Synthesis of 2-arylbenzimidazoles via microwave Suzuki-Miyaura reaction of unprotected 2-chlorobenzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2008.09.043

A series of 2-arylbenzimidazoles were synthesized via microwave-mediated Suzuki-Miyaura coupling of 2-chloro benzimidazoles and either arylboronic acids or aryltrifluoroborate salts. The most notable aspect of the present work is that there is no need for

Full text of DOI:10.1016/j.tetlet.2008.09.043

Tetrahedron Letters 49 (2008) 6667–6669
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Tetrahedron Letters
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Synthesis of 2-arylbenzimidazoles via microwave Suzuki–Miyaura
reaction of unprotected 2-chlorobenzimidazoles
b
Brad M. Savall a, , Jill R. Fontimayor
*
a Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
b Summer Intern at Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-arylbenzimidazoles were synthesized via microwave-mediated Suzuki–Miyaura coupling of
2-chloro benzimidazoles and either arylboronic acids or aryltrifluoroborate salts. The most notable aspect
of the present work is that there is no need for protection of the benzimidazoles. In addition, reaction
conditions were optimized to reduce homo coupling of pyridylboronic acids.
Received 18 August 2008
Revised 6 September 2008
Accepted 9 September 2008
Available online 13 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Benzimidazoles are privileged structural units not only in the
pharmaceutical industry but also in several other fields such as
agricultural, electronic, and polymer chemistry.1–4 Therefore,
methods for the introduction of the benzimidazole unit are useful
across a range of diverse areas. Although there are several methods
for the synthesis of 2-arylbenzimidazoles via condensation of phe-
nylene diamines onto benzaldehydes and benzoic acids,5 we were
interested in developing a more modular method for the direct
introduction of preformed benzimidazoles onto an aryl nucleus.
Such a strategy would be useful for the convergent synthesis of
2-arylbenzimidazoles.
As part of our efforts directed toward the synthesis of novel
benzimidazole-containing structures for our histamine H4 modula-
tor program,6 we required access to variously substituted 2-aryl-
benzimidazoles. Ideally, the approach should allow access to the
free NH benzimidazoles utilizing readily available components
and catalysts directly without the need for subsequent deprotec-
tion. Given the ready availability of arylboronic acids and aryl per-
fluoroborates,7 the Suzuki–Miyaura8 reaction was a logical starting
point. Although the alternate disconnection was considered, the
limited precedence for synthesis of 2-metallo benzimidazoles
was discouraging.
Prior to the initiation of this work, there was only one literature
example of a Suzuki coupling of a 2-chlorobenzimidazole.9 This
Letter nicely demonstrated the use of microwave conditions for
the Suzuki coupling of halogen-substituted heterocycles, including
one example of an N-methyl-protected benzimidazole. We used
these optimized conditions as our starting point for investigating
the use of the Suzuki–Miyaura reaction for the analogous coupling
of unprotected 2-chlorobenzimidazoles. More recently, we became
aware of the new catalyst systems reported by Nolan and co-work-
ers,10,11 which also effectively catalyze the Suzuki–Miyaura
coupling with 2-chlorobenzimidazoles. This report prompted us
to describe our work with coupling of 2-chlorobenzimidazoles
and boronic acid derivatives under Suzuki–Miyaura conditions.
Following the optimized conditions of Gong and He,9 the Suzuki–
Miyaura reaction between an unprotected 2-chlorobenzimidazole
and 3-benzyloxyboronic acid led to very clean conversion to the
desired product in 23% isolated yield. Simply extending the reaction
time to 30 min increased the yield to 80% (Table 1).12
In addressing the scope of the reaction, we were particularly
interested in the behavior of ortho-substituted arylboronic acids
in this coupling reaction since such couplings can be problematic.
Application of the above-mentioned protocol to 2-meth-
oxyphenylboronic acid with a 30 min reaction time resulted in
clean conversion to the desired product, albeit in lower than
desired yield (Table 1). The corresponding 5-chloro-2-methoxy-
boronic acid also coupled in low yield. When we extended this
protocol to the synthesis of the 2-methoxy pyridine derivative,
we obtained a moderate yield; in addition, we detected a substan-
tial amount of by-product derived from the homo-coupling of the
pyridylboronic acid.
At this point, we initiated an optimization strategy which in-
volved a scan of commonly used Pd sources as well as investigation
of the switch to trifluoroborate salts as coupling partners. As seen
in Table 2, 10% PdCl2(PPh3)2 combined with a perfluoroborate salt
provided the best conversion.
With an efficient route for coupling the unprotected 2-chloro-
benzimidazoles, we looked at examining the scope of coupling
partners. As seen in Table 3, the reaction is quite general in regard
to the perfluoroborate coupling partner. ortho-Substitution does
not appear to dramatically inhibit the reaction, and coupling part-
ners with electron donating and withdrawing groups couple well.
However, neither 4-hydroxyphenyl perfluoroborate nor benzyl
perfluoroborate yielded desired products under these conditions.
Although the reactions were generally very clean, we were
plagued by presence of the homo-coupled product in the case of
* Corresponding author. Tel.: +1 858 320 3393.
E-mail address: bsavall@prdus.jnj.com (B. M. Savall).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.043

6668
B. M. Savall, J. R. Fontimayor / Tetrahedron Letters 49 (2008) 6667–6669
Table 1
Table 3
Initial Suzuki–Miyaura conditions
Scope of aryl coupling partners
(HO)2B Ar
F3BK Ar
PdCl2(PPh3)2
K2CO3 (aq)
Pd (see below)
K2CO3 (aq)
N
N
N
N
N
N
Cl
N
H
Ar
Cl
Ar
CH3CN
150 °C μW
N
H
CH3CN
150 °C μW
H
H
Ar–BF3K
% Conv.a
Yield (%)
86
Ar–B(OH)2
Pd source (10 mol %)
PdCl2(PPh3)2
Time (min)
Yield (%)
(HO)2B
>95
>99
KF3B
OMe
OMe
5
30
23
80
OBn
OMe
88
77
72
(HO)2B
(HO)2B
KF3B
PdCl2(PPh3)2
30
40
MeO
>99
89
OMe
KF3B
PdCl2(PPh3)2
PdCl2(PPh3)2
30
30
27
50
Me
Cl
KF3B
KF3B
(HO)2B
OMe
N
92
90
95
95
95
79
68
90
0b
0b
Cl
the pyridine cores. Switching our source of palladium to
KF3B
KF3B
KF3B
F
13,14
PdCl2(dppf)ÁCH2Cl2
significantly suppressed the homo-cou-
pling such that we were able to access the 2-methoxy pyridyl
derivative in >90% yield with less than 3% homo coupling product
observed (Table 4).
CN
OH
Finally, we did a limited scan of the 2-chloro benzimidazoles
and found that the reaction is generally tolerant of both electron-
withdrawing- and electron-donating substituents (Table 5).
Although the reaction with a 5-fluoro substituent consumed
>95% of 2-chloro benzimidazole, the reaction was low yielding
and contained many by-products. Interestingly, a similar coupling
with 2-chloro-5-fluoro-4-methyl-benzimidazole gave a good yield
of desired product (74%).
KF3B
a
Percent conversion judged by disappearance of 2-chloro benzimidazole by
HPLC.
b
No product detected by mass spectral analysis ESI(pos) or ESI(neg).
Table 2
Table 4
Scan of Suzuki–Miyaura conditions
Pyridyl coupling partners
MeO
BLn
LnB Ar
Pd (see below)
K2CO3 (aq)
Pd (below)
K2CO3 (aq)
N
N
Cl
N
H
N
N
OMe
OMe
Cl
N
H
N
CH3CN
µW
N
H
CH3CN
150 °C μW 20min
N
H
BLn
Pd source
Pd (%)
Conv.a (%)
Ar–BLn
Pd source (10 mol %)
Time (min)
30
Yield (%)
B(OH)2
KBF3
B(OH)2
KBF3
B(OH)2
KBF3
B(OH)2
KBF3
KBF3
KBF3
KBF3
KBF3
Pd(OAc)2
Pd(OAc)2
Pd(DBA)2
Pd(DBA)2
Pd2(DBA)3
Pd2(DBA)3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCI2(dppf)ÁCH2CI2
PdCI2(dppf)ÁCH2CI2
PdCI2(dppf)ÁCH2CI2
10
10
10
10
10
10
10
10
1
56
12
24
36
23
31
60
>99
45
87
78
29
(HO)2B
OMe
PdCl2(PPh3)2
50
40
90
90
N
O
O
PdCl2(PPh3)2
30
30
30
B
OMe
N
OMe
KF3B
KF3B
PdCl2(PPh3)2
10
5
1
N
N
OMe
PdCI2(dppf)ÁCH2CI2
a
Percent conversion judged by disappearance of 2-chloro benzimidazole via
HPLC.

B. M. Savall, J. R. Fontimayor / Tetrahedron Letters 49 (2008) 6667–6669
6669
Table 5
wave-mediated Suzuki–Miyaura cross coupling of readily available
trifluoroborates and 2-chlorobenzimidazoles.
Scope of benzimidazole coupling partners
OMe
KF3B
Supplementary data
PdCl2(PPh3)2
K2CO3 (aq)
R
R
N
N
Supplementary data (synthetic procedures and spectral infor-
mation) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2008.09.043.
Cl
OMe
CH3CN
150 °C μW
N
H
N
H
Ar–Cl
% Conv.
>95
Yield (%)
References and notes
N
Cl
86
59
69
20
69
74a
1. Cassidy, P. E. Thermally Stable Polymers; Marcel Dekker Inc.: New York,
1980.
N
H
2. Perry, R. J.; Wilson, B. D. J. Org. Chem. 1993, 58, 7016–7021.
3. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X.-H.;
Hostomsky, Z.; Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J.; Curtin, N. J.;
Newell, D. R.; Calvert, A. H.; Griffin, R. J.; Golding, B. T. J. Med. Chem. 2003, 46,
210–213.
4. Haruno, A.; Miyoshi, K.; Oda, N.; Hagiwara, Y.; Yamashita, T.; Konno, Y.;
Kazuno, H.; Taiho Pharmaceutical Co, Ltd, Japan. WO, 2006; Vol. A1,
p 147.
MeO
F3C
F
N
Cl
>95
>95
>95
>95
>95
N
H
N
5. Beaulieu, P. L. Synthesis 2003, 11, 1683–1692.
Cl
6. Lee-Dutra, A.; Arienti, K. L.; Buzard, D. J.; Hack, M. D.; Khatuya, H.; Desai, P. J.;
Nguyen, S.; Thurmond, R. L.; Karlsson, L.; Edwards, J. P.; Breitenbucher, J. G.
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N
H
N
Cl
N
H
Me
Me
N
Cl
12. Representative
benzimidazole:
experimental
procedure:
2-(4-Methoxy-phenyl)-1H-
N
H
A
suspension
of
2-chlorobenzimidazole
(76 mg,
0.50 mmol), 4-methoxy phenyl boronic acid (100 mg, 0.66 mmol) and
PdCl2(PPh3)3 (30 mg, 0.1 mmol) in CH3CN (1.0 ml), and K2CO3 were heated
to 150 °C for 30 min in microwave. The reaction mixture was cooled to
room temperature and extracted with CHCl3 or CHCl3/IPA. The organic
Me
F
N
Cl
layers were dried over Na2SO4, and filtered and concentrated to give
a
N
H
crude solid that was often >90% pure. The solid could be further purified
by SiO2 chromatography with 0–4% acetone/CH2Cl2 and dried under
vacuum to yield 96 mg, 86% yield of 2-(4-methoxy-phenyl)-1H-
benzimidazole.
a
Coupling performed on m-O-benzylpotassium trifluoroborate.
13. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J. Am.
Chem. Soc. 1984, 106, 158–163.
14. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314–321.
In conclusion, we report a simple and efficient method for the
direct synthesis of unprotected 2-aryl benzimidazoles using micro-