Heterocyclizations towards 2-arylbenzimidazoles via intermolecular coupling of 2-nitroanilines and aryl aldehydes

Article abstract of DOI:10.3987/com-01-9381

The reductive intermolecular coupling/heterocyclization reaction between 2-nitroaniline and aromatic aldehydes towards 2-substituted and 1,2-disubstituted benzimidazoles was accomplished in the presence of 2-bromo-2-nitropropane/Zn in a MeOH/CH₂

Full text of DOI:10.3987/com-01-9381

HETEROCYCLES, Vol. 57, No. 1, 2002, pp. 5 - 10, Received, 31st October, 2001
HETEROCYCLIZATIONS
TOWARDS
2-ARYLBENZ-
IMIDAZOLES VIA INTERMOLECULAR COUPLING OF 2-
NITROANILINES AND ARYL ALDEHYDES
Byeong Hyo Kim,* Rongbi Han, Tae Hee Han, Young Moo Jun, Woonphil
Baik, † and Byung Min Lee‡
Department of Chemistry, Kwangwoon University, Seoul, 139-701, Korea
E-mail: bhkim@daisy.gwu.ac.kr
†Department of Chemistry, Myong Ji University, Kyung Ki Do, Korea
‡Korea Research Institute of Chemical Technology, Taejon, Korea
Abstract - The reductive intermolecular coupling/heterocyclization reaction between 2-
nitroaniline and aromatic aldehydes towards 2-substituted and 1,2-disubstituted benzimidazoles
was accomplished in the presence of 2-bromo-2-nitropropane/Zn in a MeOH/CH2Cl2 solution
at room temperature.
Benzimidazole and its derivatives present interesting biological activities such as bacteriostats,
bactericides, insecticides, fungicides, sedatives, anticarcinogens, and phycopharmacological agents.1
Although there are several ways leading to benzimidazoles, traditional methods of 2-arylbenzimidazole
preparation involve the condensation and cyclization of benzoic acid derivatives with o-diamino aromatic
compounds in the presence of a mineral acid with high temperature.2 Metal catalyzed reaction of o-
phenylenediamines with haloaromatics or aromatic aldehydes is another candidate for 2-
arylbenzimidazole preparation.3
During the course of our investigation of heterocyclic compound formation via reductive cyclization
reaction of nitroarenes, 4, 5 we have found that the nitro group can be reduced by 2-bromo-2-nitropropane
(BNP)/Zn and it can initiate the heterocyclization when it has a proper functional group at the ortho
position. Thus o-nitro substituted aromatic carbonyl, imino, or azo compounds are successfully
transformed into heterocyclic compounds such as 2,1-benzisoxazoles, benzotriazoles, and quinolines. All
of those reactions are accomplished from a reductive reaction of the ortho nitro functional group and the
following cyclization. Since 2-nitroaniline and aromatic aldehydes can couple with each other to

form 2-NO2-Ph-N=CH-Ar in situ, the imine intermediate should undergo a cyclization to form
benzimidazoles in the presence of BNP/Zn similar to our previous heterocyclization reactions. This
realization prompted us to attempt the reductive intermolecular hetero ring formation reaction. Herein we
wish to report the reductive intermolecular coupling/cyclization reaction of 2-nitroaniline and aromatic
aldehydes toward benzimidazoles in presence of BNP/Zn dust in MeOH/CH2Cl2 solution at room
temperature.
Ochoa et al. reported high temperature thermal cyclocondensation of o-phenylenediamines with aromatic
aldehydes primarily producing three cyclized products (benzimidazoles and quinoxaline) with a variable
product ratio depending on the substrate and a combined yield of less than 60% (eq. 1).2d It is well known
that aryl aldehydes couple with anilines easily to form Ph-N=CH-Ar. If we use 2-nitroaniline in place of
o-phenylenediamines and use a proper reducing system, we may have more chance to improve the
cyclocondensation reaction.
NH2
N
N
N
R2
R2
4 R2-CHO
350 oC
N
N
R2
R2
R2
(1)
R1
NH2
N
H
R1
R1
R1
As control experiments, various reaction conditions were attempted to facilitate the reductive
intermolecular coupling reaction of 2-nitroaniline with benzaldehyde and the results are summarized in
Table 1. Reactions of 2-nitroaniline (1) with benzaldehyde (2a) in the presence of Zn produced a low
yield of the desired 2-arylbenzimidazole (3a) (Table 1, entry 1). However, addition of BNP to the reaction
mixture led to a more efficient reductive intermolecular coupling reaction. The overall yield toward 2-
substituted and 1,2-disubstituted benzimidazoles was improved considerably accompanied by only a trace
amount of quinoxaline. Furthermore, while the reactions in methanol produced relatively low yields of 3a
and 4b (Table 1, entries 3, 4), the reactions using co-solvent MeOH/CH2Cl2 dramatically increased the
overall yield of cyclized products at room temperature. In addition, as shown in Table 1, the reaction
carried out in a 1 : 1 mixture (v/v) of MeOH/CH2Cl2 completed most successfully compared to other
mixtures. The optimum conditions were obtained with 2-nitroaniline/aldehyde (2 equiv.)/BNP (2
equiv.)/Zn (2 equiv.) in MeOH/CH2Cl2 (v/v = 1 : 1) at room temperature (Table 1, entry 8, 90% of
combined yield).
When we applied the acidic Zn reduction conditions [1 (1 equiv.)/2a (2 equiv.)/Zn (5 equiv.)/ aq. HCl (5
equiv.) in MeOH at room temperature], the reaction was completed within an hour, however, overall
yield was decreased to 51% [3a (22%) and 4b (29%)] without any starting materials left. It reveals that
reduction by BNP/Zn is more efficient than the traditional acidic Zn condition for the reductive

Table 1. Selected control experiments for reductive intermolecular coupling/heterocyclization reaction
NH2
NO2
N
N
N
Ph
Ph
Ph
Ph-CHO
Zn
BNP
N
H
1
2a
2a
3a
4a
isolated yield (%)
1
Zn
BNP
solvent
temp. time
entry
(mmol)
(mmol)
(mmol) (mmol)
(h)
MeOH (mL) : CH2Cl2 (mL)
(¡É)
3a
4a
1a
2
0.5
4.0
3.0
3.0
-
0.5
2.0
-
rt
rt
24
9
19
41
trace
36
0.3
0.3
0.3
0.6
0.3
0.3
3.6
3.6
3.6
3.6
0.36
0.36
0.36
0.36
3b
rt
50
rt
30
44
25
19
26
38
16
28
33
4
-
3.0
0.3
0.3
5
6
7
5.0
1.0
1.5
0.5
0.5
0.5
0.3
0.3
0.3
0.3
0.3
0.6
3.6
3.6
0.36
0.36
1.5
0.5
rt
rt
4
42
24
19
39
24
8
9
3.0
1.5
0.6
0.6
0.5
0.5
rt
rt
12
30
57
52
33
13
0.3
0.3
0.6
0.3
a80% of 1 was recovered. b1 (49%) and 2 (5%) were recovered.
heterocyclization. The role of BNP is believed to be an electron acceptor due to its low-lying antibonding
π-orbital and the utility of BNP has been described by Russell et al.6 and by us.5
To disclose the reaction path and/or the intermediates of the reaction, various control experiments were
examined. Our diverse efforts to detect the probable 2-NO2-Ph-N=CH-Ph intermediate (5a) failed
probably because of fast reduction by BNP/Zn as well as fast follow-up cyclization toward 2-
arylbenzimidazoles. On the other hand, for the reaction in the absence of BNP (Table 1, entry 1), i.e. the
nitro reduction is slowed down, 5a (~1%) was detected on GCMS as a possible intermediate. To elucidate
amino intermediacy of the reaction, the reaction of 4-NO2-Ph-CH=N-Ph (1 equiv.) in the presence of BNP
(2 equiv.)/Zn (10 equiv.) in MeOH/CH2Cl2 (v/v = 1 : 1) at room temperature was tried. After 30 min, the
formation of 4-NH2-Ph-N=CH-Ph (~6%) was observed on GCMS analysis and most of organic materials
were consumed within 3 h possibly polymerizing by coupling reaction between amino and imino groups.
Smith et al. reported coupling reaction of 1 with 2a in refluxing toluene to afford 5a.7 In addition, the
reduction potential of Ph-CH=N-Ph was -1.60 V, while that of nitrobenzene was -1.13 V (0.1 M
TBAP/MeOH, working electrode; glassy carbon, scan rate; 60 mV/sec) which strongly supported our
observation, i.e. nitro group is reduced selectively over the imino group. We also tried to analyze the
reaction mixture prior to the reaction [1 (1 equiv.)/2a (2 equiv.)/ BNP (2 equiv.)/Zn (10 equiv.) in
MeOH/CH2Cl2 (v/v = 1/1) at room temperature for 2 h] was completed. In addition to the products 3a and
4a, 2-(Ph-CH=N)-Ph-N=CH-Ph (7a, ~6%) were detected on GCMS analysis which is another possible

intermediate for the cyclization reaction. Thus, the pathway 1) coupling of 1 with 2a to form 5a, 2) nitro
group reduction, 3) reductive cyclization seems quite convincing. It seems intramolecular path a (or a’)
and intermolecular path b (or b’) are competing with each other. When 1,2-diaminobenzene and
benzaldehyde (2 equiv.) were reacted in MeOH/CH2Cl2 (v/v = 1/1), 3a and 4a were obtained in 41 and
47% yields respectively within an hour via the competition reaction between path a’ and b’ that is quite
remarkable also compared to Ochoa’s claim. Based on our and other’s results, a plausible reaction path is
shown in Scheme 1.
Scheme 1
Ph
NH
N
2
ArCHO
NO
NO
2
2
5a
NO
1)
2
N
H
N
N
Ph
2) SET
N
H
Ph
-acetone, -NO2
a
b
SET based
3a
Ph
N
reductive cyclization
a'
O
N
Ph
Ph
N
Ionic
N
N
N
N
PhCHO
b'
cyclization
Ph
NH
2
Ph
Ph
6a
7a
4a
In order to test the possibility of BNP/Zn condition utilization, we examined the reductive intermolecular
coupling reaction of 2-nitroaniline with aromatic aldehydes under the optimized conditions. Results are
summarized in Table 2. In most cases, good to excellent yields of 2-substituted and 1,2-disubstituted
benzimidazoles were obtained easily.
Typical procedure for the reductive intermolecular coupling reaction is as follows. To a stirred solution of
2-nitroaniline (41.4 mg, 0.3 mmol), aldehyde (0.6 mmol) and zinc dust (196 mg, 3.0 mmol) in MeOH (0.5
mL)/CH2Cl2 (0.5 mL) was added 2-bromo-2-nitropropane (0.064 mL, 0.6 mmol) at room temperature.
The reaction mixture was stirred for a fixed time, and poured into a solution of aqueous 10% NH4Cl. The
mixture was extracted with CH2Cl2 (3 × 30 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v = 5/95 - 10/90) through
the silica gel column to give 3 and 4. All of synthesized new compounds are fully characterized.8
In conclusion, we have established a one-step reaction route for benzimidazole derivative

formation from 2-nitroaniline/aldehydes by using 2-bromo-2-nitropropane and Zn dust under mild
conditions.
Table 2. The reactions of 2-nitroaniline/aldehyde (2 equiv.) with BNP (2 equiv.)/Zn (10 equiv.) in MeOH/CH2Cl2 (v/v =
1/1) at room temperaturea
MeOH/CH2Cl2
rt
NH2
NO2
N
N
N
Ar
Ar
Ar
Zn
ArCHO
BNP
N
H
1
2
3
4
isolated yield (%)
isolated yield (%)
time
time
(h)
entry
entry
ArCHO
ArCHO
(h)
3
4
3
4
CHO
CHO
CHO
CHO
26 (3g)
55 (4g)
1
2
10
23
57 (3a)
19 (3b)
7
8
33 (4a)
53 (4b)
24
6
CHO
OMe
CHO
35 (3h)
42 (3i)
36 (3j)
43(4h)
19 (4i)
3
4
12
24
40 (3c)
34 (3d)
40 (3e)
41 (3f)
59 (4c)
57 (4d)*
45 (4e)
56 (4f)
40
9
Cl
CHO
OEt
CHO
CHO
18
24
43
43 (4j)
29 (4k)
14 (4l)b
10
11
12
EtO
N
CHO
5
6
25
21
44 (3k)
Cl
Cl
CHO
CHO
-
Br
aAll reactions were carried out with 0.3 mmol of 2-nitroaniline. b2-Nitroaniline was recovered (75%).
ACKNOLEDGEMENTS
This work was supported by the Brain Korea 21 Project and partly by Kwangwoon University in the year
2001.
REFERENCES AND NOTES
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o
1
8. Spectral data for the selected new compounds : 4g; white solid, mp 96.5-98.4 C (haxane), H NMR (300
MHz, CDCl3) δ 2.23 (s, 3H), 2.30 (s, 3H), 5.35 (s, 2H), 6.80-6.88 (m, 2H), 7.04 (d, 1H, J = 7.3 Hz), 7.12-7.27
(m, 6H), 7.32-7.37 (m, 1H), 7.52 (s, 1H), 7.78-7.83 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 154.4, 143.1, 138.8,
138.6, 136.5, 136.2, 130.7, 130.2, 129.9, 128.9, 128.5, 128.5, 126.6, 126.0, 123.1, 122.9, 122.6, 119.9, 110.5,
48.4, 21.5, 21.4; IR (KBr) 3064, 2909, 1608, 1449, 1386, 1250 cm-1 ; GC-MS m/z (rel. intensity) 312 (100, M+),
297 (5), 221 (5), 207 (5), 192 (4), 180 (2), 116 (2), 105 (80), 90 (6), 77 (11); HRMS (EI) calcd for C22H20N2
312.1626, found 312.1622. Anal. Calcd for C22H20N2: C, 84.58; H, 6.45; N, 8.97. Found: C, 84.45; H, 6.50; N,
9.04. 4i; white solid, mp 114.3-115.5 oC (acetone), 1H NMR (300 MHz, CDCl3) δ 5.23 (s, 2H), 6.88 (d, 1H, J =
6.8 Hz), 7.06 (s, 2H), 7.14-7.35 (m, 6H), 7.38-7.44 (m, 1H), 7.65 (d, 1H, J = 1.5 Hz), 7.82 (d, 1H, J = 8.1 Hz);
13C NMR (300 MHz, CDCl3) δ 152.5, 143.0, 138.1, 135.9, 135.2, 134.9, 131.6, 130.5, 130.1, 130.0, 129.5,
128.2, 127.0, 126.2, 124.0, 123.6, 123.1, 120.3, 110.4, 47.8; IR (KBr) 3064, 2917, 1596, 1568, 1437, 1363,
1080 cm-1 ; GC-MS m/z (rel. intensity) 352 (91, M+), 317 (8), 281 (3), 241 (6), 227 (6), 214 (3), 192 (5), 177 (2),
152 (4), 125 (100), 90 (19), 77 (5); HRMS (EI) calcd for C20H14N2Cl2 352.0534, found 352.0532. Anal. Calcd
for C20H14N2Cl2: C, 68.00; H, 3.99; N, 7.93. Found: C, 68.05; H, 3.98; N, 7.99.