Synthesis of benzimidazoles from 1,1-dibromoethenes

Article abstract of DOI:10.1016/j.tetlet.2008.10.030

A mild and efficient method for the preparation of substituted benzimidazoles from 1,1-dibromoethenes and o-diaminobenzenes is described. The reaction employs DABCO as the base and NMP as the solvent. A variety of substitutions on both 2-aryl-1,1-dibromoethenes and o-diaminobenzenes are tolerated. This new procedure is carried out under mildly basic conditions, which may provide a complementary route to the existing preparations of benzimidazoles.

Full text of DOI:10.1016/j.tetlet.2008.10.030

Tetrahedron Letters 49 (2008) 7284–7286
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Tetrahedron Letters
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Synthesis of benzimidazoles from 1,1-dibromoethenes
*
Wang Shen , Todd Kohn, Zice Fu, XianYun Jiao, Sujen Lai, Michael Schmitt
Chemistry Research and Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the preparation of substituted benzimidazoles from 1,1-dibromoethenes
and o-diaminobenzenes is described. The reaction employs DABCO as the base and NMP as the solvent. A
variety of substitutions on both 2-aryl-1,1-dibromoethenes and o-diaminobenzenes are tolerated. This
new procedure is carried out under mildly basic conditions, which may provide a complementary route
to the existing preparations of benzimidazoles.
Received 25 September 2008
Revised 4 October 2008
Accepted 6 October 2008
Available online 11 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Benzimidazoles are a common motif in medicinal chemistry,
and have found their way to compounds in clinical testing and
drugs in clinical use. For example, telmisartan1 (an AT1 antagonist
marketed for hypertension) and bilastine2 (a selective H1
antagonist in phase 3 for allergic rhinitis) feature substituted
benzimidazoles.3 Numerous methods exist for the preparation of
benzimidazoles.4 The most common one involves the cyclization
of o-diaminoarenes with carboxylic acids or their derivatives under
acidic conditions.5 Benzimidazoles can also be prepared from the
coupling of aldehydes with o-diaminobenzenes under oxidative
conditions6 or with 2-nitroanilines under reductive conditions.7
More recently, transition metal-catalyzed amination followed by
condensation has also been reported for the preparation of various
benzimidazoles8 (see Fig. 1).
N
N
N
N
O
OH
Telmisartan
O
N
N
OH
N
O
Bilastine
Figure 1. Selected drugs containing a benzimidazole substructure.
Previously in our laboratory, 1,1-dibromoethenes were found to
be versatile substrates for the palladium-catalyzed syntheses of
isocoumarins, trisubstituted alkenes unsymmetrical alkynes, and
1,3-dialkynes.9,10 During the course of that investigation, 1,1-di-
bromoethenes were also found to serve as synthons for carboxyl
groups. For examples, amides11 and amidines12 could be prepared
in excellent yields from the reaction between 2-aryl-1,1-dibromo-
ethenes and alkyl amines (Scheme 1). However, attempts to use
aniline instead of alkylamines yielded no desired amide, but only
recovered starting dibromoalkene 1a.11a The lack of reactivity
was attributed to the weak nucleophilicity of aniline.13
H
N
H2O
Ar
Ar
R
O
Br
H2N
R
Ar
Br
(R = Alkyl)
H
N
R
N
anhyd.
R
Scheme 1. Reaction of dibromoalkenes with alkylamines.
Since o-diaminobenzenes are stronger nucleophiles than ani-
line, it was envisioned that they may react with 2-aryl-1,1-di-
bromoethenes to give benzimidazoles in a similar fashion to the
formation of amidines. Furthermore, the mild reaction conditions
of this procedure could provide an attractive alternative to the
preparation of this class of important heterocyclic compounds.
During the initial screening of reaction conditions, it was found
that prolonged heating of 1,1-dibromoalkene 1a, o-diaminobenz-
ene 2a, and diisopropylethylamine (DIEA) in NMP gave the desired
benzimidazole 3a in moderate yield (Table 1, entry 1). Unlike the
formation of amides and amidines (Scheme 1),11,12 this reaction
requires an additional base besides 2a, as the employment of
3 equiv of 2a (entry 2) in the absence of another stronger base
yielded no desired product. During the investigation of the bases
for this reaction, it was found that strong bases such as DBU and
cesium carbonate in NMP led to rapid disappearance of starting
* Corresponding author. Tel.: +1 650 244 2482.
E-mail address: shenw@amgen.com (W. Shen).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.030

W. Shen et al. / Tetrahedron Letters 49 (2008) 7284–7286
7285
Table 1
Br
Optimization of benzimidazole formationa
3 eqiv. DBU
Br
(1)
(2)
DMSO, 0 oC,
30 min
N
Br
Br
+
H2N
H2N
MeO2C
1a
MeO2C
4a, 41%
Br
N
MeO2C
H
MeO2C
1a
Solvent
2a
3a
H2N
1.2 eqiv. DABCO
NMP, 100 oC, 0.5 h
N
Base (equiv)
T (°C), t (h)
100, 48
100, 14
100, 14
100, 14
120, 20
100, 7
80, 40
120, 4
100, 7
100, 7
120, 24
Yield (%)
4a +
HN
3a, 76%
H2N
2a (1.5 eqiv.)
1
2
3
4
5
6
7
8
9
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DIEA (3)
None
Cs2CO3 (2)
DBU (3)
Pyridine (3)
DABCO (2.2)
DABCO (2.2)
DABCO (2.2)
DABCO (2.2)
DABCO (2.2)
DABCO (2.2)
64
MeO2C
0b
Decc
Dec.
Dec.
73
Scheme 3. Formation of benzimidazole from alkynyl bromide.
82
61
55
on the nitrogen are well tolerated, leading to corresponding 1,2-
disubstituted benzimidazoles in good yields. Substitutions on the
aromatic ring of o-diaminobenzenes have minimal impact on the
formation of benzimidazole 3, even with mildly electron-with-
drawing groups (2i, 2l). However, no product was isolated from
the reaction of 2a with o-diaminopyridines (2g, 2h), presumably
due to its lower nucleophilicity than other diamines.
Substitutions on the aryl group in dibromoalkenes are also well
tolerated, as electron-withdrawing (1a, 1e), electron neutral (1c,
1f), and electron rich (1d) substitutions on 2-aryl-1,1-dibromoeth-
10
11
DMSO
1,4-diox.
51
0d
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), base and anhydrous solvent
(5 mL).
b
3 equiv of 2a are used, recovery of 1a.
c
Decomposition (dec.) of 1a without formation of 3a (HPLC monitoring).
d
Reaction was run in a sealed tube (1,4-diox = 1,4-dioxane).
material 1a, albeit with no desired product formed. On the other
hand, employment of pyridine as a mild base resulted in decompo-
sition with no desired product detected after prolong heating.14
However, when 1,4-diazabicyclo[2.2.2]octane (DABCO) was used,
good yield of benzimidazoles was obtained after seven hours at
100 °C (Table 1, entry 6).
When the reaction temperature was lowered from 120 to 100 to
80 °C (Table 1, entries 6–8), the yield was improved albeit with
longer reaction time. A strong polar aprotic solvent is required
for the reaction. No product was observed in a moderately polar
1,4-dioxane solvent (entry 11) even after prolong heating (starting
material remains). Based on the survey, reaction conditions exem-
plified by entry 6 were used to carry on the exploration of the
scope and limitation of this reaction.
Table 2
Preparation of benzimidazolesa
R2
HN
R2
N
R3
5
6
R3
Br
1
DABCO
NMP, 100 oC
R1
R1
+
2
Br
4
N
H2N
3
1
3
2
R1
o-Diaminobenzene (2)
R2 (2x)
Prod,
yield (%)
R2
4-(MeO2C)C6H4-(1a)
H
H
Me
3-Me (2b)
4-Br (2c)
H (2d)
3b, 49
3c, 54
3d, 68
A plausible mechanism is proposed in Scheme 2. It is believed
that alkynyl bromides 4 is generated upon treatment of dibromide
1 with a suitable base.15 Alkynylamine 5 is then formed through
amine displacement of bromide, which is followed by an intra-
molecular cyclization to give the desired product 3. The proposi-
tion of 2-arylethynyl bromide 4 as the active intermediate stems
from experimental observations. Upon treatment of 1,1-dibromo-
ethene 1a with DBU in DMSO at 0 °C (Scheme 3, Eq. 1), alkynyl bro-
mide is isolated at 41% yield from dibromide 1.16 It is then reacted
with o-diaminobenzene 2a under prior optimized reaction condi-
tions to afford benzimidazole 3a in 30 min and 76% yield. It is
worth noting that much shorter reaction time is required to con-
vert 4a to the desired product as compared to dibromide 1a.
The optimized reaction conditions (Table 1, entry 6) were
applied to the syntheses of a wide variety of benzimidazoles as
shown in Table 2. Both alkyl (2d, 2k) and aryl (2f) substituents
H2N
(2e)
3e, 84
3f, 63
3g, 0
H2N
Ph
H (2f)
(2g)
H2N
N
H2N
H2N
N
(2h)
3h, 0
H2N
H
H
3-Cl–5-CF3 (2i)
4-Cl (2j)
3i, 60
3j, 70
EtO2C-(1b)
H
N
(2k)
3k, 73
N
Bn
H2N
H2N
Br
Base
HBr
Ph-(1c)
H
Ph
H (2a)
H (2f)
3l, 53
3m, 55
Ar
+
Br
Ar
Br
H2N
4
1
2
4-(MeO)Ph-(1d)
2-Py-(1e)
2-PhC6H4-(1f)
a
H
Ph
H (2a)
H (2f)
3n, 86
3o, 70
H
N
H
H
H (2a)
4-CN (2l)
3p, 65
3q, 71
Ar
N
Ar
H
Me
H (2a)
H (2d)
3r, 86
3s, 70
H2N
N
H
3
5
Reaction conditions: 1 (2.0 mmol), o-diaminobenzene (3.0 mmol), and DABCO
(4.4 mmol) in NMP (10 mL) were heated at 100 °C for 8–10 h.
Scheme 2. A plausible mechanism.

7286
W. Shen et al. / Tetrahedron Letters 49 (2008) 7284–7286
W.; Tomaszewski, M.; Walpole, C.; Hodzic, L.; St-Onge, S.; Godbout, C.; Salois,
D.; Payza, K. Bioorg. Med. Chem. Lett. 2008, 18, 3695.
enes all afforded good yields of benzimidazoles. Furthermore, the
steric hindrance from ortho-substitution (1f) on 2-aryl-1,1-di-
bromoethenes has no impact to the reactivity or to the yield.
Under the reaction conditions described herein for the forma-
tion of benzimidazoles, 2-alkyl-1,1-dibromoethenes yielded no
corresponding benzimidazoles when alkyl groups are electroni-
cally neutral or donating.17 However, electron-withdrawing ethyl
3,3-dibromoacrylate 1b reacts with o-diaminobenzenes readily to
give the desired benzimidazoles 3j, 3k. These products may serve
as versatile intermediates for the preparation of a wide variety of
2-alyklbenzimidazoles.18
4.
A
comprehensive review in: Grimmett, M. R. Imidazole and Benzimidazole
Synthesis; Academic Press: San Diego, 1997.
5. Representative recent publications: (a) Hornberger, K. R.; Adjabeng, G. M.;
Dickson, H. D.; Davis-Ward, R. G. Tetrahadron Lett. 2006, 47, 5359; (b) Wang, R.;
Lu, X.-x.; Yu, X.-q.; Shi, L.; Sun, Y. J. Mol. Catal. A: Chem. 2007, 266, 198.
6. Recent publications: (a) Mukhopadhyay, C.; Tapaswi, P. K. Tetrahedron Lett.
2008, 49, 6237; (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.
7. (a) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis 2005, 47; (b)
Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth. Commun. 2007, 37,
1375.
8. (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598; (b) Evindar,
G.; Batey, R. A. Org. Lett. 2003, 5, 133.
In summary, we have developed a new method for the prepara-
tion of substituted benzimidazoles in good to excellent yields. This
method employs mildly basic conditions, which complement the
existing methods for benzimidazole synthesis under acidic or oxi-
dative/reductive conditions. Preparation of heterocycles from the
reaction of 1,1-dibromoethene 1 with other nucleophiles (e.g.,
2-aminophenol and 2-aminothiophenol) is under investigation.19
9. (a) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625; (b) Shen, W.; Wang, L. J.
Org. Chem. 1999, 64, 8873; (c) Shen, W. Synlett 2000, 737; (d) Shen, W.; Thomas,
S. A. Org. Lett. 2000, 2, 2857.
10. Recent application of 1,1-dibromoalkenes in palladium-catalyzed reactions: (a)
Chelucci, G.; Capitta, F.; Baldino, S.; Pinna, G. A. Tetrahedron Lett. 2007, 48,
6514; (b) Riveiros, R.; Saya, L.; Sestelo, J. P.; Sarandeses, L. A. Eur. J. Org. Chem.
2008, 1959; (c) Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 538.
11. (a) Shen, W.; Kunzer, A. Org. Lett. 2002, 4, 1315; (b) Huh, D. H.; Jeong, J. S.; Lee,
H. B.; Ryn, H.; Kim, Y. G. Tetrahedron 2002, 58, 9925.
12. Huh, D. H.; Ryu, H.; Kim, Y. G. Tetrahedron 2004, 60, 9857.
13. Recently, a single example of benzimidazole formation from 2,2-dibromovinyl
trifluoromethyl ketone and o-diaminobenzene was reported: Bozhenkov, G. V.;
Frolov. Y. L.; Toryashinova, D. S.-D.; Levkovskaya, G. G.; Mirskova, A. N. Russ. J.
Org. Chem. 2003, 39, 807 (Zh. Org. Khim. 2003, 39, 857).
14. Other bases tried without success: tetramethylguanidine (TMG), DBN, sodium
carbonate, and N-methylmorphyline (NMM).
15. Alkynylbromides have been proposed as intermediates in reactions involving
1,1-dibromoalkenes, see Refs. 9b,11,12.
Acknowledgments
The authors would like to thank Dr. Yong-Jae Kim for the help in
preparing this manuscript. Appreciation also goes to Mr. Aaron
Kunzer for early exploration of this methodology.
References and notes
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dibromoethenes may be explained by the requirement of a very strong base
such as NaHMDS or LDA to form alkynyl bromide: Grandjean, D.; Pale, P.;
Chuche, J. Tetrahedron Lett. 1994, 35, 3529.
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18. Recent application of 2-benzimidazaole acetic acid derivatives: (a) Dener, J. M.;
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Klinghofer, V.; Johnson, E.; Frost, D.; Konawho, C.; Jarvis, K.; Bouska, J.; Marsh,
K. C.; Rosenberg, S. H.; Giranda, V. L.; Penning, T. D. Bioorg. Med. Chem. Lett.
2008, 18, 3955; (b) Verbist, B. M. P.; De Cleyn, M. A. J.; Surkyn, M.; Fraiponts, E.;
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Wei, Z.; Woo, S.; Luo, X.; Cheng, Y.-X.; Yang, H.; Srivastava, S.; Zhou, F.; Brown,
19. Preliminary results with 2-aminophenol and 2-aminothiophenol indicated that
conditions for the formation of benzimidazoles are not optimal.