Synthesis of six new 2-aryl-N-biphenyl benzimidazoles and crystal structure of methyl 4′-[(2-p-chlorophenyl-1H-benzimidazole-1-yl)-methyl]biphenyl-2- carboxylate

Article abstract of DOI:10.1002/jhet.5570410424

Six new 2-aryl-N-biphenyl benzimidazoles were designed and synthesized, starting with O-phenylenediamine and carboxylic acids via cyclization, followed by N-alkylation. All new compounds were identified by ¹H NMR, IR, MS spectra and elemental analysis. The crystal structure of methyl 4′-[(2-p-chlorophenyl-1H benzimidazole-1-yl)methyl]biphenyl-2-carboxylate (4f) was determined by single crystal X-ray diffraction.

Full text of DOI:10.1002/jhet.5570410424

Jul-Aug 2004
Synthesis of Six New 2-Aryl-N-biphenyl Benzimidazoles and Crystal
Structure of Methyl 4'-[(2-p-Chlorophenyl-1H-benzimidazole-1-yl)-
methyl]biphenyl-2-carboxylate
621
1
1
1
2
1
Zhou Zhiming , Yu Weifa , Zhang Jun , Zhao Xinqi , Yu Congxuan
(1
R & D Center for Pharmaceuticals, Beijing Institute of Technology, Beijing, P. R. China. 100081)
(2
School of Material Science and Engineering, Beijing Institute of Technology, Beijing, P. R. China. 100081)
Received January 2, 2004
Six new 2-aryl-N-biphenyl benzimidazoles were designed and synthesized, starting with O-phenylenedi-
amine and carboxylic acids v i a cyclization, followed by N-alkylation. All new compounds were identified by
1
H NMR, IR, MS spectra and elemental analysis. The crystal structure of methyl 4'-[(2- p-chlorophenyl-1H
benzimidazole-1-yl)methyl]biphenyl-2-carboxylate (4 f) was determined by single crystal X-raydiff r a c t i o n .
J. Heterocyclic Chem., 41, 621 (2004).
The renin-angiotensin system (RAS) plays an important
role in the control of blood pressure and the regulation of
volume and electrolyte homeostasis [1,2]. Angiotensin II
N-biphenylbenzimidazoles, which are unknown so far, we
designed and synthesized six new 2-aryl-N-biphenyl benz-
imidazole derivatives.
(
AII) is regarded as a major mediator of hypertensive dis-
Treatment of o-phenylenediamine (1) with carboxylic
acids (2a-2f) in propylene glycol at range 150-180 ºC for
10-18 hours led to benzimidazole derivatives (3a-3f)
respectively, which in turn react with methyl 4-(bro-
momethyl)-biphenyl-2'-carboxylate in DMF to afford the
2-aryl-N-biphenylbenzimidazoles (4a-4f) respectively.
The synthetic route is shown in Scheme I.
orders, including essential hypertension [3]. Despite the
clinical efficacy of the angiotensin converting enzyme
(
such as dry cough and angioedema, caused by potentiation
of bradykinin, substance P and other active peptides, non-
peptide angiotensin II receptor antagonists are of interest
ACE) inhibitors, these compounds induce side effects
[
4-6]. The antihypertensive activity of nonpeptide
angiotensin antagonist has been demonstrated in the clinic
7,8]. The antihypertensive activity of 2-alkyl-N-biphenyl
Benzimidazole heterocyclic derivatives were synthe-
sized by condensation of o-phenylenediamine and car-
boxylic acids. The catalysts typically utilized for this reac-
tion are hydrochloric acid, phosphonic acid and polyphos-
phonic acid [11-13], and new methods continued to be
reported, such as these by propylene glycol [14] and
p-toluenesulfonic acid [15].
During our study for the synthetic process of
Telmisartan, the effects of different catalysts on the yield
of the key intermediate of Telmisartan, 2-n-propyl-4-
methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole, was
investigated. Experimental results showed that the yield of
the condensation step was 12.4% without catalyst, 25.6%
with phosphonic acid, 53.2% with polyphosphonic acid
and 71.2% with propylene glycol. Accordingly, propylene
glycol was chosen as catalyst in the synthesis of 2-substi-
tuted benzimidazoles of interest.
[
fused benzimidazoles as angiotensin II receptor antago-
nists has already been established [9,10]. In the course of
our study, we optimized the synthesis of Telmisartan (I)
using a green catalytic procedure in higher overall yields.
In order to examine the antihypertensive activity of 2-aryl-
The result of the reaction between o-phenylenediamine
and unsubstituted benzoic acid was shown in entry 3a in
(
I)
Scheme I
1 6 5 1 3 6 5 1 3 6 5 1 6 5 1 6 5 1 6 5
a: R =C H ; b: R =m-CH C H ; c: R =p-CH C H ; d: R =O-ClC H ; e : R = m-ClC H f: R = p-ClC H

622
Z. Zhiming, Y. Weifa, Z. Jun, Z. Xinqi, Y. Congxuan
Vol. 41
Table 1. When reacted at 160 ºC for 12 hours, 72.6% yield
of 2-phenylbenzimidazole was obtained. Analogues of a
reactant where the carboxylic group was deactivated by
an electron-donating group (m-methyl, p-methyl) also led
to moderate yields after a longer time (3 b: 18 h, 78.5%;
Table 2
Results and Reaction Conditions of 2-Aryl-N-biphenylbenzimidazoles 4a-4f
Entry
R1
Time/h.
Temp.
ºC)
Yield
(%)
Mp/ºC
(
3
c: 13 h, 78.8%). The carboxylic group can be activated
4a
C6H5
m- CH3C6H5
12
8
4
10
8
9
r. t.
r. t.
r. t.
r. t.
r. t.
r. t.
65.7
70.6
77.5
85.9
75.7
61.8
120~ 122
136~ 138
148~ 150
140~ 142
116~ 118
154~ 156
4
4
4
4
b
c
d
e
by an electron-withdrawing group on the phenyl ring par-
ticularly those on the meta- and para-positions. This
resulted in good yields of 2-substituted benzimidazoles
using the same 12 h reaction time to give 3 e: 75.4% and
p- CH C H
3
6 5
o- ClC6H5
m- ClC6H5
p- ClC6H5
4f
3
f: 71.6%. The field effect and steric hinderance that
probably existed in the o rt h o-position reduced the yield of
-substituted benzimidazole at the same reaction time
12h) (3 d: 63.5%).
It was reported that the use of NaH and KO
2
(
meters. The hydrogen atoms attached to carbon atoms
were placed at idealized positions, with C-H distances
taken from the default settings of the refinement program.
The drawing of the molecular structure and the higher
occupancy in the three-dimensional packing arrangement
are shown in Figures 1-3.
t
-Bu were
similar when used in the N-alkylation process [10,16].
H o w e v e r, hydrogen is generated during the reaction
process when NaH is used, which is dangerous, thus KOt-
Bu was chosen as the N-alkylation reagent.
Single-crystal X-ray diffraction studies were performed
on compound 4 f. Selected data are contained in Tables 3 to
5. An ORTEP drawing of 4f showing the molecular confor-
mation and atom-labeling scheme is depicted in Figure 1.
In the molecular structure of 4f, all the five rings are pla-
nar, but the co-planarity among them is poor. The plane of
the imidazole ring is deviated from the planes of the
phenyl rings of the benzimidazolyl and 4-chlorophenyl
moieties by 1.28(10)º and 45.40(10)º respectively. The
deviation angle between the planes of the phenyl rings of
the biphenyl moieties is 60.36(8)º. The angle doesn't agree
well with those of related structures found in N-(4-
biphenyl) urea [45.41(17)º] and 2,4-dicarbonitrile-
biphenyl[44.1(1)º ] [17, 18] maybe due to the co-effect of
bulky 2- p-chlorophenylbenzimidazolyl and carboxylate.
The plane of the phenyl ring of the benzimidazolyl moiety
is deviated from that of the 4-chlorophenyl moiety is
46.65(9)º. In fact, the dihedral angle on the two phenyl
rings of biphenyl moiety may be relevant to antihyperten-
sive activity, but this needs to be confirmed by bio-activity
screening.
As shown in Table 2, the product yield (4a) of the reac-
tion between 2-unsubstitutedphenylbenzimidazole and
methyl 4-(bromomethyl)biphenyl-2'- carboxylate at room
temperature for 12 hours was 65.7% (Table 2, entry 4a). It
seems that the electron-donating group (methyl) on the
2-substituted phenyl ring of benzimidazole could increase
electronic density on the nitrogen atom of the N-H group,
which improves the nucleophilicity of the nitrogen atom,
hence reaction time was reduced (4 b: 8h; 4 c: 4h). The
nucleophilicity of nitrogen atom could be activated by
chlorine on the 2-substituted phenyl ring of benzimida-
zole, which was demonstrated by a shorter reaction time
(8-10 h for 4d-4e). The activating ability of the substituent
group at different positions varied, the ortho-chlorine
achieving the best result (4d: yield 85.9%).
Table 1
Results and Reaction Conditions of 2-Arylbenzimidzoles 3a-3f
Entry
R1
Time/h Temp.
ºC)
Yield Mp / ºC
(%)
(
The normal inter-ring bond distance for unsubstituted
biphenyl is 1.507 Å, but for C (7)-C (8) in 4f this value
become 1.492(2) Å (Table 5), consistent with that of
related structure in polychlorinatedbiphenyl [1.485(6) Å],
2-fluorobiphenyl [1.483(4) Å] and ethylbiphenyl [1.485(3)
Å], and with the theoretically calculated value of 1.488Å
3
3
3
3
3
3
a
b
c
d
e
f
C6H5
m- CH3C6H5
12
18
13
12
12
12
160
170
160
150
170
180
72.5 294~ 295(295)
78.5 218~ 220
78.8 286~ 288(270)
63.5 236~ 238(234)
75.4 238~ 240(238)
71.6 230~ 232(303)
p- CH C H
3
6 5
o- ClC6H5
m- ClC H
6
5
p- ClC6H5
2
between two sp -hybridized C atoms [17, 18].
A crystal of 4f suitable for X-ray analysis was obtained
by slow evaporation of AcOEt/CH Cl solution. X-ray dif-
An interesting aspect of the crystal structure here pre-
sented is the occurrence of two weak C-H···O interactions
in 4f, taking place among the neighboring molecules. The
hydrogen bond distance of O2···C14H and O2···C28H is
2.541 Å and 2.512 Å respectively (Figure 3). The latter is
shorter than that of the former, maybe due to the fact that
two hydrogen bonds for the latter exist in adjacent two
molecules other than a single one in the case of the former.
2
2
fraction data were collected on a Rigaku RAXIS RAPID
IP diffractometer, using graphite monochromated Mo Kα
radiation (l=0.71073 Å). The structure was solved by
direct method and refined by full-matrix least-squares
methods using SHELXS98 program. All non-hydrogen
atoms were refined with anisotropic displacement para-

Jul-Aug 2004
Synthesis of Six New 2-Aryl-N-biphenyl Benzimidazoles
623
Table 3
Single Crystal X-Ray Crystallographic Analysis of 4f
Table 5
Selected Bond Lengths (Å) and Angles (deg) for 4f
Bonds
Distances
Bonds
Angles
Formula
C
H Cl N O
21 2 2
28
Formula weight
Temperature, K
Wavelength, Å
Crystal system
Space group
a, Å
b, Å
c, Å
α, Å
β, Å
452.92
293(2)
Mo Kα= 0.71073
Triclinic
Cl(1)-C(19)
O(1)-C(1)
O(1)-C(28)
O(2)-C(1)
N(1)-C(15)
C(1)-C(2)
C(4)-C(5)
1.7311(19)
1.330(2)
1.438(2)
1.186(2)
1.380(2)
1.490(2)
1.382(3)
1.385(2)
1.492(2)
1.377(3)
1.381(3)
1.394(3)
1.376(3)
1.405(3)
C(1)-O(1)-C(28)
C(22)-N(1)-C(14)
C(3)-C(2)-C(7)
C(4)-C(5)-C(6)
C(6)-C(7)-C(8)
C(11)-C(10)-C(9)
N(2)-C(15)-C(16)
C(18)-C(19)-C(20)
C(23)-C(22)-C(27)
N(1)-C(22)-C(27)
C(25)-C(26)-C(27)
N(2)-C(27)-C(22)
N(2)-C(27)-C(26)
C(22)-C(27)-C(26)
117.18(15)
125.00(14)
119.47(15)
119.82(17)
116.79(15)
120.42(15)
123.88(15)
121.04(17)
122.38(18)
105.99(15)
117.6(2)
P-1
8.7001(17)
10.681(2)
12.929(3)
99.62(3)
106.66(3)
91.54(3)
1131.2(4)
2, 1.330
0.45 x 0.35 x 0.35
472
C(6)-C(7)
C(7)-C(8)
C(22)-C(23)
C(23)-C(24)
C(24)-C(25)
C(25)-C(26)
C(26)-C(27)
γ, Å
V, Å3
109.89(16)
130.26(18)
119.85(18)
Z; density (calc), g/cm3
Crystal size, mm
F (000)
Absorption coef., mm-1
Reflections collected
Independent reflections
R indices
0.198
9465
4951
1
2
R = 0.0694, wR = 0.1430
0.284 and -0.260
-3
Largest diff. peak and hole, e/Å
Table 4
4
Atomic Coordinates (x 10 ) and Equivalent Isotropic Displacement
2
3
Parameters (Å x 10 ) for 4f
Atom
x
y
z
U (eq)
Cl1
O1
O2
N1
N2
C1
C2
C3
C4
C5
C6
C7
C8
1287(1)
-6591(2)
-4261(2)
1661(2)
2698(2)
-5523(2)
-6124(2)
-7625(2)
-8289(2)
-7479(2)
-5977(2)
-5259(2)
-3604(2)
-3273(2)
-1708(2)
-443(2)
-776(2)
-2317(2)
1279(2)
2126(2)
1935(2)
517(2)
169(1)
-7177(1)
-6203(2)
-2809(1)
-818(1)
3225(1)
-884(1)
-741(1)
81(1)
64(1)
84(1)
44(1)
52(1)
45(1)
41(1)
54(1)
62(1)
59(1)
50(1)
40(1)
39(1)
41(1)
41(1)
39(1)
51(1)
51(1)
46(1)
44(1)
44(1)
44(1)
47(1)
52(1)
63(1)
57(1)
46(1)
58(1)
67(1)
69(1)
62(1)
50(1)
69(1)
-1804(1)
-1711(1)
-1306(1)
-2524(1)
-3066(2)
-4180(2)
-4777(2)
-4256(1)
-3138(1)
-2679(1)
-2783(1)
-2396(1)
-1913(1)
-1836(2)
-2204(2)
-1423(2)
-1193(1)
-96(1)
-6709(2)
-6856(2)
-7520(2)
-7613(2)
-7044(2)
-6408(2)
-6314(2)
-5665(2)
-4420(2)
-3850(2)
-4524(2)
-5787(2)
-6342(2)
-3964(2)
-1600(2)
-1219(2)
-1521(2)
-1086(2)
-352(2)
Figure 1. A perspective view of the molecular of 4f.
C9
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
C20
C21
C22
C23
C24
C25
C26
C27
C28
131(1)
293(2)
1143(1)
1942(2)
1743(2)
729(2)
-2793(2)
-3702(2)
-4569(2)
-4534(2)
-3623(2)
-2726(2)
291(2)
1524(2)
2951(3)
3159(2)
1981(2)
1797(2)
2228(3)
2819(3)
3017(2)
2608(2)
-6149(3)
-39(2)
-471(2)
-2789(2)
-3725(2)
-3377(2)
-2140(2)
-1205(2)
-1544(2)
-7054(2)
Figure 2. Packing of the molecule of compound 4f in the unit
U (eq) is defined as one third of the trace of the orthogonalized Uij tensor.
cell showing its hydrogen network.

624
Z. Zhiming, Y. Weifa, Z. Jun, Z. Xinqi, Y. Congxuan
Vol. 41
1
white solid: mp 120-122 ºC; H NMR (CDCl ): δ 3.60 (s, 3H),
3
5
.5 (s, 2H), 7.13 (d, J=8.2 Hz , 2H), 7.25-7.73 (m, 13H), 7.82 (d,
+
J=7.8 Hz , 1H), 7.88 (d, J=8.0 Hz, 1H); ms: m/z 418 (M );
IR(KBr): 3019, 2944, 1721, 1459, 1441, 1386, 1288, 1243, 1118,
-
1
7
60, 701cm .
Anal. Calcd. for C28H N O : C, 80.38; H, 5.26; N, 6.70.
2
2 2 2
Found: C, 80.35; H, 5.30; N, 6.99.
Methyl 4'-[(2-m-Methylphenyl-1H-benzimidazole-1-yl)methyl]-
biphenyl-2-carboxylate (4b).
This compound was prepared from compound 3b using the pro-
cedure as described for compound 4 a in 70.6% yield, white solid,
1
mp 136~ 138 ºC; H NMR (CDCl ): δ 2.39 (s, 3H), 3.60 (s, 3H),
3
5.50 (s, 2H), 7.14 (d, J=8.2 Hz, 2H), 7.24-7.53 (m, 11H), 7.60 (s,
1
H), 7.82 (d, J=7.8 Hz, 1H), 7.87(d, J=7.9 Hz, 1H); ms: m/z 432
+
-1
(M ); IR (KBr): 3033, 2946, 1723, 1449, 1281, 1188, 742 cm .
A n a l. Calcd. for C N O : C, 80.56; H, 5.56; N, 6.48.
H
9 24 2 2
2
Found: C, 80.52; H, 5.55; N, 6.49.
Methyl 4'-[(2-p-Methylphenyl-1H-benzimidazole-1-yl)methyl]-
biphenyl-2-carboxylate (4c).
Figure 3. Hydrogen bond interaction of 4f.
This compound was prepared from compound 3c using the
procedure as described for compound 4a in 77.5% yield as white
EXPERIMENTAL
General Methods.
1
solid: mp 148-150 ºC; H NMR (CDCl ): δ 2.40 (s, 3H), 3.60 (s,
3
3H), 5.47 (s, 2H), 7.13 (d, J=8.1 Hz, 2H), 7.22-7.34 (m, 8H), 7.39
(
dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.50 (dt, J=7.5 Hz, J=1.3 Hz, 1H),
Melting points were determinated using XT4 microscope melt-
ing point apparatus and are uncorrected. Infrared (IR) spectra
7.60 (d, J=8.1 Hz, 2H), 7.82 (dd, J=7.7 Hz, J=1.3 Hz, 1H), 7.86
+
(d, J=8.1 Hz, 1H); ms: m/z 432 (M ); IR (KBr): 3030, 2944,
-1
were recorded on a Nicolet Magna IR 560 spectrophotometer and
1730, 1473, 1457, 1287, 1246, 1184, 1088, 829, 762, 738 cm .
A n a l. Calcd. for C29H24N2O2: C, 80.56; H, 5.56; N, 6.48.
Found: C, 80.53; H, 5.54; N, 6.47.
1
were run as KBr pellets unless otherwise indicated. H NMR
spectra (400MHz) were measured on an ARX400 instrument.
Chemical shifts are reported in δ (ppm) relative to internal
tetramethylsilane. Mass spectra were recorded on a ZAB-HS
mass spectrometer using EI ionization. Elemental analyses were
within ± 0.3% of theoretical values and were performed on an
Elementar Vario EL.
Methyl 4'-[(2-o-Chlorophenyl-1H-benzimidazole-1-yl)methyl]-
biphenyl-2-car-boxylate (4d).
This compound was prepared from compound 3d using the
procedure as described for compound 4a in 85.9% yield as a
1
white solid: mp 140-142 ºC ; H NMR (CDCl ): δ 3.57 (s, 3H),
3
2-Phenyl benzimidazole.
5
.30 (s, 2H),7.0 (d, J=8.3 Hz , 2H), 7.15-7.89 (m, 14H); ms: m/z
+
Under N atmosphere, a mixture of benzoic acid (0.12 mol)
452 (M ); IR (KBr): 3051, 2945, 1719, 1441, 1389, 1287, 1241,
1117, 1045, 762 cm .
Anal. Calcd. for C
2
-1
and o-phenylenediamine (10.8 g, 0.1 mol) was heated at 160 ºC
in 80 ml of propylene glycol for 12 h. Propylene glycol was
removed by distillation under vacuum, then to the residue was
added 50 mL alcohol and activated charcoal. After filtration, to
the filtrate was added with 100 mL water to give a colorless solid,
after collection by filtration the filter cake was washed by water
to furnish white solid 2-phenyl benzimidazole (3a) 14.1 g
H
ClN O : C, 74.25; H, 4.64; N, 6.18.
2 2
2
8
21
Found: C, 74.22; H, 4.62; N, 6.20.
Methyl 4'-[(2-m-Chlorophenyl-1H-benzimidazole-1-yl)methyl]-
biphenyl-2-carboxylate (4e).
This compound was prepared from compound 3e using the
procedure as described for compound 4a in 75.7% yield as a
(72.7%); mp 294-295 ºC (ref [12], 294.5-295.5ºC).
1
Compounds 3b-3f were prepared using the procedure as
white solid: mp 118-120 ºC; H NMR (CDCl3): δ 3.60 (s, 3H),
described for 2-phenyl benzimidazole [19].
5.48 (s, 2H), 7.11 (d, J=8.1 Hz, 2H), 7.25-7.74 (m, 11H), 7.73 (s,
1
H), 7.82 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H); ms: m/z 452
Methyl 4'-[(2-Phenyl-1H-benzimidazol-1-yl) methyl] biphenyl-
+
(
M ); IR (KBr): 3034, 2940, 1721, 1442, 1376, 1281, 1251,
2-carboxylate (4a).
-1
1
063, 761 cm .
To a solution of 1.0 g (5.37 mmol) of 3a in 30 ml of DMF was
Anal. Calcd. for C H ClN O : C, 74.25; H, 4.64; N, 6.18.
28 21 2 2
added potassium tert-butylate 0.7 g (6.25 mmol), the mixture was
stirred for 30 min at ambient temperature, and methyl 4-(bromo-
methyl)biphenyl-2'-carboxylate 1.65 g (5.40 mmol) was added.
After stirring for 14 h the mixture was poured into water (120 ml)
and extracted with ethyl acetate (3x50 ml). The combined
Found: C, 74.26; H, 4.65; N, 6.18.
Methyl 4'-[(2-p-Chlorophenyl-1H-benzimidazole-1-yl)methyl]-
biphenyl-2-carboxylate (4f).
This compound was prepared from compound 3f using the
extracts were dried (MgSO ) and evaporated. The residue was
purified by silica gel column chromatography eluting with ethyl
procedure as described for compound 4a in 61.8% yield as a
4
1
white solid: mp 154-156 ºC; H NMR (CDCl ): δ 3.62 (s, 3H),
3
acetate/light petroleum (30:70/v:v) to give 4a (1.42 g, 66%)as a
5.49 (s, 2H), 7.11 (d, J=7.8 Hz, 2H), 7.27-7.54 (m,10 H), 7.66 (d,

Jul-Aug 2004
Synthesis of Six New 2-Aryl-N-biphenyl Benzimidazoles
625
J=7.9 Hz, 2H), 7.84 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H);
[8] P. C. Wong, T. B. Barnes, A. T. Chiu, D. D. Christ, J. V.
Duncia, W. F. Herblin, P. B. M. W. M. Timmermans, Cardiovasc. Drug
Rev., 9, 317 (1991).
+
ms: m/z 452 (M ); IR (KBr): 3033, 2935, 1728, 1454, 1249,
-1
1
094, 843, 752, 704 cm .
[9] A. P. Thomas, C. P. Allot, K. H. Gibson, J. S. Major, B. B.
Anal. Calcd. for C
H
ClN O : C, 74.25; H, 4.64; N, 6.18.
2 2
28
21
Masek,, A. A. Oldham, A. H. Ratcliffe, D. A. Roberts, S. T. Russell, D.
A. Thomason, J. Med. Chem., 35, 877 (1992).
Found: C, 74.24; H, 4.63; N, 6.18.
[
10] U. J. Ries, G. Mihm, B. Narr, K. M. Rasselbach, H.
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