One-pot synthesis of benzimidazoles from gem-dibromomethylarenes using o-diaminoarenes

Article abstract of DOI:10.1016/j.tetlet.2010.09.080

A one-pot synthesis of benzimidazoles from gem-dibromomethylarenes is described. The reaction shows the method to prepare a variety of benzimidazole analogues with excellent yield.

Full text of DOI:10.1016/j.tetlet.2010.09.080

Tetrahedron Letters 51 (2010) 6493–6497
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of benzimidazoles from gem-dibromomethylarenes using
o-diaminoarenes
⇑
Chandrappa Siddappa, Vinaya Kambappa, Ananda Kumar C. Siddegowda, Kanchugarakoppal S. Rangappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of benzimidazoles from gem-dibromomethylarenes is described. The reaction shows
the method to prepare a variety of benzimidazole analogues with excellent yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 August 2010
Revised 14 September 2010
Accepted 18 September 2010
Available online 29 September 2010
Keywords:
gem-Dibromomethylarenes
Benzimidazole
bis-Benzimidazole
o-Diaminoarenes
Pyridines
The benzimidazole nucleus is the key building block for a variety
of compoundsthat play crucial role in the activity of a number of bio-
logicallyimportantmolecules.1 Benzimidazole derivatives havesev-
eral therapeutic applications such as antiulcer,2 antihelminthic
(Thiabendazole),3 antihypertensive (BIBR277),4 anticoagulant
(Chlorothiophene benzimidazole),5 antiallergic,6 analgesic,7 anti-
inflammatory,8 antimicrobial,9 antiviral,10 antiparasitic11
anticancer (Hoechst 33258)12 (see Fig. 1).
, and
It is also reported that the benzimidazole nucleus is an essential
part of many antineoplastic derivatives13 (TREANDA)Ò (bendamus-
tine hydrochloride) containing alkylating group and benzimidazole
component has been used for the treatment of chronic lymphocytic
leukemia.
Several methods have been reported for the synthesis of benz-
imidazoles.14 The most common one involves the cyclization of
o-diaminoarenes with carboxylic acids or their derivatives under
acidic condition.15 Benzimidazoles can also be prepared by the
coupling of aldehydes with o-diaminoarene under oxidative condi-
tions16 or with 2-nitroanilines under reductive conditions.17 More
recently, transition metal-catalyzed amination followed by con-
densation has been reported for the preparation of various
benzimidazoles.18,19
The substitution of the carboxylic acid or aldehyde component
with an alternative functional group has not been reported so far.
Therefore, the development of a simple and stable substitute for
these aromatic acids or aldehydes by using inexpensive and readily
Figure 1. Selected drugs containing benzimidazole substructure.
available reagents would extend the scope of the reaction in organ-
ic synthesis. Recently, gem-dihalomethylarenes have received con-
siderable attention due to their application in the preparation of
aldehydes.20 To our knowledge, the use of gem-dihalomethylarenes
is limited to the synthesis of aldehydes and
a,b-unsaturated
carboxylic acids,21 there is no published report on their use to syn-
thesize biologically active molecules like benzimidazoles. Herein,
we report a new, rapid, and efficient method for the synthesis of
benzimidazole through the reaction between gem-dibromometh-
ylarenes and different o-diaminoarenes.
The synthetic approach starting from the corresponding com-
mercially available methyl analogues using radical bromination
was documented.22 Our approach was initiated using a mixture
of benzal bromide (gem-1,3-bis (dibromomethyl) benzene)1a
⇑
Corresponding author. Tel.: +91 821 2419661; fax: +91 821 2412191.
E-mail address: rangappaks@gmail.com (K.S. Rangappa).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.080

6494
C. Siddappa et al. / Tetrahedron Letters 51 (2010) 6493–6497
Table 1
Synthesis of benzimidazoles from gem-dibromomethylarenes using different o-diaminoarenes
Entry
Substratea
Different o-diaminoarenes (R and R1)
Product
Time (h)
2
Yieldb (%)
90
Br
Br
N
R = –H
R1 = –H
2a
N
H
1
3a
1a
N
R = n-butyl
R
N
2
3
1a
1 = –H
2
2
89
88
2b
3b
3c
N
N
R = n-heptyl
1a
R
1 = –H
2c
Br
Br
H
N
R = –H
R1 = –H
2a
S
4
2
79
1b
S
N
3d
Br
Br
N
R = –H
R1 = –H
2a
Br
S
5
6
2
2
84
90
N
H
S
Br
3e
1c
Br
Br
Br
N
R = –H
R1 = –H
2a
N
N
H
N
3f
Br
1d
Br
N
N
R = Benzyl
R
N
7
1d
1 = –H
2
91
2d
3g
Br
Br
CF3
R = n-Butyl
R1=
NC
OCH3
O
N
N
N
H
CF3
NC
OCH
8
2
90
3
O
N
1e
H
2e
3h
CF3
NC
OCH3
O
O
R =
R1=
N
N
N
H
CF3
9
1c
2
94
NC
O
O
N
H
2f
3i
CF3
R = n-hexyl
NC
OCH3
O
R1=
2g
N
N
N
H
10
1e
2
93
CF3
NC
O
N
3j
H

C. Siddappa et al. / Tetrahedron Letters 51 (2010) 6493–6497
6495
Table 1 (continued)
Entry
Substratea
Different o-diaminoarenes (R and R1)
Product
Time (h)
Yieldb (%)
R = n-Butyl
CF3
NC
O
R1=
CF3
N
N
N
H
11
1a
1a
1a
2
95
NC
O
N
H
3k
2h
CF3
R = n-hexyl
NC
O
R1=
CF3
NC
N
N
H
N
12
2
92
O
N
H
3l
2i
CF3
NC
O
O
R =
N
R1=
CF3
NC
N
H
13
14
15
2
2
2
89
88
89
N
O
N
H
O
2j
3m
CF3
Br
Br
R = n-Butyl
NC
F
O
F
R1=
CF3
NC
N
N
N
H
1f
O
N
H
3n
2k
Br
Br
CF3
R = n-Butyl
NC
Br
O
R1=
CF3
NC
N
N
H
Br
1g
N
O
N
H
2l
3o
N
R = Benzyl
R
N
16
17
1a
1a
1 = H
2
2
91
90
2m
3p
N
R=
N
NC
R1= H
2n
NC
3q
a
Substrates are prepared from the commercial methyl analogues by radical bromination.
Isolated yields.
b
(1.0 equiv) and o-diaminobenzene 2a (2.0 equiv) with anhydrous
pyridine/DMF(3:1) in the presence of catalytic quantity
morpholine were screened. While piperidine, pyrrolidine, DBU,
and morpholine catalyzed the reaction to give quantitative yield
in 3–5 h, the other bases did not promote this reaction. Encouraged
by this success, the other gem-dibromomethylarenes 3(a–q) were
subjected to cyclization reaction with different o-diaminoarenes
to yield the corresponding benzimidazoles in excellent yield. The
results are depicted in Table 1.
The reaction was further probed by treating gem-1,3-bis
(dibromomethyl)benzene with excess of o-diaminobenzene
(4 equiv) using the same procedure as described in Scheme 1 to
a
(0.2 equiv) of potassium tertiary butoxide (t-BuOK) followed by
the addition of iodine (0.4 equiv) and catalytic amount of benzoyl
peroxide (0.2 equiv) and refluxed for 2 h. The starting material
was consumed in 2 h as indicated by TLC analysis and the obtained
benzimidazole 3a was isolated with 90% yield. Use of 2.0 equiv of
o-diaminobenzene was found to be optimal for the complete
conversion of 1a to 3a. Various base catalysts such as DBU, trieth-
ylamine, N-ethyldiisopropylamine, DABCO, K2CO3, CsCO3,and

6496
C. Siddappa et al. / Tetrahedron Letters 51 (2010) 6493–6497
R1
R1
Br
Br
H2N
N
Pyridine/ DMF (3:1)
Ar
Ar
t-BuOK, I2 / Benzoyl peroxide
N
HN
reflux, 2 h
R
79-95 %
R
1
2
3
Scheme 1. General approach to synthesis of benzimidazoles.
H
Br
Br
N
H2N
Br
Br
N
N
Pyridine/ DMF (3:1)
t-BuOK, I2 / Benzoyl peroxide
N
H2N
reflux, 2.5 h
H
excess (4.0 eq)
87 %
Scheme 2. Synthesis of 2-(3-(1H-benzoimidazol-2-yl)phenyl)-1H-benzoimidazole.
7. Elmer, G. I.; Pieper, J. O.; Goldberg, S. R.; George, F. R. Psychopharmacology (Berl.)
1995, 117, 23–31.
8. Mader, M.; de Dios, A.; Shih, C.; Anderson, B. D. Bioorg. Med. Chem. Lett. 2008,
18, 179–183.
9. Arjmand, F.; Mohani, B.; Ahmad, S. Eur. J. Med. Chem. 2005, 40, 1103–1110.
10. Chien, T. C.; Saluja, S. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2004, 47,
5743–5752.
11. Valdez, J.; Cedillo, R.; Hernandez-Campos, A.; Yepez, L.; Hernandez-Luis, F.;
Navarrete-Vazquez, G.; Tapia, A.; Cortes, R.; Hernandez, M.; Castillo, R. Bioorg.
Med. Chem. Lett. 2002, 12, 2221–2224.
12. Kus, C.; Ayhan-Kilcigil, G.; Ozbey, S.; Kaynak, F. B.; Kaya, M.; Coban, T.; Can-Eke,
B. Bioorg. Med. Chem. 2008, 16, 4294–4303.
13. Badawey, E.; Kappe, T. Eur. J. Med. Chem. 1995, 30, 327–332.
14. Imidazole and Benzimidazole Synthesis; Grimmett, M. R., Ed.; Academic Press:
San Diego, 1997.
15. (a) Hornberger, K. R.; Adjabeng, G. M.; Dickson, H. D.; Davis-Ward, R. G.
Tetrahedron Lett. 2006, 47, 5359–5361; (b) Wang, R.; Lu, X. X.; Yu, X. Q.; Shi, L.;
Sun, Y. J. Mol. Catal. A: Chem. 2007, 266, 198–201.
16. (a) Mukhopadhyay, C.; Tapaswi, P. K. Tetrahedron Lett. 2008, 49, 6237–6240; (b)
Lin, C.; Lai, P. T.; Liao, S. K. S.; Hung, W.-T.; Yang, W.-B.; Fang, J.-M. J. Org. Chem.
2008, 73, 3848–3853.
obtain 2-(3-(1H-benzoimidazol-2-yl)phenyl)-1H-benzoimidazole
(Scheme 2) in 87% yield.23–25
gem-Dibromomethylarenes being stable and readily accessible
substitutes for noncommercial and some of the unstable alde-
hydes, this transformation would extend the scope in organic
synthesis. In addition, it is worthy to note that both aromatic and
heteroaromatic gem-dibromomethylarenes bearing various func-
tionalities such as amide, halogen, cyano, trifluoro methyl and
methoxy groups survived the reaction and provided high yield of
corresponding benzimidazoles.
In conclusion, we have demonstrated a general methodology
wherein gem-dibromomethylarenes could be employed for the
first time in the cyclization protocol for the direct synthesis of bio-
logically important benzimidazoles. As this reaction provides
benzimidazoles in a single step from gem-dibromomethylarenes,
this approach provides one of the easiest pathways for accessing
this class of valuable compounds from easily available starting
materials, and a wide range of multisubstituted benzimidazoles
could be generated accordingly for chemical library construction.
We believe that this transformation would have many potential
applications in synthetic chemistry.
17. (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis 2005, 47–56; (b)
Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth. Commun. 2007, 37,
1375–1379.
18. (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598–2601; (b)
Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133–136.
19. Curini, M.; Epifano, F. Synlett 2004, 1832–1834.
20. Coleman, G. H.; Honeywell, G. E.. In Organic Synthesis; John Wiley and Son: New
York, 1943; Collect. Vol. II. pp 89–91.
21. Augustine, J. K.; Arthoba Naik, Y.; Mandal, A. B.; Chowdappa, N.; Praveen, V. B. J.
Org. Chem. 2007, 72, 9854–9856.
Acknowledgment
22. (a) Mandal, A. B.; Augustine, J. K.; Quattropani, A.; Bombrun, A. Tetrahedron
Lett. 2005, 46, 6033–6036; (b) Choong, I. C.; Lew, W.; Lee, D.; Pham, P.; Burdett,
M. T.; Lam, J. W.; Wiesmann, C.; Luong, T. N.; Fahr, B.; DeLano, W. L.; McDowell,
R. S. J. Med. Chem. 2002, 45, 5005–5022; (c) Khatuya, H. Tetrahedron Lett. 2001,
42, 2643–2644; (d) Aujard, I.; Chouaha, B.; Marine, G.; Odile, R.; Jean-Bernard,
B.; Pierre, N.; Ludovic, J. Chem. Eur. J. 2006, 12, 6865–6879; (e) Derdau, V.;
Oekonomopulos, R.; Gerrit, S. J. Org. Chem. 2003, 68, 5168–5173; (f) Tyeklar, Z.;
Jacobson, R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D. J. Am. Chem. Soc.
1993, 115, 2677–2689.
23. Condensation of pyridinium cations with active methylene compounds has
been documented but has not been applied to bis-pyridinium cations: Richard
H. Kline, US3989738; Appl. No. 597803, 1976.
24. Representative procedure for the synthesis of benzimidazoles analogues
3(a–q) (Scheme 1):
The authors are grateful to UGC, Govt. of India for the financial
support to K.S.R. under the projects vide No. F. 31-143/2005(SR).
Supplementary data
Supplementary data (1H NMR, 13C NMR of 3(a–h) and 3(p–q)
and mass spectra of all the synthesized compounds described in
schemes (1–2)) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.09.080.
To a mixture of benzal bromide 1a (1 g, 0.004 mol) and o-diaminobenzene 2a
(0.86 g, 0.008 mol) in pyridine (3 ml)/DMF (1 ml) was added t-BuOK (0.179 g,
0.0016 mol) then followed by addition of I2 (0.2 g, 0.0016 mol) and benzoyl
peroxide (0.19 g, 0.0008 mol), and the reaction mixture was refluxed for 2 h.
The completion of reaction was confirmed by TLC. The black reaction mixture
was concentrated and the obtained residue was dissolved in water, then
extracted with ethyl acetate (2 Â 30 ml), the combined organic phase was
washed with water and brine solution, dried over anhydrous sodium sulfate.
The organic phase was evaporated and the crude product was purified by
column chromatography using silica gel (60/120 mesh) with petroleum ether/
ethyl acetate (9/1) to afford 0.7 g (90%) of benzimidazole 3a as a off white solid.
Selected spectral data:
References and notes
1. Tanious, F. A.; Hamelberg, D.; Bailly, C.; Czarny, A.; Boykin, D. W.; Wilson, W. D.
J. Am. Chem. Soc. 2004, 126, 143–153.
2. Kuhler, T. C.; Swanson, M.; Shcherbuchin, V.; Larsson, H.; Mellgard, B.;
Sjostrom, J. E. J. Med. Chem. 1998, 41, 1777–1788.
3. Mavrova, A.; Anichina, K. K.; Vuchev, D. I.; Tsenov, J. A.; Denkova, P. S.; Kondeva,
M. S.; Micheva, M. K. Eur. J. Med. Chem. 2006, 41, 1412–1420.
4. Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka, T. J. Med. Chem.
1996, 39, 5228–5235.
5. Mederski, W. W.; Dorsch, D.; Anzali, S.; Gleitz, J.; Cezanne, B.; Tsaklakidis, C.
Bioorg. Med. Chem. Lett. 2004, 14, 3763–3769.
Compound 3d: 0.31 g of compound was isolated as brownish solid; Rf (10%
EtOAc/hexane) 0.70; mp: 203–205 °C: 1H NMR (CDCl3, 400 MHz) d: 7.9–7.92
(1H, d, J = 8.2 Hz, Ar-H), 7.82–7.8 (1H, d, J = 7.8 Hz, Ar-H), 7.72–7.0 (1H, d,
6. Richards, M. L.; Lio, S. C.; Sinha, A.; Tieu, K. K.; Sircar, J. C. J. Med. Chem. 2004, 47,
6451–6454.

C. Siddappa et al. / Tetrahedron Letters 51 (2010) 6493–6497
6497
J = 7.4 Hz, Ar-H), 7.62–7.58 (1H, m, Ar-H), 7.5–7.46 (1H, m, Ar-H), 7.23–7.21
(1H, d, J = 8.0 Hz, Ar-H), 7.20–7.17 (1H, m, Ar-H); dC (100.6 MHz, CDCl3), 146.9,
165.9, 162.7, 148, 144.9, 137.1, 136.7, 136, 134.6, 132, 131.1, 130.9, 129.2,
129.1, 128.7, 128.6, 127.5, 122.8, 122.6, 122.1, 121.6, 110.3, 34.2, 31.8, 23.1,
133.6, 132.7, 130.7, 129.2, 128.6, 128.4, 128.2, 126.6, 122.5, 111.1; IR
m
max (KBr,
22.7, 14.1; IR m
max (KBr, cmÀ1): 3386, 3121, 2228, 1684, 1321; MS (ESI+ion); m/
cmÀ1): 3413, 2947, 1450, 1275, 1275, 1024, 969, 742; MS (ESI) [M+H]+: 201.1.
Compound 3f: 0.375 g of compound was isolated as pale brownish solid; Rf
(10% EtOAc/hexane) 0.50; mp: 186–188 °C; 1H NMR (DMSO-d6, 400 MHz) d:
13.3 (1H, s, –NH), 8.58–8.56 (1H, d, J = 7.8 Hz, Ar-H), 8.34–8.33 (1H, s, Ar-H),
8.16–8.14 (1H, d, J = 7.6 Hz, Ar-H), 7.78–7.76 (1H, d, J = 8.0 Hz, Ar-H), 7.64–7.62
(1H, d, J = 7.8 Hz, Ar-H), 7.3–7.25 (2H, m, Ar-H); dC (100.6 MHz, DMSO-d6),
156.5, 152.5, 148.7, 147.4, 145.5, 134.5, 133.7, 129.4, 127.7, 125.2, 124.9,
z = 493.1 [M+H].
Compound 3q: 0.56 g of compound was isolated as pale yellow solid; Rf (10%
EtOAc/hexane) 0.50; mp: 219–221 °C; 1H NMR (CDCl3, 400 MHz) d: 8.19–8.17
(1H, d, J = 8.0 Hz, Ar-H), 7.89–7.87 (1H, d, J = 8.0 Hz, Ar-H), 7.63–7.59 (4H, m,
Ar-H), 7.48–7.44 (2H, m, Ar-H), 7.36–7.32 (1H, m, Ar-H), 7.29–7.25 (2H, m, Ar-
H), 7.2–7.14 (2H, m, Ar-H), 5.5 (2H, S, –CH2); dC (100.6 MHz, CDCl3), 154, 143,
141.6, 135.6, 132.9, 132.5, 130.2, 129.6, 129.1, 126.7 123.4, 123.1, 120.2, 118.2,
112, 110, 48; IR mmax (KBr, cmÀ1): 2926, 2229, 1609, 1460, 829, 745; MS (ESI)
[M+1]+: 310.1.
117.2; IR m
max (KBr, cmÀ1): 3179, 1601, 1445, 1137, 995, 738; MS (ESI) [M+H]+:
274.2, [M+2]+: 276.0.
Compound 3h: 0.8 g of compound was isolated as off white solid; Rf (10%
EtOAc/hexane) 0.45; mp: 241–243 °C; 1H NMR (DMSO-d6): d: 10.95 (s, 1H, –
CONH), 8.53–8.51 (1H, d, J = 8.4 Hz, Ar-H), 8.45–8.43 (1H, d, J = 8.2 Hz, Ar-H),
8.34–8.32 (1H, d, J = 7.6 Hz, Ar-H), 8.15–8.13 (1H, d, J = 7.2 Hz, Ar-H), 7.98–7.93
(1H, m, Ar-H), 7.88–7.86 (1H, d, J = 7.4 Hz, Ar-H), 7.55–7.53 (1H, d, J = 7.4 Hz,
Ar-H), 7.35–7.30 (2H, m, Ar-H), 7.15–7.13 (1H, d, J = 7.0 Hz, Ar-H), 4.40–4.35
(2H, t, J = 12.0 Hz, –NCH2), 3.93 (3H, s, –OCH3), 1.63–1.50 (2H, m, –CH2), 1.13–
1.03 (2H, m, –CH2), 0.7 (3H, t, J = 12.0 Hz, –CH3); dC (100.6 MHz, DMSO-d6),
25. Compound characterization data for: 2-(3-(1H-benzoimidazol-2-yl)phenyl)-
1H-benzoimidazole (Scheme 2). 0.31 g (87%) of brownish red solid. Rf (20%
EtOAc/hexane) 0.75; mp: 279–282 °C; 1H NMR (DMSO-d6, 400 MHz) d: 13.09
(2H, br s, –NH), 8.27–8.23 (2H, m, Ar-H), 7.94–7.92 (1H, d, J = 8.0 Hz, Ar-H),
7.61–7.55 (4H, m, Ar-H), 7.50–7.48 (2H, d, J = 8.1 Hz, Ar-H), 7.22–7.16 (4H, m,
Ar-H); dC (100.6 MHz, DMSO-d6), 154.1, 143.9, 135.8, 134.9, 131.1, 130.7, 129.8,
127.4, 122.2, 121.8, 111.4; IR mmax (KBr, cmÀ1): 3420, 1635, 1409, 1273, 1112,
959, 745; MS (ESI) [M+H]+: 311.1.