Synthesis of highly functionalized 2-(substituted biphenyl) benzimidzoles via Suzuki-Miyaura cross coupling reaction

Article abstract of DOI:10.1002/jhet.5570440645

(Chemical Equation Presented) A facile and convenient method for the synthesis of highly functionalized 2-(substitutedbiphenyl) based benzimidazoles has been reported by the application of Suzuki-Miyaura cross coupling reaction.

Full text of DOI:10.1002/jhet.5570440645

Nov-Dec 2007
1521
Synthesis of Highly Functionalized 2-(Substituted biphenyl)
Benzimidzoles Via Suzuki-Miyaura Cross Coupling Reaction
Ramanatham Vinodkumar*†, Kotarkonda Rajagopal and Nayakanti Devanna*
Janus Research Laboratories P. Ltd., Plot No: 80, Rajiv Gandhi Nagar, Prasanthi Nagar Extn., Kukatpally,
Hyderabad (A.P.)-500 072, India. E-mail: rvinodk@yahoo.com
Received January 6, 2007
COOH
Ar-B(OH)2
Pd(PPh3)4
Eaton's
NH2
NH2
N
N
Reagent
Ar
Br
+
100 0C /
5 hr
Na2CO3,
N
H
N
H
Toluen/THF/H2O
80 oC / 3 hr.
Br
( 1 )
( 3 )
( 4-10 )
( 2 )
A facile and convenient method for the synthesis of highly functionalized 2-(substitutedbiphenyl) based
benzimidazoles has been reported by the application of Suzuki-Miyaura cross coupling reaction.
J. Heterocyclic Chem., 44, 1521 (2007).
reaction on a solid support, one requires specifically
different formyl boronic acids, which restricts the
applicability of this method for generating libraries for
biological screening. The third method is in three steps
starting with Suzuki coupling of the haloaryl carbo-
nitriles with formylboronic acids and coupling the latter
with diamines to obatain the benzimidazoles [12b]. This
is clear indication of the fact that there is no general and
useful methodology for the synthesis of these title
compounds. In recent times, Suzuki-Miyaura cross
coupling reaction has gained wide acceptance as a very
useful methodology for the synthesis various natural and
non-natural products [13].
Previously, we have reported the synthesis of
functionalized dibenzylglycine derivatives via Suzuki-
Miyaura cross coupling reaction [14]. In continuation of
our work on Suzuki-Miyaura cross coupling reactions, the
present paper describes the application of the latter
reaction to generate a convenient route for the synthesis of
the title compounds. Hence, in this regard, OPDA (1) was
reacted with 4-bromobenzoic acid (2) in the presence of
Eaton’s Reagent [15] (1:10 mixture of phosphorous
pentoxide - methanesulfonic acid, an efficient and
convenient alternative to PPA for cyclodehydration
reactions) at 100 °C 5 hr, followed by a simple work up
yielding the known 2-(4-bromophenyl)benzimidazole (3)
[16], which was previously reported by the PPA mediated
cyclisation of compound (1) with compound (2)
(Scheme-1).
INTRODUCTION
Benzimidazoles generally come under the group of broad
spectrum anti-helmintic agents useful against veterinary
parasites and also possess medicinal importance [1].
Further, its nucleus is also a constituent part in the naturally
occurring Vitamin-B12 and its derivatives [2].
Benzimidazole moiety provides an interesting theme for the
synthesis of various biologically active compounds [3] and
the biological activities of the latter are very well
documented as well [4]. Of the hundreds of derivatives
tested, those therapeutically have useful modifications at 2-
or 5-position of the benzimidazole ring system [5-8]. Some
of them like thiabendazole, mebendazole and albendazole
are widely used as anti-helmintic drugs [9]. In this
communication, we wish to report our results towards the
synthesis of some novel and functionalized 2-(substituted-
biphenyl) based benzimidazoles by the utilization of
Suzuki-Miyaura cross coupling reaction.
RESULTS AND DISCUSSION
We have been interested in the synthesis of 2-(substi-
tutedbiphenyl) based benzimidazoles in connection with
our on-going project on benzimidazole derivatives of
potential biological activities [10]. Literature survey
revealed that there are only a couple of methods
available for the synthesis of 2-biphenylbenzimidazoles,
the first one, by the condensation of o-phenylenediamine
(OPDA) with 4-phenylbenzaldehyde to get the Schiff’s
base and oxidative cyclisation of the latter with
Cu(OAc)2 giving the title compounds [11]. Secondly,
from the reaction of OPDA with polymer-esterified
biaryl aldehydes, prepared from polymer bound aryl
halides and formyl benzene boronic acids [12], where
the required aldehyde was synthesized by the cross-
coupling reaction of 4-Iodobenzoic acid with
4-formylbenzene-boronic acid. However, in case of the
Scheme-1
COOH
Eaton's
Reagent
NH2
NH2
N
Br
+
100 °C /
5 hr
N
H
Br
( 1 )
( 3 )
( 2 )

1522
R. Vinodkumar, K. R. Gopal and N. Devanna
Vol 44
Table 1 (continued)
Product
The advantage with the use of Eaton’s reagent in place of
conventional dehydrating agent polyphosphoric acid (PPA)
is that Eaton’s reagent can be easily handled and since it is
a mobile colorless liquid. Further, the excess reagent can be
easily destroyed by simple addition of water to the reaction
mixture or by an aqueous solution of sodium bicarbonate.
Compound (3) was then treated with phenylboronic acid
(Ar = Ph) under Suzuki-Miyaura cross coupling conditions
to obtain the known 2-biphenylbenzimidazole (4)12 in 78 %
yield (Scheme-2). Similarly, the reaction of compound (3)
was then extended with other substituted aryl boronic acids
and the physical properties of the products (5-10) thus
obtained are summarized in Table-1.
Sr.
No.
4.
M.P
( °C )
Yield
( % )
N
CN
CHO
F
272 -274
269 -272
285 -289
297 -301
78
80
78
82
N
H
( 7 )
( 8 )
N
5.
6.
7.
N
H
N
N
H
( 9 )
N
Cl
Scheme - 2
N
H
( 10 )
Ar-B(OH)2
N
N
Pd(PPh3)4
Ar
Br
EXPERIMENTAL
Na2CO3,
N
H
N
H
Toluen/THF/H2O
80 oC / 3 hr.
( 3 )
( 4-10 )
Synthesis of 2-(Substitutedbiphenyl)-1H-benzimidazoles
by Suzuki Coupling Reactions (General Procedure). To a
solution of compound 4 (10 mm) in a mixture of toluene-THF
mixture (1:1) was added aryl boronic acid (12 mm), anhydrous
sodium carbonate (12 mm) and water (2 ml). The reaction
mixture was then degassed for 20 min and the tris(triphenyl-
phosphine) (10 mol%) was added and the reaction mixture was
heated to 70-80 °C for several 3-4 h till the starting material
disappears on tlc. The solvent from the reaction mixture was
concentrated under vacuum, dichloromethane (20 ml) was added
and the layers were separated, washed with water, brine and
dried over anhydrous magnesium sulfate. Evaporation of the
solvent gave the crude products, which were purified either by
crystallization using appropriate solvent systems or by column
chromatography.
2-(4'-p-Toluylphenyl)-1H-benzimidazole (5). This compound
was obtained as an off-white solid (ethyl alcohol); 1H nmr
(CDCl3-DMSO-d6): ꢀ 1.77 (s, 3H), 6.57 (dd, J = 6.2 & 2.6Hz,
2H), 6.65 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 7.6Hz, 3H), 7.10 (d, J
= 8.0 Hz, 3H), 7.63 (d, J = 8.0 Hz, 2H); 13C-nmr (CDCl3-
DMSO-d6)(100 MHz): 20.94, 111.17, 118.79, 122.44, 126.55,
126.79, 127.06, 128.92, 129.52, 136.83, 137.31, 141.76, 151.39;
ms: m/z: 285 (M+) ; Anal. Calcd. for C20H16N2 C, 84.48; H, 5.67;
N, 9.85. Found: C, 84.06; H, 5.55; N, 9.92.
In conclusion, we have demonstrated that highly
functionalized 2-substitutedbiphenyl based benzimida-
zoles could be conveniently synthesized from 3 and aryl
boronic acids via Suzuki-Miyaura cross-coupling
reaction. The advantage of the present method is that
starting compound 3 could be easily synthesized. The
commercial availability of a wide variety of boronic acids
eliminates the restriction of looking for only formyl
boronic acids as in the existing method [12] makes this
method a more attractive choice for the chemists working
in this area. Moreover, compounds (5), (7), (8) and (9)
provides access to further synthetic modifications for the
dendritic cores, whose applicability is well known as
hosts for molecular recognitions in biological systems.
The method described herein is useful to synthesize
compounds with known pharmacophoric scaffolds, and
hence is ideally suited for the generation of combinatorial
libraries.
Table-1
2-(4'-p-Anisylphenyl)-1H-benzimidazole (6). This compound
was obtained as an off-white solid (ethyl alcohol); 1H nmr
(CDCl3-DMSO-d6): ꢀ 3.71 (s, 3H), 6.85 (d, J = 9.2Hz, 2H), 7.12
(dd, J = 6.0 & 3.2Hz, 2H), 7.44 (d, J = 9.2Hz, 2H), 7.52-7.55
(m, 4H), 8.15 (d, J = 8.4Hz, 2H). 13C nmr (CDCl3-DMSO-d6)
(100 MHz): 55.36, 114.37, 122.70, 123.04, 126.93, 127.61,
128.08, 128.48, 131.95, 132.36, 142.67, 151.11, 159.65; ms:
m/z: 301 (M+); Anal. Calcd. for C20H16N2O, C: 79.98; H: 5.37;
N: 9.33. Found: C: 79.68; H: 5.08; N: 9.11.
2-(4'-(4-Cyanophenyl)phenyl)-1H-benzimidazole (7). This
compound was obtained as an pale yellow solid (ethyl alcohol);
1H-nmr (CDCl3-DMSO-d6): ꢀ 7.16 (dd, J = 6.0 & 2.8Hz, 2H),
7.55 (dd, J = 6.0 & 2.6Hz, 2H), 7.64-7.70 (m, 6H), 8.24 (d, J =
8.4Hz, 2H). 13C nmr (CDCl3-DMSO-d6) (100 MHz): 111.02,
115.16, 118.73, 122.54, 127.46, 127.50, 127.58, 130.42, 132.58,
139.99, 144.53, 151.04. ms: m/z: 296 (M+); Anal. Calcd. for
Physical data for the synthesized compounds (4 -10).
Sr.
No.
1.
Product
M.P
Yield
( % )
( °C )
N
296 -298
(Lit12- 296
-298)
78
79
81
N
H
( 4 )
N
2.
3.
CH3
280 -281
N
H
( 5 )
N
OCH3
264 -266
N
H
( 6 )

Nov-Dec 2007
Synthesis Of Highly Functionalized 2-(Substitutedbiphenyl)benzimidazoles
1523
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compound was obtained as an off-white solid (ethyl alcohol);
1H-nmr (DMSO-d6): ꢀ 7.21-7.37 (m, 4H), 7.61 (brs, 2H), 7.81-
7.88 (m, 4H), 8.26 (d, J = 8.2Hz, 2H), 12.97 (s, 1H). 13C nmr
(CDCl3-DMSO-d6) (75 MHz): 115.90, 116.19, 122.37, 127.23,
127.31, 128.89, 129.00, 129.33, 135.93, 140.43, 151.10, 160.72,
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79.15; H: 4.54; N: 9.72. Found: C: 79.02; H: 4.49; N: 9.68.
2-(4'-(4-Chlorophenyl)phenyl)-1H-benzimidazole (10). This
compound was obtained as an off-white solid (ethyl alcohol);
1H-nmr (DMSO-d6/TMS): ꢀ 7.22 (s, 2H), 7.55-7.68 (m, 4H),
7.80-7.90 (m, 4H), 8.29 (d, J=7.8Hz, 2H), 13.03 (s, 1H); 13C nmr
(DMSO-d6/TMS): ꢀ 111.60, 122.00, 122.84, 127.25, 127.34,
128.68, 129.20, 129.67, 132.98, 138.26, 140.08, 151.00; ms:
m/z: 304 (M+); Anal. Calcd. for C19H13ClN2, C, 74.88; H, 4.30;
N, 9.19; Found: C, 74.89; H, 4.47; N, 9.17.
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