1-(2-Nitro­benz­yl)-1H-pyrrole-2-carbaldehyde

Chen, X.; Liu, Y.; Liu, D.-K.; Wang, P.-B.

doi:10.1107/S1600536811018459

organic compounds

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ISSN: 2056-9890

Volume 67| Part 6| June 2011| Page o1473

doi:10.1107/S1600536811018459

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1-(2-Nitrobenzyl)-1H-pyrrole-2-carbaldehyde

Xu Chen,^a Ying Liu,^b ^* Deng-Ke Liu ^b and Ping-Bao Wang ^b

^aHenan University, Henan 475004, People's Republic of China, and ^bTianjin Institute of Pharmaceutical Research, Tianjin 300193, People's Republic of China
^*Correspondence e-mail: liudk@tjipr.com

(Received 9 May 2011; accepted 16 May 2011; online 20 May 2011)

In the title compound, C₁₂H₁₀N₂O₃, the five- and six-membered rings form a dihedral angle of 83.96 (6)°. The nitro group is twisted by 5.92 (8)° from the plane of the attached benzene ring. In the crystal, weak intermolecular C—H⋯O hydrogen bonds link the molecules into columns in the [100] direction, with a short distance of 3.725 (3) Å between the centroids of benzene rings inside these columns.

Related literature

The title compound is an intermediate in the synthesis of lixivaptan (systematic name N-[3-chloro-4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide), a vasopressin receptor antagonist with high V2 receptor affinity. For preliminary studies of lixivaptan, which is now undergoing Phase III clinical trials, see, for example, Ku et al. (2009 ). For the synthesis of the title compound, see: Albright et al. (1998 ).

Experimental

Crystal data

C₁₂H₁₀N₂O₃
M_r = 230.22
Triclinic, $[P \overline 1]$
a = 7.2643 (8) Å
b = 8.3072 (10) Å
c = 9.2570 (12) Å
α = 104.10 (2)°
β = 96.463 (11)°
γ = 96.92 (2)°
V = 531.98 (11) Å³
Z = 2
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 113 K
0.20 × 0.18 × 0.10 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005 ) T_min = 0.979, T_max = 0.990
6867 measured reflections
2544 independent reflections
1517 reflections with I > 2σ(I)
R_int = 0.040

Refinement

R[F² > 2σ(F²)] = 0.037
wR(F²) = 0.095
S = 0.95
2544 reflections
154 parameters
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.28 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O3ⁱ	0.95	2.41	3.1919 (17)	139
C8—H8⋯O3ⁱⁱ	0.95	2.37	3.3107 (17)	170
Symmetry codes: (i) -x+1, -y+1, -z+1; (ii) x+1, y, z.

Data collection: CrystalClear (Rigaku/MSC, 2005); cell refinement: CrystalClear; data reduction: CrystalClear; 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 global, I. DOI: 10.1107/S1600536811018459/cv5092sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811018459/cv5092Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536811018459/cv5092Isup3.cdx

Supporting information file. DOI: 10.1107/S1600536811018459/cv5092Isup4.cml

checkCIF report

Comment top

Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that Lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted (Ku et al., 2009). Herewith we present the crystal structure of the title compound (I), is an intermediate used in the synthesis of Lixivaptan.

In (I), the pyrrole ring and the benzene ring form a dihedral angle of 83.96 (6)°. Nitro group is twisted from the plane of attached benzene ring with a dihedral angle of 5.92 (8)°. In the crystal structure, weak intermolecular C—H···O hydrogen bonds (Table 1) further assemble these molecules into columns propagated in direction [100], with the short distance of 3.725 (3)Å between the centroids of benzene rings inside these columns.

Related literature top

The title compound is an intermediate in the synthesis of lixivaptan (systematic name N-[3-chloro-4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide), a vasopressin receptor antagonist with high V2 receptor affinity. For preliminary studies of lixivaptan, which is now undergoing Phase III clinical trials, see, for example, Ku et al. (2009). For the synthesis of the title compound, see: Albright et al. (1998).

Experimental top

(I) was prepared from pyrrole-2-carboxaldehyde and 2-nitrobenzyl bromide in the solution of sodium hydride in N,N-dimethylformamide under argon. Colourless crystals (m.p. 138 °C) were obtained in a yield of 95% as crude product. Single crystals were grown from petroleum ether-ethyl acetate (2:1) solution.

Computing details top

Data collection: CrystalClear (Rigaku/MSC, 2005); cell refinement: CrystalClear (Rigaku/MSC, 2005); data reduction: CrystalClear (Rigaku/MSC, 2005); 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 molecular structure of (I), with the atomic numbering and 50% probability displacement ellipsoids.

1-(2-Nitrobenzyl)-1H-pyrrole-2-carbaldehyde top

Crystal data top

C₁₂H₁₀N₂O₃	Z = 2
M_r = 230.22	F(000) = 240
Triclinic, P1	D_x = 1.437 Mg m⁻³
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.2643 (8) Å	Cell parameters from 1889 reflections
b = 8.3072 (10) Å	θ = 2.3–28.0°
c = 9.2570 (12) Å	µ = 0.11 mm⁻¹
α = 104.10 (2)°	T = 113 K
β = 96.463 (11)°	Prism, colourless
γ = 96.92 (2)°	0.20 × 0.18 × 0.10 mm
V = 531.98 (11) Å³

Data collection top

Rigaku Saturn CCD area-detector diffractometer	2544 independent reflections
Radiation source: rotating anode	1517 reflections with I > 2σ(I)
Multilayer monochromator	R_int = 0.040
Detector resolution: 14.22 pixels mm^-1	θ_max = 28.0°, θ_min = 2.3°
ω and ϕ scans	h = −9→9
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)	k = −10→10
T_min = 0.979, T_max = 0.990	l = −12→12
6867 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.095	H-atom parameters constrained
S = 0.95	w = 1/[σ²(F_o²) + (0.0455P)²] where P = (F_o² + 2F_c²)/3
2544 reflections	(Δ/σ)_max < 0.001
154 parameters	Δρ_max = 0.24 e Å⁻³
0 restraints	Δρ_min = −0.28 e Å⁻³

Crystal data top

C₁₂H₁₀N₂O₃	γ = 96.92 (2)°
M_r = 230.22	V = 531.98 (11) Å³
Triclinic, P1	Z = 2
a = 7.2643 (8) Å	Mo Kα radiation
b = 8.3072 (10) Å	µ = 0.11 mm⁻¹
c = 9.2570 (12) Å	T = 113 K
α = 104.10 (2)°	0.20 × 0.18 × 0.10 mm
β = 96.463 (11)°

Data collection top

Rigaku Saturn CCD area-detector diffractometer	2544 independent reflections
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)	1517 reflections with I > 2σ(I)
T_min = 0.979, T_max = 0.990	R_int = 0.040
6867 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.037	0 restraints
wR(F²) = 0.095	H-atom parameters constrained
S = 0.95	Δρ_max = 0.24 e Å⁻³
2544 reflections	Δρ_min = −0.28 e Å⁻³
154 parameters

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'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
O1	0.73782 (17)	0.83214 (12)	0.55982 (12)	0.0507 (4)
O2	0.80539 (16)	0.77297 (12)	0.33569 (12)	0.0402 (3)
O3	0.39124 (13)	0.35491 (12)	0.08896 (11)	0.0281 (2)
N1	0.76728 (15)	0.73149 (14)	0.44833 (13)	0.0255 (3)
N2	0.78470 (15)	0.30999 (13)	0.04974 (12)	0.0206 (3)
C1	0.75954 (17)	0.55405 (15)	0.45094 (15)	0.0202 (3)
C2	0.73377 (18)	0.52045 (17)	0.58762 (15)	0.0258 (3)
H2	0.7209	0.6085	0.6714	0.031*
C3	0.72705 (19)	0.35811 (18)	0.60071 (16)	0.0291 (3)
H3	0.7088	0.3334	0.6935	0.035*
C4	0.74712 (19)	0.23132 (17)	0.47785 (16)	0.0284 (3)
H4	0.7449	0.1196	0.4869	0.034*
C5	0.77038 (18)	0.26669 (16)	0.34158 (16)	0.0244 (3)
H5	0.7827	0.1777	0.2583	0.029*
C6	0.77633 (17)	0.42904 (16)	0.32299 (14)	0.0198 (3)
C7	0.79970 (19)	0.46275 (15)	0.17131 (14)	0.0220 (3)
H7A	0.7028	0.5293	0.1451	0.026*
H7B	0.9238	0.5311	0.1800	0.026*
C8	0.93194 (19)	0.24383 (17)	−0.00619 (15)	0.0251 (3)
H8	1.0605	0.2868	0.0300	0.030*
C9	0.86490 (19)	0.10454 (17)	−0.12366 (15)	0.0275 (3)
H9	0.9382	0.0351	−0.1829	0.033*
C10	0.66954 (19)	0.08388 (15)	−0.14002 (15)	0.0237 (3)
H10	0.5857	−0.0025	−0.2124	0.028*
C11	0.61976 (18)	0.21166 (15)	−0.03203 (14)	0.0200 (3)
C12	0.43411 (19)	0.24082 (17)	−0.00666 (15)	0.0226 (3)
H12	0.3335	0.1635	−0.0708	0.027*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0839 (10)	0.0285 (6)	0.0404 (7)	0.0147 (6)	0.0260 (7)	−0.0002 (5)
O2	0.0676 (8)	0.0260 (6)	0.0292 (6)	0.0057 (5)	0.0086 (6)	0.0110 (5)
O3	0.0241 (5)	0.0363 (6)	0.0267 (6)	0.0097 (4)	0.0074 (4)	0.0094 (5)
N1	0.0252 (6)	0.0239 (6)	0.0257 (7)	0.0043 (5)	0.0009 (5)	0.0042 (5)
N2	0.0180 (6)	0.0239 (6)	0.0197 (6)	0.0037 (5)	0.0028 (5)	0.0054 (5)
C1	0.0153 (6)	0.0201 (7)	0.0250 (8)	0.0017 (5)	0.0001 (5)	0.0072 (6)
C2	0.0202 (7)	0.0340 (8)	0.0216 (8)	0.0021 (6)	0.0024 (6)	0.0056 (6)
C3	0.0245 (8)	0.0399 (9)	0.0249 (8)	0.0001 (7)	0.0004 (6)	0.0160 (7)
C4	0.0248 (8)	0.0274 (7)	0.0355 (9)	−0.0001 (6)	−0.0011 (6)	0.0172 (7)
C5	0.0226 (7)	0.0222 (7)	0.0273 (8)	0.0024 (6)	0.0001 (6)	0.0068 (6)
C6	0.0139 (6)	0.0229 (7)	0.0222 (7)	0.0020 (5)	0.0002 (5)	0.0065 (6)
C7	0.0236 (7)	0.0212 (7)	0.0203 (7)	0.0016 (6)	0.0019 (6)	0.0051 (6)
C8	0.0178 (7)	0.0332 (8)	0.0273 (8)	0.0065 (6)	0.0060 (6)	0.0114 (6)
C9	0.0295 (8)	0.0315 (8)	0.0260 (8)	0.0123 (6)	0.0098 (6)	0.0095 (6)
C10	0.0270 (7)	0.0225 (7)	0.0210 (7)	0.0017 (6)	0.0028 (6)	0.0058 (6)
C11	0.0192 (7)	0.0234 (7)	0.0183 (7)	0.0023 (5)	0.0020 (5)	0.0082 (5)
C12	0.0205 (7)	0.0278 (7)	0.0215 (7)	0.0024 (6)	0.0014 (6)	0.0116 (6)

Geometric parameters (Å, º) top

O1—N1	1.2175 (14)	C4—H4	0.9500
O2—N1	1.2247 (14)	C5—C6	1.3968 (18)
O3—C12	1.2260 (15)	C5—H5	0.9500
N1—C1	1.4745 (16)	C6—C7	1.5207 (17)
N2—C8	1.3571 (16)	C7—H7A	0.9900
N2—C11	1.3909 (16)	C7—H7B	0.9900
N2—C7	1.4602 (15)	C8—C9	1.3750 (19)
C1—C2	1.3881 (17)	C8—H8	0.9500
C1—C6	1.4000 (18)	C9—C10	1.3952 (18)
C2—C3	1.3787 (19)	C9—H9	0.9500
C2—H2	0.9500	C10—C11	1.3834 (17)
C3—C4	1.3837 (19)	C10—H10	0.9500
C3—H3	0.9500	C11—C12	1.4335 (17)
C4—C5	1.3867 (18)	C12—H12	0.9500

O1—N1—O2	122.35 (12)	C1—C6—C7	123.58 (11)
O1—N1—C1	118.45 (12)	N2—C7—C6	113.43 (10)
O2—N1—C1	119.20 (11)	N2—C7—H7A	108.9
C8—N2—C11	108.47 (11)	C6—C7—H7A	108.9
C8—N2—C7	125.06 (11)	N2—C7—H7B	108.9
C11—N2—C7	126.43 (10)	C6—C7—H7B	108.9
C2—C1—C6	122.84 (12)	H7A—C7—H7B	107.7
C2—C1—N1	115.52 (12)	N2—C8—C9	108.95 (12)
C6—C1—N1	121.64 (12)	N2—C8—H8	125.5
C3—C2—C1	119.42 (13)	C9—C8—H8	125.5
C3—C2—H2	120.3	C8—C9—C10	107.48 (12)
C1—C2—H2	120.3	C8—C9—H9	126.3
C2—C3—C4	119.60 (13)	C10—C9—H9	126.3
C2—C3—H3	120.2	C11—C10—C9	107.74 (12)
C4—C3—H3	120.2	C11—C10—H10	126.1
C3—C4—C5	120.23 (13)	C9—C10—H10	126.1
C3—C4—H4	119.9	C10—C11—N2	107.36 (11)
C5—C4—H4	119.9	C10—C11—C12	127.39 (13)
C4—C5—C6	122.05 (13)	N2—C11—C12	125.25 (12)
C4—C5—H5	119.0	O3—C12—C11	126.96 (13)
C6—C5—H5	119.0	O3—C12—H12	116.5
C5—C6—C1	115.84 (12)	C11—C12—H12	116.5
C5—C6—C7	120.58 (12)

O1—N1—C1—C2	−5.10 (18)	C11—N2—C7—C6	82.11 (15)
O2—N1—C1—C2	173.91 (12)	C5—C6—C7—N2	9.06 (17)
O1—N1—C1—C6	174.59 (12)	C1—C6—C7—N2	−170.91 (11)
O2—N1—C1—C6	−6.41 (19)	C11—N2—C8—C9	0.35 (14)
C6—C1—C2—C3	1.07 (19)	C7—N2—C8—C9	−177.37 (12)
N1—C1—C2—C3	−179.24 (11)	N2—C8—C9—C10	−0.30 (15)
C1—C2—C3—C4	0.36 (19)	C8—C9—C10—C11	0.14 (15)
C2—C3—C4—C5	−1.2 (2)	C9—C10—C11—N2	0.08 (14)
C3—C4—C5—C6	0.6 (2)	C9—C10—C11—C12	179.91 (12)
C4—C5—C6—C1	0.72 (19)	C8—N2—C11—C10	−0.26 (14)
C4—C5—C6—C7	−179.26 (12)	C7—N2—C11—C10	177.42 (11)
C2—C1—C6—C5	−1.58 (19)	C8—N2—C11—C12	179.89 (12)
N1—C1—C6—C5	178.76 (11)	C7—N2—C11—C12	−2.4 (2)
C2—C1—C6—C7	178.40 (12)	C10—C11—C12—O3	−179.65 (12)
N1—C1—C6—C7	−1.26 (19)	N2—C11—C12—O3	0.2 (2)
C8—N2—C7—C6	−100.58 (14)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C2—H2···O3ⁱ	0.95	2.41	3.1919 (17)	139
C8—H8···O3ⁱⁱ	0.95	2.37	3.3107 (17)	170

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) x+1, y, z.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₀N₂O₃
M_r	230.22
Crystal system, space group	Triclinic, P1
Temperature (K)	113
a, b, c (Å)	7.2643 (8), 8.3072 (10), 9.2570 (12)
α, β, γ (°)	104.10 (2), 96.463 (11), 96.92 (2)
V (Å³)	531.98 (11)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.20 × 0.18 × 0.10

Data collection
Diffractometer	Rigaku Saturn CCD area-detector diffractometer
Absorption correction	Multi-scan (CrystalClear; Rigaku/MSC, 2005)
T_min, T_max	0.979, 0.990
No. of measured, independent and observed [I > 2σ(I)] reflections	6867, 2544, 1517
R_int	0.040
(sin θ/λ)_max (Å⁻¹)	0.659

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.037, 0.095, 0.95
No. of reflections	2544
No. of parameters	154
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.24, −0.28

Computer programs: CrystalClear (Rigaku/MSC, 2005), 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
C2—H2···O3ⁱ	0.95	2.41	3.1919 (17)	139
C8—H8···O3ⁱⁱ	0.95	2.37	3.3107 (17)	170

Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) x+1, y, z.

Acknowledgements

The authors thank Mr Hai-Bin Song at Nankai University for the X-ray diffraction measurements and helpful suggestions.

References

Albright, J. D., Reich, M. F., Delos Santos, E. G., Dusza, J. P., Sum, F. W., Venkatesan, A. M., Coupet, J., Chan, P. S., Ru, X., Mazandarani, H. & Bailey, T. (1998). J. Med. Chem. 41, 2442–2444. Web of Science CrossRef CAS PubMed Google Scholar
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