Aqueous 1M glucose solution as a novel and fully green reaction medium and catalyst for the oxidant-free synthesis of 2-arylbenzimidazoles

Article abstract of DOI:10.1080/00397911.2010.492460

The reaction of various o-phenylenediamines and substituted benzaldehydes was carried out in 1M glucose solution as reaction medium and catalyst under one-pot oxidantfree conditions. The desired products were obtained at 60 °C with good to excellent yields, and the reaction was performed chemoselectively without formation of 1,2-disubstituted benzimidazoles. No need for any extra oxidant, simple workup, and use of carbohydrates as fully green promoters are some advantages of the present work.

Full text of DOI:10.1080/00397911.2010.492460

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Aqueous 1 M Glucose Solution as a Novel
and Fully Green Reaction Medium and
Catalyst for the Oxidant-Free Synthesis
of 2-Arylbenzimidazoles
Shahnaz Rostamizadeh a , Reza Aryan a & Hamid Reza Ghaieni a
a Faculty of Science, Department of Chemistry, K. N. Toosi University
of Technology, Tehran, Iran
Version of record first published: 29 Apr 2011
To cite this article: Shahnaz Rostamizadeh, Reza Aryan & Hamid Reza Ghaieni (2011): Aqueous 1 M
Glucose Solution as a Novel and Fully Green Reaction Medium and Catalyst for the Oxidant-Free
Synthesis of 2-Arylbenzimidazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:12, 1794-1804
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Synthetic Communications1, 41: 1794–1804, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492460
AQUEOUS 1 M GLUCOSE SOLUTION AS A NOVEL
AND FULLY GREEN REACTION MEDIUM AND
CATALYST FOR THE OXIDANT-FREE SYNTHESIS OF
2-ARYLBENZIMIDAZOLES
Shahnaz Rostamizadeh, Reza Aryan, and Hamid Reza Ghaieni
Faculty of Science, Department of Chemistry, K. N. Toosi University of
Technology, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract The reaction of various o-phenylenediamines and substituted benzaldehydes was
carried out in 1 M glucose solution as reaction medium and catalyst under one-pot oxidant-
free conditions. The desired products were obtained at 60 ꢀC with good to excellent yields,
and the reaction was performed chemoselectively without formation of 1,2-disubstituted
benzimidazoles. No need for any extra oxidant, simple workup, and use of carbohydrates
as fully green promoters are some advantages of the present work.
Keywords 2-Arylbenzimidazoles; 1 M glucose solution; o-phenylenediamine; Schiff
bases; oxidant-free conditions
INTRODUCTION
Benzimidazoles have a crucial position as one of the important heterocyclic
motifs in medicinal and pharmaceutical chemistry. Previously, their antivirus activi-
ties against influenza,[1a] human cytomegalovirus,[1b] and HIV[1c] have turned the
researchers’ attention toward designing novel structural analogs with remarkable
significant applications in medicine. Also, this attention has led to creating novel
antimicrobial agents,[2] unique KV1.5 potassium channel blockers,[3] and
Received April 19, 2010.
Address correspondence to Shahnaz Rostamizadeh, Faculty of Science, Department of Chemistry,
K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran. E-mail: shrostamizadeh@
yahoo.com
1794

AQUEOUS 1 M GLUCOSE SOLUTION
1795
NR2B-selective N-methyl-D-aspartate vanilloid receptor-1[4] antagonists, new inhi-
bitors of hKSP,[5] dipeptidyl peptidase III,[6] and vascular endothelial growth
factor-2 tyrosine kinase.[7] More important, fresh DNA binding and antitumor
agents[8] are some of the newly developed applications of these medicinally impor-
tant heterocyclic compounds.
One of the most important methodologies for the preparation of benzimida-
zoles is the oxidative cyclodehydrogenation of Schiff bases prepared from the reac-
tion of o-phenylenediamine with aldehydes using a suitable oxidizing agent. The
commercial availability of a vast number of aldehydes has certainly caused this
two-step process to be extensively investigated by chemists (Scheme 1).
Various oxidants have been examined so far for this two-step process, and they
include nitrobenzene (high-boiling oxidant=solvent),[9] 1,4-benzoquinone,[10]
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),[11] tetracyanoethylene,[12] benzofur-
oxan,[13] MnO2,[14] Pb(OAc)4,[15] oxone,[16] and NaHSO3.[17] However, most of these
procedures suffer from serious drawbacks such as toxic or environmentally harmful
by-products, laborious workup, poor yields of isolation products, or prolonged reac-
tion times.[18,19] Only a few oxidant-free protocols have also been established so far,
such as synthesis of benzimidazoles via anaerobic oxidation of carbon–nitrogen
bond in water,[18] microwave-assisted one-pot synthesis of 2-(substituted phenyl)ben-
zimidazoles,[19] the application of L-proline in CHCl3,[20] using molecular oxygen as
the oxidant,[21] using ionic liquids [Bmim]BF4 as media and promoter,[22] and
L-prolinium nitrate as organocatalyst under solvent-free conditions.[23]
Green chemistry has emerged as a very important area of research because of
environmental and social concerns.[24] The focus of green chemistry fields of research
has shifted somehow toward employing biobased materials with diverse structures,
such as sugars, for the purposes of synthesis and catalysis as an emerging area of
research in green and sustainable chemistry. An important research challenge for
green chemistry will also be accessing the biobased building blocks to fulfill this
requirement.[25] Besides their importance in biochemistry and biology, carbohydrates
have played a serious role in today’s organic chemistry research as raw materials for
the synthesis of various organic compounds and more importantly as chiral ligands
in asymmetric synthesis. Glucose, as one of the sugars with a simple and straightfor-
ward polyhydroxy structure, has been used as a ligand with a modified structure for
Scheme 1. Oxidative cyclodehydrogenation methodology for the synthesis of 2-arylbenzimidazoles.

1796
S. ROSTAMIZADEH, R. ARYAN, AND H. R. GHAIENI
some synthetic and asymmetric catalysis purposes. Some of these applications
include asymmetric epoxidation of chalcones and simple olefins,[26] enantioselective
Michael addition of nitropropanes to chalcones,[27] and asymmetric conjugate addi-
tions to cyclohexenones.[28] In addition, aqueous 1 M glucose has been used as
medium and promoter in the synthesis of 2,6-dioxohexahydropyrimidines through
an isocyanide-based multicomponent reaction.[29]
Given these considerations, we decided to study the possibility of employing
aqueous 1 M glucose as a fully green medium and promoter in the synthesis of
2-arylbenzimidazoles as an important class of heterocycles.
RESULTS AND DISCUSSION
The model reaction employed for this study is represented in Scheme 1. At the
beginning, o-phenylenediamine (1 mmol) and benzaldehyde (1 mmol) were poured
into a container having different volumes of 1 M glucose solution and stirred at dif-
ferent temperatures. The reaction did not result in the desired product, 2-phenylben-
zimidazole, at ambient temperature, and only a mixture of reactants and some schiff
base was obtained (Table 1, entries 1–4). To find the optimized reaction conditions,
the temperature was raised from ambient temperature up to reflux condition
(Table 1, entries 5–9).
According to these results, when we performed the reaction with 5 ml 1 M glu-
cose solution at 60 ꢀC and under reflux conditions, the time and yield of the reaction
were almost the same (Table 1, entries 6 and 7). When we applied 3 ml 1 M glucose as
medium and promoter, the yields were apparently lower and reaction times were
Table 1. Screening reaction conditions for the aqueous 1 M glucose solution–promoted synthesis of
2-phenylbenzimidazole
Aqueous 1 M D-glucose
volume (ml)
Temperature
(ꢀC)
Time
(h)
Yield
(%)b
Entrya
1
Comments
1
25
20
—
A mixture of reactants and
some Schiff base
2
3
4
5
6
7
8
2
3
5
3
5
5
3
25
25
20
20
20
18
7.5
6
—
—
—
47
88
89
66
"
"
25
60
"
Reactants were consumed
60
Reflux
Reflux
—
—
—
14
aReaction conditions: o-phenylenediamine (1 mmol), benzaldehyde (1 mmol), and different volumes of
aqueous 1 M glucose solution.
bIsolated yield.

AQUEOUS 1 M GLUCOSE SOLUTION
1797
Scheme 2. Aqueous 1 M D-glucose solution–promoted synthesis of substituted 2-arylbenzimidazoles.
longer (Table 1, entries 5 and 8). The best conditions were applying the reaction in
5 ml aqueous 1 M glucose solution at 60 ꢀC.
To evaluate the scope and generality of this procedure, we used a variety of o-
phenylenediamine and benzaldehyde derivatives for the synthesis of 2-arylbenzimi-
dazole derivatives (Scheme 2, Table 2).
As can be seen, various 2-arylbenzimidazole derivatives were prepared with
good to excellent yields in short reaction times except for entries 4, 12, and 13.
We observed prolonged reaction times, but the yields were still satisfactory.
The reason for the observed short reaction times in the other entries in Table 2
could be explained by considering the structure of possible intermediates in the syn-
thesis of 2-arylbezimidazoles (Scheme 1). In the last step of the process, oxidation of
1,2-dihydrobenzimidazole intermediate took place. It is worth mentioning that in
this process, we did not use any extra oxidant, and only air oxygen and heating assist
oxidation of this intermediate. So, in entries 4, 12, and 13, the presence of
electron-withdrawing groups Cl and CO2H has led to lower reaction rates and yields.
Entry 14 shows a different situation in which a substituted benzaldehyde with
electron-donating group NHAc and 3,4-diaminobenzoic acid reacted in a shorter
reaction time, proving this assumption. When we performed this reaction with o-
phenylenediamine, 4-nitrobenzaldehyde, and 3-nitrobenzaldehyde under optimized
conditions, these reactions led to formation of only the Schiff base and not the
desired 2-arylbenzimidazole (Scheme 3).
However, the reaction was also carried out with the other derivatives of o-phe-
nylenediamine and benzaldehyde with very good results. In addition, to realize the
chemoselectivity of the process, we performed the reaction of 1 mmol o-phenylene-
diamine and 2 mmol of benzaldehyde and obtained only the monosubstituted
2-phenylbenzimidazole as the sole product with no sign of 1-phenylmethyl-2-phenyl-
benzimidazole. Similar tests were carried out with 4-methylbenzene-1,2-diamine
(Table 2, entry 7) and 4,5-dimethylbenzene-1,2-diamine (Table 2, entry 9) and 2
equivalent of benzaldehyde. Again, only the products C7 and C9 were obtained.
So, the present protocol showed a high level of generality and chemoselectivity in
the synthesis of 2-arylbenzimidazoles.

1798
S. ROSTAMIZADEH, R. ARYAN, AND H. R. GHAIENI
Table 2. Synthesis of various 2-aryl benzimidazoles promoted by aqueous 1 M solution of D-glucose
o-Diamine
derivative
Benzaldehyde
derivative
Time Yield
(%)
Entry
1
Product
Product (h)
A1
A1
A1
A1
B1
B2
B3
B4
C1
C2
C3
C4
7.5
6
88
2
3
4
91
94
81
5.5
10
5
6
A1
A1
B5
B6
C5
C6
7
89
93
6.5
7
8
9
A2
A2
A3
B1
B6
B1
C7
C8
C9
6
6
7
84
89
92
10
11
A3
A3
B3
B4
C10
C11
6.5
7.5
93
86
12
A4
B1
C12
10
89
(Continued )

AQUEOUS 1 M GLUCOSE SOLUTION
1799
Table 2. Continued
o-Diamine
derivative
Benzaldehyde
derivative
Time Yield
(%)
Entry
13
Product
Product (h)
A4
B4
C13
C14
10
7
92
14
A4
B5
93
aIsolated yield.
Scheme 3. Reaction of o-phenylynediamine with nitro-substituted benzaldehydes.
CONCLUSION
In summary, we developed a novel protocol for the preparation of 2-arylben-
zimidazoles using aqueous 1 M glucose solution as medium and promoter under
oxidant-free conditions at 60 ꢀC. The main advantages of the present protocol are
(i) good to excellent yields of products, (ii) no use of any toxic solvent or reagent,
(iii) not using oxidant, (iii) use of fully green promoter glucose, (iv) high level of
generality of substituents, and (v) chemoselectivity of the reaction.
EXPERIMENTAL
General Considerations
Melting points were recorded on a Buchi B-540 apparatus. Infrared (IR) spec-
tra were recorded on an ABB Bomem model FTLA200-100 instrument. H and 13
1
C
NMR spectra were measured with a Bruker DRX-300 Avance spectrometer at 300
and 75 MHz using tetramethylsilane (TMS) as an internal standard. Chemical shifts
(d) are reported relative to TMS, and coupling constants (J) are reported in hertz
(Hz). Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer
with 70 eV ionization potential. Elemental analyses of new compounds were per-
formed with a Vario EL III 0 serial no. 11024054 instrument.

1800
S. ROSTAMIZADEH, R. ARYAN, AND H. R. GHAIENI
General Experimental Procedure for the Synthesis of
2-Arylbenzimidazoles Under Oxidant-Free Conditions Using
Aqueous 1 M Glucose Solution
o-Phenylenediamine derivative (1 mmol) and benzaldehyde derivative (1 mmol)
were added to a round-bottomed flask containing aqueous 1 M glucose solution
(5 mL), and the mixture was stirred at 60 ꢀC for the time specified in Table 2. After
completion of the reaction, the mixture was vacuum filtered after cooling to room
temperature by a Buchi funnel, and the residues were crystallized from the mixture
of ethanol=water or dichloromethane=petroleum ether, dried at room temperature,
and characterized by physical and spectral properties.
Spectral and Analytical Data for Substituted 2-Arylbenzimidazoles
2-Phenyl-1H-benzimidazole (C1). Light yellow solid; mp 286–288 ꢀC (lit.[30]
ꢁ1
1
ꢀ
=
mp 289–291 C). IR (KBr): 1621 (C N), 3447 cm (NH). H NMR (300 MHz,
DMSO-d6): d 13.31 (s, 1H), 8.27 (d, 2H, J ¼ 3.0), 7.69 (m, 2H), 7.59 (s, 3H), 7.34
(m, 2H). 13CNMR (75 MHz, DMSO-d6): d ¼ 114.65, 123.62, 127.13, 127.35,
129.20, 131.23, 136.34, 150.16.
2-(4-Methylphenyl)-1H-benzimidazole (C2). Light yellow solid; mp
269–272 ꢀC (lit.[18] mp 277 C). IR (KBr): 1617 (C N), 3060, 3435 (NH) cmꢁ1. H
1
ꢀ
=
NMR (300 MHz, DMSO-d6): d 12.87 (s, 1H), 8.10 (d, 2H, J ¼ 8.1 Hz), 7.61 (m,
2H), 7.33 (d, 2H, J ¼ 8.1 Hz), 7.19 (m, 2H), 2.35 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): d 20.96, 111.21, 118.72, 121.59, 126.42, 127.50, 129.52, 139.56, 151.45.
2-(4-Methoxyphenyl)-1H-benzimidazole (C3). Light yellow solid; mp
ꢁ1
1
221–224 ꢀC (lit.[30] mp 224–226 C). IR (KBr): 1612 (C N), 3420 cm (NH). H
NMR (300 MHz, DMSO-d6): d 12.73 (s, 1H), 8.11 (d, 2H, J ¼ 9.0 Hz), 7.54 (s,
2H), 7.16 (m, 2H), 7.11 (d, 2H, J ¼ 9.0 Hz), 3.82 (s, 3H).
ꢀ
=
2-(4-Chlorophenyl)-1H-benzimidazole (C4). Light yellow solid; mp 286–
ꢁ1
1
289 ꢀC (lit.[30] mp 292–294 C). IR (KBr): 1597 (C N), 3420 cm (NH). H NMR
(300 MHz, DMSO-d6): d 12.98 (s, 1H), 8.18 (d, 2H, J ¼ 9.0 Hz), 7.62 (d, 3H,
J ¼ 9.0 Hz), 7.52 (d, 1H, J ¼ 6.0 Hz), 7.21 (m, 2H).
ꢀ
=
2-(4-N-Acetylaminophenyl)-1H-benzimidazole (C5). Pale yellow solid; mp
(NH). 1H NMR (300 MHz,
ꢁ1
ꢀ
=
190–192 C IR (KBr): 1588 (C N), 3389 cm
DMSO-d6): d 12.74 (s, 1H), 10.21 (s, 1H), 8.13 (d, 2H, 8.1 Hz), 7.78 (d, 2H,
J ¼ 8.1 Hz), 7.47–7.62 (m, 2H), 7.17–7.22 (m, 2H) 2.1 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): d 24.18, 119.05, 122.17, 127.18, 129.72, 138.66, 140.76, 153.19, 168.74.
MS (EI): m=e ¼ 251. Anal. calc. for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found:
C, 71.97; H, 5.44; N, 16.53.
2-(4-Benzyloxyphenyl)-1H-benzimidazolꢁe1 (C6). Pale yellow solid; mp
(NH). 1H NMR (300 MHz,
ꢀ
=
260–262 C IR (KBr): 1597 (C N), 3403 cm
DMSO-d6): d 12.74 (s, 1H), 8.11 (d, 2H, J ¼ 8.4 Hz), 7.48 (d, 2H, J ¼ 6.6 Hz),
7.34–7.43 (m, 5H), 7.18 (d, 4H, J ¼ 8.4 Hz). 13C NMR (75 MHz, DMSO-d6): d
69.44, 111.10, 115.27, 118.58, 121.52, 122.98, 127.87, 128.07, 128.55, 136.86,

AQUEOUS 1 M GLUCOSE SOLUTION
1801
143.96, 151.36, 159.76. MS (EI): m=e ¼ 300 (Mþ). Anal. calc. for C20H16N2O: C,
79.98; H, 5.37; N, 9.33. Found: C, 79.74; H, 5.64; N, 9.59.
5-Methyl-2-Phenyl-1H-benzimidazole (C7) (mixture of two regioiso-
mers). Light yeꢁll1ow solid; mp 234–238 ꢀC (lit.[31] mp 242–243 ꢀC). IR (KBr): 1591
1
=
(C N), 3422 cm (NH). H NMR (300 MHz, DMSO-d6): d 12.77 (bs, 1H), 8.15
(d, 2H, J ¼ 7.5 Hz), 7.52 (d, 2H, J ¼ 7.5 Hz), 7.47 (d, 2H, J ¼ 7.5 Hz), 7.30 (s, 1H),
7.02 (t, 1H, J ¼ 9 Hz), 2.42 (s, 3H). 13C NMR (75 MHz, DMSO-d6): d 21.28,
21.36, 110.82, 111.02, 118.45, 118.62, 123.22, 123.95, 126.21, 128.74, 128.89,
129.66, 130.31, 130.55, 131.83, 133.02, 135.25, 141.95, 144.18, 150.70, 151.11.
2-(4-Benzyloxyphenyl)-5-methyl-1H-benzimidazoleꢁ1 (C8). Pale yellow
(NH). 1H NMR
ꢀ
=
solid; mp 189–194 C. IR (KBr): 1611 (C N), 3392 cm
(300 MHz, DMSO-d6): d 7.65 (dd, 2H, J1 ¼ 8.7 Hz, J2 ¼ 4.2 Hz), 7.46 (d, 2.7 Hz,
J ¼ 6.9 Hz), 7.28–7.42 (m, 9.2H), 7.23 (s, 0.8H), 7.14 (dd, 2H, J1 ¼ 8.7 Hz,
J2 ¼ 2.7 Hz), 7.03 (t, 1.2H, J ¼ 8.4 Hz), 6.92 (d, 4H, J ¼ 4.5 Hz), 5.44 (s, 1H), 5.17
(s, 1H), 2.40 (s, 3H), 2.38 (s, 3H). 13C NMR (75 MHz, DMSO-d6): d 21.21, 21.48,
69.20, 110.61, 115.00, 115.058, 122.76, 127.30, 127.41, 127.75, 127.84, 128.44,
128.51, 129.18, 130.40, 130.47, 131.08, 131.75, 136.16, 136.77, 136.97, 152.65,
157.65. MS (EI): m=e ¼ 314 (Mþ). Anal. calc. for C21H18N2O: C, 80.23; H, 5.77;
N, 8.91. Found: C, 79.89; H, 6.09; N, 8.59.
5,6-Dimethyl-2-phenyl-1H-benzimidazole (C9). Pale yellow solid; mp
ꢁ1
1
244–247 ꢀC (lit.[32] mp 250–252 C). IR (KBr): 1586 (C N), 3417 cm (NH). H
NMR (300 MHz, DMSO-d6): d 12.64 (bs, 1H), 8.13 (d, 1H, J1 ¼ 6.6 Hz), 7.76 (s,
1H), 7.22–7.33 (m, 4H), 6.96 (d, 1H, J1 ¼ 6.6 Hz), 2.31 (s, 6H). 13C NMR
(75 MHz, DMSO-d6): d 20.08, 111.09, 119.60, 125.94, 127.43, 129.48, 131.46,
137.18, 151.40. MS (EI): m=e ¼ 222 (Mþ). Anal. calc. for C15H14N2: C, 81.05; H,
6.35; N, 12.60. Found: C, 80.76; H, 6.72; N, 12.31.
ꢀ
=
2-(4-Methoxyphenyl)-5,6-dimethyl-1H-benzimidazole (C10)ꢁ. 1Pale yellow
(NH). 1H
ꢀ
=
crystalline solid; mp 205–229 C. IR (KBr): 1599 (C N), 3392 cm
NMR (300 MHz, DMSO-d6): d 12.78 (bs, 1H), 7.90 (s, 2H), 7.02 (s, 2H), 6.90 (s,
2H), 3.80 (s, 3H), 2.10 (s, 6H). 13C NMR (75 MHz, DMSO-d6): d 18.60, 19.28,
55.27, 114.09, 116.24, 117.62, 123.55, 127.77, 130.00, 133.29, 134.84, 141.53,
154.25, 161.32. MS (EI): m=e ¼ 252 (Mþ). Anal. calc. for C16H16N2O: C, 76.16;
H, 6.39; N, 11.10. Found: C, 75.85; H, 6.72; N, 11.32.
2-(4-Chlorophenyl)-5,6-dimethyl-1H-benzimidazole (C11). Milky crystal-
ꢁ1
line solid; mp 259–263 C. IR (KBr): 1609 (C N), 3432 cm (NH). 1H NMR
(300 MHz, DMSO-d6): d 7.98 (d, 2H, J ¼ 7.8 Hz), 7.52 (d, 2H, J ¼ 7.8 Hz), 6.97 (s,
2H). 2.09 (s, 6H). 13C NMR (75 MHz, DMSO-d6): d 18.59, 19.37, 116.37, 117.61,
123.50, 128.74, 128.96, 129.88, 132.22, 135.02, 135.74, 142. 17, 152.98. MS (EI):
m=e ¼ 256 (Mþ). Anal. calc. for C15H13ClN2: C, 70.18; H, 5.10; N, 10.91. Found:
C, 69.81; H, 5.43; N, 10.59.
ꢀ
=
2-Phenyl-1H-benzimidazole-5-carboxylic acid (C12). Milky crystalline
ꢁ1
solid; mp 303–308 ꢀC (lit.[32] mp 325 C). IR (KBr): 1621 (C N), 3451 cm (NH).
1H NMR (300 MHz, DMSO-d6): d 7.90 (d, 1H, J ¼ 8.4 Hz), 7.81 (d, 1H, J ¼ 8.4 Hz),
7.75 (m, 1H), 7.23–7.29 (m, 3H), 7.01 (d, 2H, J ¼ 6.9 Hz). 13C NMR (75 MHz,
ꢀ
=

1802
S. ROSTAMIZADEH, R. ARYAN, AND H. R. GHAIENI
DMSO-d6): d 113.08, 119.04, 123.66, 127.30, 128.47, 128.91, 129.12, 130.31, 136.67,
145.99, 156.04, 167.67. MS (EI): m=e ¼ 238 (Mþ). Anal. calc. for C14H10N2O2: C,
70.58; H, 4.23; N, 11.76. Found: C, 70.27; H, 4.61; N, 11.39.
2-(4-Chlorophenyl)-1H-benzimidazole-5-carboxylic acid (C13). Milky
ꢀ
=
=
crystalline solid; mp 165–168 C. IR (KBr): 1622 (C N), 1683 (C O), 3101, 3414
1
(NH) cmꢁ1. H NMR (300 MHz, DMSO-d6): d 13.11 (s, 1H), 12.43 (s, 1H), 8.09
(d, J ¼ 9 Hz, 3H), 7.75 (m, 1H), 7.64 (d, J ¼ 9 Hz, 3H). 13C NMR (75 MHz,
DMSO-d6): d 122.55, 123.67, 127.77, 127.89, 128.73, 134.11, 148.22, 156.63,
167.80. MS (EI): m=e ¼ 272 (Mþ). Anal. calcd. for C14H8ClN2O2: C, 61.66; H,
3.33; Cl, 13.00; N, 10.27. Found: C, 62.21; H, 2.43; N, 10.41.
2-(4-N-Acetylaminophenyl)-1H-benzimidazole-5-carboxylic acid (C14).
ꢀ
=
=
Milky crystalline solid; mp 179–183 C. IR (KBr): 1603 (C N), 1695 (C O), 1667
ꢁ1
1
=
(C O), 3987 cm (NH). H NMR (300 MHz, DMSO-d6): d 12.82 (bs, 1H), 10.22
(s, 1H), 8.02 (s, 1H), 7.86 (d, 1H, J ¼ 8.4 Hz), 7.74 (d, 1H, J ¼ 8.4 Hz), 7.49 (d,
2H, J ¼ 7.8 Hz), 6.95 (d, 2H, J ¼ 7.8 Hz), 2.08 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): d 24.15, 112.93, 118.77, 123.85, 124.87, 126.49, 129.79, 131.04, 135.66,
138.70, 146.02, 155.83, 167.69, 168.79. MS (EI): m=e ¼ 295 (Mþ). Anal. calc. for
C16H13N3O3: C, 65.08; H, 4.44; N, 14.23. Found: C, 64.76; H, 4.81; N, 14.57.
ACKNOWLEDGMENT
The authors gratefully acknowledge the Research Council of K. N. Toosi
University of Technology for partial financial support of this work.
REFERENCES
1. (a) Tamm, I. Inhibition of influenza and mumps virus multiplication by 4,5,6-trichloro-
(or 5,6,7-) trichloro-1-b-D-ribofuranosyl-benzimidazole. Science 1954, 126, 847–848; (b)
Migawa, M. T.; Giradet, J. L.; Walker, J. A.; Koszalka, G. W.; Chamberlain, S. D.;
Drach, J. C.; Townsend, L. B. Design, synthesis, and antiviral activity of a-nucleosides:
D- and L-isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles. J. Med.
Chem. 1998, 41, 1242–1251; (c) Porcari, A. R.; Devivar R. V.; Kucera, L. S.; Drach, J. C.;
Townsend, L. B. Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-
2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-
(b-D-ribofuranosyl)benzimidazole. J. Med. Chem. 1998, 41, 1252–1262.
2. Shingalapur, R. V.; Hosamani, K. M.; Keri, R. S. Synthesis and evaluation of in vitro
anti-microbial and anti-tubercular activity of 2-styryl benzimidazoles. Eur. J. Med. Chem.
2009, 44, 4244–4248.
3. Lloyd, J.; Finlay, H. J.; Atwal, K.; Kover, A.; Prol, J.; Yan, L.; Bhandaru, R.; Vaccaro,
W.; Huynh, T.; Huang, C. S.; Conder, M. L.; Jenkins-West, T.; Sun, H.; Li, D.; Levesque,
P. Dihydropyrazolopyrimidines containing benzimidazoles as K(V)1.5 potassium channel
antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 5469–5473.
4. McCauley, J. A.; Theberge, C. R.; Romano, J. J.; Billings, S. B.; Anderson, K. D.;
Claremon, D. A.; Freidinger, R. M.; Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly,
T. M.; Condra, C. L.; Xia, M.; Cunningham, M. E.; Bednar, B.; Stump, G. L.; Lynch, J.
J.; Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton, N. J. NR2B-Selective

AQUEOUS 1 M GLUCOSE SOLUTION
1803
N-methyl-D-aspartate antagonists: Synthesis and evaluation of 5-substituted benzimida-
zoles. J. Med. Chem. 2004, 47, 2089–2096.
5. Lahue, B. R.; Ma, Y.; Shipps, Jr. G. W.; Seghezzi, W.; Herbst, R. Substituted benzimida-
zoles: A novel chemotype for small molecule hKSP inhibitors. Bioorg. Med. Chem. Lett.
2009, 19, 3405–3409.
´
ˇ
ˇ
´
´
6. Agic, D.; Hranjec, M.; Jajcanin, N.; Starcevic, K.; Karminski-Zamola, G.; Abramic, M.
Novel amidino-substituted benzimidazoles: Synthesis of compounds and inhibition of
dipeptidyl peptidase III. Bioorg. Chem. 2007, 35, 153–169.
7. Potashman, M. H.; Bready, J.; Coxon, A.; DeMelfi, Jr. T. M.; DiPietro, L.; Doerr, N.;
Elbaum, D.; Estrada, J.; Gallant, P.; Germain, J.; Gu, Y.; Harmange, J.-C.; Kaufman,
S. A.; Kendall, R.; Kim, J. L.; Kumar, G. N.; Long, A. M.; Neervannan, S.; Patel,
V. F.; Polverino, A.; Rose, P.; van der Plas, S.; Whittington, D.; Zanon, R.; Zhao, H.
Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vas-
cular endothelial growth factor-2 receptor tyrosine kinase inhibitors. J. Med. Chem. 2007,
50, 4351–4373.
´
´
8. Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic, M.; Suman, L.; Pavelic, K.; Karminski-
Zamola, G. Novel cyano- and amidino-substituted derivatives of styryl-2-benzimidazoles
and benzimidazo[1,2-a]quinolines: Synthesis, photochemical synthesis, DNA binding, and
antitumor evaluation, part 3. J. Med. Chem. 2007, 50, 5696–5711.
9. (a) Grimmet, M. R. Imidazoles and their fused bezo derivatives; In Comprehensive Hetero-
cyclic Chemistry; A. R. Katritzky, C. W. Rees (Eds.); Pergamon Press: Oxford, 1984, vol.
5, pp. 457–480; (b) Harapanhalli, R. S.; McLaughlin, L. W.; Howell, R. W.; Rao, D. V.;
Adelstein, S. J.; Kassis, A. I. [I-125=I-127]IodoHoechst 33342: Synthesis, DNA binding,
and biodistribution. J. Med. Chem. 1996, 39, 4804–4809.
10. Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.;
Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.; Shrader,
W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L. Development
˚
of serine protease Inhibitors displaying a multicentered short (<2.3 A) hydrogen bond
binding mode: Inhibitors of urokinase-type plasminogen activator and factor Xa.
J. Med. Chem. 2001, 44, 2753–2771.
11. Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Van Haverbeke, Y. 2,3-Dichloro-5,6-
dicyano-1,4-benzoquinone, a mild catalyst for the formation of carbon–nitrogen bonds.
Tetrahedron 1995, 51, 5813–5818.
12. Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.; Itoh, K. In situ generation and
synthetic application of 2-phenylbenzimidazoline to the selective reduction of carbon–
carbon double bonds of electron-deficient olefins. Bull. Chem. Soc. Jpn. 1987, 60, 737–746.
13. Patzold, F.; Zeuner, F.; Heyer, T. H.; Niclas, H. J. Dehydrogenations using benzofurox-
ane as oxidant. Synth. Commun. 1992, 22, 281–288.
14. Bhatnagar, I.; George, M. V. Oxidation with metal oxides, 2: Oxidation of chalcone
phenylhydrazones, pyrazolines, o-aminobenzylidine anils, and o-hydroxy benzylidine
anils with manganese dioxide. Tetrahedron 1968, 24, 1293–1298.
15. Stephens, F. F.; Bower, J. D. The preparation of benzimidazoles and benzoxazoles from
Schiff’s bases 1. J. Chem. Soc. 1949, 2971–2972.
A
practical Oxone(R)-mediated,
´
16. Beaulieu, P. L.; Hache, B.; von Moos, E. A.
high-throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines
and aldehydes and its application to preparative scale synthesis. Synthesis 2003,
1683–1692.
17. Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.; Fraga-Spano, S.; Macielag, M. J.;
Werblood, H. M.; Foleno, B. D.; Webb, G. C.; Barrett, J. F.; Hlasta, D. J. Amidino
benzimidazole inhibitors of bacterial two-component systems. Bioorg. Med. Chem. Lett.
2001, 11, 1545–1548.

1804
S. ROSTAMIZADEH, R. ARYAN, AND H. R. GHAIENI
18. Gogoi, P.; Konwar, D. An efficient and one-pot synthesis of imidazolines and benzimida-
zoles via anaerobic oxidation of carbon–nitrogen bonds in water. Tetrahedron Lett. 2006,
47, 79–82.
´
19. Navarrete-Vazquez, G.; Moreno-Diaz, H.; Estrada-Soto, S.; Torres-Piedra, M.; Leon-
Rivera, I.; Tlahuext, H.; Mun˜oz-Mun˜iz, O.; Torres-Gomez, H. Microwave-assisted
´
one-pot synthesis of 2-(substituted phenyl)-1H-benzimidazole derivatives. Synth. Com-
mun. 2007, 37, 2815–2825.
20. Varala, R.; Nasreen, A.; Enugala, R.; Adapa, S. R. L-proline catalyzed selective synthesis
of 2-aryl-1-arylmethyl-1H-benzimidazoles. Tetrahedron Lett. 2007, 48, 69–72.
21. Lin, S. N.; Yang, L. A simple and efficient procedure for the synthesis of benzimidazoles
using air as the oxidant. Tetrahedron Lett. 2005, 46, 4315–4319.
22. Ma, H. Q.; Wang, Y. L.; Li, J. P.; Wang, J. Y. Selective synthesis of 2-aryl-1-arylmethyl-
1H-1,3-benzimidazoles promoted by ionic liquid. Heterocycles 2007, 71, 135–140.
23. Rostamizadeh, S.; Aryan, R.; Ghaieni, H. R.; Amani, A. M. Solvent-free chemoselective
synthesis of some novel substituted 2-arylbenzimidazoles using amino acid-based proli-
nium nitrate ionic liquid as catalyst. J. Heterocycl. Chem. 2009, 46, 74–78.
24. Anastas, P. T.; Kirchhoff, M. M. Origins, current status, and future challenges of green
chemistry. Acc. Chem. Res. 2002, 35, 686–694.
´
25. Horvath, I. T.; Anastas, P. T. Innovations and green chemistry. Chem. Rev. 2007, 107,
2169–2173.
26. (a) Shing, T. K. M.; Leung, G. Y. C. Asymmetric epoxidation catalyzed by D-glucose-
, P.; Keglevich, G.;
derived uloses. Tetrahedron 2002, 58, 7545–7552; (b) Bako, T.; Bako
´ ´
Bombicz, P.; Kubinyi, M.; Pal, K.; Bodor, S.; Mako, A.; Toke, L. Phase-transfer cata-
}
lyzed asymmetric epoxidation of chalcones using chiral crown ethers derived from
´
´
D-glucose, D-galactose, and D-mannitol. Tetrahedron: Asymmetry 2004, 15, 1589–1595.
´
27. Bako, T.; Bako, P.; Keglevich, G.; Bathori, N.; Czugler, M.; Tatai, J.; Novak, T.; Parlagh,
G.; Toke, L. Enantioselective Michael addition of 2-nitropropane to chalcone analogues
´
´
´
}
catalyzed by chiral azacrown ethers based on a-D-glucose and D-mannitol. Tetrahedron:
Asymmetry 2003, 14, 1917–1923.
´
28. Dieguez, M.; Ruiz, A.; Claver, C. Chiral diphosphites derived from D-glucose in the copper-
catalyzed conjugate addition of diethylzinc to cyclohexenone. Tetrahedron: Asymmetry
2001, 12, 2895–2900.
29. Yavari, I.; Karimi, E.; Djahaniani, H. Isocyanide-based multicomponent synthesis of
functionalized 2,6-dioxohexahydropyrimidines in 1 M aqueous glucose. Synth. Commun.
2007, 37, 2593–2599.
30. Du, H.; Wang, Y.-G. A rapid and efficient synthesis of benzimidazoles using hypervalent
iodine as oxidant. Synthesis 2007, 675–678.
31. Perry, R. J.; Wilson, B. D. A novel palladium-catalyzed synthesis of 2-arylbenzimidazoles.
J. Org. Chem. 1993, 58, 7016–7021.
32. Sharghi, H.; Asemani, O.; Khalifeh, R. New one-pot procedure for the synthesis of
2-substituted benzimidazoles. Synth. Commun. 2008, 38, 1128.