NMR time scale that varying solution
temperatures does not cause changes in the spectra [22–
25]. In these cases, the time-averaged signals are
observed in the spectra. It should be noted that unlike
Table 1
1H-NMR chemical shifts (ppm) and coupling constants J (Hz) of 2-aminobenzimidazoles 2a–f (solvent DMSO-d6).
Comp.
4-H
5-H
6-H
7-H
NH
NACH3 NH2
2a
2b
–
7.68 (d, 3J ¼ 8.1)
7.11 (dd, 3J ¼ 8.1; 7.3)
7.87
7.50 (d, 3J ¼ 7.3)
7.18 (d, 3J ¼ 8.6)
11.49
11.35
–
–
6.49
6.90
7.93 (d, 4J ¼ 2.3)
–
(dd, 3J ¼ 8.6; 4J ¼ 2.3)
3
2c
–
7.76 (dd, J ¼ 8.3; 4J ¼ 1.0) 6.98 (dd, 3J ¼ 8.3; 7.7)
7.48
(dd, 3J ¼ 7.7; 4J ¼ 1.0)
–
–
3.56 s
3.58 s
7.30
6.94
2d
7.92 (d, 4J ¼ 2.2)
–
7.88
(dd, 3J ¼ 8.7; 4J ¼ 2.2)
–
7.31 (d, 3J ¼ 8.7)
3
2e
2f
7.18 (d, 3J ¼ 8.8) 7.93 (dd, J ¼ 8.8; 4J ¼ 2.3)
8.06 (d, 4J ¼ 2.3)
–
–
3.59 s
3.51 s
7.20
6.88
7.47 (d, 3J ¼ 8.8) 7.10 (dd, J ¼ 8.8; 4J ¼ 8.2)
7.49 (d, 3J ¼ 8.2)
–
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
2-Amino-X-Nitrobenzimidazoles as Precursors of Food Borne
Carcinogens: A New Approach to IQ Synthesis
295
Table 2
13C-NMR chemical shifts (ppm) and coupling constants JCAH (Hz) of 2-aminobenzimidazoles 2a–f (solvent DMSO-d6).
Comp. 2-C
3a-C
4-C
5-C
6-C
7-C
7a-C
NACH3
2aa
2ba
2c
157.6 131.0b
158.8 140.0b
146.3b
114.0
1J ¼ 166.9
146.3b
119.5
1J ¼ 162.5
116.2
119.6b
1J ¼ 163.6
111.1
126.9b
–
106.0
1J ¼ 170.0
138.6 d
139.9b
–
1J ¼ 166.2
1J ¼ 164.4
159.1 134.1 d
3J ¼ 9.2
116.7 dd
1J ¼ 164.8; 3J ¼ 6.6
142.7 d
116.8 d
112.8 dd
138.5 d
3J ¼ 6.3
141.8 d
28.8 q
1J ¼ 140.2
3J ¼ 7.4
1J ¼ 165.1
114.7 dd
1J ¼ 163.3; 3J ¼ 8.9
107.0 d
2d
2e
158.2 140.3 mc
109.5 dd
29.0 q
1J ¼ 140.1
1J ¼ 166.6; 3J ¼ 4.4
3J ¼ 5.5
1J ¼ 166.9; J ¼ 3.7
1J ¼ 165.9
3J ¼ 9.1
3
159.6 134.6b
113.4 d
117.8 dd
149.6 d
3J ¼ 8.8
114.9 dd
103.5 dd
138.9 dd
28.8 q
1J ¼ 164.4
120.3 dd
1J ¼ 165.9; 3J ¼ 3.7
1J ¼ 168.1; 3J ¼ 4.8 J ¼ 9.2; 3J ¼ 5.2 J ¼ 140.4
3
1
2f
158.0 127.4 d
120.1 d
146.7 d
3J ¼ 9.2
134.1 d
3J ¼ 10.3
32.6 q
1J ¼ 140.8
3J ¼ 4.8 1J ¼ 161.8; 3J ¼ 8.1
1J ¼ 164.0
1J ¼ 166.2; J ¼ 7.7
3
a Measured at 60ꢀC.
b Broad signal.
c Multiplet.
EXPERIMENTAL
monitoring and purity of products were accomplished by TLC on
silica-gel plates (Fluka). Stains were visualized by UV light (254
and 366 nm) or by iodine vapors. Elemental analyses were deter-
mined with a Thermo Fingion CHNS(O) 1112 instrument.
General procedure for preparation of 2-amino-4-nitro-
benzimidazole (2a) and 2-amino-5-nitrobenzimidazole
(2b). A mixture of nitro-o-phenylenediamine 1a or 1b (1.0 g,
6.52 mmol) and cyanogen bromide (0.95 g, 8.96 mmol, 1.4
1H-, 13C-, and 15N-NMR spectra of the studied compounds
were recorded on Bruker DPX-400 and AV-400 spectrometers
(400.13, 100.61, and 40.56 MHz, respectively) at room tem-
perature or 60ꢀC using DMSO-d6 as a solvent. 1H, 13C, and
15N chemical shifts (d in ppm) were measured with accuracy
of 0.01, 0.05, and 0.1 ppm, respectively, and referred to TMS
1
(1H, 13C) and nitromethane (15N). H-1H, 13C-1H, and 15N-1H
eq) was refluxed in methanol (25 mL) for
4 h (TLC
1
coupling constants (J in Hz) are accurate to 0.1 Hz. Some H-
CHCl3:MeOH 10:1). After cooling, reaction mixture was alkal-
ized with 30% NaOH solution, and solvent was evaporated
under reduced pressure. The rest was recrystallized twice from
water with addition of charcoal to afford compounds 2a (0.62
g, 55%) and 2b (0.65 g, 53%), respectively.
2-Amino-4-nitrobenzimidazole (2a) Yellow-orange needles,
mp 282–287ꢀC ([21b] 275–279ꢀC). Anal. Calcd. for C7H6N4O2:
C, 47.19; H, 3.39; N, 31.45. Found: C, 47.21; H, 3.37; N, 31.49.
2-Amino-5-nitrobenzimidazole monohydrate (2b) Yellow
solid, mp 126–130ꢀC ([21a] 222–223ꢀC (hemihydrate)). Anal.
Calcd. for C7H8N4O3: C, 42.86; H, 4.11; N, 28.56. Found: C,
42.91; H, 4.09; N, 28.58.
NMR signals were assigned using 1H-1H two-dimensional
(2D) spectra (NOESY), whereas the 13C- and 15N-NMR signal
assignment was made on the basis of 2D NMR methods
HSQC-GP 1H-13C, HMBC-GP 1H-13C, and HMBC-GP
1H-15N, correspondently, and also with account data reported
1
in refs. 22–27. Two-dimensional inverse H-detected heteronu-
clear shift correlation spectra were obtained with standard
pulse sequences [28]. HMBC spectra were recorded with an
acquisition time of 0.2 s, a spectral width of 6000 Hz, 1024
1
points in the H dimension and 17 and 20 kHz spectral width
for 15N and 13C dimension, 512 increments and, aiming at
long-range coupling constant of 5 and 10 Hz for 15N and 13C,
respectively, with a relaxation delay of 2 s.
Scheme 2
Melting points were determined on Koffler’s apparatus using a
digital thermometer (DT012C) and are uncorrected. The reaction
Table 3
15N-NMR chemical shifts (ppm) and coupling constants JNH (Hz) of
2-aminobenzimidazoles 2a–f (solvent DMSO-d6).
Comp.
1-N
3-N
NH2
NO2
1
2aa
2ba
2c
2d
2e
–
–
ꢁ318.4, JNH ¼ 88.6
ꢁ8.8
ꢁ7.8
ꢁ8.6
ꢁ7.6
ꢁ7.9
ꢁ8.9
1
–
–
ꢁ317.2, JNH ¼ 88.4
1
ꢁ262.5
ꢁ258.1
ꢁ261.6
ꢁ260.1
ꢁ186.5
ꢁ186.3
ꢁ181.2
ꢁ186.6
ꢁ316.8, JNH ¼ 88.9
1
ꢁ319.5, JNH ¼ 87.9
1
ꢁ315.9, JNH ¼ 89.6
1
2f
ꢁ320.8, JNH ¼ 87.4
a We cannot accumulate these signals on account of prototropy
exchange in solution, and the 15N-NMR chemical shifts can be in field
of 185–205 ppm, see refs. 22–24.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

296
M. Bella, V. Milata, and L. I. Larina
Vol 49
[5] Friedlander, P. Chem Ber 1882, 15, 2572.
General procedure for preparation of methylated 2-ami-
´
ˇ
[6] Milata, V.; Ilavsky, D.; Lesko, J. Collect Czech Chem
nonitrobenzimidazoles (2c–f). A mixture of N-methylated
nitro-o-phenylenediamine 1c–f (0.25 g, 1.5 mmol) and cyano-
gen bromide (0.22 g, 2.1 mmol, 1.4 eq) was refluxed in metha-
nol (7.5 mL) until all starting material was consumed (2–6 h,
TLC CHCl3:MeOH 10:1). After cooling, reaction mixture was
charcoaled, filtered into a beaker, and alkalized with 30%
NaOH solution. Separated crystals or solids were collected by
suction, washed with water to remove rests of inorganic mate-
rials, and dried to give compounds 2c (0.27 g, 94%) 2d (0.27
g, 94%), 2e (0.24 g, 83%), and 2f (0.23 g, 80%), respectively.
2-Amino-1-methyl-4-nitrobenzimidazole (2c) Golden-brown
needles, mp 300–304ꢀC. Anal. Calcd. for C8H8N4O2: C, 50.00;
H, 4.20; N, 29.15. Found: C, 50.10; H, 4.18; N, 29.19.
2-Amino-1-methyl-5-nitrobenzimidazole (2d) Yellow solid,
mp 342–350ꢀC. Anal. Calcd. for C8H8N4O2: C, 50.00; H,
4.20; N, 29.15. Found: C, 49.96; H, 4.21; N, 29.13.
2-Amino-1-methyl-6-nitrobenzimidazole (2e) Yellow solid,
mp 305–309ꢀC. Anal. Calcd. for C8H8N4O2: C, 50.00; H,
4.20; N, 29.15. Found: C, 50.09; H, 4.17; N, 29.12.
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2-Amino-3-methylimidazo[4,5-f]quinoline (4) To a suspen-
sion of 2-aminobenzimidazole 2d (1.92 g, 10 mmol) in methanol
(100 mL), freshly activated Raney nickel catalyst (prepared from 4
g of RaNi alloy) was added, and reaction mixture was stirred vigo-
rously under hydrogen atmosphere (200 kPa) overnight. After the
reduction was complete, 1,1,3,3-tetramethoxypropane (2.46 g, 15
mmol) was added, and the catalyst was filtered off. The filtrate was
slowly heated with magnetic stirring in an oil bath till the tempera-
ture in the oil bath reached 100ꢀC within 2 h. Thereafter reaction
mixture was allowed to cool, and the solvent was evaporated under
reduced pressure. To the rest, polyphosphoric acid (40 g) was
added, and the resulting mixture was mechanically stirred with a
glass rod while the temperature in the oil bath was raised to 120ꢀC
and stirring continued at this temperature for 30 min. After cooling,
reaction mixture was diluted with ice-water (150 mL), charcoaled,
filtered into a beaker, and alkalized with concentrated ammonia.
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Acknowledgments. The authors are grateful to the Slovak Grant
Agency (Project 01/0660/11) and the Slovak Research and Devel-
opment Agency (APVV-0339-10) for financial support.
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Journal of Heterocyclic Chemistry
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