Synthesis and crystal structure of 2-trifluoromethyl-1-[(2′-1H- tetrazole-5-yl-biphenyl-4-yl) methyl]benzimidazole

Article abstract of DOI:10.1023/B:JOCC.0000044086.71468.e9

The crystal structure of 2-trifluoromethyl-1-[(2′-1H-tetrazle-5-yl- biphenyl-4-yl) methyl]-benzimidazole and a methylene chloride have been determined by X-ray crystallography. The compound crystallizes in the monoclinic space group, P2₁/n with

Full text of DOI:10.1023/B:JOCC.0000044086.71468.e9

Journal of Chemical Crystallography, Vol. 34, No. 9, September 2004 (ꢀC 2004)
Synthesis and crystal structure of
2-trifluoromethyl-1-[(2ꢀ-1H-tetrazole-5-yl-biphenyl-4-yl)
methyl]benzimidazole
Weifa Yu,(1) Zhiming Zhou,(1)∗ Xinqi Zhao,(2) and Congxuan Yu(1)
Received June 22, 2004
The crystal structure of 2-trifluoromethyl-1-[(2ꢁ-1H-tetrazle-5-yl-biphenyl-4-yl) methyl]-
benzimidazole and a methylene chloride have been determined by X-ray crystal-
lography. The compound crystallizes in the monoclinic space group, P21/n with
◦
˚
˚
˚
cell dimensions a = 10.931(2) A, b = 12.31(3) A, c = 17.901(4) A, β = 102.45(3) ,
V = 2352.9(8) A , Dcalc = 1.427 g/cm3, Z = 4, µ = 0.324 mm−1, and F(000) =
3
˚
1032, and its structure was refined to R1 = 0.0663 and wR2 = 0.1668 for 1910
observed reflections(I > 2σ(I)). Intermolecular hydrogen bonds were identified be-
tween the N and H atoms of intermolecular benzimidazole group and tetrazole
group.
KEY WORDS: X-ray crystal structure; angiotensin; biphenyltetrazole.
Introduction
receptor antagonist, we report the synthesis
and crystal structure of 2-trifluoromethyl-
1-[(2ꢁ-1H-tetrazole-5-yl-biphenyl-4-yl)methyl]
Since the discovery by DuPont of orally
active nonpeptide angiotensin II antagonist,
losartan,1,2 numerous patents and publications
on AII antagonists have appeared over the past
few years. Most of them contain a biphenyl-
tetrazole moiety or biphenyl carboxylic acid
moiety linked to a heterocycle by a methylene
group.3−5 Biphenyl tetrazole moiety may play
important roles in pharmaceutical core. In order
to find new aspects for the structure-activity
relationships of nonpeptide angiotensin II
benzimidazole (5).
Experimental
Melting points were determinated using XT4
microscope melting point apparatus and were un-
corrected. Infrared (IR) spectra were recorded
on a Nicolet Magna IR 560 spectrophotome-
ter and were run as KBr pellets unless other-
wise indicated. 1H-NMR spectra (400 MHz) were
measured on an ARX400 instrument. Chemical
shifts are reported in δ units relative to inter-
nal tetramethylsilane. Mass spectra were recorded
on a ZAB-HS mass spectrometer in EI. Elemen-
tal analyses were performed on an Elementar
Vario EL.
(1) Research & Development Center for Pharmaceuticals, Beijing
Institute of Technology, Beijing, People’s Republic of China.
(2) School of Material Science and Engineering, Beijing Institute of
Technology, Beijing, People’s Republic of China.
∗ To whom correspondence should be addressed; e-mail: zzm@
bit.edu.cn.
597
ꢀ
C
1074-1542/04/0900-0597/0 2004 Springer Science+Business Media, Inc.

598
Yu, Zhou, Zhao, and Yu
102–104◦C; Anal. Calcd.(%) for C22H14F3N2: C,
70.02; H, 3.71; N, 11.14. Found(%): C, 70.14; H,
3.85; N, 11.01. IR cm−1: 3060, 2224, 1520, 1275,
1
1197, 1144, 1093, 764, 748. H NMR(CDCl3):
δ 5.61(s,2H), 7.21–7.99(m, 12H). MS(EI), m/z:
377(96) (M+ = 1), 192(100).
A mixture of 2-trifluoromethyl-1-[(2ꢁ-cyano-
biphenyl-4-yl)methyl]benzimidazole (0.6 g,
1.59 mmol), sodium azide (0.47 g,7.2 mmol),
and Et3N·HCl (0.7 g, 5 mmol) in 1-methyl-2-
pyrrolidinone (15 mL) is stirred at 160◦C for
12 h. After cooling, the mixture is diluted with
H2O (50 mL), acidified to pH 3 with 4N HCl, and
extracted with EtOAc (3 × 50 mL). The organic
layer was washed with H2O (3 × 50 mL), then
the combined extracts were dried (MgSO4) and
evaporated and the solid residue was purified by
silica gel column chromatography eluting with
ethyl acetate/ethanol (80:20/v:v) to give 5(0.2 g,
30.3%) as a white solid: m.p. 114–116◦C; Anal.
Calcd.(%) for C22H15F3N6: C, 62.86; H, 3.57; N,
20.0. Found(%): C, 62.71; H, 3.43; N, 20.16. IR:
3049, 2974, 2820, 2698, 1526, 1477, 1434, 1278,
Preparation of 2-trifluoromethyl-1-
[(2ꢁ-1H-tetrazle-5-yl-biphenyl-4-yl)methyl]
benzimi-dazole ꢀ5ꢀ
To o-phenylenediamine (10.8 g, 0.10 mol)
in propylene glycol (80 mL) was added trifluo-
roacetic acid (13.68 g, 0.12 mol) and the solution
was heated at 70◦C for 12 h, and then cooled to
room temperature. Ice cold water (50 cm3) was
added to force the precipitation of a white solid,
which was collected and dissolved in hot ethanol
(50 mL). The solution was filtered over activated
carbon and the filtrate was added to ice cold wa-
ter (100 mL) to give white solid. The filtrate cake
was washed by water to furnish white solid 2-
(trifluoromethyl)-1H-benzimidazole 14.3 g(yield
77%), m.p. 208–210◦C (lit6. 209–211◦C).
1
1187, 1146, 990, 280, 739. H NMR (DMSO):
δ 5.70 (s, 1H), 5.75(s, 2H), 7.01–7.87 (m, 12H).
MS(EI), m/z: 420(M+ = 1).
X-ray analysis
The single crystals were obtained by slow
evaporation of a methylene chloride solution
of the compound at room temperature. The
structure of the crystal was characterized as
C22H15F3N6·CH2Cl2. A colourless single crystal
with dimensions of 0.35 mm × 0.15 mm ×
0.10 mm was selected for X-ray diffraction
analysis (Table 1). The data were collected
on a Rigaku RAXIS RAPID IP diffractometer
with a graphite-monochromated MoKα radi-
To a solution of 1.0 g (5.37 mmol) of 2-
(trifluoromethyl)-1H-benzimidazole in 30 mL of
DMF was added potassium tert-butylate 0.7 g
(6.25 mmol), the mixture was stirred for 30 min
at ambient temperature, and 4-(bromomethyl)
biphenyl-2ꢁ-nitrile 1.60 g (5.88 mmol) was added.
After stirring for 12 h the mixture was poured into
water (120 mL) and extracted with ethyl acetate
(3 × 50 mL). The combined extracts were dried
(MgSO4) and evaporated. The residue was puri-
fied by silica gel column chromatography elut-
ing with ethyl acetate/light petroleum (10:90/v:v)
to give 4(1.45 g, 71.5%) as a white solid: m.p.
˚
ation (λ = 0.71073 A) at 93(2) K. A total of
16280 reflections and 4123 independent ones
(Rint = 0.0427) were collected within the range
of 2.33 < θ < 25◦ by using ω scan technique, of
which 1910 observed reflections with I > 2σ(I)
were used in the structural analysis. The structure
was solved by direct methods and refined by full-

Crystal structure of benzimidazole
599
Table 1. Crystallographic Data and Structure Refinement
Empirical formula
CCDC deposit no.
Formula weight
Temperature
C23H17Cl2F3N6
CCDC-228076
505.33
293(2) K
Measurement device
Measurement method
Wavelength
Rigaku RAXIS RAPID IP
Oscillation
˚
0.71073 A
Crystal system
Monoclinic
Space group
Unit cell dimensions
P21/n
˚
˚
˚
a = 10.931(2) A
b = 12.314(3) A
c = 17.901(4) A
α = 90◦
β = 102.45(3)◦
γ = 90◦
3
˚
2352.9(8) A
Volume
Refls. No. for cell measurement 16280
Z
4
Density (calculated), Mg/m3
Absorption coefficient, mm−1
F(000)
1.427
0.324
1032
Crystal shape/Crystal color
Crystal size
θ range for data collection, deg
Limiting indices
Block/Colorless
0.35 × 0.15 × 0.10 mm
2.33–25.00
−12 ≤ h ≤ 12, −14 ≤ k ≤ 14,
−21 ≤ l ≤ 20
16280
Fig. 1. Molecular structure of the title compound (50%
Reflections collected
probability ellipsoids).
Completeness to θ = 25.00
Independent reflections 4123
Reflections with I > 2σ(I)
Data/restraints/parameters
Max. and min. transmission
Refinement method
99.7%
[R(int) = 0.0427]
1910
4123/0/312
SHELXL-98. Figure 1 shows the molecular
structure of the title compound, and Fig. 2 depicts
the packing diagram of the molecules in a unit
cell.
0.968 and 0.893
Full-matrix least-squares on F2
1.142
R1 = 0.0663, wR2 = 0.1668
R1 = 0.1273, wR2 = 0.1785
0.0155(17)
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole,
0.492 and −0.444
Results and discussion
−3
˚
e/A
Figure 1 shows the molecular structure of
the title compound with atom numbering scheme.
Figure 2 shows clearly solvent CH2Cl2 was
packed in unit cell. The selected bond lengths and
bond angles are listed in Table 2.
matrix least-squares techniques, using anisotropic
thermal parameters for all non-hydrogen atoms.
All the hydrogen atoms were fixed on the ideal-
ized positions isotropically, but they were only
included during the structure factor calculations.
The final cycle of full-matrix least-squares
refinement gave R1 = 0.0663, wR2 = 0.1668
(w = 1/[σ2(Fo2) + (0.0686P)2+ 0.0000P], where
X-ray analysis shows that the bond lengths
of C(22) F(1), C(22) F(2), and C(22) F(3) are
˚
different, 1.307, 1.319, and 1.333 A respec-
tively. The single bond length of C(21) C(22) is
˚
˚
1.470(6) A, shorter than common one (1.54 A);
There is an intermolecular hydrogen bond in the
crystal of the title compound. The intermolecu-
lar hydrogen bond N(4) HN4· · ·N(6) is formed
between tetrazole group and benzimidazole with
P = (Fo2 + 2Fc2)/3). S = 1.142 and (ꢀ/σ)max
=
0.000. The maximum peak on the final difference
Fourier map is 0.492 and the minimum peak
3
˚
−0.444e/A . Programs used to calculate are

600
Yu, Zhou, Zhao, and Yu
Fig. 2. Packing of the title compound in a unit cell.
the distance of N(4)· · ·N(6)(a) 2.822 A and the an-
gle of N(7) H(4)· · ·O(2)(a) 156(4) (a: −x + 1/2,
y + 1/2, −z + 1/2), respectively Table 3.
of 1.367(5) A and 1.346(4) A, respectively. These
values are consistent with those observed previ-
ously for the tetrazole ring.7
˚
˚
˚
In the tetrazole ring, the N2 N3distance of
1.292(5) A is clearly a double bond, significantly
shorter than the N1 N2 and N3 N4 signal bonds
In the benzimidazol moiety, the C21 N6
bond has a strong double-bond character, the dis-
tance of it is 1.309(5) A, while that of C21 N5 is
1.358(4) A. In biphenyl moiety, the inter-ring dis-
tance C(7) C(8) 1.492(5) A of the title compound
˚
˚
˚
˚
˚
is shorter than that of unsubstituted biphenyl
1.507 A.
The dihedral angles between the tetrazole
plane and the plane of phenyl ring attached to
it is 45.82(2)◦, The deviation angle between the
planes of the phenyl rings of the biphenyl moi-
eties is 47.67(18)◦, while the values in 2-butyl-6-
dimethoxymethyl-5-phenyl-2-{[2ꢁ-(1H-tetrazole-
5-yl)biphenyl-4-yl]methyl}-1H-imidazol[5,4-b]
pyridine are 58.8(5)◦ and 45.8(5)◦, respectively.8
Table 2. Selected Bond Lengths [A] and Angles [deg] for 5
˚
F(1) C(22)
F(3) C(22)
N(1) N(2)
N(3) N(4)
N(5) C(21)
N(5) C(14)
N(6) C(20)
C(7) C(8)
1.307(5) F(2) C(22)
1.331(5) N(1) C(1)
1.367(5) N(2) N(3)
1.346(4) N(4) C(1)
1.358(4) N(5) C(15)
1.470(4) N(6) C(21)
1.388(4) C(1) C(2)
1.492(5) C(21) C(22)
1.319(5)
1.323(5)
1.292(5)
1.335(4)
1.377(5)
1.309(5)
1.459(5)
1.470(6)
C(1) N(1) N(2)
N(2) N(3) N(4)
C(21) N(5) C(15)
C(15) N(5) C(14)
N(1) C(1) N(4)
N(4) C(1) C(2)
C(2) C(7) C(8)
N(5) C(15) C(20)
N(6) C(21) N(5)
F(2) C(22) C(21)
106.0(3) N(3) N(2) N(1)
105.5(3) C(1) N(4) N(3)
105.9(3) C(21) N(5) C(14) 129.1(3)
124.7(3) C(21) N(6) C(20) 104.6(3)
107.4(3) N(1) C(1) C(2)
127.3(3) C(6) C(7) C(8)
122.6(3) C(9) C(8) C(7)
106.2(3) N(5) C(15) C(16) 132.2(4)
113.6(3) F(1) C(22) C(21) 112.2(4)
113.3(4) F(3) C(22) C(21) 111.6(4)
111.1(3)
110.1(3)
˚
Table 3. Hydrogen Bonds for 5 [A and deg.]
125.2(3)
119.0(4)
121.6(3)
D
H. . .A
d (D H) d (H. . .A) d (D. . .A) <(DHA)
N(4) HN4. . .N(6)#1 0.98(5) 1.90(5) 2.822(5) 156(4)
Note. Symmetry transformations used to generate equivalent atoms:
#1 −x + 1/2, y + 1/2, −z + 1/2.

Crystal structure of benzimidazole
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