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Acta Cryst. (2008). E64, o563    [ doi:10.1107/S1600536808003607 ]

4-[(5R*,10bR*)-2-Methyl-1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzoic acid

V. Kettmann and J. Svetlík

Abstract top

In the title compound, C18H16N2O3, a potential inhibitor of the cyclooxygenase-2 isoenzyme, the pyrazoline ring exists in a flattened envelope conformation with one C atom deviating by 0.463 Å from the mean plane of the remaining four atoms. The puckering of the central oxazine ring is more severe, with one N atom and one C atom displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the mean plane defined by the other four atoms; the conformation is that of a half-chair. As a result, the molecule as a whole is not planar. The carboxyl group is involved in an intermolecular O-H...N hydrogen bond, which links the molecules into centrosymmetric dimers.

Comment top

Recently, based on a pharmacophoric model of the cyclooxygenase-2 (COX-2) inhibitors (Palomer et al., 2002) as novel anticancer drugs (Subbaramaiah et al., 2002), we designed and prepared a series of 2- and 5-substituted derivatives containing the tricyclic system shown in Fig. 1. In order to recognize enzyme binding requirements for this fused heterocycle, we selected the 2-methyl-5-carboxyphenyl derivative, for single-crystal X-ray analysis. The compound was obtained as a 1:1 mixture of the cis (1a) and trans (1 b) diastereomers and we report here the structure of the cis isomer.

The molecular structure and atom-numbering scheme is shown in Fig. 2. Bond distances and angles are close to those generally expected. The atom O6 is essentially sp2-hybridized and involved in conjugation with the benzo ring as indicated by the valence angle at this atom and a non-equivalency of the O6—C5 and O6—C7 bonds.

The most interesting feature of the structure—the spatial relationship between the pharmacophoric elements (hydrophobic groups and H-bond donors/acceptors)—is given by conformation of the (partially) saturated rings. Thus, the pyrazoline ring adopts a flat-envelope conformation with atom C13 (at the flap) deviating by 0.463 Å from the mean plane of the remaining atoms. The central oxazine ring is also non-planar and is puckered in such a manner that the four atoms O6, C7, C12 and C13 are planar to within 0.006 (2) Å, while atoms N4 and C5 are displaced by 0.235 (6) and 0.370 (2) Å, respectively, on opposite sides of the plane. As a result of the relatively severe puckering of the central ring, the molecule as a whole is non-planar but consists of two approximately planar segments, C5/O6/C7–C13 and C13/C1/C2/N3/N4/C5, folded about the C5···C13 line [dihedral angle 71.7 (1)°]. The carboxyphenyl substituent is rotated by 39.8 (1)° from the mean plane of the oxazine ring.

The crystal packing is dominated by a hydrogen bond between centrosymmetrically related molecules (Table 1) which result in formation of hydrogen-bonded dimers.

Related literature top

For related literature, see: Palomer et al. (2002); Subbaramaiah et al. (2002); Světlík et al. (2005).

Experimental top

Synthesis of the title compound has been described previously (Světlík et al., 2005). In short, a solution of 4-carboxybenzaldehyde (0.30 g, 2 mmol) and pyrazoline (0.35 g, 2 mmol) in ethyl acetate (14 ml) and methanol (1 ml) was left to react at room temperature for 1 h. The resulting precipitate was filtered off and crystallized from ethanol to obtain (1a) (70% yield; m.p. 474–480 K) as colourless crystals. Crystals suitable for the X-ray analysis were obtained by slow crystallization from acetone.

Refinement top

H atoms were visible in difference maps, but were placed geometrically and subsequently treated as riding atoms with distances C—H = 0.93 Å (CHarom), 0.97 (CH2) or 0.98 Å (CH) and 0.96 Å (CH3) and O—H = 0.82 Å (COOH); Uiso of the H atoms were set to 1.2 (1.5 for the methyl and carboxy H atoms) times Ueq of the parent atom.

Computing details top

Data collection: XSCANS (Siemens, 1991); cell refinement: XSCANS (Siemens, 1991); data reduction: XSCANS (Siemens, 1991); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The cis title compound (1a) and its trans isomer (1 b).
[Figure 2] Fig. 2. Molecular structure with displacement ellipsoids drawn at 35% probability for non-H atoms.
4-[(5R*,10bR*)-2-Methyl-1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazin-5-yl]benzoic acid top
Crystal data top
C18H16N2O3Z = 2
Mr = 308.33F000 = 324
Triclinic, P1Dx = 1.365 Mg m−3
Hall symbol: -P 1Melting point: 477 K
a = 6.638 (2) ÅMo Kα radiation
λ = 0.71073 Å
b = 10.997 (3) ÅCell parameters from 20 reflections
c = 11.141 (3) Åθ = 7–18º
α = 70.78 (2)ºµ = 0.09 mm−1
β = 80.85 (3)ºT = 296 (2) K
γ = 79.15 (2)ºPrism, colourless
V = 750.1 (4) Å30.30 × 0.20 × 0.15 mm
Data collection top
Siemens P4
diffractometer		Rint = 0.019
Radiation source: fine-focus sealed tubeθmax = 30.0º
Monochromator: graphiteθmin = 2.0º
T = 296(2) Kh = −1→9
ω/2θ scansk = −14→14
Absorption correction: nonel = −15→15
5341 measured reflections3 standard reflections
4312 independent reflections every 97 reflections
3216 reflections with I > 2σ(I) intensity decay: none
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.051H-atom parameters constrained
wR(F2) = 0.152  w = 1/[σ2(Fo2) + (0.0853P)2 + 0.0987P]
where P = (Fo2 + 2Fc2)/3
S = 1.01(Δ/σ)max = 0.001
4312 reflectionsΔρmax = 0.29 e Å−3
210 parametersΔρmin = −0.22 e Å−3
Primary atom site location: structure-invariant direct methodsExtinction correction: none
Crystal data top
C18H16N2O3γ = 79.15 (2)º
Mr = 308.33V = 750.1 (4) Å3
Triclinic, P1Z = 2
a = 6.638 (2) ÅMo Kα
b = 10.997 (3) ŵ = 0.09 mm−1
c = 11.141 (3) ÅT = 296 (2) K
α = 70.78 (2)º0.30 × 0.20 × 0.15 mm
β = 80.85 (3)º
Data collection top
Siemens P4
diffractometer		Rint = 0.019
Absorption correction: none3 standard reflections
5341 measured reflections every 97 reflections
4312 independent reflections intensity decay: none
3216 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.051210 parameters
wR(F2) = 0.152H-atom parameters constrained
S = 1.01Δρmax = 0.29 e Å−3
4312 reflectionsΔρmin = −0.22 e Å−3
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
xyzUiso*/Ueq
C10.3065 (2)0.63515 (13)0.03856 (13)0.0364 (3)
H1A0.33690.6320−0.04850.044*
H1B0.43380.61490.07800.044*
C20.1553 (2)0.54630 (12)0.11427 (12)0.0324 (3)
N30.01255 (17)0.59887 (10)0.18002 (10)0.0314 (2)
N40.05040 (17)0.72620 (10)0.16410 (10)0.0304 (2)
C5−0.1328 (2)0.81721 (13)0.17228 (12)0.0342 (3)
H5−0.09110.89760.17360.041*
O6−0.25382 (16)0.84950 (11)0.06661 (9)0.0440 (3)
C7−0.1451 (2)0.87381 (13)−0.05137 (12)0.0371 (3)
C8−0.2589 (3)0.93655 (15)−0.15442 (14)0.0479 (4)
H8−0.39990.9630−0.14090.057*
C9−0.1623 (3)0.95933 (18)−0.27641 (16)0.0586 (5)
H9−0.23811.0010−0.34580.070*
C100.0466 (3)0.92058 (17)−0.29635 (15)0.0560 (5)
H100.11160.9354−0.37920.067*
C110.1589 (3)0.86000 (14)−0.19372 (13)0.0449 (4)
H110.30030.8352−0.20790.054*
C120.0646 (2)0.83525 (12)−0.06896 (12)0.0347 (3)
C130.1871 (2)0.76641 (13)0.04385 (12)0.0330 (3)
H130.28080.82220.05100.040*
C140.1724 (2)0.40903 (14)0.11858 (15)0.0418 (3)
H14A0.29250.35980.15890.063*
H14B0.18400.40440.03320.063*
H14C0.05170.37370.16650.063*
C15−0.2727 (2)0.76809 (12)0.29245 (12)0.0329 (3)
C16−0.2086 (2)0.75161 (17)0.40981 (14)0.0448 (4)
H16−0.08300.77520.41370.054*
C17−0.3307 (3)0.70033 (17)0.52093 (14)0.0462 (4)
H17−0.28650.68900.59950.055*
C18−0.5184 (2)0.66557 (13)0.51636 (12)0.0342 (3)
C19−0.5837 (2)0.68431 (14)0.39930 (13)0.0374 (3)
H19−0.71030.66210.39520.045*
C20−0.4614 (2)0.73595 (14)0.28820 (13)0.0381 (3)
H20−0.50700.74920.20960.046*
C21−0.6403 (2)0.60087 (13)0.63696 (13)0.0361 (3)
O7−0.5895 (2)0.58142 (13)0.74163 (10)0.0520 (3)
O8−0.80628 (16)0.56450 (11)0.61698 (10)0.0454 (3)
H8A−0.85710.51790.68450.068*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0382 (7)0.0364 (7)0.0318 (6)−0.0088 (5)0.0038 (5)−0.0084 (5)
C20.0362 (6)0.0317 (6)0.0286 (6)−0.0074 (5)−0.0017 (5)−0.0077 (5)
N30.0364 (6)0.0285 (5)0.0281 (5)−0.0088 (4)−0.0002 (4)−0.0065 (4)
N40.0362 (5)0.0290 (5)0.0256 (5)−0.0104 (4)0.0017 (4)−0.0072 (4)
C50.0423 (7)0.0310 (6)0.0282 (6)−0.0086 (5)0.0016 (5)−0.0082 (5)
O60.0434 (5)0.0498 (6)0.0273 (5)−0.0018 (5)−0.0005 (4)−0.0009 (4)
C70.0514 (8)0.0290 (6)0.0273 (6)−0.0098 (6)−0.0004 (5)−0.0034 (5)
C80.0585 (9)0.0417 (8)0.0359 (7)−0.0042 (7)−0.0097 (7)−0.0015 (6)
C90.0890 (14)0.0478 (9)0.0316 (7)−0.0059 (9)−0.0143 (8)−0.0009 (6)
C100.0856 (13)0.0474 (9)0.0279 (7)−0.0115 (9)0.0037 (8)−0.0058 (6)
C110.0624 (9)0.0362 (7)0.0313 (7)−0.0126 (7)0.0087 (6)−0.0072 (5)
C120.0507 (8)0.0253 (6)0.0270 (6)−0.0126 (5)0.0018 (5)−0.0055 (4)
C130.0368 (6)0.0331 (6)0.0288 (6)−0.0134 (5)0.0036 (5)−0.0079 (5)
C140.0464 (8)0.0351 (7)0.0449 (8)−0.0074 (6)−0.0004 (6)−0.0149 (6)
C150.0403 (7)0.0287 (6)0.0276 (6)−0.0059 (5)0.0024 (5)−0.0081 (5)
C160.0447 (8)0.0600 (9)0.0340 (7)−0.0227 (7)0.0018 (6)−0.0147 (6)
C170.0524 (9)0.0628 (10)0.0270 (6)−0.0203 (7)−0.0002 (6)−0.0139 (6)
C180.0396 (7)0.0322 (6)0.0289 (6)−0.0055 (5)0.0031 (5)−0.0098 (5)
C190.0359 (7)0.0410 (7)0.0329 (6)−0.0087 (5)−0.0014 (5)−0.0076 (5)
C200.0426 (7)0.0417 (7)0.0277 (6)−0.0085 (6)−0.0042 (5)−0.0063 (5)
C210.0405 (7)0.0337 (6)0.0311 (6)−0.0055 (5)0.0038 (5)−0.0097 (5)
O70.0637 (7)0.0646 (7)0.0285 (5)−0.0204 (6)0.0024 (5)−0.0126 (5)
O80.0457 (6)0.0506 (6)0.0336 (5)−0.0165 (5)0.0032 (4)−0.0029 (4)
Geometric parameters (Å, °) top
C1—C21.4934 (19)C11—C121.3915 (19)
C1—C131.5249 (19)C11—H110.930
C1—H1A0.970C12—C131.5101 (19)
C1—H1B0.970C13—H130.980
C2—N31.2730 (17)C14—H14A0.960
C2—C141.4776 (19)C14—H14B0.960
N3—N41.4178 (15)C14—H14C0.960
N4—C51.4335 (18)C15—C201.376 (2)
N4—C131.4793 (17)C15—C161.3839 (19)
C5—O61.4409 (17)C16—C171.379 (2)
C5—C151.5047 (18)C16—H160.930
C5—H50.980C17—C181.384 (2)
O6—C71.3637 (17)C17—H170.930
C7—C121.379 (2)C18—C191.3783 (19)
C7—C81.387 (2)C18—C211.4856 (19)
C8—C91.371 (2)C19—C201.380 (2)
C8—H80.930C19—H190.930
C9—C101.377 (3)C20—H200.930
C9—H90.930C21—O71.2053 (17)
C10—C111.375 (2)C21—O81.3140 (18)
C10—H100.930O8—H8A0.820
C2—C1—C13100.79 (11)C7—C12—C13120.90 (12)
C2—C1—H1A111.6C11—C12—C13121.16 (14)
C13—C1—H1A111.6N4—C13—C12111.46 (11)
C2—C1—H1B111.6N4—C13—C1100.98 (10)
C13—C1—H1B111.6C12—C13—C1112.93 (11)
H1A—C1—H1B109.4N4—C13—H13110.4
N3—C2—C14122.55 (13)C12—C13—H13110.4
N3—C2—C1113.23 (12)C1—C13—H13110.4
C14—C2—C1124.16 (12)C2—C14—H14A109.5
C2—N3—N4108.71 (11)C2—C14—H14B109.5
N3—N4—C5114.05 (10)H14A—C14—H14B109.5
N3—N4—C13107.26 (9)C2—C14—H14C109.5
C5—N4—C13114.20 (10)H14A—C14—H14C109.5
N4—C5—O6113.73 (11)H14B—C14—H14C109.5
N4—C5—C15112.11 (11)C20—C15—C16119.21 (13)
O6—C5—C15106.99 (11)C20—C15—C5121.22 (12)
N4—C5—H5107.9C16—C15—C5119.55 (13)
O6—C5—H5107.9C17—C16—C15120.12 (14)
C15—C5—H5107.9C17—C16—H16119.9
C7—O6—C5115.49 (11)C15—C16—H16119.9
O6—C7—C12122.64 (12)C16—C17—C18120.50 (13)
O6—C7—C8116.04 (14)C16—C17—H17119.8
C12—C7—C8121.29 (14)C18—C17—H17119.8
C9—C8—C7119.60 (17)C19—C18—C17119.28 (13)
C9—C8—H8120.2C19—C18—C21120.86 (13)
C7—C8—H8120.2C17—C18—C21119.74 (13)
C8—C9—C10120.15 (16)C18—C19—C20120.10 (13)
C8—C9—H9119.9C18—C19—H19119.9
C10—C9—H9119.9C20—C19—H19119.9
C11—C10—C9119.92 (15)C15—C20—C19120.77 (13)
C11—C10—H10120.0C15—C20—H20119.6
C9—C10—H10120.0C19—C20—H20119.6
C10—C11—C12121.10 (16)O7—C21—O8123.78 (13)
C10—C11—H11119.4O7—C21—C18123.50 (14)
C12—C11—H11119.4O8—C21—C18112.71 (12)
C7—C12—C11117.93 (14)C21—O8—H8A109.5
C13—C1—C2—N3−15.79 (15)N3—N4—C13—C1−29.67 (12)
C13—C1—C2—C14166.98 (12)C5—N4—C13—C1−157.08 (11)
C14—C2—N3—N4174.46 (11)C7—C12—C13—N411.07 (17)
C1—C2—N3—N4−2.82 (15)C11—C12—C13—N4−167.94 (12)
C2—N3—N4—C5148.89 (11)C7—C12—C13—C1123.94 (13)
C2—N3—N4—C1321.40 (13)C11—C12—C13—C1−55.08 (17)
N3—N4—C5—O6−68.94 (13)C2—C1—C13—N426.12 (12)
C13—N4—C5—O654.89 (15)C2—C1—C13—C12−93.01 (13)
N3—N4—C5—C1552.60 (14)N4—C5—C15—C20−112.18 (15)
C13—N4—C5—C15176.43 (10)O6—C5—C15—C2013.15 (17)
N4—C5—O6—C7−44.40 (16)N4—C5—C15—C1666.12 (17)
C15—C5—O6—C7−168.75 (11)O6—C5—C15—C16−168.55 (12)
C5—O6—C7—C1217.97 (19)C20—C15—C16—C171.7 (2)
C5—O6—C7—C8−164.03 (12)C5—C15—C16—C17−176.64 (14)
O6—C7—C8—C9−177.12 (14)C15—C16—C17—C18−0.4 (3)
C12—C7—C8—C90.9 (2)C16—C17—C18—C19−0.8 (2)
C7—C8—C9—C10−0.3 (3)C16—C17—C18—C21175.18 (15)
C8—C9—C10—C11−0.6 (3)C17—C18—C19—C200.7 (2)
C9—C10—C11—C120.9 (3)C21—C18—C19—C20−175.28 (13)
O6—C7—C12—C11177.24 (13)C16—C15—C20—C19−1.9 (2)
C8—C7—C12—C11−0.7 (2)C5—C15—C20—C19176.45 (13)
O6—C7—C12—C13−1.8 (2)C18—C19—C20—C150.7 (2)
C8—C7—C12—C13−179.70 (13)C19—C18—C21—O7179.54 (14)
C10—C11—C12—C7−0.2 (2)C17—C18—C21—O73.6 (2)
C10—C11—C12—C13178.82 (14)C19—C18—C21—O81.05 (19)
N3—N4—C13—C1290.51 (12)C17—C18—C21—O8−174.89 (13)
C5—N4—C13—C12−36.89 (15)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O8—H8A···N3i0.821.932.7356 (17)168
Symmetry codes: (i) −x−1, −y+1, −z+1.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O8—H8A···N3i0.821.932.7356 (17)168
Symmetry codes: (i) −x−1, −y+1, −z+1.
Acknowledgements top

This work was supported by the Grant Agency of the Slovak Republic, project Nos. 1/4298/07 and 1/4299/07.

references
References top

Palomer, A., Cabré, F., Pascual, J., Campos, J., Trujillo, M. A., Entrena, A., Gallo, M. A., Garcia, L., Mauleón, D. & Espinosa, A. (2002). J. Med. Chem. 45, 1402–1411.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Siemens (1991). XSCANS. Siemens Analytical X-ray Instruments Inc., Madison, Wisconsin, USA.

Spek, A. L. (2003). J. Appl. Cryst. 36, 7–13.

Subbaramaiah, K., Norton, L., Gerald, W. & Dannenberg, A. J. (2002). J. Biol. Chem. 277, 18649–18659.

Světlík, J., Pronayova, N. & Kubista, J. (2005). J. Heterocycl. Chem. 42, 1143–1147.