Acta Cryst. (2009). E65, o984 [ doi:10.1107/S1600536809012173 ]
In the title compound, C11H10N2O2, a potential inhibitor of the cyclooxygenase-2 isoenzyme, the pyrazoline ring exists in a flat-envelope conformation while the puckering of the central oxazine ring is more severe. As a result, the molecule as a whole is non-planar. The formal sp3 pyrazoline N atom is sp2 hybridized, with the lone-pair electrons delocalized through conjugation with the carbonyl group rather than the double bond of the pyrazoline ring.
The synthesis of the title compound, (I), has been described (Světlík et al., 2005). In short, a solution of 4,5-dihydro-(2-hydroxyphenyl)-3-methyl-1H-pyrazole (0.35 g, 2 mmol) and N,N'-carbonyldiimidazole (0.36 g, 2.2 mmol) in benzene (15 ml) were refluxed for 200 mins. After removal of the solvent, the oily residue was dissolved in dichloromethane (25 ml), washed with 10% HCl, water and dried (MgSO4). The solution was then concentrated under reduced pressure to give (I) (90% yield; m.p. 433–434 K) as colourless crystals.
The H atoms were visible in difference maps and were subsequently treated as riding atoms with distances C—H = 0.93 Å (CHarom), 0.97 (CH2), 0.98 Å (CH) and 0.96 Å (CH3), and with Uiso(H) set to 1.2 (1.5 for the methyl H atoms) times Ueq(parent atom). In the absence of significant anomalous scattering effects, 370 Friedel pairs were averaged in the final refinement.
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, 2009); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).
![[Figure 1]](./tk2391fig1thm.gif)
| Fig. 1. Displacement ellipsoid plot of (I) with the labelling scheme for the non-H atoms, which are drawn with displacement ellipsoids at the 35% probability level. |
| C11H10N2O2 | Dx = 1.333 Mg m−3 |
| Mr = 202.21 | Melting point: 433 K |
| Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
| Hall symbol: P 2ac 2ab | Cell parameters from 20 reflections |
| a = 7.240 (2) Å | θ = 7–18° |
| b = 8.835 (2) Å | µ = 0.09 mm−1 |
| c = 15.755 (4) Å | T = 296 K |
| V = 1007.8 (4) Å3 | Prism, colourless |
| Z = 4 | 0.30 × 0.25 × 0.20 mm |
| F(000) = 424 |
| Siemens P4 diffractometer | Rint = 0.021 |
| Radiation source: fine-focus sealed tube | θmax = 30.0°, θmin = 2.6° |
| graphite | h = −1→10 |
| ω/2θ scans | k = −1→12 |
| 2285 measured reflections | l = −1→22 |
| 1674 independent reflections | 3 standard reflections every 97 reflections |
| 1343 reflections with I > 2σ(I) | intensity decay: none |
| 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)] = 0.055 | Hydrogen site location: inferred from neighbouring sites |
| wR(F2) = 0.161 | H-atom parameters constrained |
| S = 0.96 | w = 1/[σ2(Fo2) + (0.058P)2 + 0.7099P] where P = (Fo2 + 2Fc2)/3 |
| 1674 reflections | (Δ/σ)max = 0.003 |
| 137 parameters | Δρmax = 0.26 e Å−3 |
| 0 restraints | Δρmin = −0.22 e Å−3 |
| C11H10N2O2 | V = 1007.8 (4) Å3 |
| Mr = 202.21 | Z = 4 |
| Orthorhombic, P212121 | Mo Kα radiation |
| a = 7.240 (2) Å | µ = 0.09 mm−1 |
| b = 8.835 (2) Å | T = 296 K |
| c = 15.755 (4) Å | 0.30 × 0.25 × 0.20 mm |
| Siemens P4 diffractometer | Rint = 0.021 |
| 2285 measured reflections | θmax = 30.0° |
| 1674 independent reflections | 3 standard reflections every 97 reflections |
| 1343 reflections with I > 2σ(I) | intensity decay: none |
| R[F2 > 2σ(F2)] = 0.055 | H-atom parameters constrained |
| wR(F2) = 0.161 | Δρmax = 0.26 e Å−3 |
| S = 0.96 | Δρmin = −0.22 e Å−3 |
| 1674 reflections | Absolute structure: ? |
| 137 parameters | Flack parameter: ? |
| 0 restraints | Rogers parameter: ? |
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. Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane) - 6.4736 (0.0083) x + 3.9501 (0.0194) y + 0.3894 (0.0333) z = 1.1812 (0.0071) * 0.0059 (0.0012) C1 * -0.0108 (0.0022) C2 * 0.0108 (0.0022) N3 * -0.0060 (0.0012) N4 - 0.3338 (0.0055) C10B Rms deviation of fitted atoms = 0.0087 7.0450 (0.0031) x - 0.1068 (0.0223) y + 3.6269 (0.0223) z = 1.0294 (0.0128) Angle to previous plane (with approximate e.s.d.) = 29.57 (0.16) * -0.0027 (0.0010) O6 * 0.0053 (0.0019) C6A * -0.0050 (0.0018) C10A * 0.0024 (0.0009) C10B -0.6963 (0.0054) N4 - 0.5900 (0.0063) C5 Rms deviation of fitted atoms = 0.0041 7.0642 (0.0025) x - 0.1723 (0.0086) y + 3.4371 (0.0150) z = 0.9846 (0.0059) Angle to previous plane (with approximate e.s.d.) = 0.82 (0.08) * -0.0143 (0.0023) O6 * -0.0087 (0.0029) C6A * 0.0109 (0.0030) C7 * 0.0160 (0.0032) C8 * -0.0063 (0.0031) C9 * -0.0177 (0.0029) C10 * -0.0034 (0.0027) C10A * 0.0234 (0.0023) C10B Rms deviation of fitted atoms = 0.0140 - 6.2356 (0.0052) x + 4.4868 (0.0103) y - 0.2799 (0.0136) z = 1.4163 (0.0043) Angle to previous plane (with approximate e.s.d.) = 31.34 (0.08) * -0.2463 (0.0027) C10B * 0.1374 (0.0029) C1 * 0.0194 (0.0039) C2 * -0.0476 (0.0032) N3 * -0.0351 (0.0028) N4 * 0.0138 (0.0033) C5 * 0.1614 (0.0027) O6 * 0.0426 (0.0034) C11 * -0.0456 (0.0025) O5 Rms deviation of fitted atoms = 0.1123 |
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. |
| x | y | z | Uiso*/Ueq | ||
| C1 | 0.1064 (5) | 0.4867 (4) | −0.11974 (19) | 0.0540 (8) | |
| H1A | 0.0197 | 0.5671 | −0.1328 | 0.065* | |
| H1B | 0.2107 | 0.4926 | −0.1582 | 0.065* | |
| C2 | 0.0157 (5) | 0.3341 (4) | −0.1229 (2) | 0.0600 (9) | |
| N3 | −0.0199 (4) | 0.2741 (3) | −0.05137 (18) | 0.0581 (7) | |
| N4 | 0.0479 (4) | 0.3750 (3) | 0.00991 (16) | 0.0484 (6) | |
| C5 | 0.0201 (5) | 0.3524 (4) | 0.0925 (2) | 0.0523 (8) | |
| O5 | −0.0494 (5) | 0.2447 (3) | 0.12627 (15) | 0.0761 (9) | |
| O6 | 0.0794 (4) | 0.4709 (3) | 0.14279 (14) | 0.0583 (7) | |
| C6A | 0.1009 (4) | 0.6157 (3) | 0.1075 (2) | 0.0475 (7) | |
| C7 | 0.0800 (5) | 0.7370 (4) | 0.1622 (2) | 0.0594 (9) | |
| H7 | 0.0532 | 0.7219 | 0.2193 | 0.071* | |
| C8 | 0.1000 (6) | 0.8811 (4) | 0.1297 (3) | 0.0675 (11) | |
| H8 | 0.0873 | 0.9643 | 0.1654 | 0.081* | |
| C9 | 0.1389 (5) | 0.9035 (4) | 0.0445 (3) | 0.0669 (11) | |
| H9 | 0.1507 | 1.0011 | 0.0230 | 0.080* | |
| C10 | 0.1601 (5) | 0.7788 (4) | −0.0086 (3) | 0.0569 (8) | |
| H10 | 0.1858 | 0.7931 | −0.0659 | 0.068* | |
| C10A | 0.1430 (4) | 0.6339 (3) | 0.0233 (2) | 0.0431 (6) | |
| C10B | 0.1680 (5) | 0.4926 (3) | −0.02737 (18) | 0.0429 (6) | |
| H10B | 0.2971 | 0.4598 | −0.0235 | 0.051* | |
| C11 | −0.0392 (8) | 0.2580 (7) | −0.2042 (3) | 0.0990 (19) | |
| H11A | −0.0912 | 0.1605 | −0.1918 | 0.149* | |
| H11B | 0.0677 | 0.2458 | −0.2396 | 0.149* | |
| H11C | −0.1290 | 0.3190 | −0.2331 | 0.149* |
| U11 | U22 | U33 | U12 | U13 | U23 | |
| C1 | 0.060 (2) | 0.0602 (18) | 0.0414 (14) | −0.0014 (17) | 0.0052 (15) | −0.0004 (14) |
| C2 | 0.062 (2) | 0.071 (2) | 0.0464 (16) | −0.011 (2) | 0.0099 (16) | −0.0100 (16) |
| N3 | 0.0687 (18) | 0.0535 (14) | 0.0521 (14) | −0.0145 (16) | 0.0099 (14) | −0.0113 (13) |
| N4 | 0.0602 (15) | 0.0425 (12) | 0.0424 (12) | −0.0082 (13) | 0.0002 (12) | 0.0010 (10) |
| C5 | 0.069 (2) | 0.0450 (15) | 0.0434 (14) | −0.0054 (17) | −0.0015 (16) | 0.0022 (13) |
| O5 | 0.116 (2) | 0.0590 (14) | 0.0528 (13) | −0.0199 (17) | 0.0073 (15) | 0.0105 (12) |
| O6 | 0.0811 (18) | 0.0495 (12) | 0.0442 (11) | −0.0036 (13) | −0.0074 (13) | 0.0021 (9) |
| C6A | 0.0454 (15) | 0.0438 (15) | 0.0532 (17) | −0.0029 (14) | −0.0089 (14) | −0.0026 (13) |
| C7 | 0.058 (2) | 0.0586 (19) | 0.0614 (19) | 0.0009 (18) | −0.0116 (17) | −0.0163 (17) |
| C8 | 0.061 (2) | 0.0489 (18) | 0.092 (3) | 0.0013 (18) | −0.013 (2) | −0.023 (2) |
| C9 | 0.055 (2) | 0.0353 (14) | 0.110 (3) | −0.0010 (15) | −0.005 (2) | −0.0001 (18) |
| C10 | 0.0453 (16) | 0.0542 (19) | 0.071 (2) | −0.0042 (15) | −0.0013 (17) | 0.0076 (18) |
| C10A | 0.0356 (13) | 0.0404 (13) | 0.0533 (16) | 0.0044 (12) | −0.0012 (13) | −0.0006 (12) |
| C10B | 0.0420 (14) | 0.0383 (13) | 0.0484 (15) | −0.0037 (12) | 0.0046 (13) | 0.0062 (12) |
| C11 | 0.106 (4) | 0.137 (4) | 0.054 (2) | −0.050 (4) | 0.016 (2) | −0.038 (3) |
| C1—C2 | 1.501 (5) | C7—C8 | 1.380 (5) |
| C1—C10B | 1.523 (4) | C7—H7 | 0.9300 |
| C1—H1A | 0.9700 | C8—C9 | 1.385 (6) |
| C1—H1B | 0.9700 | C8—H8 | 0.9300 |
| C2—N3 | 1.272 (4) | C9—C10 | 1.393 (5) |
| C2—C11 | 1.499 (5) | C9—H9 | 0.9300 |
| N3—N4 | 1.403 (4) | C10—C10A | 1.381 (4) |
| N4—C5 | 1.332 (4) | C10—H10 | 0.9300 |
| N4—C10B | 1.477 (4) | C10A—C10B | 1.493 (4) |
| C5—O5 | 1.200 (4) | C10B—H10B | 0.9800 |
| C5—O6 | 1.381 (4) | C11—H11A | 0.9600 |
| O6—C6A | 1.404 (4) | C11—H11B | 0.9600 |
| C6A—C10A | 1.371 (4) | C11—H11C | 0.9600 |
| C6A—C7 | 1.383 (4) | ||
| C2—C1—C10B | 101.0 (3) | C7—C8—H8 | 119.6 |
| C2—C1—H1A | 111.6 | C9—C8—H8 | 119.6 |
| C10B—C1—H1A | 111.6 | C8—C9—C10 | 119.5 (3) |
| C2—C1—H1B | 111.6 | C8—C9—H9 | 120.3 |
| C10B—C1—H1B | 111.6 | C10—C9—H9 | 120.3 |
| H1A—C1—H1B | 109.4 | C10A—C10—C9 | 120.3 (3) |
| N3—C2—C1 | 115.7 (3) | C10A—C10—H10 | 119.8 |
| N3—C2—C11 | 121.1 (4) | C9—C10—H10 | 119.8 |
| C1—C2—C11 | 123.2 (3) | C6A—C10A—C10 | 118.8 (3) |
| C2—N3—N4 | 105.9 (3) | C6A—C10A—C10B | 116.5 (3) |
| C5—N4—N3 | 121.6 (3) | C10—C10A—C10B | 124.7 (3) |
| C5—N4—C10B | 125.7 (3) | N4—C10B—C10A | 107.7 (2) |
| N3—N4—C10B | 112.3 (2) | N4—C10B—C1 | 100.6 (3) |
| O5—C5—N4 | 127.9 (3) | C10A—C10B—C1 | 120.3 (3) |
| O5—C5—O6 | 118.5 (3) | N4—C10B—H10B | 109.2 |
| N4—C5—O6 | 113.6 (3) | C10A—C10B—H10B | 109.2 |
| C5—O6—C6A | 119.9 (2) | C1—C10B—H10B | 109.2 |
| C10A—C6A—C7 | 122.4 (3) | C2—C11—H11A | 109.5 |
| C10A—C6A—O6 | 121.0 (3) | C2—C11—H11B | 109.5 |
| C7—C6A—O6 | 116.6 (3) | H11A—C11—H11B | 109.5 |
| C8—C7—C6A | 118.2 (4) | C2—C11—H11C | 109.5 |
| C8—C7—H7 | 120.9 | H11A—C11—H11C | 109.5 |
| C6A—C7—H7 | 120.9 | H11B—C11—H11C | 109.5 |
| C7—C8—C9 | 120.8 (3) | ||
| C10B—C1—C2—N3 | 14.6 (4) | C8—C9—C10—C10A | −0.2 (6) |
| C10B—C1—C2—C11 | −168.2 (4) | C7—C6A—C10A—C10 | −1.9 (5) |
| C1—C2—N3—N4 | −2.2 (4) | O6—C6A—C10A—C10 | 179.1 (3) |
| C11—C2—N3—N4 | −179.4 (4) | C7—C6A—C10A—C10B | 177.9 (3) |
| C2—N3—N4—C5 | 174.6 (4) | O6—C6A—C10A—C10B | −1.2 (4) |
| C2—N3—N4—C10B | −12.4 (4) | C9—C10—C10A—C6A | 1.5 (5) |
| N3—N4—C5—O5 | 5.9 (7) | C9—C10—C10A—C10B | −178.3 (3) |
| C10B—N4—C5—O5 | −166.1 (4) | C5—N4—C10B—C10A | −40.0 (4) |
| N3—N4—C5—O6 | −173.5 (3) | N3—N4—C10B—C10A | 147.3 (3) |
| C10B—N4—C5—O6 | 14.4 (5) | C5—N4—C10B—C1 | −166.7 (3) |
| O5—C5—O6—C6A | −158.0 (4) | N3—N4—C10B—C1 | 20.6 (3) |
| N4—C5—O6—C6A | 21.5 (5) | C6A—C10A—C10B—N4 | 30.5 (4) |
| C5—O6—C6A—C10A | −28.5 (5) | C10—C10A—C10B—N4 | −149.8 (3) |
| C5—O6—C6A—C7 | 152.4 (3) | C6A—C10A—C10B—C1 | 144.7 (3) |
| C10A—C6A—C7—C8 | 1.0 (5) | C10—C10A—C10B—C1 | −35.6 (5) |
| O6—C6A—C7—C8 | −180.0 (3) | C2—C1—C10B—N4 | −19.1 (3) |
| C6A—C7—C8—C9 | 0.4 (6) | C2—C1—C10B—C10A | −137.0 (3) |
| C7—C8—C9—C10 | −0.8 (6) |
This work was supported by the Grant Agency of the Slovak Republic, project No. 1/4298/07.
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Recently, as part of our on-going project aimed at developing new therapeutic agents, we focused our attention on 2-pyrazoline derivatives, which are known to possess cyclooxygenase-2 (COX-2) inhibitory activity (Jahng et al., 2004), a feature which is of importance in treatment of inflammation (Ramatunge et al., 2004) and cancer (Subbaramaiah et al., 2002). In an effort to develop more potent and selective COX-2 inhibitors, we prepared a series of 2- and 5-substituted derivatives containing the tricyclic system featured in the title compound, (I), which still incorporates the putative COX-2 pharmacophore (Palomer et al., 2002). Thus, the main aim of this work was to establish the spatial distribution of the pharmacophoric elements, viz. the hydrophobic groups and H-bond acceptors, which are responsible for binding of a compound to the COX-2 enzyme. To achieve this, we selected the title 2-methyl derivative, (I), for a single-crystal X-ray analysis.
The most interesting feature of (I), Fig. 1, is the spatial relationship between the pharmacophoric groups which is determined by the conformation of the (partially) saturated rings. Thus, the pyrazoline ring adopts a flat-envelope conformation with atom C10B as the flap; the deviation of the out-of-plane atom from the mean plane of the remaining four atoms is 0.334 (6) Å. The central six-membered ring is also non-planar and is puckered in such a manner that the four atoms O6, C6A, C10A and C10B are planar to within 0.004 (2) Å, while atoms N4 and C5 are displaced by 0.696 (5) and 0.590 (6) Å, respectively, to the same side of this 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: O6,C6A,C7,C8,C9,C10,C10A,C10B [r.m.s. deviation 0.014 (3) Å] and C10B,C1,C2,C11,N3,N4,C5,O5,O6 [r.m.s. deviation 0.112 (3) Å], folded about the O6···C10B line [dihedral angle 31.3 (1)°].
The N3—N4 and C2—N3 bonds have pure single- and double-bond character, respectively (Burke-Laing & Laing, 1976). Even though the N4 atom is not involved in conjugation with the pyrazoline double bond, it is sp2 hybridized with its lone-pair electrons delocalized through conjugation with the adjacent carbonyl function as shown by the N4—C5 bond length (1.332 (4) Å), which is comparable to that typically found for amides (Allen et al., 1987).