6-Meth­oxy-2-methyl-1-m-tolyl-1H-benzimidazole hemihydrate

Fang, X.-B.; Fang, L.; Liu, X.-Y.

doi:10.1107/S1600536811031060

organic compounds

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ISSN: 2056-9890

Volume 67| Part 9| September 2011| Page o2263

doi:10.1107/S1600536811031060

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6-Methoxy-2-methyl-1-m-tolyl-1H-benzimidazole hemihydrate

Xu-Bin Fang,^a ^* Lei Fang ^a and Xu-Ying Liu ^a

^aDepartment of Chemistry and Chemical Engineering, Southeast University, Nanjing, People's Republic of China
^*Correspondence e-mail: fanglei24@googlemail.com

(Received 17 May 2011; accepted 2 August 2011; online 6 August 2011)

The title compound, C₁₆H₁₆N₂O·0.5H₂O, is a substituted 1-phenylbenzimidazole, which belongs to the class of ATP-site inhibitors of the platelet-derived growth-factor receptor. In the crystal, the components are linked by an O—H⋯N hydrogen bond.

Related literature

For related structures, see: Zhong (2004 ). For medicinal background, see: Palmer (1998 ).

Experimental

Crystal data

C₁₆H₁₆N₂O·0.5H₂O
M_r = 261.32
Orthorhombic, P b c n
a = 16.0752 (16) Å
b = 13.9140 (14) Å
c = 12.6450 (13) Å
V = 2828.3 (5) Å³
Z = 8
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 293 K
0.25 × 0.23 × 0.21 mm

Data collection

Bruker APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ) T_min = 0.980, T_max = 0.983
13133 measured reflections
2720 independent reflections
2018 reflections with I > 2σ(I)
R_int = 0.029

Refinement

R[F² > 2σ(F²)] = 0.081
wR(F²) = 0.155
S = 1.03
2720 reflections
178 parameters
H-atom parameters constrained
Δρ_max = 0.69 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1W—H1W⋯N2	0.85	2.08	2.911 (3)	166

Data collection: SMART (Bruker, 2000 ); cell refinement: SAINT (Bruker, 2000); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536811031060/aa2011sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811031060/aa2011Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536811031060/aa2011Isup3.cml

checkCIF report

Comment top

1-Phenylbenzimidazoles are shown to be a new class of ATP-site inhibitors of the platelet derived growth factor receptor (PDGFR), with clear evidence of the relationship between their molecular features and their inhibitory activity (Palmer, 1998). However, few structure-activity relationship studies involving 1-phenylbenzimidazoles have been published and the QSAR models reported were not completely satisfactory (Zhong, 2004). The synthesis of these compounds is relatively uncomplicated, many methods have been proposed in the past years. We have successfully synthesized the title compound as a key analogue of 1-phenylbenzimidazole.

Related literature top

For related structures, see: Zhong (2004). For medicinal background, see: Palmer (1998).

Experimental top

N-(2-amino-5-methoxyphenyl)-N-m-tolylacetamide (1 g, 3.70 mmol) was dissolved in 40 ml of 18% hydrochloric acid, and the solution was cooled to 0°C. A solution of NaNO₂ (0.28 g, 4.07 mmol) in 1 ml of water was added under stirring, and the mixture was stirred for 10 min. Copper powder (1 g) was then added, and the mixture was stirred for 30 min at room temperature. The reaction solution was heated to 70°C and stirred for 3 h. The mixture was extracted with ethyl acetate (2×50 ml), and the extract was washed with a 3% aqueous solution of NaHCO₃ and water, respectively. The organic phase was dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography. Yield 0.46 g (49%).

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SAINT (Bruker, 2000); data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

	Fig. 1. The asymmetric unit of the title compound. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. The dimeric structure of the title compound is built via O—H···N hydrogen bonding between water molecule and N atoms of imidazole rings.

6-Methoxy-2-methyl-1-m-tolyl-1H-benzimidazole hemihydrate top

Crystal data top

C₁₆H₁₆N₂O·0.5H₂O	F(000) = 1112
M_r = 261.32	D_x = 1.227 Mg m⁻³
Orthorhombic, Pbcn	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2n 2ab	Cell parameters from 2720 reflections
a = 16.0752 (16) Å	θ = 2.4–28.0°
b = 13.9140 (14) Å	µ = 0.08 mm⁻¹
c = 12.6450 (13) Å	T = 293 K
V = 2828.3 (5) Å³	Plate-like, colourless
Z = 8	0.25 × 0.23 × 0.21 mm

Data collection top

Bruker APEX CCD diffractometer	2720 independent reflections
Radiation source: fine-focus sealed tube	2018 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.029
ϕ and ω scans	θ_max = 26.0°, θ_min = 2.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −17→19
T_min = 0.980, T_max = 0.983	k = −17→17
13133 measured reflections	l = −15→14

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.081	H-atom parameters constrained
wR(F²) = 0.155	w = 1/[σ²(F_o²) + (0.0196P)² + 3.0292P] where P = (F_o² + 2F_c²)/3
S = 1.03	(Δ/σ)_max < 0.001
2720 reflections	Δρ_max = 0.69 e Å⁻³
178 parameters	Δρ_min = −0.20 e Å⁻³
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0037 (5)

Crystal data top

C₁₆H₁₆N₂O·0.5H₂O	V = 2828.3 (5) Å³
M_r = 261.32	Z = 8
Orthorhombic, Pbcn	Mo Kα radiation
a = 16.0752 (16) Å	µ = 0.08 mm⁻¹
b = 13.9140 (14) Å	T = 293 K
c = 12.6450 (13) Å	0.25 × 0.23 × 0.21 mm

Data collection top

Bruker APEX CCD diffractometer	2720 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	2018 reflections with I > 2σ(I)
T_min = 0.980, T_max = 0.983	R_int = 0.029
13133 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.081	0 restraints
wR(F²) = 0.155	H-atom parameters constrained
S = 1.03	Δρ_max = 0.69 e Å⁻³
2720 reflections	Δρ_min = −0.20 e Å⁻³
178 parameters

Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.6204 (2)	0.6782 (2)	0.2566 (2)	0.0725 (8)
H1A	0.5851	0.6253	0.2539	0.087*
C2	0.6771 (2)	0.6930 (3)	0.1781 (3)	0.0851 (10)
H2A	0.6809	0.6497	0.1223	0.102*
C3	0.7285 (2)	0.7711 (3)	0.1814 (3)	0.0863 (11)
H3A	0.7671	0.7800	0.1274	0.104*
C4	0.72472 (19)	0.8370 (2)	0.2623 (3)	0.0789 (10)
C5	0.66713 (18)	0.8218 (2)	0.3437 (3)	0.0699 (8)
H5A	0.6636	0.8650	0.3996	0.084*
C6	0.61540 (17)	0.7422 (2)	0.3404 (2)	0.0624 (7)
C8	0.5560 (2)	0.6505 (2)	0.4939 (2)	0.0681 (8)
C9	0.6135 (2)	0.5667 (2)	0.4845 (3)	0.0848 (10)
H9A	0.6020	0.5215	0.5401	0.127*
H9B	0.6700	0.5884	0.4903	0.127*
H9C	0.6055	0.5361	0.4172	0.127*
C10	0.4610 (2)	0.7482 (2)	0.5473 (2)	0.0681 (8)
C11	0.3959 (2)	0.7953 (3)	0.5984 (3)	0.0819 (10)
H11A	0.3717	0.7687	0.6585	0.098*
C12	0.3683 (2)	0.8807 (3)	0.5596 (3)	0.0756 (9)
H12A	0.3245	0.9120	0.5932	0.091*
C13	0.40456 (18)	0.9223 (2)	0.4699 (2)	0.0677 (8)
C14	0.46999 (17)	0.8783 (2)	0.4176 (2)	0.0611 (7)
H14A	0.4946	0.9056	0.3583	0.073*
C15	0.49675 (18)	0.7910 (2)	0.4588 (2)	0.0592 (7)
C16	0.4029 (2)	1.0538 (3)	0.3480 (3)	0.0863 (10)
H16A	0.3731	1.1123	0.3341	0.129*
H16B	0.3979	1.0116	0.2883	0.129*
H16C	0.4605	1.0683	0.3601	0.129*
N1	0.55804 (15)	0.72736 (17)	0.42521 (18)	0.0628 (6)
N2	0.49971 (19)	0.66035 (18)	0.5677 (2)	0.0764 (7)
O1	0.36911 (13)	1.00859 (17)	0.43877 (19)	0.0811 (7)
O1W	0.5000	0.5327 (2)	0.7500	0.0961 (11)
H1W	0.4912	0.5668	0.6953	0.144*
C7	0.7786 (3)	0.9187 (3)	0.2623 (4)	0.1196 (16)
H7A	0.8138	0.9166	0.2011	0.179*
H7B	0.8123	0.9180	0.3250	0.179*
H7C	0.7459	0.9764	0.2609	0.179*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.077 (2)	0.076 (2)	0.0645 (18)	0.0169 (17)	0.0040 (16)	0.0042 (16)
C2	0.092 (2)	0.093 (3)	0.070 (2)	0.029 (2)	0.0057 (19)	0.0060 (19)
C3	0.081 (2)	0.104 (3)	0.074 (2)	0.038 (2)	0.0189 (18)	0.019 (2)
C4	0.0568 (18)	0.074 (2)	0.106 (3)	0.0035 (16)	0.0035 (18)	0.033 (2)
C5	0.0636 (18)	0.0701 (19)	0.076 (2)	0.0092 (16)	0.0030 (15)	0.0106 (16)
C6	0.0602 (17)	0.0685 (18)	0.0584 (16)	0.0054 (15)	0.0027 (13)	0.0111 (14)
C8	0.083 (2)	0.0562 (17)	0.0649 (18)	−0.0107 (16)	0.0003 (16)	0.0009 (14)
C9	0.110 (3)	0.066 (2)	0.079 (2)	0.0055 (19)	−0.004 (2)	0.0036 (17)
C10	0.077 (2)	0.0635 (18)	0.0634 (17)	−0.0187 (16)	0.0101 (15)	−0.0055 (14)
C11	0.083 (2)	0.089 (2)	0.074 (2)	−0.025 (2)	0.0264 (18)	−0.0117 (18)
C12	0.0671 (19)	0.079 (2)	0.081 (2)	−0.0068 (17)	0.0137 (17)	−0.0201 (18)
C13	0.0566 (17)	0.075 (2)	0.0714 (19)	−0.0066 (15)	−0.0019 (15)	−0.0158 (16)
C14	0.0597 (16)	0.0658 (17)	0.0579 (16)	−0.0049 (14)	0.0025 (13)	−0.0022 (14)
C15	0.0563 (15)	0.0632 (17)	0.0582 (15)	−0.0087 (14)	0.0045 (13)	−0.0069 (13)
C16	0.090 (2)	0.081 (2)	0.088 (2)	0.011 (2)	−0.005 (2)	0.0008 (19)
N1	0.0676 (15)	0.0610 (14)	0.0599 (13)	−0.0022 (12)	0.0055 (12)	0.0042 (11)
N2	0.0991 (19)	0.0625 (15)	0.0677 (16)	−0.0165 (15)	0.0114 (15)	0.0024 (13)
O1	0.0725 (13)	0.0838 (15)	0.0870 (16)	0.0143 (12)	−0.0013 (12)	−0.0094 (13)
O1W	0.144 (3)	0.0619 (19)	0.082 (2)	0.000	0.002 (2)	0.000
C7	0.100 (3)	0.097 (3)	0.163 (4)	−0.008 (2)	0.008 (3)	0.013 (3)

Geometric parameters (Å, º) top

C1—C2	1.363 (5)	C10—C11	1.394 (4)
C1—C6	1.387 (4)	C10—N2	1.395 (4)
C1—H1A	0.9300	C11—C12	1.359 (5)
C2—C3	1.366 (5)	C11—H11A	0.9300
C2—H2A	0.9300	C12—C13	1.401 (4)
C3—C4	1.375 (5)	C12—H12A	0.9300
C3—H3A	0.9300	C13—C14	1.385 (4)
C4—C5	1.400 (4)	C13—O1	1.386 (4)
C4—C7	1.429 (5)	C14—C15	1.389 (4)
C5—C6	1.385 (4)	C14—H14A	0.9300
C5—H5A	0.9300	C15—N1	1.391 (4)
C6—N1	1.429 (3)	C16—O1	1.417 (4)
C8—N2	1.307 (4)	C16—H16A	0.9600
C8—N1	1.378 (4)	C16—H16B	0.9600
C8—C9	1.492 (4)	C16—H16C	0.9600
C9—H9A	0.9600	O1W—H1W	0.8500
C9—H9B	0.9600	C7—H7A	0.9600
C9—H9C	0.9600	C7—H7B	0.9600
C10—C15	1.392 (4)	C7—H7C	0.9600

C2—C1—C6	119.9 (3)	C12—C11—H11A	120.4
C2—C1—H1A	120.1	C10—C11—H11A	120.4
C6—C1—H1A	120.1	C11—C12—C13	121.2 (3)
C1—C2—C3	120.2 (4)	C11—C12—H12A	119.4
C1—C2—H2A	119.9	C13—C12—H12A	119.4
C3—C2—H2A	119.9	C14—C13—O1	124.1 (3)
C2—C3—C4	121.7 (3)	C14—C13—C12	121.3 (3)
C2—C3—H3A	119.1	O1—C13—C12	114.7 (3)
C4—C3—H3A	119.1	C13—C14—C15	116.3 (3)
C3—C4—C5	118.4 (3)	C13—C14—H14A	121.9
C3—C4—C7	120.2 (4)	C15—C14—H14A	121.9
C5—C4—C7	121.4 (4)	C14—C15—N1	131.4 (3)
C6—C5—C4	119.7 (3)	C14—C15—C10	123.2 (3)
C6—C5—H5A	120.1	N1—C15—C10	105.4 (3)
C4—C5—H5A	120.1	O1—C16—H16A	109.5
C5—C6—C1	120.1 (3)	O1—C16—H16B	109.5
C5—C6—N1	118.8 (3)	H16A—C16—H16B	109.5
C1—C6—N1	121.2 (3)	O1—C16—H16C	109.5
N2—C8—N1	112.6 (3)	H16A—C16—H16C	109.5
N2—C8—C9	124.6 (3)	H16B—C16—H16C	109.5
N1—C8—C9	122.8 (3)	C8—N1—C15	106.6 (2)
C8—C9—H9A	109.5	C8—N1—C6	126.9 (3)
C8—C9—H9B	109.5	C15—N1—C6	126.4 (2)
H9A—C9—H9B	109.5	C8—N2—C10	105.7 (3)
C8—C9—H9C	109.5	C13—O1—C16	117.2 (2)
H9A—C9—H9C	109.5	C4—C7—H7A	109.5
H9B—C9—H9C	109.5	C4—C7—H7B	109.5
C15—C10—C11	118.8 (3)	H7A—C7—H7B	109.5
C15—C10—N2	109.8 (3)	C4—C7—H7C	109.5
C11—C10—N2	131.4 (3)	H7A—C7—H7C	109.5
C12—C11—C10	119.2 (3)	H7B—C7—H7C	109.5

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1W···N2	0.85	2.08	2.911 (3)	166

Experimental details

Crystal data
Chemical formula	C₁₆H₁₆N₂O·0.5H₂O
M_r	261.32
Crystal system, space group	Orthorhombic, Pbcn
Temperature (K)	293
a, b, c (Å)	16.0752 (16), 13.9140 (14), 12.6450 (13)
V (Å³)	2828.3 (5)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	0.08
Crystal size (mm)	0.25 × 0.23 × 0.21

Data collection
Diffractometer	Bruker APEX CCD diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996)
T_min, T_max	0.980, 0.983
No. of measured, independent and observed [I > 2σ(I)] reflections	13133, 2720, 2018
R_int	0.029
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.081, 0.155, 1.03
No. of reflections	2720
No. of parameters	178
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.69, −0.20

Computer programs: SMART (Bruker, 2000), SAINT (Bruker, 2000), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1W···N2	0.85	2.08	2.911 (3)	166.0

Acknowledgements

The authors thank the National Natural Science Foundation of China and the Program for Young Excellent Talents in Southeast University for financial support.

References

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Palmer, B. D. (1998). J. Med. Chem. 41, 5457–5465. Web of Science CrossRef CAS Google Scholar
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Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
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