New one-pot procedure for the synthesis of 2-substituted benzimidazoles

Article abstract of DOI:10.1080/00397910701863657

A highly selective synthesis of 2-substituted benzimidazole derivatives from the reaction of o-phenylendiamine derivatives and aromatic aldehydes in the presence of an organic salt, NH4OAc, in absolute ethanol is presented. The products were obtained by evaporating the solvent followed by a simple recrystallization with excellent yields. Copyright Taylor & Francis Group, LLC.

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New One‐Pot Procedure for the Synthesis of
2‐Substituted Benzimidazoles
Hashem Sharghi a , Omid Asemani a & Reza Khalifeh a
a Department of Chemistry, Shiraz University, Shiraz, Iran
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Synthesis of 2‐Substituted Benzimidazoles, Synthetic Communications: An International Journal for Rapid
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Synthetic Communicationsw, 38: 1128–1136, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701863657
New One-Pot Procedure for the Synthesis
of 2-Substituted Benzimidazoles
Hashem Sharghi, Omid Asemani, and Reza Khalifeh
Department of Chemistry, Shiraz University, Shiraz, Iran
Abstract: A highly selective synthesis of 2-substituted benzimidazole derivatives from
the reaction of o-phenylendiamine derivatives and aromatic aldehydes in the presence
of an organic salt, NH4OAc, in absolute ethanol is presented. The products were
obtained by evaporating the solvent followed by a simple recrystallization with
excellent yields.
Keywords: Aldehyde, benzimidazole derivatives, excellent yields, synthesis
INTRODUCTION
Developing easy-handling, efficient, and environmentally compatible
chemical processes or methodologies for widely used organic compounds
from simple and nontoxic reagents is one of the major challenges for
synthetic chemists. The synthesis of benzimidazole derivatives has gained
importance in recent years, because they exhibit illustrious biological and
pharmacological activities and are used as antiviral agents,[1] selective neuro-
peptide YY1 receptor antagonists,[2] factor Xa inhibitors,[3] potential
antitumor agents,[4] antimicrobial agents,[5] smooth muscle cell proliferation
inhibitors.[6] They are used in diverse areas of chemistry[7] and are very
important intermediates in organic reactions.[8]
In spite of their significance from pharmacological, industrial, and
synthetic points of view, comparatively few methods for the preparation of
benzimidazoles have been reported. The traditional synthesis of
Received in the U.K. June 27, 2007
Address correspondence to Hashem Sharghi, Department of Chemistry, Shiraz
University, Shiraz 71454, Iran. E-mail: shashem@chem.susc.ac.ir
1128

Synthesis of 2-Substituted Benzimidazoles
1129
benzimidazoles includes the condensation of o-phenylendiamine with
carboxylic acid or its derivatives under harsh dehydrating conditions,[9] or
use of strong acids such as polyphosphoric acid[10] or mineral acids[11] and
the condensation of o-phenylendiamine with aldehyde in refluxing nitroben-
zene[12] or in the presence of acidic catalysts.[13] Benzimidazoles have also
been prepared on a solid phase to provide a combinatorial approach.[14]
However, many of these methods have several drawbacks such as (a) low
yields, (b) use of expensive reagents, (c) tedious workup procedures, (d)
more than one step in their synthesis, (e) long reaction times, (f) co-occurrence
of several side reactions, and (g) poor selectivity. In recent years, some
methods have been developed where iodine,[15] silica sulfuric acid,[16]
[18]
L-proline,[17] and In(OTf)3
are used to meet some of these problems.
However, the search continues for the synthesis of benzimidazoles with oper-
ational simplicity, economic viability, reusability, and greater selectivity.
RESULTS AND DISCUSSION
Herein we report a simple and highly selective procedure for the condensation
reaction of o-phenylendiamine derivatives with different aldehydes using
ammonium acetate in absolute ethanol (Scheme 1). The method is simple,
isolation of the products from the reaction mixture is easy, and the yields
are high.
The efficacy of using other ammonium salts in the condensation reaction
of o-phenylendiamine and benzaldehyde are shown in Table 1. As can be seen
in Table 1, the most efficient ammonium salt for this reaction is ammonium
acetate, and therefore it was chosen for further study. Absolute ethanol was
also the best among the solvents tested (H2O, EtOH 96%, CH3CN, CH2Cl2).
Under optimized reaction conditions, we obtained exclusively
2-substituted products 3, and either no N-alkylated products 4 were
observed or they could be found only in trace amounts in just a few cases
(Scheme 1). This selectivity could be useful in preparing a small library of
2-substituted benzimidazoles in excellent yields. We studied the scope of
the reaction by varying the o-phenylendiamines (1a–5a) for condensation
with benzaldehyde under optimized conditions, and the results are shown in
Scheme 1.

1130
H. Sharghi, O. Asemani, and R. Khalifeh
Table 1. Condensation reaction of o-phenylendiamine (1.0 mmol) with
benzaldehyde (1.05 mmol) using different ammonium salts (1 mmol) in
absolute ethanol at 75 8C
Entry
Ammonium salt
Time (h)
Yield (%)a
1
2
No salt
NH4I
NH4Cl
10
0.0
61
58
74
45
52
61
66
84
95
3.5
2.5
3.5
2.0
4.5
4.0
2.5
5.0
4.5
3
4
NH4F
5
NH4SO4
NH4PO4
NH4H2PO4
NH4O2CH
NaOAc
NH4OAc
6
7
8
9
10
aIsolated yields.
Table 2. Condensation reaction of o-phenylendiamine (1.0 mmol) with different alde-
hydes (1.05 mmol) using ammonium acetate (1 mmol) in absolute ethanol at 75 8C.
o-Phenyl
Compound 3 endimine
Time
(h) Yieldsa
Aldehyde
Melting points
295 (295)[15]
246
3a
3b
3c
3d
3e
3f
1a
2a
3a
4a
5a
1a
1a
1a
1a
1a
1a
1a
1a
C6H5CHO
C6H5CHO
C6H5CHO
C6H5CHO
C6H5CHO
4.5 95
5.5 91
5.5 95
7.5 92
325
214
10
80
222
4-MeOC6H4CHO 5.0 87
226 (226–227)[19]
276–277 (275–276)[19]
302–303 (301)[20]
233–234 (234)[21]
262
3g
3h
3i
4-MeC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
4-CNC6H4CHO
4-iPrC6H4CHO
3-NO2C6H4CHO
2,6-
4.0 92
8.0 85
4.0 93
5.5 95
4.5 89
6.5 90
6.5 90
3j
3k
3l
250–251
201
279
3m
DiClC6H3CHO
b-Naphtaldehyde 12
2-OHC6H4CHO
3n
3o
1a
1a
78
83
217
242 (242)[21]
9
aIsolated yields.

Synthesis of 2-Substituted Benzimidazoles
1131
Table 2. Among the various o-phenylendiamines tested, the order of reactivity
in terms of yields and reaction times to benzaldehyde was as follows:
1a . 3a . 2a . 4a . 5a.
Then we studied the generality and selectivity of ammonium acetate
catalysis for the condensation of electronically divergent aromatic
aldehydes with o-phenylendiamine. In all cases, the reaction was clean and
1
carried out within 4–12 h. All products were characterized by IR, H NMR,
and 13C NMR. The present protocol was efficient for aromatic aldehyhes
bearing either electron-donating or electron-withdrawing substituents
(Table 2).
The proposed mechanism for NH4OAc-catayzed synthesis of 2-substi-
tuted benzimidazoles may be visualized to occur via a sequence of reactions
as depicted in Scheme 2. Path I involves (i) formation of benzylidene-o-phe-
nylendiamine via iminium catalysis, (ii) protonation of the benzyliden-o-phe-
nylendiamine and ring closure, leading to a five-membered ring either in a
sequential or concerted manner,[17] or (iii) air oxidation of the dihydrobenzi-
midazole.[18] Path II involves the activation of the aldehyde carbonyl oxygen
by the acetic acid produced by the heating of ammonium acetate salt through
intermolecular hydrogen binding and subsequent condensation with o-pheny-
lendiamine, followed by steps (ii) and (iii) to form 2-substituted benzimida-
zoles as shown in Scheme 2.[17]
To sum up, we have developed a practical, new, and very simple
procedure for the selective synthesis of 2-substituted benzimidazole deriva-
tives using the commercially available and cheap salt, ammonium acetate,
Scheme 2. Proposed mechanism for NH4OAc-catalyzed 2-substituted benzimidazole
synthesis.

1132
H. Sharghi, O. Asemani, and R. Khalifeh
in absolute ethanol. Mild reaction conditions, use of an environmentally safe
solvent (ethanol), low cost, availability of the catalyst, and operational simpli-
city are among the advantages of the present work.
EXPERIMENTAL
General Procedure
For each reaction, diamine (1 mmol), aldehyde (1.05 mmol), and ammonium
acetate (1 mmol) were mixed in absolute ethanol in a 50-ml, round-bottomed
flask equipped with a magnetic stirrer. The flask, loosely capped, and was
heated in an oil bath with a temperature of 75 8C for the time specified in
Table 2. Progress of reactions was thin-layer chromatography monitored by
(TLC) using n-hexane/ethyl acetate (7:1). After the reaction was
completed, the solvent was evaporated to give the crude product, which was
purified by recrystallization or in a few cases using short-column chromato-
graphy with n-hexane/ethyl acetate (10:1) as eluent.
Data
Unknown compounds or compounds for which incomplete physical data were
reported in the literature were characterized by FT-IR (Shimadzu FT-IR 8300
spectrophotometer), NMR (1H, 13C), and elemental analysis.
5-Methyl-2-phenyl-1H-1,3-benzimidazole (3b): White crystals; mp 246 8C. IR
(KBr): 3410 (w), 3039 (m), 2882 (m), 1450 (s), 1402 (m), 698 (m); 1H NMR
(DMSO-d6, 250 MHz) d (ppm): 2.35 (S, 3H), 7.00 (d, 1H, J ¼ 8.1 Hz), 7.36–
7.55 (m, 5H), 8.14 (d, 2H, J ¼ 7.6 Hz), 12.75 (S, 1H); 13C NMR (DMSO-d6,
62.9 MHz) d (ppm): 21.3, 111.1, 118.4, 123.5, 126.2, 128.8, 129.2, 129.5,
130.3, 131.1, 150.9; mass m/z (%): 209 (Mþ þ 1, 7.7), 208 (Mþ, 33). Anal.
calcd. for C14H12N2: C, 80.74; H, 5.81. Found: C, 80.39; H, 5.68.
2-Phenyl-1H-1,3-benzimidazole-5carboxylic acid (3c): White crystals; mp
325 8C. IR (KBr): 3340 (m), 3058 (m), 2921 (b), 1687 (s), 1296 (s), 771
1
(m) cm21; H NMR (DMSO-d6, 250 MHz) d (ppm): 7.27–7.51 (m, 3H),
7.65–7.93 (m, 2H), 8.08–8.22 (m, 3H); 13C NMR (DMSO-d6, 62.9 MHz) d
(ppm): 122.7, 123.5, 124.0, 125.0, 126.7, 128.3, 129.2, 129.6, 130.3, 142.4,
153.7, 168.0; mass m/z (%): 239 (Mþ þ 1, 1.7), 238 (Mþ, 12.8), 221 (9.9),
193 (7.2), 149 (8.7), 123 (7.7). Anal. calcd. for C14H10N2O2: C, 70.58; H,
4.23. Found: C, 71.02; H, 4.08.
Phenyl(2-phenyl-1H-1,3-benzimidazole-5-yl)methanone (3d): Pale yellow
crystals; mp 214 8C. IR (KBr): 3398 (m), 3116 (m), 1639 (m), 1614 (s),

Synthesis of 2-Substituted Benzimidazoles
1133
1
1321 (s), 1282 (m); H NMR (DMSO-d6, 250 MHz) d (ppm): 7.39–7.58
(m, 10H), 7.81 (s, 1H), 8.05 (m, 2H), 13.14 (s, 1H); 13C NMR (OMSO-d6,
62.9 MHz) d (ppm): 124.1, 126.7, 128.3, 129.0, 129.4, 130.4, 132.0. 132.8,
138.0, 154.1, 195.60; mass m/z (%): 299 (Mþ þ 1, 1.3), 298 (Mþ, 4.4), 281
(1.1), 221 (6.7), 194 (3.8), 105 (36.8). Anal. calcd. for C20H14N2O: C,
80.52; H, 4.73. Found: C, 81.06; H, 4.97.
2-Phenyl-3H-imidazo[4,5-c]pyridine (3e): White crystals; mp 222 8C. IR
(KBr): 3435 (w), 3049 (s), 1624 (m), 1466 (s), 1427 (m), 1286 (s), 698 (s);
1H NMR (DMSO-d6, 250 MHz) d (ppm): 7.51–7.58 (m, 4H), 8.20 (d, 2H,
J ¼ 6.0 Hz), 8.29 (d, 1H, J ¼ 5.4 Hz), 8.95 (s, 1H), 13.24 (s, 1H); 13C NMR
(DMSO-d6, 62.9 MHz) d (ppm): 109.0, 126.9, 127.3, 129.0, 129.4, 130.5,
139.0, 141.1, 142.5, 153.6; mass m/z (%): 196 (Mþ þ 1, 0.4), 195 (Mþ; 3.1).
Anal. calcd. for C12H9N3: C, 73.83; H, 4.65. Found: C, 73.65; H, 4.77.
4-(1H-1,3-Benzimidazol-2-yl)benzonitrile (3j): White crystals; mp 262 8C. IR
(KBr): 3417 (m), 3047 (w), 2912 (w), 2222 (m), 1605 (m), 1454 (m), 1408 (s),
1
837 (s), 748 (s) cm21. H NMR (DMSO-d6, 250 MHz) d (ppm): 723–768
(m, 4H), 8.00 (d, 2H, J ¼ 8.1 Hz), 8.32 (d, 2H, J ¼ 8.1 Hz), 13C NMR
(DMSO-d6, 62.9 MHz) d (ppm): 111.7, 111.8, 118.6, 119.3, 122.2, 123.3,
127.0, 132.9, 134.2, 149.3; mass m/z (%): 220 (Mþ þ 1, 14), 219 (Mþ,
100), 102 (20). Anal. calcd. for C14H9N3: C, 76.70; H, 4.14. Found: C,
76.53; H, 4.22.
2-(4-Isopropylphenyl)-1H-1,3-benzimidazole (3k): White crystals; mp 250–
251 8C. IR (KBr): 3425 (w), 3055 (w), 2873 (m), 2951 (s), 1439 (s), 1273
1
(m), 741 (m) cm21. H NMR (CDCl3, 250 MHz) d (ppm): 1.19 (d, 6H,
J ¼ 6.9 Hz), 2.85 (m, 1H), 7.17–7.26 (m, 4H), 7.57 (m, 2H), 7.96 (d, 2H,
J ¼ 8.3 Hz). 13C NMR (DMSO-d6, 62.9 MHz) d (ppm): 23.6, 33.3, 121.9,
126.4, 127.7, 129.1, 129.4, 134.5, 150.3, 151.3; mass m/z (%): 237
(Mþ þ 1, 17), 236 (Mþ, 62), 221 (100), 193 (13), 116 (72). Anal. calcd. for
C16H16N2: C, 81.32; H, 6.82. Found: C, 81.20; H, 6.74.
2-(3-Nitrophenyl)-1H-1,3-benzimidazole (3l): Pale yellow crystals; mp
201 8C. IR (KBr): 3437 (w), 3078 (w), 1529 (s), 1348 (s), 732 (m) cm21
.
1H NMR (CDCl3, 250 MHz) d (ppm): 7.20–7.39 (m, 2H), 7.61–7.67
(m, 3H), 8.25 (d, 1H, J ¼ 8.4 Hz), 8.43 (d, 1H, J ¼ 7.8 Hz), 8.77 (t, 1H,
J ¼ 1.8 Hz). 13C NMR (DMSO-d6, 62.9 MHz) d (ppm): 116.0, 120.8,
122.7, 124.2, 130.6, 131.6, 132.4, 136.9, 148.3, 149.0; mass m/z (%): 240
(Mþ þ 1, 17), 239 (Mþ, 100), 193 (67). Anal. calcd. for C13H9N3O2: C,
65.27; H, 3.79. Found: C, 65.41; H, 3.68.
2-(2,6-Dichlorophenyl)-1H-1,3-benzimidazole (3m): White crystals; mp
279 8C. IR (KBr): 3430 (w), 3058 (w), 1553 (w), 1429 (s), 1329 (w), 777
(m), 741 (m) cm21 1H NMR (CDCl3, 250 MHz) d (ppm): 7.11–7.30
.

1134
H. Sharghi, O. Asemani, and R. Khalifeh
(m, 6H), 7.54 (d, 2H, J ¼ 2.32 Hz). 13C NMR (DMSO-d6, 62.9 MHz) d
(ppm): 115.4, 122.2, 128.3, 130.4, 132.4, 135.0, 137.0, 146.6; mass m/z
(%): 267 (Mþ þ 4, 0.1), 265 (Mþ þ 2, 7), 263 (100) (Mþ), 228 (58), 193
(71). Anal. calcd. for C13H8Cl2N2: C, 59.34; H, 3.06. Found: C, 59.16; H, 3.15.
2-(2-Naphtyl)-1H-1,3-benzimidazole (3n): White crystals; mp 217 8C. IR
(KBr): 3425 (w), 3047 (m), 1605 (w), 1447 (m), 1385 (m), 748 (s) cm21
.
1H NMR (CDCl3, 250 MHz) d (ppm): 7.19 (dd, 2H, J1 ¼ 6.0 Hz,
J2 ¼ 3.0 Hz), 7.37–7.40 (m, 2H), 7.59–7.77 (m, 5H), 8.11 (dd, 1H,
J1 ¼ 8.6, J2 ¼ 1.7), 8.49 (s, 1H). 13C NMR (CDCl3, 62.9 MHz) d (ppm):
115.2, 123.2, 123.6, 126.5, 126.8, 127.2, 127.8, 128.5, 129.0, 134.2, 138.1,
145.9, 151.6; mass m/z (%): 245 (Mþ þ 1, 43), 244 (Mþ, 100), 153 (58).
Anal. calcd. for C17H12N2: C, 83.58; H, 4.95. Found: C, 83.40; H, 4.97.
ACKNOWLEDGMENTS
We gratefully acknowledge the support of this work by the Shiraz University
Research Council and Shiraz Faculty of Pharmacy. We are also grateful to
H. Sajedian Fard his for helpful cooperation.
REFERENCES
1. (a) Tebbe, M. J.; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee, C. C.;
Sattelberg, T. R.; Mckinney, E.; Tang, C. J. Antirhino/enteroviral vinylacetylene
benzimidazoles: a study of their activityand oral plasma levels in mice. J. Med.
Chem. 1997, 40, 3937–3946; (b) 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-(a-D-ribofuranosyl) benzimidazole. J. Med. Chem.
1998, 41, 1252–1262; (c) Roth, M.; Morningstar, M. L.; Boyer, P. L.;
Hughes, S. H.; Bukheit, R. W.; Michejda, C. J. Synthesis and biological activity
of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase: 2-aryl-substi-
tuted benzimidazoles. J. Med. Chem. 1997, 40, 4199–4207; (d) 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 r-nucleosides: D-and
L-Isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl) benzimidazoles.
J. Med. Chem. 1998, 41, 1242–1251; (e) Tamm, I. Inhibition of influenza and
mumps virus multiplication by 4,5,6- (or 5,6,7-) trichloro-1-b-D-Ribofuranosyl-
benzimidazole. Science 1954, 126, 1235–1236.
2. Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman, A.;
Gackenheimer, S. L.; Bruns, R. F.; Hipskind, A.; Britton, T. C.; Cantrell, B. E.;
Gehlert, D. R. Synthesis and evaluation of a series of novel 2-[(4-Chlorophenoxy)-
methyl]-benzimidazoles as selective neuropeptide Y Y1 receptor antagonists.
J. Med. Chem. 1998, 41, 2709–2719.

Synthesis of 2-Substituted Benzimidazoles
1135
3. Zhao, J.; Arnaiz, D.; Griedel, B.; Sakata, B.; Dallas, J.; Whitlow, M.; Trinh, L.;
Post, J.; Liang, A.; Morrissey, M.; Shaw, K. Design, synthesis, and in vitro biologi-
cal activity of benzimidazole based factor Xa inhibitors. Bioorg. Med. Chem. Lett.
2000, 10, 963–966.
4. Denny, W. A.; Rewcastle, G. W.; Bagley, B. C. Potential antitumor agents, 59:
Structure–activity relationships for 2-phenylbenzimidazole-4-carboxamides, a
new class of “minimal” DNA-intercalating agents which may not act via topoi-
somerase I1. J. Med. Chem. 1990, 33, 814–819.
5. (a) Forseca, T.; Gigante, B.; Gilchrist, T. L. A short synthesis of phenanthro[2,3-
d]imidazoles from dehydroabietic acid: application of the methodology as a con-
venient route to benzimidazoles. Tetrahedron 2001, 57, 1793–1799;
(b) Parikh, A. R.; Khunt, M. D. Proceedings of the 222nd ACS National
Meeting, Chicago, IL, 2001, 73.
6. Elokdah, H. M.; Chai, S. Y.; Sulkowski, T. S. US Patent 5, 764, 473, 1998; Chem.
Abstr. 1998, 129, 58784g.
7. Stevenson, C.; Davies, R.; Jeremy, H. Photosensitization of guanine-specific DNA
damage by 2-phenylbenzimidazole and the sunscreen agent 2-phenylbenzimida-
zole-5-sulfonic acid. Chem. Toxicol 1999, 12, 38–45.
8. (a) Bai, Y.; Lu, J.; Shi, Z.; Yang, B. Synthesis of 2,15-hexadecanedione as a
precursor of muscone. Synlett 2001, 544–546; (b) Hasegawa, E.; Yoneoka, A.;
Suzuki, K.; Kato, T.; Kitazume, T.; Yangi, K. Reductive transformation of a,b-
epoxy ketones and other compounds promoted through photoinduced electron
transfer processes with 1,3-dimethyl-2-phenylbenzimidazoline (DMPBI). Tetra-
hedron 1999, 55, 12957–12968.
9. (a) Preston, P. N. In Chemistry of Heterocyclic Compounds; Weissberger, A. and
Taylor, E. C. Eds.; John Wiley and Sons: New York, 1981, Vol. 40; (b) Chi, Y.-C.;
Sun, C.-M. Soluble polymer-supported synthesis of
a
benzimidazole
library. Synlett, 2000, pp. 591–594; (c) Huang, W.; Scarborough, R. M. A new
“traceless” solid-phase synthesis strategy: synthesis of a benzimidazole library.
Tetrahedron Lett. 1999, 40, 2665–2668; (d) Dudd, L. M.; Venardou, E.; Garcia-
Verdugo, E.; Licence, P.; Blake, A. J.; Wilson, C.; Poliakoff, M. Synthesis of ben-
zimidazoles in high-temperature water. Green Chemistry 2003, 5, 187–192.
10. Preston, P. N. Benzimidazoles; congenereric tricyclic compounds. In Chemistry of
Heterocyclic Compounds, Part 1; Weissberger, A. and Taylor, E. C. Eds.; Wiley:
New York, 1981, Vol. 40, p. 6.
11. Grimmet, M. R. Imidazoles and their benzoderivatives. In Comprehensive Hetero-
cyclic Chemistry; Kartitzky, A. R. and Ress, W. Eds.; Pergamon: Oxford, 1984,
Vol. 5, p. 457.
12. Sun, Q.; Yan, B. Single bead IR monitoring of a novel benzimidazole synthesis.
Bioorg. Med. Chem. Lett. 1998, 8, 361–364.
13. (a) Pertry, R. J.; Wilson, B. D. A novel palladium-catalyzed synthesis of 2-arylben-
zimidazoles. J. Org. Chem. 1993, 58, 7016–7021; (b) Esser, F.; Ehrengart, P.;
Ignanatow, H. P. Cyclic guanidines part 6: Synthesis of benzimidazoles by intra-
molecular vicarious nucleophilic substitution of hydrogen. J. Chem. Soc. Perkin
Trans. 1 1999, 1153–1154; (c) Anastasiou, D.; Campi, E. M.; Chaouk, H.;
Jackson, W. R. Synthesis of benzimidazoles containing a fused alicyclic ring by
rhodium-catalysed hydroformylation of N-alkenyl-1,2-diaminobenzenes. Tetrahe-
dron 1992, 48, 7467–7478; (d) Brain, C. T.; Brunton, S. A. An intramolecular
palladium-catalysed aryl amination reaction to produce benzimidazoles. Tetrahe-
dron Lett. 2002, 43, 1893–1895; (e) Perumal, S.; Mariappan, S.; Selvaraj, S. A

1136
H. Sharghi, O. Asemani, and R. Khalifeh
microwave-assisted synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in
the presence of K-10. Arkivoc 2004, 8, 46–51.
14. (a) Wu, Z.; Rea, P.; Wickam, G. “One-pot” nitro reduction–cyclisation solid phase
route to benzimidazoles. Tetrahedron Lett. 2000, 41, 9871–9874, and references
cited therein; (b) Mazurov, A. Traceless synthesis of benzimidazoles on solid
support. Bioorg. Med. Chem. Lett. 2000, 10, 67–70.
15. Gogoi, P.; Konwar, D. An efficient and one-pot synthesis of imidazolines and ben-
zimidazoles via anaerobic oxidation of carbon–nitrogen bonds in water. Tetrahe-
dron Lett. 2006, 47, 79–82.
16. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokesh, S.; Baghbanzadeh, M. Selective
synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles in water at ambient temp-
erature. Tetrahedron Lett. 2006, 47, 2557–2560.
17. Valara, 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.
18. Trivedi, R.; De, S. K.; Gibbs, R. A. A convenient one-pot synthesis of 2-substituted
benzimidazoles. J. Mol. Catal. A: Chemical 2006, 245, 8–11.
19. George, B.; Papadopoulos, E. P. Heterocycles from N-ethoxycarbonylthioamides
and dinucleophilic reagents, 2: five-membered rings containing two heteroatoms
at 1,3-positions. J. Org. Chem. 1977, 42, 441–443.
20. Cohen, V. I. Synthesis of some benzimidazole, benzoxazole and benzothiazole
derivatives: Action of aliphatic selenoesters on some o-phenylenediamine,
o-aminophenol, and o-aminothiophenol and their derivatives. J. Heterocycl.
Chem. 1977, 14, 1321–1323.
`
21. Alloum, A. B.; Bougrin, K.; Soufiaoui, M. Synthese chimioselective des benzimi-
dazoles sur silice traitee par le chlorure du thionyle. Tetrahedron Lett. 2003, 44,
´
´
5935–5937.